Medicine, Faculty of
Medicine, Department of
DSpace
UBCV
McCallum, Rylan Kevin
Master of Science - MSc
University of British Columbia
Background: Indigenous Peoples are extremely diverse and have unique cultural and social histories that have allowed them to remain resilient through decades of colonialism aimed to disrupt the health of their communities. Chronic diseases, including cancer, diabetes, and atherosclerotic cardiovascular disease (ASCVD) are leading causes of morbidity and mortality and disproportionately impacts Indigenous populations. In high income countries, such as Canada, Indigenous populations experience ASCVD rates 1.5 to 2.5 times higher than their non-Indigenous counterparts. There are several factors which contribute to this disproportionate burden of ASCVD, including systematic racism and discrimination in healthcare, however, social determinants of health, such as these, are often overlooked when designing and implementing healthcare strategies in the current western-based medical system. Methods: To generate background knowledge, we conducted a comprehensive narrative review examining existing studies and grey literature on the prevalence of ASCVD in Indigenous populations in Canada and discuss recommendations for future addressment strategies (Chapter 1). To understand major risk factors for ASCVD, we conducted a systematic review and meta-analysis estimating the prevalence of hypercholesterolemia in Indigenous populations (Chapter 2). Addressing the need to understand how Indigenous patients view equitable cardiovascular care, we conducted a prospective observational study assessing the cardiovascular care of Indigenous patients with premature ASCVD (Chapter 3). Results: Our findings reveal significantly higher rates of ASCVD in Indigenous populations compared to non-Indigenous populations. While hypercholesterolemia and familial hypercholesterolemia, significant risk factors for ASCVD, were found to be inadequately studied in Indigenous populations, we estimated the pooled-prevalence of hypercholesterolemia to be 28.9%, demonstrating it is extremely common in Indigenous populations. To address ASCVD, Indigenous populations should be provided access to evidence-based cardiovascular care which we found increases medication uptake and significantly improves lipid profiles, decreasing risk of recurrent cardiovascular events for Indigenous patients. Conclusion: Indigenous populations are significantly impacted by ASCVD and major risk factors, including hypercholesterolemia. We recommend the establishment of collaborative alliances with Indigenous communities to augment the accessibility of screening and testing services, thereby enhancing Indigenous Peoples' awareness of ASCVD, and major associated risk factors, and affording them the autonomy to participate in screening initiatives at their discretion.
INDIGENOUS CARDIOVASCULAR HEALTH: ASSESSING DISEASE, RISK FACTORS, AND PATIENT CARE by Rylan Kevin McCallum B.Sc., The University of British Columbia, 2021 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty of Graduate and Postdoctoral Studies (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2024 © Rylan Kevin McCallum, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: INDIGENOUS CARDIOVASCULAR HEALTH: ASSESSING DISEASE, RISK FACTORS, AND PATIENT CARE___________________________________________________________ Submitted by Rylan Kevin McCallum in partial fulfillment of the requirements for the degree of __Master of Science__________________________________________________ in __Experimental Medicine______________________________________________ Examining Committee Dr. Liam Brunham, Associate Professor, General Internal Medicine Division, UBC___________ Supervisor Dr. Jacques Genest, Professor, Department of Experimental Medicine, McGill University______ Supervisory Committee Member Dr. Laura Arbour, Professor, Department of Medical Genetics, UBC_______________________ Supervisory Committee Member Dr. Kimberly Huyser, Associate Professor, Department of Sociology, UBC_________________ Additional Examiner iii Abstract Background: Indigenous Peoples are extremely diverse and have unique cultural and social histories that have allowed them to remain resilient through decades of colonialism aimed to disrupt the health of their communities. Chronic diseases, including cancer, diabetes, and atherosclerotic cardiovascular disease (ASCVD) are leading causes of morbidity and mortality and disproportionately impacts Indigenous populations. In high income countries, such as Canada, Indigenous populations experience ASCVD rates 1.5 to 2.5 times higher than their non-Indigenous counterparts. There are several factors which contribute to this disproportionate burden of ASCVD, including systematic racism and discrimination in healthcare, however, social determinants of health, such as these, are often overlooked when designing and implementing healthcare strategies in the current western-based medical system. Methods: To generate background knowledge, we conducted a comprehensive narrative review examining existing studies and grey literature on the prevalence of ASCVD in Indigenous populations in Canada and discuss recommendations for future addressment strategies (Chapter 1). To understand major risk factors for ASCVD, we conducted a systematic review and meta-analysis estimating the prevalence of hypercholesterolemia in Indigenous populations (Chapter 2). Addressing the need to understand how Indigenous patients view equitable cardiovascular care, we conducted a prospective observational study assessing the cardiovascular care of Indigenous patients with premature ASCVD (Chapter 3). Results: Our findings reveal significantly higher rates of ASCVD in Indigenous populations compared to non-Indigenous populations. While hypercholesterolemia and familial hypercholesterolemia, significant risk factors for ASCVD, were found to be inadequately studied in Indigenous populations, we estimated the pooled-prevalence of hypercholesterolemia to be iv 28.9%, demonstrating it is extremely common in Indigenous populations. To address ASCVD, Indigenous populations should be provided access to evidence-based cardiovascular care which we found increases medication uptake and significantly improves lipid profiles, decreasing risk of recurrent cardiovascular events for Indigenous patients. Conclusion: Indigenous populations are significantly impacted by ASCVD and major risk factors, including hypercholesterolemia. We recommend the establishment of collaborative alliances with Indigenous communities to augment the accessibility of screening and testing services, thereby enhancing Indigenous Peoples' awareness of ASCVD, and major associated risk factors, and affording them the autonomy to participate in screening initiatives at their discretion. v Lay Summary Indigenous Peoples are extremely diverse with unique cultural and social histories which empower transformative health for their communities. Heart disease impacts Indigenous populations unequally when compared to non-Indigenous populations and requires adequate addressment. Our comprehensive research, spanning narrative reviews and systematic studies reveals significant gaps in understanding heart disease in Indigenous communities, as well as major risk factors including high cholesterol. Our findings demonstrate that access to specialized cardiovascular care, for diagnostic testing, treatment planning, medication management, interventional procedures, and follow-up is crucial, with potential to enhance medication use and reduce cardiovascular events in Indigenous populations. We propose collaborative alliances with Indigenous communities, that respect and honor the needs of cultures, to improve heart disease screening, testing accessibility, and cardiovascular care. Our work aims to guide equitable healthcare strategies, addressing the unique needs of Indigenous populations to combat heart disease. vi Preface This thesis is the original intellectual product of the author, Rylan Kevin McCallum, conducted under the direct supervision of Dr. Liam R. Brunham. The supervisory committee included Dr. Laura Arbour and Dr. Jacques Genest. Additional Indigenous scholars were consulted in the creation of this work including Dr. Miles Marchand, Dr. Keegan Marchand, Justin Turner, and Janelle Kasperski. Data collection was completed by Rylan Kevin McCallum. Data analysis was completed by Rylan Kevin McCallum, Dr. Adam Kramer, and Dr. Leo Akioyamen. Drs. Brunham, Arbour, and Genest, provided substantial guidance, constructive feedback, and edits throughout the development of this document. Drs. Miles Marchand, Keegan Marchand, Iulia Iatan, Danielle Pinheiro Muller and Diana Vikulova also contributed to guidance and editing of this work. This research was approved by the UBC Providence Health Care Research Ethics Board (PHC REB) Certificate Number H20-00758 and sub-study certificate number H23-01423. Chapter 3 involving Indigenous patients and Indigenous patient data was overseen by a Providence Health Care Indigenous advisory team in accordance with TCPS 2: CORE Chapter 9 requirements to ensure that results benefit Indigenous Peoples. Every chapter of this work was designed and implemented in accordance with the Ownership, Control, Access, and Possession (OCAP) principles that help govern Indigenous health research. This research was led and developed by a team of Indigenous health researchers, and non-Indigenous researchers who specialize in the field of Indigenous health. The first chapter of this work is a narrative review conducted with Dr. Keegan Marchand to understand and gather background information on the prevalence of atherosclerotic cardiovascular disease in Indigenous populations in Canada. vii The second chapter is a systematic review and meta-analysis which aimed to estimate the prevalence of hypercholesterolemia, severe hypercholesterolemia, and familial hypercholesterolemia (FH) in global Indigenous populations. Chapter 2 of this work is published: McCallum, R, Kramer, A, Marchand, M, Akioyamen, L, Genest, J, Brunham, L. Estimating the Prevalence of Hypercholesterolemia in Indigenous Populations: A Systematic Review and Meta-Analysis. JACC Adv. 2023 May, 2 (3) 100315. The third chapter is a cohort study working with patients enrolled in the SAVE BC biobank. The Indigenous patients in the biobank were invited to be part of a survey assessment used to understand and gain insight into the cardiovascular care they received, while being involved in a specialized cardiovascular biobank. viii Table of Contents Abstract.........................................................................................................................................iii Lay Summary................................................................................................................................ v Preface........................................................................................................................................... vi Table of Contents........................................................................................................................viii List of Tables............................................................................................................................... xii List of Figures............................................................................................................................. xii List of Abbreviations ................................................................................................................. xv Acknowledgments ..................................................................................................................... xvi Chapter 1: Introduction............................................................................................................... 1 1.1 The Burden of Atherosclerotic Cardiovascular Disease....................................................1 1.2 History of Colonization on Cardiovascular Health of Indigenous Peoples...................... 2 1.3 Genetics of Atherosclerotic Cardiovascular Disease in Indigenous Populations............. 4 1.4 Ongoing Racism in Cardiovascular Medicine.................................................................. 6 1.5 The Prevalence of Atherosclerotic Cardiovascular Disease............................................. 7 1.5.1 Atherosclerotic Cardiovascular Disease in First Nations Populations...................... 9 1.5.2 Atherosclerotic Cardiovascular Disease in Métis Populations................................ 10 1.5.3 Atherosclerotic Cardiovascular Disease in Inuit Populations.................................. 11 1.6 Preventing Atherosclerotic Cardiovascular Disease...................................................... 13 1.7 Enhancing Access to Cardiovascular Medicine...............................................................14 1.8 Cardiovascular Disease Interventions in Indigenous Populations...................................16 1.9 Innovative Collaborations to Address Cardiovascular Disease.......................................17 2.0 Conclusions......................................................................................................................19 ix Chapter 2: Estimating the Prevalence of Hypercholesterolemia in Indigenous Populations: A Systematic Review and Meta-Analysis.................................................................................. 21 2.1 Introduction .................................................................................................................... 21 2.2 Methods........................................................................................................................... 22 2.2.1 Population Selection................................................................................................ 22 2.2.2 Search Strategy........................................................................................................ 23 2.2.3 Eligibility and Study Selection................................................................................ 24 2.2.4 Data Extraction........................................................................................................ 24 2.2.5 Data Analysis........................................................................................................... 25 2.2.6 Sensitivity Analyses................................................................................................. 26 2.3 Results............................................................................................................................. 26 2.3.1 Search Results and Study Characteristics................................................................ 26 2.3.2 Prevalence of Hypercholesterolemia....................................................................... 27 2.3.3 Elevated LDL-Cholesterol....................................................................................... 29 2.3.4 Geographic Reporting in Indigenous Populations................................................... 34 2.3.5 Meta-regression........................................................................................................ 35 2.3.6 Publication Bias....................................................................................................... 36 2.3.7 Sensitivity analyses.................................................................................................. 36 2.4 Discussion....................................................................................................................... 37 2.5 Study Limitations............................................................................................................ 42 2.6 Conclusions..................................................................................................................... 43 Chapter 3: Assessing the Care of Indigenous Patients with Premature Atherosclerotic Cardiovascular Disease.............................................................................................................. 44 x 3.1 Introduction .................................................................................................................... 44 3.2 Methods........................................................................................................................... 45 3.2.1 Study Design and Population................................................................................... 45 3.2.2 Indigenous Ethnicity................................................................................................ 46 3.2.3 Outcomes................................................................................................................. 46 3.2.4 Statistical Analysis................................................................................................... 47 3.2.5 Ethical Considerations............................................................................................. 47 3.3 Results............................................................................................................................. 48 3.3.1 Baseline Characteristics........................................................................................... 49 3.3.2 Clinical Presentation and Revascularization........................................................... 53 3.3.3 Use of Cardiovascular Medication.......................................................................... 54 3.3.4 Treatment Efficacy.................................................................................................. 56 3.3.5 Indigenous Cardiovascular Care Assessment Survey............................................. 58 3.3.6 Indigenous Perspectives on Risk and Prevention.................................................... 59 3.3.7 Indigenous Perspectives on Care and Treatment.................................................... 60 3.3.8 Indigenous Survey Thematic Analysis.................................................................... 62 3.4 Discussion....................................................................................................................... 63 3.5 Limitations...................................................................................................................... 68 3.6 Conclusions..................................................................................................................... 68 Chapter 4: Conclusion ............................................................................................................... 70 4.1 Concluding lessons ........................................................................................................ 70 4.2 Knowledge Sharing and Future Directions .................................................................... 72 xi References ................................................................................................................................... 74 Appendices ................................................................................................................................ 101 Appendix A ........................................................................................................................ 101 Appendix B ........................................................................................................................ 106 Appendix C ........................................................................................................................ 110 Appendix D ........................................................................................................................ 114 Appendix E ........................................................................................................................ 115 Appendix F ......................................................................................................................... 116 Appendix G ........................................................................................................................ 118 Appendix H ........................................................................................................................ 119 Appendix I ......................................................................................................................... 120 Appendix J ......................................................................................................................... 121 Appendix K ........................................................................................................................ 126 Appendix L ........................................................................................................................ 139 xii List of Tables Table 3.1: Baseline characteristics of Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease……………………………………………………….…52 Table 3.2: Hospital characteristics of the Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease………………………………………………54 Table 3.3: Cardiovascular disease medication at baseline and last follow-up of Indigenous and non-Indigenous patients with atherosclerotic cardiovascular disease…………………….….…55 Table 3.4: Comparison of baseline and follow-up laboratory values between Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease………………57 xiii List of Figures Figure 1.1: Downstream impacts of the colonization leading to common clinical associated risk factors of cardiovascular disease………………………………………………………………....3 Figure 1.2: Prevalence of cardiovascular diseases (CVD) in Indigenous populations in Canada …………………………………………………………………………………………....8 Figure 2.1: PRISMA Flowchart of the Inclusion of Studies for Meta-analysis.……………..…28 Figure 2.2: Pooled Prevalence of Hypercholesterolemia in Indigenous Populations……….…..30 Figure 2.3: Pooled Prevalence of Hypercholesterolemia Grouped by LDL-Cholesterol Based Cut-off…………………………………………………………………………………………....32 Figure 2.4: Sub-group analysis for prevalence of hypercholesterolemia.……………..……..…33 Figure 2.5: World map of included Indigenous populations…………………….……………...35 Figure 2.6: Comparison of hypercholesterolemia data between Indigenous populations and the general population……………………………………………………………..………………....38 Figure 3.1: Inclusion criteria of Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease.……………….…………………………..……………...51 Figure 3.2: Treatment efficacy in Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease……………….….………………………..……………...56 Figure 3.3: Demographic survey results from Indigenous patients with premature atherosclerotic cardiovascular disease……………….….……………………….………………..……………...59 Figure 3.4: Indigenous patients’ perceptions on cardiovascular risk and access to care or treatment.………………………………………………………………………………………...61 xiv Figure 3.5: Indigenous patient recommendations for improving cardiovascular care and outcomes.………………………………………………………………………………………...63 xv List of Abbreviations ACS – acute coronary syndrome ASCVD – atherosclerotic cardiovascular disease BMI – body mass index CAD – coronary artery disease CI – confidence interval CVD – cardiovascular disease FH – familial hypercholesterolemia HDL-C – high-density lipoprotein cholesterol IHD – ischemic heart disease IQR - interquartile range LDL-C – low-density lipoprotein cholesterol LLT – lipid-lowering therapy MI – myocardial infarction NSTEMI – non-ST‐segment–elevation myocardial infarction OCAP – Ownership, Control, Access, and Possession OR – odds ratio SAVE BC – Study to Avoid cardioVascular Events in British Columbia SD – standard deviation STEMI - ST‐segment–elevation myocardial infarction xvi Acknowledgements I want to first thank my supervisor, mentor, and role model Dr. Liam Brunham, without your belief that Indigenous health matters this work would not have been possible. Thank you, Liam, for creating space for me and for allowing me to push boundaries in a space that is not fully ready for Indigenous ideas and methodologies. Thank you for never allowing critiques from others to prevent this work from happening; and for that I am forever grateful. To another huge idol, role model, and support, Dr. Laura Arbour, your guidance and insight is the reason any work I accomplish now and in the future is possible, you are one of the main reasons I am pursuing a career in Indigenous health. Dr. Jacques Genest, Je souhaite sincèrement vous remercier pour votre précieux accompagnement tout au long de ma thèse universitaire. Votre expertise, soutien et motivation ont joué un rôle essentiel dans la réussite de ce parcours académique. Merci infiniment d'avoir partagé votre savoir et d'avoir été une source constante d'inspiration. C'est grâce à votre mentorat que j'ai pu concrétiser cette réalisation. Thank you to my mom, Joyce, and my dad, Kevin, for supporting me in every way I needed through this journey of academia, I couldn’t be here without you and all your love. Thank you to my incredible grandparents, for teaching me to draw and paint, and nurturing my artistic side, which allowed me to incorporate meaning and culture into this thesis. Thank you to my friend Heather, sister, Makenzie, and brother, Jordan, for helping me with wording my drafts and any excel problems. Thank you to Allison Beardsworth for employing me, and being such an incredible supportive friend, throughout my master’s degree. Running the Indigenous Undergraduate Research Mentorship Program with you, Jessica, and Sarah, meant the world to me and was the reason I got into research in the first place. A special thank you to Jessica for helping with scholarship applications and setting me up with my mentorship and tutoring position. Thank you xvii to the incredible Indigenous scholars, professors, faculty, and my friends, Drs. Andrea Reid, Shandin Pete, Danielle Ignace, and Tabitha Robin for allowing me to be part of such an incredible team of Indigenous excellence. Thank you for creating space for people like us and being there to look up to when times were hard. The RISE team, for myself and so many other Indigenous students provides hope that Indigenous scholars can succeed no matter how many absurd and ridiculous obstacles we must face. I would also like to acknowledge and thank my incredible lab members Iulia, Diana, Kate, Eric, Nicole, Danielle, and Luba, for there constant feedback and support. 1 Chapter 1: Introduction 1.1 The Burden of Atherosclerotic Cardiovascular Disease Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide (Vaduganathan et al., 2022). In 2020, an estimated 19 million people died from CVD, representing over 30% of all global mortality (Tsao et al., 2022). Atherosclerotic cardiovascular disease (ASCVD) is commonly defined in Canada as clinical conditions of atherosclerotic origin, including coronary artery disease (CAD), ischemic heart disease (IHD), acute coronary syndrome (ACS), myocardial infarction (MI), stable and unstable angina, stroke, transient ischemic attack, documented carotid disease, peripheral arterial disease (PAD) and abdominal aortic aneurysm (Pearson et al., 2021). In Canada, ASCVD is one of the leading causes of morbidity and mortality for all ethnicities (Government of Canada, 2017). Race and ethnicity have long been described a non-modifiable risk factors for ASCVD, alongside genetic predisposition, sex, gender, and age. Racial and ethnic disparities in ASCVD prevalence and outcomes have been reported across many groups, including Black, Hispanic, and Asian populations when compared to White populations (Post et al., 2022). However, limited data exists on the prevalence of ASCVD in Indigenous populations. Indigenous Peoples in Canada, including First Nations, Métis, and Inuit, are extremely heterogeneous, with diverse cultural practices, languages, and histories that have shaped their communities for millennia. Indigenous Peoples are one of Canada’s fasting growing populations, comprising almost 6% of the country’s total population, and expected to increase to over 3 million individuals by 2041 (Government of Canada, 2022). Although over 50% of the Indigenous population now lives in urban settings, which could allow for increased access to healthcare, Indigenous men and women continue to have significantly lower life expectancies compared to the rest of the Canadian population 2 (Government of Canada, 2019). There are many factors that contribute to cardiovascular health disparities Indigenous communities face, including Canada’s colonial history and ongoing systemic racism and discrimination in the Canadian healthcare system (In Plain Sight, 2020; Schultz et al., 2021). 1.2 History of Colonization on Cardiovascular Health of Indigenous Peoples Colonization sought to dismantle the foundational sociocultural, economic, educational, and health structures of Indigenous communities and greatly influences the cardiovascular health of Indigenous Peoples (Reading, 2015). Colonization, marked by land displacement, ecological destruction, genocide, language and cultural prohibitions, and the spread of communicable diseases (Paradies, 2016), holds a frequently overlooked role in the development of ASCVD. Although the public health discourse is increasingly recognizing the impact of colonization on the health of Indigenous Peoples, the field of cardiovascular medicine has only recently begun acknowledging its consequences on physical and mental health (Breathett et al., 2020; Schultz et al., 2021) There are numerous impacts of colonization that actively contribute to common clinical risk factors associated with an increased rate of ASCVD (Figure 1.1). Colonization has been linked to a multitude of cardiovascular risk factors including diabetes, smoking, obesity, and hypertension (Allaire et al., 2023; Breathett et al., 2020; Halseth, 2019). Colonization disrupted Indigenous Peoples use of traditional diets, which were integrally linked with promoting cardiovascular health, and replaced them with the use of western diets consisting of processed meats, refined fats and oils, and simple carbohydrates (Clemente-Suárez et al., 2023; Sarker et al., 2019). In contrast to western diets, traditional diets involved the promotion of active lifestyle patterns including cultural activities such as hunting and gathering (Sarker et al., 3 2019). The imposition of colonial policies by the Government of Canada led to loss of traditional lands and bans on the practice of Indigenous culture and traditional gathering techniques, further contributing to ASCVD and negative cardiovascular health outcomes for Indigenous Peoples. Figure 1.1: Downstream impacts of the colonization leading to common clinical associated risk factors of cardiovascular disease. 4 1.3 Genetics of Atherosclerotic Cardiovascular Disease in Indigenous Populations There are many established risk factors for ASCVD, both acquired and inherited. Previous studies indicate a heritability range of 40% to 70% for ASCVD, underscoring the strong genetic contributions to the disease pathology (Aherrahrou et al., 2020). Recent genome-wide association studies (GWAS), including over half a million people, identified over 160 loci significantly associated with ASCVD (Aherrahrou et al., 2020). GWAS relies heavily on the availability of large datasets which are often from populations of European ancestry, resulting in a direct exclusion of Indigenous Peoples from genomic research, as well as the indirect harms of genetic knowledge and precision medicine not being relevant or useful for Indigenous communities (Caron et al., 2020). In addition, GWAS utilizes case-control studies (Tam et al., 2019), therefore the choice of control groups is likely not relevant when comparisons are made to Indigenous populations. Indigenous communities are extremely diverse and have been shaped by their environments for millennia, and GWAS currently lacks the ability to account for environmental factors that differ between Indigenous and non-Indigenous populations. GWAS also utilizes control groups that do not reflect the specific environmental contexts of the Indigenous population leading to inaccuracies when analyzing true genetic associations with ASCVD. In the event GWAS did include genetic data from Indigenous populations, we must recognize and address there could still exist bias due to smaller sample sizes and lack of statistical power to detect genetic associations. As they currently-exist, large-scale genetic databases and studies are not generalizable and lack representation of Indigenous populations. Indigenous voices have historically been excluded when designing and building genetic databases, as well as when planning the storage and usage of genetic data (Caron et al., 2020). 5 Without proper Indigenous representation, the clinical benefits and success of genomic medicine will disproportionately less for Indigenous Peoples. As the use of genetic data becomes wide-spread and increasingly beneficial, the genomes of Indigenous Peoples are being sought after for their unique variation, including novel genotype-phenotype associations used to advance precision medicine (Tsosie et al., 2021). This has resulted in the misuse and exploitation of Indigenous genomic data, for example with the Nuu-chah-nulth and Havasupai Peoples (Garrison et al., 2019). There are many rare genetic variants with strong effect sizes that contribute to the development of ASCVD, however, if we are not able to safely gather and store background genetic variation in Indigenous populations, possible beneficial or harmful genetic variants will continue to be overlooked. Goals surrounding genetic studies involving Indigenous communities need to be re-shaped to improve effective engagement of Indigenous individuals and communities. This includes a shift towards educating Indigenous Peoples on genomics, such as the work being done by SING Canada to build Indigenous scientific literacy surrounding genomics, bioinformatics, and decolonial bioethics (Garrison et al., 2019). This also includes creating and advancing Indigenous-led genomic databases and biobanks, including the Indigenous Background Variant Library operated by the Silent Genomes Project (Caron et al., 2020), as well as the Native Biodata Consortium’s genetic biobank located on sovereign Indigenous land, completely operated, and overseen by Indigenous scientists and tribal members (Tsosie et al., 2021). The goal of these projects is to restructure data ownership and control allowing Indigenous Peoples to govern their own genetic data and ensure all results benefit Indigenous communities. 6 1.4 Ongoing Racism in Cardiovascular Medicine The presence of racism in the healthcare system can be traced back to historical factors including colonization, residential schools, and Indian hospitals, which continue to generationally disrupt the cardiovascular health of Indigenous Peoples in Canada. The establishment of racially-segregated “Indian hospitals” in the mid-20th century inflicted harm to the health of Indigenous communities, subjecting patients to experimental treatments and suboptimal care (Schultz et al., 2021). Over twenty-nine of these hospitals were formed across Canada to institutionalize Indigenous Peoples who were not welcome in general community hospitals or healthcare settings (Schultz et al., 2021). The In Plain Sight Report (2020), details the continued Indigenous-specific racism and discrimination within the Canadian healthcare system, limiting Indigenous access to preventive and primary medical care. This ongoing systemic racism contributes to Indigenous patients delaying their presentation to healthcare settings for treatment and includes patients being less likely to have a primary care physician, resulting in Indigenous patients 75% more likely to use costly emergency care services (In Plain Sight, 2020). In regard to ASCVD-specific treatment, Indigenous patients are less likely to undergo a coronary angiogram and wait longer to receive an angiogram compared to non-Indigenous patients (Schultz et al., 2020; Vigneault et al., 2021; Wei-Randall et al., 2013). Indigenous patients were found to delay their presentation for care after experiencing symptoms of ASCVD and less likely to have access to a family physician and cardiologist (Bresee et al., 2014; Schultz et al., 2020; Vigneault et al., 2021). These findings contribute to Indigenous patients having significantly higher utilization of emergency departments for cardiovascular problems compared 7 to non-Indigenous Canadians (In Plain Sight, 2020; Srugo et al., 2023), often necessitating emergent treatment rather than preventative care. These delays in receiving cardiovascular care also contribute to the higher rates of major adverse cardiac events (MACE), including death, ACS, stroke, and non-planned cardiac admission, in urban and rural Indigenous populations (Brown, 2012), and the increased risk of long-term ASCVD outcomes in Indigenous populations compared to other ethnicities (d’Entremont et al., 2023). 1.5 The Prevalence of Atherosclerotic Cardiovascular Disease The Government of Canada records longitudinal data on the prevalence of ASCVD in Canada, however its definition is broad defined by self-reported hypertension, heart disease and/or stroke (Government of Canada, 2016b). Using this definition of ASCVD we see significantly higher rates in First Nations (17.8%), Métis (17.4%) and Inuit (16.3%) communities compared to non-Indigenous Canadians (15.2%) (Government of Canada, 2016b). However, using a standardized definition of ASCVD, which only includes clinical conditions of atherosclerotic origin, it appears longitudinal data does not exist for Indigenous Peoples in Canada. In the non-Indigenous population in Canada, the prevalence of ASCVD has been a major focus of recent study with Blais et al. (2020), reporting a prevalence rate of 7.3% in Quebec, Mackinnon et al. (2022), reporting a prevalence of 7.82% in Ontario, and Chen et al. (2021), reporting a prevalence of 8.99% in Alberta. Although the prevalence of ASCVD is not well understood in the Indigenous populations, there are a handful of individual studies that demonstrate a significantly higher burden of disease in Indigenous compared to non-Indigenous populations (Figure 2). 8 Figure 1.2: Prevalence of cardiovascular diseases (CVD) in Indigenous populations in Canada. Results are reported as prevalence rate (%) in Indigenous (including First Nations, Métis, and Inuit) and non-Indigenous populations. Significance is shown for studies which reported a p-value less than 0.05 when comparing rates in 9 Indigenous and non-Indigenous populations. Comparable non-Indigenous rates were included for studies which reported a comparison. Age and sex standardized rates were used when available. 1.5.1 Atherosclerotic Cardiovascular Disease in First Nations Populations The burden of ASCVD varies significantly between Indigenous populations, due in large part to the diversity of these communities. Despite significant heterogeneity, when analyzing studies reporting the prevalence of ASCVD in First Nations populations, we found significantly higher rates compared to non-First Nations populations in Canada. Anand et al., found the prevalence of ASCVD in First Nations to be 18.4% compared to 8.53% in their non-First Nations counterparts (Anand et al., 2001). Focusing solely on IHD, the First Nations Health Authority in British Columbia (BC) reported significantly higher rates of IHD in First Nations people (6.7%) compared to the non-First Nations BC population (5.9%).(British Columbia, 2020) In Manitoba, Dyck et al. (2021), found significantly higher rates of IHD in areas with a higher population density of Indigenous Peoples, even after adjusting for socio-economic factors. Prevalence rates were as high as 14.7% in Cross Lake First Nation, 14.5% in Peguis First Nation and 13.1% in Norway House Cree Nation, compared to approximately 10.4% in the non-Indigenous population (Dyck et al., 2021). In Saskatchewan, where over 10% of the First Nations population in Canada resides, the age-standardized prevalence of IHD is approximately 6.3% in the general population, significantly lower than the health regions with higher proportions of First Nations Peoples including the Northern (7.3%), Kelsey Trail (6.7%), and Prince Albert Parkland (7.2%) regions (Government of Canada, 2016a; Mann, 2015). These higher rates are critical as IHD is the most common cause of First Nations cardiovascular mortality, representing 62% of all cardiovascular deaths for First Nations men and 45% for First Nations women (Tjepkema et al., 2012). In addition to increased rates of ASCVD, First Nations 10 populations have been shown to have higher rates of cardiovascular mortality, all-cause hospital admission, acute MI hospital admission, and IHD hospital admission when compared to non-First Nations people (In Plain Sight, 2020; Schultz et al., 2018). Screening and treatment of ASCVD, which includes IHD, needs to be made a priority for healthcare providers to collaborate with and offer screening services to First Nations populations. 1.5.2 Atherosclerotic Cardiovascular Disease in Métis Populations Métis people are a distinctly recognized Indigenous group and constitute 30% of Canada's Indigenous population, however, Métis-specific health research is lacking in Canada (Gmitroski et al., 2023; Government of Canada, 2021b). There is extremely limited Métis-specific healthcare services and Métis patients are frequently excluded from non-Insured health benefits and federally funded programs (Gmitroski et al., 2023). Additionally, pan-Indigenous health approaches may overlook the unique identities and health needs of the Métis, resulting in continued health inequities for Métis people and discrimination when accessing healthcare services. The Aboriginal Peoples’ Survey (2006), was one of the first studies to report on chronic disease rates in Métis populations and found that approximately 7% of Métis self-reported “heart problems”. Tjepkema et al. (2011), found that Métis women experienced approximately twice the rate of death due to IHD and Métis men experienced 1.6 times the rate of death due to IHD, when compared to non-Indigenous Canadians. The prevalence of IHD in the Manitoba Métis population is significantly higher than the non-Métis population ranging from 10.3-12.2% in Métis compared to 7.3-8.7% in other Manitobans (Bartlett et al., 2012; Martens et al., 2011). Martens et al., also found rates of myocardial infarction (MI) were 5.4 per 1000 Métis compared to 4.3 per 1000 for other Manitobans (Martens et al., 2011). The Métis Nation of Ontario (MNO) 11 released a report, detailing higher rates of hospital re-admission for Métis patients and an increased burden of ASCVD in the Métis population (Atzema et al., 2015). The prevalence of acute coronary syndrome (ACS) in the Métis in Ontario was 1.8 times higher than the rest of the Ontario population (1.94% compared to 1.11%, respectively) (Atzema et al., 2015). The prevalence of congestive heart failure was 1.3 times higher in the Métis (1.79%), compared to the rest of the Ontario population (1.4%) (Atzema et al., 2015). The Métis Nation of Alberta published a report demonstrating significantly higher prevalence rates of IHD in Métis (6.13%) compared to non-Métis populations in Alberta (4.34%), with men more likely to experience IHD in both groups (Randall et al., 2018). Every year from 2007 to 2016, the incidence of IHD was higher amongst Métis than non-Métis Albertans, with 25% more diagnoses of IHD for Métis citizens compared to non-Métis Albertans (Randall et al., 2018). In a recent report including over 14,000 citizens, the Métis Nation of British Columbia demonstrated significantly higher rates of IHD in the Métis population (9.1%) compared to the non-Métis population (7.1%) in British Columbia (Metis Nation of British Columbia, 2021). It is evident Métis people face disproportionate rates of ASCVD and targeted interventions and screening strategies are needed to address the distinct cardiovascular health challenges faced by the Métis population in Canada. 1.5.3 Atherosclerotic Cardiovascular Disease in Inuit Populations The Inuit are a distinct Indigenous population with over 75% of the population residing in Inuit Nunangat, which spans the Northwest Territories, Yukon, Nunavut, northern areas of Newfoundland and Labrador (Nunatsiavut) and Quebec (Nunavik) (Government of Canada, 2009a). The Inuit include approximately 65,000 people who are culturally distinct from Métis and First Nations Peoples and encounter unique challenges and racial discrimination when 12 accessing healthcare systems (Government of Canada, 2009a). For decades, Inuit were believed to be protected from ASCVD, due to their involvement in strenuous physical activities and consumption of products from fishing, hunting, and gathering, however, the prevalence of ASCVD in Inuit was never sufficiently investigated (Fodor et al., 2014). Bjerregaard et al. (2003), examined evidence on Inuit having a lower prevalence of ASCVD and concluded that existing data was scarce and involved unreliable mortality statistics. Although Inuit have culturally cardio-protective diets and lifestyles, Inuit populations in Canada were also colonized and experienced lifestyle and dietary changes and restrictions that impact their cardiometabolic risks, with increasing numbers of Inuit now living in urban centres. Canadian census data found significantly higher rates of "heart problems", defined as self-reported hypertension, heart disease and/or stroke, in Inuit (8.6%) compared to non-Indigenous Canadians (5.3%) (Garner, Carriere, et al., 2010). A report analyzing ASCVD demonstrated that Inuit have significantly higher rates of IHD (3.1%) compared to non-Indigenous Canadians (2.1%) (Randall et al., 2012). Chateau-Degat et al. (2010), found a similar rate of IHD in the Inuit population reporting a prevalence of 2.6%. It was recently demonstrated in Greenland Inuit populations that around 13% exhibit signs of IHD, as evaluated by ischemic electrocardiogram (ECG) findings (Jørgensen et al., 2008), compared to pre-westernization findings in ECG data from the 1960’s, which showed lower rates of IHD closer to 5.5% in Greenland Inuit (Kjaergaard et al., 2009). Hu et al. (2019), found higher rates of MI, stroke, diabetes, obesity, and hypertension in Inuit populations compared to the general Canadian population. However, Hu et al. (2019), also reported Inuit men and women exhibit better lipid profiles than non-Indigenous Canadians, with hyperlipidemia rates of 29.0% versus 46.5% in males and 28.4% versus 35.2% in females. Although traditional Inuit diets may offer cardiovascular benefits, Inuit populations need access 13 to cardiovascular screening and education surrounding ASCVD. This is due to the change in Inuit cardiovascular risk profiles over recent decades including the increasing rates of ASCVD, diabetes, obesity, and decreased use of a traditional Inuit diet (Chateau-Degat et al., 2010; Kjaergaard et al., 2009). 1.6 Preventing Atherosclerotic Cardiovascular Disease Indigenous populations in Canada experience disproportionately high rates of ASCVD, however, treatment and prevention measures remain significantly understudied. Although First Nations, Métis and Inuit populations are diverse, there are many themes that can be applied and discussed involving these Indigenous groups across Canada. For example, recognized importance of screening and addressment is critical across communities. ASCVD screening in Indigenous patients with diabetes should also be increased, as all Indigenous populations in Canada have been found to have higher rates of diabetes (Cheran et al., 2023), and ASCVD is responsible for two-thirds of deaths in people with diabetes (Low Wang et al., 2016). The Truth and Reconciliation Commission of Canada has called for measurable goals to address health outcome gaps between Indigenous and non-Indigenous communities (National Centre for Truth and Reconciliation, 2015). These goals have been targeted specifically to cardiovascular health in a recent “Calls to Action” which highlight that novel approaches are needed to better address ASCVD inequity in Indigenous populations in Canada due to the unique challenges Indigenous Peoples face (Aziz & Marchand et al., 2022; Bonneau et al., 2018). Current barriers to accessing cardiovascular treatment include geographical location, cultural and linguistic differences, and mistrust rooted in intergenerational trauma and previous mistreatment in the healthcare system. As it stands, Indigenous patients face delays in ASCVD diagnosis and treatment, and are more 14 likely to present with advanced ASCVD (Vervoort et al., 2022). This highlights the need for a focus on ASCVD prevention, which will require addressing the above barriers. There is also a need for clinical trials and medical registries to prioritize safe and compensated participation of Indigenous individuals, aiming to mitigate assumptions about the generalizability of scientific findings to Indigenous Peoples. Schultz et al. (2018), found significant differences in vascular resistance and arterial elastance in Indigenous and non-Indigenous groups and noted how there are no studies assessing cardiovascular structure and function of Indigenous patients despite the significantly higher rates of ASCVD in this population. 1.7 Enhancing Access to Cardiovascular Medicine Cardiovascular medication use has been found to be underutilized in Indigenous populations (Pace et al., 2020). Indigenous access to western forms of cardiovascular medication is hindered by several factors. These include pharmacy locations, especially for rural, remote, and on-reserve populations, limited transportation infrastructure, and cultural barriers, including a lack of Indigenous and culturally competent healthcare providers (In Plain Sight, 2020). Financial constraints, including out-of-pocket medication costs, also play a role, especially for Métis and non-Status First Nations patients excluded from non-Insured health benefits (Gmitroski et al., 2023). Another major barrier for Indigenous patients face when accessing medication are systemic disparities, including discrimination and insensitivity from pharmacists and medication providers (In Plain Sight, 2020) Pharmacies and governments responsible for the health of Indigenous Peoples in Canada are unwilling to transport various medications sufficiently and safely to these rural and remote areas. Increased initiatives to address this medication health disparity are desperately needed. For example, researchers have recently 15 partnered with rural First Nations communities to develop drones that can deliver medicines and other medical supplies to isolated communities following telehealth consultations, however, community collaboration, increased telehealth services, and funding are required to ensure success of these innovative programs (Flemons et al., 2022; University of British Columbia, 2022). Health insurance and coverage for medications are also often lacking for Indigenous Peoples. The First Nations Health Authority (FNHA) in BC addresses some of these barriers for Status First Nations people, in addition to the Non-Insured Health Benefits Inuit and out-of-province Status First Nations have access to (Gallagher et al., 2015). However, Métis patients and many non-status First Nations face disparities in financial costs and access to medication. Indigenous patient adherence to cardiovascular medication is critically important in reducing ASCVD-related morbidity and mortality, and although current evidence is lacking, programs aimed to improve cardiovascular health literacy have shown to be effective in increasing medication adherence (Crengle et al., 2018; Vervoort et al., 2022). Despite widespread belief, there is very limited evidence to suggest medication adherence amongst Indigenous Peoples is lower than for the general population (de Dassel et al., 2017). In Canada, First Nations patients have actually displayed higher levels of adherence to ACE inhibitors and anti-platelet medications with lower adherence to β‐blockers and statins compared to non-First Nations patients (Dahl et al., 2019). Medication prescribing and adherence involves complex socioeconomic and personal factors, which for many Indigenous patients involves lack of geographic access, mistrust in healthcare, and limited health literacy towards western forms of medication (Dahl et al., 2019; de Dassel et al., 2017). 16 Recognizing the crucial link between traditional medicines and overall health (Marsh et al., 2015), there is an emerging awareness of the benefits of integrating Indigenous traditional medicines into the prevention and treatment of ASCVD to reduce disparities for Indigenous Peoples in Canada. For generations, Indigenous Peoples have used traditional medicines, including plants, animals, land, and water, to holistically promote cardiovascular health. In response to the Truth and Reconciliation Commission’s Calls to Action, cardiovascular care providers, including cardiovascular specialists, have an obligation to understand and promote barrier-free access to traditional medicine in a culturally respectful environment (National Centre for Truth and Reconciliation, 2015). This implementation of traditional medicine into clinical settings has begun across several health institutions in Canada, with each institution creating Indigenous Community Advisory Panels and hiring Indigenous patient navigators and knowledge keepers to deliver services involving traditional medicines and healing practices (Redvers et al., 2019). 1.8 Cardiovascular Disease Interventions in Indigenous Populations Cardiovascular procedures, including surgical interventions, are less accessible for Indigenous Peoples in Canada (Vervoort et al., 2022). Limited access to interventional cardiologists and cardiovascular surgeons, as well as perceived harassment when seeking cardiovascular care contribute to lower rates of surgical interventions for ASCVD among Indigenous populations (In Plain Sight, 2020; Vervoort et al., 2022) The underrepresentation of Indigenous physicians exacerbates this issue, with less than 1% of physicians identifying as Indigenous (Canadian Medical Association, 2023). ASCVD health literacy, including around interventional cardiac procedures, remains a significant issue within Indigenous communities. 17 This contributes to the mistrust of cardiovascular practitioners and has led to a massive gap for both elective and emergent cardiovascular surgeries to treat ASCVD (McVicar et al., 2021; Vervoort et al., 2022). To address these challenges, a collaborative effort involving policymakers, healthcare providers, and Indigenous communities is imperative to enhance access, provide education, and foster trust in the healthcare system. Physicians being able to recognize and respect Indigenous perspectives is essential, emphasizing the significance of culture, community, family, and traditional activities for comprehensive health initiatives. Integrating Western and Indigenous approaches in designing digital health tools can further bridge the gap, bringing cardiovascular care closer to home and improving health outcomes (Wali et al., 2023). Acknowledging the resilience and self-determination of Indigenous communities, it is crucial to shift from deficit-based perspectives to strength-based approaches. The incorporation of cultural activities inherently tied to traditional lands and waterways, into ASCVD prevention programs such as cardiac rehabilitation will be paramount in addressing the disproportionate rates of ASCVD in Indigenous populations (Thiessen et al., 2020). 1.9 Innovative Collaborations to Address Cardiovascular Disease Indigenous Peoples value strength-based approaches to medicine that highlight connection to culture, community, family, and traditional activities as being critical aspects of health (Thiessen et al., 2020). Therefore, these themes should be the focus during the creation of Indigenous-specific cardiovascular health programs to combat the disproportionate rates of ASCVD in Indigenous populations. We propose the formation of collaborative partnerships with Indigenous communities to improve the availability of screening and testing services. This would increase awareness of ASCVD among Indigenous Peoples and empower them to make informed 18 decisions such as to participate in screening initiatives. These programs can be led by Indigenous and/or non-Indigenous healthcare researchers and providers, however, program development should begin with community consultation to ensure a culturally-integrated approach is employed and that the needs of the community are met. The principles of Indigenous data sovereignty must also be incorporated into program creation and implementation through restructuring data access and control For example, the Canadian Alliance for Healthy Hearts and Minds study’s First Nations cohort fosters numerous First Nations community partnerships which allow for the comprehensive investigation of socio-environmental and health system factors in cardiovascular risk profiles, subclinical vascular diseases, and clinical cardiovascular events (Anand et al., 2018). These Indigenous collaborative efforts are also seen in the Silent Genomes Project, aimed to improve precision medicine through establishing Indigenous community partnerships which lead the creation of an Indigenous Background Variant Library, ultimately enhancing genetic diagnosis and long-term healthcare solutions (Caron et al., 2020). In the creation of these cardiovascular health partnerships, implementation of the OCAP (Ownership, Control, Access, Possession) principles is essential ( The First Nations Information Governance Centre, 2023) as these allow Indigenous communities to govern their own data and ensure collection, interpretation, and utilization processes align with the communities’ respective values. These alliances also foster the implementation of more cost-effective patient management strategies, emphasizing prevention in the form of culturally-supportive lifestyle modifications, medication 19 adherence, and coordinated care. This transformative shift would help promote health equity, while addressing the disproportionate rates of ASCVD in Indigenous populations in Canada. 2.0 Conclusions Our findings underscore a clear need to partner with Indigenous communities and health authorities to enhance the identification, recognition, and diagnosis of ASCVD and reduce disparities in Indigenous populations in Canada. Although race and ethnicity are commonly referred to as risk factors for cardiovascular diseases, in the context of Indigenous populations, it is essential we take a strength-based perspective which underscores that Indigenous identity is not a risk factor for ASCVD; rather, the risk is linked to the historical process of colonization. We identified that distinct Indigenous-specific risk factors for ASCVD exist and contribute to the significantly higher rates of ASCVD that exist in Indigenous populations. Better understanding of colonization as a cardiovascular risk factor and the impact colonialism had on shaping our current healthcare system may help clinicians and public health professionals develop culturally sensitive interventions, prevention programs, and services to reduce Indigenous cardiovascular disparities. The existing literature on the prevalence of ASCVD within Indigenous populations in Canada is scarce, outdated, and highly variable between communities. There are also various definitions used to define cardiovascular diseases in Canada, and a clear need to establish universally adopted, precise definitions of ASCVD. To address the disproportionate rates of ASCVD Indigenous communities face, researchers must actively engage with Indigenous communities and collaborate as equal partners at every stage of the research process. The pressing need for targeted interventions and policies, along with a comprehensive understanding of the foundational health determinants, emphasizes the urgency of adopting a holistic approach 20 that integrates Western and Indigenous perspectives into primary and secondary prevention of ASCVD. Physicians and healthcare providers must recognize and respect the unique cultural lens through which Indigenous Peoples approach cardiovascular health, as healthcare providers can contribute to closing the existing gaps and improving health outcomes within Indigenous communities. 21 Chapter 2: Estimating the Prevalence of Hypercholesterolemia in Indigenous Populations: A Systematic Review and Meta-Analysis 2.1 Introduction Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide and disproportionately affects people of Indigenous ancestry (Garner et al., 2010; Smylie et al., 2018). Hypercholesterolemia or elevated low-density lipoprotein cholesterol (LDL-C) is one of the most common modifiable risk factors for ASCVD (Roth et al., 2020), with interventions aimed at reducing cholesterol levels demonstrating significant efficacy in diminishing cardiovascular risk (Miname & Santos, 2019; Perez-Calahorra et al., 2019). While there is no universal definition for hypercholesterolemia, commonly used cut-offs include an LDL-C level  3.5 mmol/L (135 mg/dL) (high) and an LDL-C  4.0 mmol/L (155 mg/dL) (very high) (Government of Canada, 2021a; Nantsupawat et al., 2019; Pearson et al., 2021). Severe hypercholesterolemia, often defined as an LDL-C  5.0mmol/L (193 mg/dL), confers ~5-fold increased risk of developing ASCVD and is considered an indication for statin therapy in many national and international guidelines (Grundy et al., 2019; Mach et al., 2020; Pearson et al., 2021). Severe hypercholesterolemia affects ~5% of the global population (Akioyamen et al., 2022; Eid et al., 2020). A subset of patients with severe hypercholesterolemia have an underlying monogenic cause, called familial hypercholesterolemia (FH), which is the most common inherited lipid disorder, affecting 1 in 310 individuals globally (Akioyamen et al., 2022; Beheshti et al., 2020). FH is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk (Beheshti et al., 2020). A recent meta-analysis demonstrated differences in the prevalence of FH between ethnic groups, ranging from 1 in 400 in Black populations, to 1 in 192 in Asian 22 populations (Toft-Nielsen et al., 2022). However, the prevalence of FH in Indigenous populations is not well established. Worldwide, Indigenous Peoples have an increased burden of chronic disease, including cardiovascular disease (IWGIA, 2006). While Indigenous populations in Canada, the United States of America (USA), Australia, and New Zealand have unique genetic, geographic, and cultural backgrounds, they share similar colonial histories (Anand et al., 2019; Schultz et al., 2021), which, in turn, have profound effects on their health. Emerging guidelines for addressing cardiovascular risk in Indigenous populations discuss the need for inclusion of hypercholesterolemia, FH, and Indigenous-specific risk factors that take into account different groups unique histories (Agostino et al., 2020; Pace et al., 2020), The goal of this study was to estimate the prevalence of hypercholesterolemia, severe hypercholesterolemia, and FH in Indigenous populations in Canada, the USA, Australia, and New Zealand. 2.2 Methods 2.2.1 Population Selection Although there are many risk factors that contribute to the development of ASCVD, including abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, and alcohol, and regular physical activity (Yusuf et al., 2004), this study focuses on hypercholesterolemia and elevated LDL-C, as they have been identified as one of the global leading risk factors (Roth et al., 2020; Yusuf et al., 2004). We also recognize that “Indigenous” is a broad term used to describe many diverse populations. Throughout this study we use Indigenous as a categorical term, as described by the United 23 Nations as “inheritors and practitioners of unique cultures and ways of relating to people and the environment. They have retained social, cultural, economic, and political characteristics that are distinct from those of the dominant societies in which they live.” According to the United Nations global census data, there are over 476 million Indigenous Peoples in over 90 countries (United Nations, 2023) This study focuses on Indigenous Peoples in Canada, the USA, Australia, and New Zealand as these are all high-income countries with Indigenous minority groups that share similar patterns of colonization and history of forced assimilation into western-European culture (Lithopoulos, 2007; Mitrou et al., 2014; Smallwood et al., 2021). Indigenous populations in these countries have been compared in previous reviews (Camp et al., 2020; Shahid et al., 2018; Voaklander et al., 2020), as western colonization has shown to disrupt Indigenous Peoples traditional ways of life and result in loss of land, natural resources, and economic opportunities (Dennis & Robin, 2020). 2.2.2 Search Strategy This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) consensus statement (Appendix A). We conducted a systematic review of the literature from inception to May 2021 that included a search for hypercholesterolemia, severe hypercholesterolemia, FH, and LDL-C in global Indigenous populations (Appendix B). The systematic review was created in consultation with two medical librarians and authors (R.K.M., L.R.B., A.I.K., J.G.) with all terms tested to ensure relevant studies were not missed. Searches were conducted in MEDLINE, EMBASE, Web of Science, Native Health Database, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The list of global Indigenous populations used for the 24 systematic review search was derived from the University of Alberta’s Native Studies website and contained over 500 distinct groups (Alberta, 2022). This included traditional names that communities use to refer to themselves, as well as Eurocentric and westernized terms non-Indigenous people use to reference Indigenous communities. Titles, abstracts, and full texts were screened by a single reviewer (R.K.M.) to ensure inclusion criteria were met and verified by two additional reviewers (L.R.B. and A.I.K). Citations were managed using the systematic review software Covidence (Covidence, 2023). The Native Health Database prohibits importation of citations into Covidence and therefore titles and abstracts were separately reviewed on the Native Health Database website. 2.2.3 Eligibility and Study Selection Studies included in this systematic review met the following pre-specified inclusion criteria: (1) published in English; (2) reported data on prevalence of hypercholesterolemia or values of elevated LDL-C; (3) study population included Indigenous adults; (4) participants were from Canada, the USA, Australia, or New Zealand; and (5) the study population was not a duplicate of another included study. To facilitate estimations of prevalence, studies were also required to report the number of hypercholesterolemia or elevated LDL-C cases along with the total study population size or number of Indigenous Peoples in the study (if the study population was not entirely composed of Indigenous Peoples). Studies were excluded if Indigenous participants could not be distinguished from non-Indigenous participants. All studies that met the above criteria were included regardless of study design. 2.2.4 Data Extraction 25 Following full-text review, we extracted data from studies that included date of publication, name of the Indigenous group, geographic location of the study, number of participants, size of Indigenous population, reported prevalence of hypercholesterolemia or elevated LDL-C, the age range of participants, the mean age of participants, percent of the population that were reported as female, percent of the participants with diabetes, and definition of hypercholesterolemia or LDL-C cut-off used to classify “elevated LDL-C”. One author (R.K.M.) performed the data extraction and conflicts arising throughout were resolved by discussion to consensus with additional reviewers (A.I.K, L.R.B.). In cases where multiple prevalence rates were reported over time, the baseline prevalence was used. In cases where multiple studies reported on the same patient cohort, the study reporting on the largest or most recent sample population was included, with duplicate publications excluded from the analysis. We included studies in which participants were taking lipid lowering medications or had comorbid diseases, as there were limited studies to select overall. 2.2.5 Data Analysis Meta-analysis of single proportions was performed to determine the overall prevalence of hypercholesterolemia using a DerSimonian-Laird random effects model. A random effects model was chosen given high heterogeneity expected between studies. Logit transformation was applied to study-level proportions. Study weights were determined using the inverse-variance method. Confidence intervals for individual studies were calculated using the Clopper-Pearson method to provide conservative estimates, and the Jackson method was used for confidence intervals of τ2 and τ (Jackson et al., 2017). We performed subgroup analyses by publication date, geographic location, and hypercholesterolemia and LDL-C definitions. Univariate meta-regression was used 26 to identify possible sources of heterogeneity in the prevalence of hypercholesterolemia. These were conducted using a mixed-effects model of the logit-transformed proportions with DerSimonian-Laird estimator for τ2 and Jackson method for confidence intervals. Variables that were assessed included sample size, proportion of females, mean age of study population, year of publication, and prevalence of diabetes in the sample population. Assessment of other prominent ASCVD risk factors, including the prevalence of smoking, hypertension, and BMI, were not possible due to limited data. Publication bias was assessed formally using Egger’s test and by visual inspection of the funnel plot of logit transformed prevalence plotted against standard error. All analyses were conducted using the meta package for R (version 4.1.2) and RStudio (2021.09.2) for Windows (Nyaga et al., 2014; Schwarzer, 2007). 2.2.6 Sensitivity Analyses Robustness of the results was evaluated by a sensitivity analysis which omitted one study at a time. We also performed a trim-and-fill analysis to estimate the influence of potentially missing studies on our overall results (Duval & Tweedie, 2000). Finally, we assessed the influence of studies approaching the limits of prevalence (0% or 100%) on our pooled prevalence estimate by repeating our primary analysis using a Freeman-Tukey double arcsine transformation for proportions under inverse-variance weighting. 2.3 Results 2.3.1 Search Results and Study Characteristics Our search strategy identified 3961 unique studies (Figure 2.1). Initial screening of title and abstract revealed 134 studies meeting search criteria. After full text review, 34 studies were 27 identified as meeting full inclusion criteria. We found no studies that reported the prevalence of FH in Indigenous populations in Canada, the USA, Australia, and New Zealand. One study reported a prevalence of severe hypercholesterolemia, defined as an LDL-C level  5.0mmol/L (193 mg/dL), of 6.6% in Indigenous Peoples (Dubé et al., 2015). Nineteen studies representing 8,662 participants reported on prevalence of hypercholesterolemia (using any definition of elevated cholesterol) and 15 studies representing 40,399 participants reported on elevated levels of LDL-C (using a defined LDL-C cut-off). The 19 studies on hypercholesterolemia used various classifications to define the disorder, including elevated total blood or serum cholesterol, prior physicians’ diagnosis, and patient self-reports (Appendix C). The 15 studies reporting on elevated LDL-C used various cut-off points as classifications for elevated LDL-C; the most common being LDL-C  4.1mmol/L (160mg/dL) (Appendix C). 28 Figure 2.1: PRISMA Flowchart of the Inclusion of Studies for Meta-analysis. Systematic review process and exclusion criteria with reasoning. Inclusion and exclusion criteria were determined by reviews and applied using Covidence software. Studies found on the Native Health Database were screened independently. Arrows indicate the flow to which the systematic review was conducted. Indication, Screening, Eligibility, and Inclusion sections provide information on each stage of the review and the total number of studies analyzed at each stage. LDL-C = low-density lipoprotein cholesterol. 29 2.3.2 Prevalence of Hypercholesterolemia Using a random effects model, we estimated a pooled-prevalence of hypercholesterolemia in all included Indigenous populations of 28.9% (95% CI, 22.4 – 36.4; range 2.1% to 88.9%) (Figure 2.2), with high between-study heterogeneity (I2 = 100%, P = 0). Limiting the analysis to included studies using LDL-C-based criteria, the pooled prevalence of hypercholesterolemia was 25.0% (95% CI, 16.5 – 35.9; range 2.1% to 82.8%) with extreme heterogeneity (I2 = 100%, P = 0) (Figure 2.3). There were 25 studies conducted in 2001 or later and 9 studies conducted during the year 2000 or prior (Figure 2.4). Studies published in 2001 or later tended towards a higher prevalence of hypercholesterolemia of 31.3% (95% CI, 23.4 – 40.4%; range 2.1% to 88.9%), compared to 22.8% (95% CI, 13.4 – 36.1%; range 4.8% to 54.0%) in the pre-2000 studies, but this was not statistically significant. 2.3.3 Elevated LDL-Cholesterol We identified 15 studies reporting on elevated LDL-C, with a specific LDL-C cut-off, in Indigenous populations in Canada, the USA, Australia, and New Zealand. This included 8 studies with a LDL-C level  3.5mmol/L (135 mg/dL) (Figure 2.4). The pooled prevalence of hypercholesterolemia based on a LDL-C  3.5 mmol/L (135 mg/dL) was 12.6% (95% CI, 7.7 – 19.9%; range 2.0% to 29.8%) (Figure 2.4). 30 Figure 2.2: Pooled Prevalence of Hypercholesterolemia in Indigenous Populations. Hypercholesterolemia is classified using any study reported definition of the disorder. Studies are listed individually by first author’s last name with year the study was published. Number of hypercholesterolemia cases, sample size, prevalence rate with 31 95% CI, and study weight along with a forest plot is included for each study analyzed. Pooled prevalence is reported using a random effects model with 95% CI and total sample size. Prev = Prevalence. 32 33 Figure 2.3: Pooled Prevalence of Hypercholesterolemia Grouped by LDL-Cholesterol Based Cut-off. Studies are separated into two groups: (1) “Cut-off Used: No”: designating all studies which did not report using an LDL-C cut-off to define hypercholesterolemia and (2) “Cut-off Used: Yes”: designating all studies using any LDL-C cut-off to define hypercholesterolemia. Studies are listed individually by first author’s last name and year of publication. Hypercholesterolemia cases, sample size, prevalence rate, 95% CI, and study weight with a forest plot is included for each study. Pooled prevalence is reported using a random effects model for each group with 95% CI and total sample size. Prev = Prevalence. 34 Figure 2.4: Sub-group analysis for prevalence of hypercholesterolemia. The year of publication subgroups were pre-2000 (including the year 2000) and post-2000. The location subgroup consisted of whether the population was in North America (Canada and the USA) or outside of North America (Australia and New Zealand). Mix location relative to the city includes studies found to be reporting on both rural and urban populations. LDL-C levels of 3.4mmol/L and 3.5 mmol/L are equivalent to 131mg/dL and 135mg/dL, respectively. 2.3.4 Geographic Reporting in Indigenous Populations Twenty-four of the 34 studies were from Indigenous groups from North America (Canada and the USA, exclusively) (Figure 2.5). The pooled-prevalence of hypercholesterolemia in Indigenous populations in North America was 24.3% (95% CI, 17.1 – 33.3%; range 2.0% to 82.8%) (Figure 2.4). In comparison, the prevalence in Indigenous Australian (Aboriginal and Torres Strait Islander) populations was higher at 40.0% (95% CI, 31.3 – 49.3%; range 15.0% to 88.9%). The search did not yield results for Indigenous groups in New Zealand. Results were also stratified according to the location of Indigenous populations relative to cities. This demonstrated similar prevalence values regardless of whether the groups were based in urban, suburban, rural, on-reserve, or mixed localities (Figure 2.4). 35 Figure 2.5: World map of included Indigenous populations. Studies that reported rates of hypercholesterolemia are depicted in red circles and studies that reported elevated LDL-C are depicted in dark blue circles. Circles are found in the general geographic location that is representative of where the study was conducted. 2.3.5 Meta-regression We evaluated potential explanatory variables affecting the prevalence of hypercholesterolemia in the Indigenous populations using linear regression analyses. Variables that were assessed include study sample size, mean population age, sex, year of publication, and prevalence of diabetes (Appendix D). Regression plots depict the effect of these variables on treatment (Appendix E). The prevalence of diabetes had a significant influence (P = 0.022) on the prevalence of hypercholesterolemia despite being a poor predictor of the variance (R2 = 0.00%), which may be a consequence of the high variability in the data around the mean. Study 36 sample size (P = 0.23, R2 = 19.61%), mean population age (P = 0.15, R2 = 0.00%), and the proportion of females in the population (P = 0.18, R2 = 1.57%) did not significantly affect the prevalence of hypercholesterolemia in this analysis. 2.3.6 Publication Bias Publication bias was evaluated by Egger’s test and by visual inspection of the funnel plot of logit transformed prevalence plotted against standard error (Appendix F). Visual inspection demonstrates possible bias toward larger, higher-powered studies with no associated asymmetry of logit transformed prevalence. The wide variation among higher-powered studies in this plot is consistent with the substantial between-study heterogeneity (I2 = 99.5%, P = 0). Egger’s test suggested against the presence of asymmetry in the funnel plot (bias estimate = 3.16 ± 4.19; P = 0.45). 2.3.7 Sensitivity analyses Sensitivity analyses (Appendix G) demonstrated the robustness of our results, with no overtly influential single-studies. Pooled prevalence estimates, when studies were omitted, fell within the 95% confidence limits of our primary analysis, and ranged from 27.4% (95% CI, 21.1 – 34.8%) to 30.7% (95% CI, 23.9 – 38.5%). Trim-and-fill analysis (Appendix H) yielded one imputed study; inclusion resulted in a pooled prevalence of 27.3% (95% CI, 21.1 – 34.6%) under the random-effects model. Prevalence estimates derived under the Freeman-Tukey double arcsine transformation did not materially differ from our primary analysis (Appendix I) 37 2.4 Discussion We conducted a systematic review and meta-analysis of hypercholesterolemia in Indigenous populations in Canada, the USA, Australia, and New Zealand. We identified no publication that reported the prevalence of FH and only one that reported the prevalence of severe hypercholesterolemia in Indigenous populations. We found that hypercholesterolemia, using any definition, was common, affecting ~1 in 3 to 1 in 4 or 28.9% of individuals in Indigenous populations. The prevalence of hypercholesterolemia was significantly higher in Indigenous populations in Australia (40.0%) compared to Indigenous populations in North America (24.3%). Through including studies reporting on elevated LDL-C, we found the prevalence of LDL-C  3.5mmol/L (135 mg/dL) to be 12.6%. These findings point to a major knowledge gap and identify that studies of the prevalence of FH and severe hypercholesterolemia should be a priority for future research in collaboration with Indigenous communities. The prevalence of hypercholesterolemia in the general population differs between countries with reports showing 28.0% in Canada, 31.7% in the USA, and 32.8% in Australia (Kalisch, 2018; CDC Gov, 2021; Government of Canada, 2021a). The prevalence of hypercholesterolemia in Indigenous populations of 28.9%, albeit with significant heterogeneity between studies, is at least as common as in the general population in Canada, the USA, or Australia (Figure 2.6) (Kalisch, 2018; CDC Gov, 2021; Government of Canada, 2021a). A limitation is the differing definitions used, which precludes direct comparison. The significantly higher rates of hypercholesterolemia in Indigenous populations in Australia (40.0%) compared to Indigenous populations in North America (24.3%) further contribute to the heterogeneity in 38 overall prevalence. The search did not yield results for Indigenous groups in New Zealand; however, the New Zealand Ministry of Health reports 9% of the Indigenous Māori population have received a diagnosis of high cholesterol and/or are prescribed cholesterol-lowering medication, as compared to 11% in New Zealand’s European population (Ministry of Health Manatū Hauora, 2021). Rates of treated dyslipidemia are also significantly higher in both rural Māori (15.7%) and urban Māori (7.1%) populations when compared with the general New Zealand population (2.8%), as well as rates of other ASCVD risk factors including obesity, diabetes, and hypertension (Cameron et al., 2012). 39 Figure 2.6: Comparison of hypercholesterolemia data between Indigenous populations and the general population. There is a clear lack of studies with Indigenous populations compared to the general population for all types of hypercholesterolemia. Using the limited data available our study found a prevalence of 28.9% for Indigenous Peoples. This compares to hypercholesterolemia rates of 28% in Canada, 31.7% in the USA, and 32.8% in Australia. There was no familial hypercholesterolemia (FH) data found for the Indigenous population. FH prevalence in the general population is approximately 1 in 310 people. Despite the fact LDL-C is an important and pragmatic marker of hypercholesterolemia and cardiovascular risk (Miller, 2009), our results suggest that increased levels of LDL-C are not adequately reported for Indigenous Peoples. This may negatively impact risk assessment and reduction of ASCVD risk in Indigenous populations. Our results identified one study reporting the prevalence of severe hypercholesterolemia, defined as an LDL-C  5.0mmol/L (193 mg/dL) (Pearson et al., 2021; Ruel et al., 2018), in Inuit populations in Canada, the USA, and Greenland and found the prevalence of severe hypercholesterolemia to be ~ 1 in 15 people or 6.57% (Dubé et al., 2015). The prevalence of severe hypercholesterolemia in the global population using the same definition is estimated to be ~1 in 20 or 5.0% (Khera et al., 2016; Ruel et al., 2018). This suggests that severe hypercholesterolemia is as common in Indigenous populations as in the general population. We also examined studies that reported the prevalence of LDL-C  3.5mmol/L (135mg/dL), as this is a clinically relevant level, corresponding to the threshold to initiate statin therapy in intermediate risk individuals (Pearson et al., 2021). We found the prevalence of LDL-C  3.5mmol/L (135 mg/dL) to be 12.6% in Indigenous populations. This is comparable to the prevalence of an LDL-C  3.5mmol/L (135 mg/dL) of 14% in non-Indigenous populations (Government of Canada, 2021a), suggesting Indigenous Peoples experience elevated LDL-C to a similar degree. 40 There exist large gaps in the field of genetics involving Indigenous populations, which coincide with our finding of limited knowledge existing on FH in global Indigenous populations. Indigenous Peoples have historically been under-represented in genetics research and from medical registries or databases used to examine genetic disorders. This includes genome-wide association studies (GWAS), as well as population databases such as the Genome Aggregation Database (gnomAD), which allow for the identification of genetic variants that collectively contribute to increased risk of disease (Gwynne et al., 2023). Although FH is the most common monogenic disorder worldwide, it remains widely underdiagnosed across most populations (Beheshti et al., 2020), including Indigenous populations. Indigenous Peoples have a long history of mistrust regarding genomics, due in part to misuse of their data and numerous broken promises surrounding Indigenous Peoples benefitting from genetic research (Arbour et al., 2006). The limited genetic knowledge that does exist on FH in Indigenous populations shows existing LDLR gene variants associated with increased LDL-C levels in Inuit populations in Alaska and Greenland (Arbour et al., 2015). Additionally, PCSK9 gene variants, associated with significantly lower levels of LDL-C, have been identified in Indigenous populations in the USA (Arbour et al., 2015). These findings, including both cardioprotective and harmful genetic variants, demonstrate how genetically diverse global Indigenous populations are and underscore the importance of advancing genomic studies in collaboration with Indigenous community partners so that all results directly benefit Indigenous communities. There exist some successful collaborations with Indigenous communities to study cardiovascular genetics, including the work being done with the Gitxsan Community in Canada to understand the effects of hereditary Long QT syndrome (Arbour et al., 2008). Through this community-initiated partnership, hundreds of Indigenous participants have been enrolled in the longitudinal study helping advance community 41 understanding of the biological, cultural, and social aspects of this rare genetic disease disproportionately impacting Indigenous people (Huisman et al., 2020; Marchand et al., 2024). Indigenous populations in Canada, the USA, Australia, and New Zealand experience significantly higher rates of chronic diseases, including cardiovascular diseases, compared to the countries non-Indigenous populations (Breathett et al., 2020; Bruce et al., 2014; Calabria et al., 2018; Ministry of Health Manatū Hauora, 2021). As a result, guidelines on cardiovascular disease prevention are beginning to recognize Indigenous patients as a high-risk group and suggest earlier screening for hypercholesterolemia compared with other cohorts (Grundy et al., 2019; Pearson et al., 2021). Our findings of a lack of studies reporting on the prevalence of severe hypercholesterolemia and FH in Indigenous patients suggest that lipid screening in these populations is likely to be underused. There are also significant disparities in the rates of lipid-lowering therapy use between ethnic groups, with ethnic minority populations receiving fewer prescriptions and being less likely to achieve cholesterol targets (Kalra, 2021). Clinical practice guidelines recommend earlier screening for dyslipidemia in Indigenous individuals because of the higher risk of ASCVD (Pearson et al., 2021). Clinicians should be aware hypercholesterolemia impacts Indigenous patients to the same extent it does non-Indigenous patients, and Indigenous patients should be screened for hypercholesterolemia, FH, and severe hypercholesterolemia. At the same time, our research identifies marked disparities in the inclusion of Indigenous populations in research related to familial hypercholesterolemia. Our findings highlight the need for additional research, in partnership with Indigenous communities, to better understand the burden of hypercholesterolemia in Indigenous populations and how it 42 contributes to the disproportionate burden of ASCVD. Including Indigenous patients in registries and clinical trials related to hypercholesterolemia may help to improve awareness and optimize screening and treatment of dyslipidemia in Indigenous populations. 2.5 Study Limitations There are limitations to this study that merit consideration. First, despite our expansive search efforts, it remains possible through restrictions in our inclusion criteria (e.g., English language) or screening practices, we may have failed to identify some relevant studies. This study focused on Indigenous populations from Canada, the USA, Australia, and New Zealand, and therefore our results cannot be applied globally, as all Indigenous groups are diverse with their own history, culture and experiences which contribute to the health of their community. This systematic review was not published on an international prospective systematic review register; however, this review followed a strict pre-specified protocol and was conducted in accordance with PRISMA guidelines. A major limitation is the lack of a standardized definition for hypercholesterolemia. We attempted to address this by using numerical cut-off values, including LDL-C  3.5 mmol/L (135 mg/dL) as a clinically relevant threshold. Given the paucity of relevant data, and to maximize the sample size for analysis, we decided to include studies containing participants with cardiovascular disease, chronic kidney disease, taking cholesterol lowering medication, or any other administered treatment; further impairing the generalizability of the results. There was extreme between-study heterogeneity likely due to the wide variation in definitions and methodology. This underscores the important observation that global Indigenous communities are under-represented in lipid-related research. 43 2.6 Conclusion In summary, we estimate the pooled prevalence of hypercholesterolemia to be 28.9% in Indigenous communities in Canada, the USA, Australia, and New Zealand, making it at least as common as in the general population. This study represents the first systematic review and meta-analysis on hypercholesterolemia in Indigenous populations. Future research is needed, in collaboration with Indigenous communities, to study the prevalence of hypercholesterolemia, severe hypercholesterolemia, and FH in Indigenous populations and to optimize the use of lipid screening and treatment in these groups to address the disproportionate burden of ASCVD that affects these communities. 44 Chapter 3: Assessing the Care of Indigenous Patients with Premature Atherosclerotic Cardiovascular Disease 3.1 Introduction Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global morbidity and mortality and disproportionately impacts Indigenous populations (Anand et al., 2001; Schultz et al., 2018). For decades, ASCVD has remained a major burden for Indigenous communities with significant disparities in diagnosis, treatment access, and health outcomes. Even in high-income countries such as Canada, Indigenous populations experience ASCVD rates 1.5 to 2.5 times higher than their non-Indigenous counterparts and are less likely to receive evidence-based cardiovascular care (Anand et al., 2001; Atzema et al., 2015; Garner et al., 2010; Vervoort et al., 2022). With a large proportion of Indigenous patients in Canada living in rural and remote locations, access to healthcare infrastructure, which is more established in urban centres, is limited. Despite a shift in the Indigenous population toward urban areas, Indigenous patients continue to face non-geographic barriers to healthcare access, including racism from healthcare providers (Findling et al., 2019; Roach et al., 2023). Social determinants of health also influence Indigenous families, and patients’ ability to access quality health care; including employment status, income, and educational attainment (Davy et al., 2016). Indigenous Peoples are less likely to receive specialized cardiovascular care, which likely contributes to disparate outcomes (In Plain Sight, 2020; Schultz et al., 2018; Vervoort et al., 2022). There is increasing interest in the pathogenesis and treatment of premature ASCVD. Premature ASCVD is typically characterized as diagnosed ASCVD in males <55 years of age and females <65 years of age. However, for the scope of this study, we define premature ASCVD as diagnosed ASCVD in males <50 years of age and females <55 years of age. There is 45 limited understanding on how premature ASCVD impacts Indigenous populations. Indigenous patients’ perceptions surrounding premature ASCVD remain unexplored and require further assessment to properly address the health inequities Indigenous communities face. Addressing the urgent need for equitable and culturally competent cardiovascular care, this study assesses the complexities of cardiovascular disease in Indigenous populations, exploring themes drawn from patient experiences to illuminate pathways for improved healthcare outcomes and advocacy. This study compares the cardiovascular risk factor profiles of Indigenous patients with premature ASCVD and assesses the perceptions and priorities of Indigenous patients regarding their cardiovascular care. 3.2 Methods 3.2.1 Study Design and Population We analyzed patient data collected through the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) from 2016 to 2023. The study design and rationale have been previously described (Brunham et al., 2018). Briefly, SAVE BC is a prospective cohort study comprised of individuals from across British Columbia and Yukon, Canada, with premature coronary artery disease (CAD), defined as angiographically confirmed stenosis of ≥ 50% in ≥ 1 epicardial artery for men ≤ 50 years of age and women ≤ 55 years of age. SAVE BC participants attend regular visits in specialized cardiovascular disease prevention clinics and are provided with recommendations for secondary screening, clinical management, and treatment. SAVE BC collects data on sociodemographic characteristics (age, sex, ethnicity), traditional cardiovascular risk factors, comorbid diseases (e.g., chronic inflammations, cancer), family history, and cardiovascular endpoints. 46 To complement clinical data, all self-identifying Indigenous patients in SAVE BC were invited to complete a survey that explored experiences and perceptions regarding the cardiovascular care they received (Appendix K). An Indigenous researcher (R.K.M.) contacted the patients by phone to describe the study and invite them to complete the assessment survey. Indigenous patient assessments were collected through an electronic survey method using the online platform Qualtrics. Data was collected and stored in a secure virtual environment. Participants were compensated financially for the time spent completing the survey and all survey data was analyzed using a thematic approach to allow for the identification of major themes from the Indigenous patient’s experiences with cardiovascular care. All thematic analyses were conducted through generated codes using the NVivo R1 software (Lumivero, 2023). 3.2.2 Indigenous Ethnicity Self-reported ethnicity was identified through clinical patient records and used to select patients who self-identify as Indigenous, including patients who identify as First Nations, Métis, and Inuit. The utilization of patients' self-reported ethnicity is considered best practice in medical research (He et al., 2021). Self-identifying Indigenous patients were invited to complete a survey exploring experiences and perceptions regarding CAD diagnosis and treatment. 3.2.3 Outcomes The primary objectives of this study were to compare clinical treatment and cholesterol target attainment between Indigenous and non-Indigenous patients at baseline and one-year follow-up. Baseline assessments were defined as the index cardiac event at which patients were 47 enrolled in SAVE BC. Rates of lipid-lowering therapy prescription were assessed using pharmacy records at the first outpatient dispense following discharge, and the last dispense within the same year. Clinical treatment targets were defined as LDL-C  1.8 mmol/L, non–high-density lipoprotein cholesterol (non-HDL-C)  2.4 mmol/L and ApoB  0.7 mg/L (Pearson et al., 2021). The secondary objective of this study involved assessing the clinical care and treatment experiences of Indigenous patients with premature CAD, to derive Indigenous-specific recommendations for improving the cardiovascular care of Indigenous patients. 3.2.4 Statistical Analysis Participants were classified according to Indigenous ethnicity as either Indigenous or non-Indigenous. Descriptive statistics were calculated for sociodemographic characteristics, cardiovascular risk factors, and other comorbidities. Continuous variables are presented as mean  standard deviation (SD), or median with interquartile ranges (IQR), and compared, as appropriate, using the student’s t-test or Mann-Whitney U test. Categorical variables are presented as counts and percentages and compared using a χ2 test or Fisher exact test. All statistical analyses were performed using RStudio (2022.12.0) software for MacOS (R Core Team, 2022). 3.2.5 Ethical Considerations and Data Sovereignty This study was approved by the UBC Providence Health Care Research Ethics Board, certificate number H20-00758 and sub-study certificate number H23-01423. The Ownership, Control, Access, and Possession (OCAP) principles developed by the National Aboriginal Health 48 Organization were used to guide the ethical conduct of this study (The First Nations Information Governance Centre, 2023). The management of information and data collection strategies were created to align with Indigenous practices and culture through being Indigenous-led, ensuring the research team has cultural safety training, having an Indigenous advisory team, ensuring the questions are culturally adapted, prioritizing respect for privacy and confidentiality, ensuring cultural validation of the findings prior to dissemination, and through fostering the long-term relationships with patients. In order to further respect Indigenous sovereignty over the data collected, the Indigenous participants were treated as partners in the research process rather than subjects. This was achieved through having a patient-partner committee review the study prior to dissemination, as well as through offering consultation on results for feedback before publication. All participants provided free prior informed consent prior to enrolment in SAVE BC, with the ability to withdraw from the study at any time. The assessment survey was created by a mix of Indigenous and non-Indigenous researchers, Indigenous patients, and First Nations and Métis community members. Participants were made aware of all potential benefits and risks in completing the assessment survey. In accordance with the Tri-Council Policy Statement (TCPS) 2 - Chapter 9 principles involving the conduct of ethical research with Indigenous Peoples of Canada, an Indigenous advisory committee was created to ensure Indigenous community oversight. This Indigenous advisory committee oversaw every stage of the project to ensure the safety of the Indigenous patients involved and that the results benefit Indigenous Peoples. Indigenous respondents to the administered questionnaire were provided a data aggregate to have access to the study results before publication. 3.3 Results 49 3.3.1 Baseline Characteristics Of the 545 patients enrolled in SAVE BC with premature CAD, 379 patients met inclusion criteria. This included 19 Indigenous (5.2%) and 360 non-Indigenous participants (Figure 3.1). The median age of the Indigenous and non-Indigenous individuals was 50 (IQR 48-54 years) and 52 (IQR 49-55 years), respectively (Table 3.1). 57.9% of the Indigenous individuals and 73.3% of the non-Indigenous individuals were male. Indigenous individuals were significantly more likely to reside in rural and remote communities (57.9%) compared to non-Indigenous individuals (16.9%) (p < 0.001). The prevalence of diabetes (47.1%) was higher in Indigenous compared to non-Indigenous individuals (20.7%) (p = 0.036). Indigenous patients had similar rates of dyslipidemia compared to non-Indigenous patients (60.0% and 61.8%, respectively) (p = 0.8). Indigenous individuals reported significantly higher rates of prior or current smoking than non-Indigenous individuals (82.4% compared to 46.4%) (p = 0.008); however, current smoking rates at baseline did not differ between Indigenous and non-Indigenous groups (23.5% and 18.2%, respectively) (p = 0.5). Indigenous individuals had significantly higher rates of peripheral arterial disease (PAD) (15.8%) compared to non-Indigenous individuals (3.1%) (p = 0.004). Few patients had a history of cerebrovascular disease, chronic kidney disease, or malignancy. Indigenous and non-Indigenous patients had similar rates of modifiable cardiovascular risk factors, with 84.2% of Indigenous and 67.8% of non-Indigenous patients presenting with 3 cardiovascular risk factors (p = 0.2) (Table 3.1). Active or prior smoking was the most common risk factor for Indigenous patients (82.4%) followed by a family history of CAD (63.2%), dyslipidemia (60.0%), diabetes (47.1%) and hypertension (41.2%). In the non-Indigenous group, the most common risk factor was dyslipidemia (61.8%) followed by a family history of CAD (57.8%), hypertension (47.0%), and a history of smoking 50 (46.4%). Obesity (body mass index ≥ 30kg/m2) was significantly more common in Indigenous patients (57.9%) than non-Indigenous groups (40.6%) (p = 0.04). 51 Figure 3.1: Inclusion criteria of Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease. ASCVD – atherosclerotic cardiovascular disease, FDR – first degree relative. 52 Table 3.1: Baseline characteristics of Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease. Values are n (%) unless otherwise specified. IQR – interquartile range. SD – standard deviation. CAD – coronary artery disease. BMI – body mass index Table 1. Baseline characteristics Characteristic Indigenous Non-Indigenous P-value N 19 360 Age, median (IQR) 50.0 (48.0, 56.0) 52 (48.0, 55.0) 0.907 Male sex 11 (57.9) 263 (73.3) 0.231 Educational attainment 0.002 University 5 (26.3) 264 (73.3) High school certificate 8 (42.1) 65 (18.1) Less than high school 2 (10.5) 18 (5.0) Community type <0.001 Urban/Suburban 8 (42.1) 299 (83.1) Rural/Remote 11 (57.9) 61 (16.9) Employment status <0.001 Full-time 7 (58.3) 223 (87.1) Part-time 0 (0.0) 15 (5.9) Long-term disability 3 (15.8) 8 (3.1) Not working 1 (5.3) 7 (2.7) Cardiovascular risk factors Hypertension 7 (41.2) 165 (47.0) 0.843 Dyslipidemia 9 (60.0) 217 (61.8) 0.855 Diabetes mellitus 8 (47.1) 73 (20.7) 0.036 Impaired fasting glucose 4 (23.5) 70 (20.2) 0.009 Obesity 11 (57.9) 123 (40.6) 0.047 BMI, mean (SD) 30.5 (4.4) 29.5 (5.6) 0.582 History of smoking 14 (82.4) 163 (46.4) 0.008 Current smoking 4 (23.5) 29 (18.2) 0.556 Family history of CAD 12 (63.2) 208 (57.8) 0.579 No. of cardiovascular risk factors 0 0 (0.0) 5 (1.39) 1 At least 1 19 (100) 355 (98.6) 1 At least 2 17 (89.5) 329 (91.4) 0.676 ³3 16 (84.2) 244 (67.8) 0.203 Comorbidities Peripheral arterial disease 3 (15.8) 11 (3.1) 0.004 Cerebrovascular disease 1 (5.3) 10 (2.9) 1 History of cancer 1 (5.3) 21 (6.0) 1 Chronic kidney disease 1 (5.3) 9 (2.6) 0.697 Values are n (%), unless otherwise specified. IQR – Interquartile range. SD - standard deviation. CAD - coronary artery disease. BMI – body mass index 53 3.3.2 Clinical Presentation and Revascularization Indigenous patients were more likely to have an index clinical presentation of ST‐segment–elevation MI (STEMI) (47.4% and 20.0%, respectively) (p = 0.02). There were similar rates of non–ST‐segment–elevation MI (NSTEMI) between groups (31.6% in the Indigenous participants and 37.8% in the non-Indigenous participants) (p = 0.6) (Table 3.2). Although Indigenous patients were more likely to live in rural/remote than urban/suburban regions, rates of STEMI did not differ significantly between rural and urban groups (p = 0.4). Non-Indigenous patients exhibited numerically higher rates of stable angina (25.3%) compared to Indigenous individuals (10.5%), however, this was not statistically significant (p = 0.2). Indigenous and non-Indigenous participants had similar rates of PCI (63.2% and 61.5%, respectively) (p- = 0.8) and CABG (21.1% and 23.6%, respectively) (p = 1). 54 Table 3.2. Hospital characteristics of the Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease. Values are n (%), unless otherwise specified. IQR – interquartile range, STEMI - ST elevation myocardial infarction, NSTEMI – non-ST elevation myocardial infarction, PCI - percutaneous coronary intervention, CABG – coronary artery bypass graft. 3.3.3 Use of Cardiovascular Medication Medication usage, based on prescription dispensation data, were available for 73.6% of Indigenous patients (n=14) and 92.8% of non-Indigenous patients (n=334) (Table 3.3). At baseline, Indigenous patients were numerically more likely to have no prescription for any cardiovascular medication (defined as lipid-lowering therapy (LLT), anti-platelets, angiotensin-converting enzyme (ACE) inhibitors, betablockers, angiotensin receptor blockers (ARBs), and calcium channel blockers) (71.4% vs. 60.8%, respectively; p = 0.8). From the time of index hospital presentation to last clinical follow-up, use of high-intensity statin medication increased significantly in Indigenous (14.3% to 85.7%, p < 0.001) and non-Indigenous (15.0% to 78.3%, p Table 2. Hospitalization characteristics Characteristic Indigenous Non-Indigenous P-value N 19 360 Age at admission, median (IQR) 49.0 (43.0, 50.0) 47.0 (43.0, 49.0) 0.726 Presentation on admission STEMI 9 (47.4) 72 (20.0) 0.020 Rural/Remote 4 (21.1) 20 (5.6) 0.438 Urban/Suburban 5 (26.3) 52 (14.4) 0.438 NSTEMI 6 (31.6) 136 (37.8) 0.636 Stable angina 2 (10.5) 91 (25.3) 0.179 Unstable angina 2 (10.5) 44 (12.2) 1 Atypical angina 0 (0.0) 12 (3.3) 1 Asymptomatic 0 (0.0) 5 (1.4) 1 Treatment characteristics PCI 12 (63.2) 214 (61.5) 0.814 CABG 4 (21.1) 82 (23.6) 1 Medical therapy 3 (15.8) 50 (14.4) 0.737 Values are n (%), unless otherwise specified. Abbreviations: CABG - coronary artery bypass grafting; IQR - interquartile range; PCI - percutaneous coronary intervention. 55 < 0.001) patients (Figure 3.2). At follow-up, the number of Indigenous and non-Indigenous without a prescription for any cardiovascular medication decreased significantly (p < 0.001) to 0.0% and 4.8%, respectively. Few Indigenous (7.1%) and non-Indigenous patients (5.1%) were not taking statins. We observed significant increases in the use of beta-blockers and anti-platelet therapies in both Indigenous and non-Indigenous groups (p-value < 0.05). Table 3.3: Cardiovascular disease medication at baseline and last follow-up of Indigenous and non-Indigenous patients with atherosclerotic cardiovascular disease. Values are n (%), unless otherwise specified. *Values do not add up to 100% as categories are not mutually exclusive. ACE – angiotensin-converting enzyme. LLT – lipid lowering therapy. PCSK9 – proprotein convertase subtilisin/kexin type 9. 56 Figure 3.2: Treatment efficacy in Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease. A – Use of lipid-lowering therapy at baseline and follow-up (most recent patient visit). B – Baseline and follow-up changes in total cholesterol and LDL-C. C – baseline and follow-up changes in ApoB. D – Percent of patients who met guideline-recommended lipid targets at most recent follow-up (LDL-C < 1.8mmol/L, ApoB level < 0.7g/L and non-HDL-C < 2.4mmol/L). ApoB – Apolipoprotein B. LLT – lipid-lowering therapy. LDL-C – low-density lipoprotein cholesterol. Non-HDL-C – Non-high-density lipoprotein cholesterol. Non-Indigen. – Non-Indigenous. ns – non-significant (p-value > 0.05). 3.3.4 Treatment Efficacy Full baseline and follow-up lipid panels were available for 89.5% of Indigenous patients (n=17) and 56.4% of non-Indigenous patients (n=203) (Table 3.4). At baseline, levels of total cholesterol, HDL-C, LDL-C, ApoB, triglycerides and Lp(a) were similar between Indigenous 57 and non-Indigenous groups. Follow-up characteristics, at one-year post-admission, showed similar levels of total cholesterol, HDL-C, LDL-C, ApoB and Lp(a), however, triglycerides were significantly higher in Indigenous (1.96 mmol/L) compared to non-Indigenous (1.40 mmol/L) patients (p = 0.01). Indigenous patients had significant reductions in total cholesterol (5.44 mmol/L to 3.38 mmol/L, p < 0.001), LDL-C (3.31 mmol/L to 1.54 mmol/L, p < 0.001) and ApoB levels (1.30 mmol/L to 0.70 mmol/L, p = 0.004) (Table 3.3). Non-Indigenous patients experienced similar significant reductions in total cholesterol, LDL-C, triglycerides, and ApoB levels (Figure 3.2). Table 3.4: Comparison of baseline and follow-up laboratory values between Indigenous and non-Indigenous patients with premature atherosclerotic cardiovascular disease. Baseline is defined as the time the patient was admitted for the major cardiovascular event. Follow-up values were calculated using the lab values closest to one-year post-event. Values are mean (standard deviation), measure in mmol/L, unless otherwise specified. HDL – high-density lipoprotein, LDL – low-density lipoprotein. Achievement of guideline-recommended lipid levels did not differ significantly between Indigenous and non-Indigenous patients. A majority of Indigenous (66.7%) and non-Indigenous (67.9%) patients reached the guideline-recommended threshold of LDL-C < 1.8mmol/L (Figure 58 3.2). Approximately 61.5% of Indigenous and 51.5% of non-Indigenous patients reached the guideline-recommended ApoB threshold of < 0.7mmol/L, while 78.6% of Indigenous and 63.2% of non-Indigenous patients reached the guideline-recommended non-HDL-C threshold of < 2.4mmol/L. 3.3.5 Indigenous Cardiovascular Care Assessment Survey After completion of the quantitative analysis comparing Indigenous and non-Indigenous patients, a survey was sent only to the Indigenous patients with premature CAD; all results that follow are strictly from Indigenous respondents. The survey response-rate was 74% from the Indigenous patients (n=14); 64% were status First Nations, 7% were non-status First Nations, and 29% were Métis (Figure 3.3). Indigenous respondents were 36% women and 64% men. Although 71% reported growing up in rural areas or on a reserve, 57% now live in urban and suburban areas. 59 Figure 3.3: Demographic survey results from Indigenous patients with premature atherosclerotic cardiovascular disease. “A” shows reported gender (men or women), “B” shows self-reported Indigenous identity by First Nations (status and non-status), Métis and Inuit (no Inuit patients were included), “C” shows participants childhood living area, and “D” shows current living area. The geographic living area is divided into four groupings: Urban, Suburban, Rural/Remote, and On-Reserve). 3.3.6 Indigenous Perspectives on Risk and Prevention Of Indigenous patients with premature CAD, 93% stated they see their health as important, with every patient stating they actively work to maintain a healthy lifestyle (Figure 3.4). Every respondent reported being worried about their heart disease and 90% of patients with 60 children reported being worried about their children having heart disease. Approximately 93% reported a family history of heart disease and 65% reported feeling they were at a higher risk of developing health problems than other people their age. Indigenous patients recognized the importance of cardiovascular screening as routine care with 100% of patients recommending their family members be screened for ASCVD. 3.3.7 Indigenous Perspectives on Care and Treatment Indigenous patients’ perspectives on care, treatment, and access were also assessed. Only 50% of respondents reported they received enough information about the cause of their heart disease and 57% reported they received enough information on their treatment options (Figure 3.4). While 71% of participants had access to a family doctor, 57% reported their healthcare provider did not understand their emotions, feelings, and concerns, with only 28% reporting their doctor seemed concerned about their health and the health of their families. Almost every Indigenous patient (93%) was taking medication for their ASCVD, however, 36% stated they could not afford their cardiovascular medications. Although a majority of patients (64%) would prefer to be treated by an Indigenous physician or nurse, no patient surveyed had ever been treated by an Indigenous healthcare professional. Less than half (43%) of the Indigenous patients reported visiting a specialized cardiovascular care provider in the past year. However, in our analysis of Indigenous participants entire care history, 93% reported visiting d the emergency room for cardiovascular care and 93% reported traveling to another city for emergent care. All Indigenous respondents stated they wished the medical care they received was available in their home community. 61 Figure 3.4: Indigenous patients’ perceptions on cardiovascular risk and access to care or treatment. Dark blue represents Strongly Agree/Yes and dark red represents Strongly Disagree/No. Grey represents Neither agree nor disagree/I don’t know/prefer not to answer. 62 3.3.8 Indigenous Survey Thematic Analysis Our survey responses from Indigenous patients with premature CAD yielded eight major themes to improve the current state of cardiovascular care (Figure 3.5). Patients underscored the importance of increasing physician awareness about Indigenous-specific services, such as Indigenous health liaisons, Indigenous patient navigators and cultural services, both within healthcare facilities and their home communities. The limited accessibility and timing of post-discharge healthcare resources emerged as a pressing concern. Moreover, Indigenous individuals advocated for the inclusion of traditional diets in healthcare provisions, emphasizing the empowering role of traditional dietary choices in fostering healthier lifestyles. Traditional foods like oolichan fish, oolichan fish oil, and salal berries were identified as particularly beneficial for their physical and mental well-being post-diagnosis. Additionally, there was a consistent call for increasing the number of Indigenous cardiovascular physicians and healthcare providers, as patients believed this would facilitate better understanding and alignment with their unique needs and experiences. Patients also emphasized the importance of allocating more time for the development of patient-specific programs and ensuring treatment and follow-up appointments are available close to home communities. Finally, Indigenous patients recommended increasing financial and physical resources for family members accompanying Indigenous patients receiving healthcare outside of their home communities. Indigenous patients discussed the many costs associated with specialized cardiovascular care, including costs for transportation, accommodation, and lost wages due to time off-work. 63 Figure 3.5: Indigenous patient recommendations for improving cardiovascular care and outcomes. Beaded heart designed by author R.K.M (not for distribution or external use). 3.4 Discussion This is one of the first studies in the world to assess clinical characteristics of Indigenous patients with premature CAD. Indigenous patients exhibited distinct cardiovascular risk profiles, 64 characterized by higher rates of diabetes, smoking, and PAD, with similar rates of dyslipidemia and hypertension, when compared to non-Indigenous patients. Encouragingly, medication prescription rates and achievement of guideline-recommended lipid targets were similar between Indigenous and non-Indigenous participants. This suggests that a specialized, multidisciplinary cardiovascular care model, such as that provided by SAVE BC, was able to overcome population level disparities that have been documented in the care of Indigenous patients. However, our survey analysis identified persistent barriers to care experienced by Indigenous patients, encompassing the necessity for increased physician awareness of Indigenous-specific services, enhanced continuing-care resources, the integration of traditional diets into healthcare practices, and an expanded number of Indigenous healthcare providers, specifically in cardiovascular health. Moreover, patients underscored the significance of tailored patient-specific programs, accessibility of treatment facilities in proximity to their home communities, and increased resources for family members accompanying patients receiving healthcare outside their home communities. Indigenous patients with CAD in our study were significantly more likely to be admitted due to STEMI compared with non-Indigenous patients (47.4% vs. 20.0%, p = 0.02). In Australia, Indigenous patients have been found to be 2.7 times more likely to experience severe coronary events compared to non-Indigenous patients (Win et al., 2021), and residents from high-percentage Indigenous areas were more likely to be hospitalized for MI but less likely to undergo revascularization procedures (Wei-Randall et al., 2013). It is important to understand the barriers to cardiovascular care Indigenous patients face when accessing health services. In a recent report on Indigenous-specific racism in healthcare, it was identified that First Nations and Métis 65 patients had significantly higher rates of emergency room use for cardiac procedures compared to non-Indigenous patients (In Plain Sight, 2020) Cardiovascular medication significantly reduces the risk of recurrent cardiovascular events, enhances patients' quality of life, and reduces risk of death (Liu et al., 2021). We found that Indigenous patients with CAD accessing specialized cardiovascular care had high rates of cardioprotective medication use, coinciding with decreased risk of recurrent cardiovascular events (Figure 3.2). Indigenous patients had high rates of statin and other lipid-lowering therapy use which was significantly higher than baseline use. Use of anti-platelet medication and beta-blockers also significantly increased from baseline to follow-up in Indigenous patients. There were also numerical increases in the use of ACE inhibitors, ARBs, and anti-hyperglycemic medication. In contrast, prior studies have identified lower medication prescription rates in Indigenous patients (Dahl et al., 2019; Pace et al., 2020), suggesting that the specialized, multidisciplinary approach of SAVE BC may be more effective to improve medication prescription and uptake. Our thematic analysis revealed that Indigenous Peoples understand the need for and importance of screening for cardiovascular disease, especially at an early age. All Indigenous patients reported they would recommend their family and community members be screened for cardiovascular disease. Of the Indigenous patients with children, 90% reported being concerned about their children having heart disease. This finding highlights the willingness of Indigenous patients to undergo screening for cardiovascular risk factors and disease in the appropriate clinical scenario, and healthcare systems must ensure that adequate access to screening tools 66 (including blood tests, electrodiagnostics, and advanced cardiac imaging) are made equitably available for Indigenous patients and communities. Our study identified that Indigenous patients endure many costs associated with specialized cardiovascular care, including costs for transportation, accommodation, co-travellers (family accompaniment), and lost wages. The barriers encountered by Indigenous patients when accessing cardiovascular care were found to significantly exacerbate stress levels not only for the patients themselves but also for their families and communities. We found a distinct financial divide emerge among our Indigenous patients, with every First Nations patient reporting acceptable affordability of prescription medication, attributed to the coverage provided by the First Nations Health Authority in British Columbia. In contrast, every Métis patient expressed an inability to afford prescription medications, underscoring a critical disparity that necessitates further investigation. It is worth noting that the Government of Canada designates Métis individuals as "Indians" under the law (Government of Canada, 2009b), however, Métis patients continue to face challenges in accessing healthcare services due to the lack of a clear federal responsibility. This discrepancy is particularly pertinent to cardiovascular care, as some Métis populations have higher rates of obesity, diabetes, and IHD compared to their First Nations and non-Indigenous counterparts (In Plain Sight, 2020; Kolahdooz et al., 2017). Racism and discrimination from physicians and nurses were also highlighted as major barriers to seeking cardiovascular care, resulting in delays in cardiovascular care that have lasting effects on Indigenous patients, families, and communities. This is similar to recent studies, where one in five Indigenous patients reported experiencing discrimination in clinical 67 encounters, while over 15% avoided seeking healthcare for themselves or family members due to anticipated discrimination, including threats and harassment.(Findling et al., 2019) Indigenous patients in our study highlighted the need for the healthcare system to recognize and promote healthy traditional practices, including traditional diets. A common theme discussed by a majority of patients was incorporating traditional Indigenous diets into cardiovascular care following hospital discharge. Indigenous populations that maintain traditional lifestyles exhibit lower rates of cardiovascular risk factors when compared to Indigenous populations more impacted by colonization (Schultz et al., 2021). With emerging western evidence for the benefits of Indigenous traditional diets (de Souza et al., 2021), the resurgence of traditional agricultural practices, and the revitalization of traditional food preparation, processing, and preservation techniques (Sarkar et al., 2019). In conjunction with the promotion of traditional diets, Indigenous patients also suggested care providers promote healthy traditional lifestyle practices as a means of cardiovascular risk reduction, while further bolstering Indigenous communities’ sense of self-determination. Traditional Indigenous diets and lifestyle practices are integrally linked and should be used to promote holistic cardiovascular health for Indigenous patients. Areas with higher numbers of ethnic minority physicians have reduced mortality rates and improved outcomes for ethnic minority populations (Snyder et al., 2023). Despite a majority of Indigenous participants preferring to be cared for by Indigenous providers, none had ever been treated by an Indigenous physician. Participants highlighted the need to increase the number of Indigenous cardiovascular care providers, as they would better understand patients’ specific 68 concerns and derive context-specific solutions. Indigenous care providers can improve access to health services for Indigenous patients, ensure services are culturally appropriate and respectful, and assist non-Indigenous care providers in delivering culturally-safe care. Indigenous healthcare resources have been shown to outperform conventional hospitals and clinics in addressing the social and cultural factors that impede Indigenous Peoples' access to healthcare (Davy et al., 2016). Increasing the number of Indigenous healthcare providers has the potential to benefit Indigenous patients by fostering culturally safe healthcare delivery and promoting trust within healthcare interactions. 3.5 Limitations Our study has several potential limitations. The sample size of the study is a major limitation. Our Indigenous sample population (5.2% of patients) was slightly under representative, as approximately 6% of the BC population is Indigenous. Although we use the term Indigenous, it is important to note that our participants included First Nations and Métis individuals, however, there were no Inuit patients evaluated, and our findings may not apply to the unique Inuit context. As our study only includes patients who are enrolled in a specialized cardiovascular care biobank, they are expected to have received increased cardiovascular care compared to the general population, and therefore our direct findings may not be reflective of general practice. Since many Indigenous patients reported being covered through government financing, such as the BC-specific FNHA, care disparities may be exacerbated in settings where government funding is not as accessible to cover care-provider visits and other out-of-pocket costs. 3.6 Conclusions 69 Premature ASCVD greatly impacts the lives of Indigenous Peoples, families, and communities. Our findings suggest that Indigenous patients who have access to specialized, multidisciplinary evidence-based cardiovascular care achieve target treatment levels, which is known to decrease the risk of recurrent cardiovascular events. However, our findings emphasize that achieving equitable clinical parameters does not necessarily translate to equitable patient experiences for Indigenous individuals. Increasing the number of Indigenous healthcare providers, adding tailored Indigenous-specific intervention strategies, and increasing resource availability following hospital discharge has the potential to improve the patient experience and health outcomes for Indigenous patients. This study highlights the need to implement early screening and innovative prevention strategies in partnership with Indigenous communities to decrease the risk of primary and secondary cardiovascular events. 70 Chapter 4. Conclusions 4.1 Concluding Lessons Current western science-based approaches to screening and treating cardiovascular disease in Indigenous populations are not reducing the major disparities in cardiovascular health and ASCVD between Indigenous and non-Indigenous people. Alongside relevant national and international calls to action to decolonize the medical system through methods that decentralize western ways of knowing, and center Indigenous Peoples and knowledges (e.g., TRC Calls to Action, DRIPA, UNDRIP), the time has come to deeply reconsider how scientific methodologies inform our actions, treatment plans, and healthcare efforts made towards Indigenous populations. It is necessary now more than ever to promote and engage in work that stives towards ethical and equitable knowledge co-existence founded in common health goals; and that begins with properly engaging to understand the goals of Indigenous communities. The aim of this work was to create background knowledge on atherosclerotic cardiovascular disease (ASCVD) and major associated risk factors, including high cholesterol, as well as to assess the care of Indigenous patients with ASCVD. Our narrative review findings demonstrate Indigenous patients value a holistic understanding of cardiovascular health which involves incorporating cultural practices, traditional knowledge, and a deep connection to the land and community throughout their care. These findings underscore a clear need to partner with Indigenous communities and health authorities to enhance the identification, recognition, and diagnosis of ASCVD and reduce disparities in Indigenous populations. Although race and ethnicity are commonly referred to as risk factors for cardiovascular diseases, in the context of Indigenous populations, colonization is a more accurate cardiovascular risk factor. There is a clear need to better understand the 71 generational impacts of colonialism on the cardiovascular health of Indigenous Peoples and the contributions it has made in shaping our current medical system and healthcare practices. Physicians and healthcare providers need to learn about the Indigenous Peoples they are treating and the unique culture which empowers them. To address disproportionate rates of ASCVD in Indigenous communities, we must actively engage with Indigenous communities and collaborate as equal partners at every stage of the research process. Physicians and healthcare providers must recognize and respect the unique cultural lens through which Indigenous Peoples approach cardiovascular health, as healthcare providers can contribute to closing the existing gaps and improving health outcomes within Indigenous communities. Our systematic review findings reveal significant disparities in the representation of Indigenous patients in familial hypercholesterolemia studies, emphasizing the need for future research in collaboration with Indigenous communities. This is crucial to understand the role of hypercholesterolemia as a risk factor for ASCVD. Inclusion of Indigenous patients in registries and clinical trials is vital for enhancing awareness and improving screening and treatment of dyslipidemia within Indigenous communities. In summary, our meta-analysis estimates a pooled prevalence of 28.9% for hypercholesterolemia in Indigenous communities, establishing the disorder as impactful to Indigenous Peoples. Optimizing the use of lipid screening and treatment in Indigenous populations is essential to address the disproportionate burden of ASCVD within Indigenous communities. Our prospective cohort study found that although premature ASCVD greatly impacts the lives of Indigenous families and communities, Indigenous patients who have access to specialized, evidence-based cardiovascular care achieve target treatment levels, which is known to decrease the risk of cardiovascular events. However, our findings emphasize that achieving 72 equitable clinical parameters does not necessarily translate to equitable patient experiences for Indigenous individuals. Increasing the number of Indigenous healthcare providers, adding tailored Indigenous-specific intervention strategies, and increasing resource availability following hospital discharge has the potential to improve Indigenous patient experience and health outcomes for these patients. This study highlights the need to implement early screening and innovative prevention strategies in partnership with Indigenous communities to decrease the risk of primary and secondary cardiovascular events. Our people are still healing from recent traumas and dealing with health systems that were not built for us. Although we currently experience disproportionate rates of cardiovascular disease, it will not always be this way. 4.2 Knowledge Sharing and Future Directions Knowledge translation (KT) is a common practice and principal consideration when conducting research with Indigenous Peoples. Throughout Indigenous knowledge systems the processes of “knowing” and “doing” are often interconnected, which is typically overlooked in western health science approaches to KT (Smylie et al., 2014), however, it is possible to adapt these existing KT systems to ensure results benefit Indigenous communities. Recognizing the importance of Indigenous voices and perspectives, this research can act as a framework for future studies involving Indigenous Peoples. We have taken deliberate steps to ensure that our research process is inclusive, respectful, and culturally sensitive. This has involved centering Indigenous leadership by having projects led by Indigenous researchers and physicians, who bring invaluable insights into shaping research methodologies that respect Indigenous cultural values and traditional practices. Prior to implementation, our research undergoes review and 73 approval by Indigenous academics and community members, ensuring relevance and responsiveness to the diverse perspectives and needs of Indigenous Peoples. Aligning with the principles outlined in the Tri-Council Policy Statement (TCPS) 2 Chapter 9 on research involving Indigenous Peoples, we also established a formal Indigenous Community Advisory Panel, fostering ongoing dialogue and collaboration with community stakeholders. As a means of Indigenous-oriented KT, we prioritize transparency and reciprocity by sharing results with Indigenous patients, in the form of a data aggregate, before publication in adherence to Ownership, Control, Access, and Possession (OCAP) principles, and disseminating knowledge through publications in academic health journals and presentations at national and international conferences. We hope this work will act as background information to be shared with physicians and health care providers, as well as Indigenous community members. Looking ahead, we plan to develop and maintain long-term partnerships to offer Indigenous communities access to culturally safe testing and screening services. We also plan to develop Indigenous-specific frameworks for health research to advance understanding of community-specific needs and advance aftercare resources, such as cardiac rehabilitation, which includes culturally sensitive and Indigenous-led programming. 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Tjepkema, M., Wilkins, R., Senécal, S., Guimond, E., & Penney, C. (2011). Potential years of life lost at ages 25 to 74 among Métis and non-Status Indians, 1991 to 2001. Health Reports, 22(1), 37–46. 99 Toft-Nielsen, F., Emanuelsson, F., & Benn, M. (2022). Familial Hypercholesterolemia Prevalence Among Ethnicities—Systematic Review and Meta-Analysis. Frontiers in Genetics, 13. https://www.frontiersin.org/article/10.3389/fgene.2022.840797 Tsao, C. W., Aday, A. W., Almarzooq, Z. I., et al. (2022). Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation, 145(8), e153–e639. https://doi.org/10.1161/CIR.0000000000001052 Tsosie, K. S., Yracheta, J. M., Kolopenuk, J. A., & Geary, J. (2021). We Have "Gifted" Enough: Indigenous Genomic Data Sovereignty in Precision Medicine. The American journal of bioethics : AJOB, 21(4), 72–75. https://doi.org/10.1080/15265161.2021.1891347 United Nations. (2023). 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Prevalence of diabetes in pregnancy among Indigenous women in Australia, Canada, 100 New Zealand, and the USA: A systematic review and meta-analysis. The Lancet Global Health, 8(5), e681–e698. https://doi.org/10.1016/S2214-109X(20)30046-2 Wali, S., Seidel, J., Spence, G., Innes, L., Innes, E., Simard, A., Mashford-Pringle, A., Ssinabulya, I., Cafazzo, J. A., & Ross, H. (2023). Heart Health Begins With Community: Community-Based Research Exploring Innovative Strategies to Support First Nations Heart Health. CJC Open, 5(9), 661–670. https://doi.org/10.1016/j.cjco.2023.06.006 Wei-Randall, H. K., Davidson, M. J., Jin, J., Mathur, S., & Oliver, L. (2013). Acute myocardial infarction hospitalization and treatment: Areas with a high percentage of First Nations identity residents. Health Reports, 24(7), 3–10. Win, K. T. H., Emeto, T. I., Adams, C., Fairley, L., Thomas, B., Thavarajah, H., Danda, N., Wai, H. N., New, R. H., Muñoz, M. A., Basu, S., & Yadav, R. (2021). Association Between Indigenous Status and Severity of Coronary Artery Disease: A Comparison of Coronary Angiogram Findings in Patients With Chest Pain Presenting to a Regional Hospital Emergency Department. Heart, Lung and Circulation, 30(8), 1193–1199. https://doi.org/10.1016/j.hlc.2020.11.006 Yusuf, S., Hawken, S., Ounpuu, S., Dans, T., Avezum, A., Lanas, F., McQueen, M., Budaj, A., Pais, P., Varigos, J., Lisheng, L., & INTERHEART Study Investigators (2004). Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet (London, England), 364(9438), 937–952. https://doi.org/10.1016/S0140-6736(04)17018-9 101 Appendices Appendix A PRISMA Checklist Published checklist for systematic review criteria using the PRISMA Guidelines (Page et al., 2021). NA = not applicable. PRISMA 2020 Checklist Section and Topic Item # Checklist item Location where item is reported TITLE Title 1 Identify the report as a systematic review. Page 1, Line 1-2 ABSTRACT Abstract 2 See the PRISMA 2020 for Abstracts checklist. Page 3, Line 1-23 INTRODUCTION Rationale 3 Describe the rationale for the review in the context of existing knowledge. Page 5, Line 2-5 & 16-17 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. Page 6, Line 2-4 METHODS Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses. Page 8, Line 14-23; Figure 1 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted. Page 7, Line 17 to Page 8, Line 6 Search strategy 7 Present the full search strategies for all databases, registers, and websites, including any filters and limits used. Page 7, Line 17 to Page 8, Line 11; Appendix A 102 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process. Page 8, Line 6-8; Page 9, Line 3-15; Figure 1 Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process. Page 8, Line 6-8 Page 9, Line 3-15; Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect. Page 9, Line 3-15; Appendix C 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information. Page 9, Line 3-15 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. Page 10: Line 2-3; Line 9-10; Line 14-20; Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. Page 9, Line 18 to Page 10, Line 11 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)). Page 9, Line 2-8; Page 10, Line 5-9 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. Page 9, Line 18 to Page 10, Line 11 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 9, Line 18 to Page 10 Line 5 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used. Page 9, Line 18 to Page 10, Line 11 103 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). Page 9, Line 19-21; Page 10 Line 2-3 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 10 Line 14-20 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). Page 10, Line 14-20 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 10, Line 14-20 PRISMA 2020 Checklist Section and Topic Item # Checklist item Location where item is reported RESULTS Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. Page 11, Line 3-5; PRISMA Flow Diagram (Figure 1) 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. PRISMA Flow Diagram (Figure 1) Study characteristics 17 Cite each included study and present its characteristics. Appendix C Risk of bias in studies 18 Present assessments of risk of bias for each included study. Page 13, Line 15-21 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimates and its precision (e.g. confidence/credible interval), ideally using structured tables or plots. Figure 2; Figure 3; Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Page 11, Line 19 to Page 12, Line 5; Page 12, Line 7-12; Page 13, Line 15-21 104 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. Page 11, Line 19 to Page 12, Line 5; Figure 2; Figure 3 20c Present results of all investigations of possible causes of heterogeneity among study results. Page 13, Line 15-21 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Page 14, Line 1-8; Appendix E Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. Page 13, Line 15-21; Page 14, Line 1-8 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed. Page 13, Line 15-21; Figure 2; Figure 3 DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence. Page 15, Line 2-13 23b Discuss any limitations of the evidence included in the review. Page 18, Line 2-17 23c Discuss any limitations of the review processes used. Page 18, Line 2-17 23d Discuss implications of the results for practice, policy, and future research. Page 17, Line 12-22 OTHER INFORMATION Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Review did not require registration (NA) 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Figure 2.1 and inclusion criteria. Full protocol was not prepared (NA) 105 24c Describe and explain any amendments to information provided at registration or in the protocol. No amendments were made after initiation of review. (NA) Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. Page 1, Line 24-29 Competing interests 26 Declare any competing interests of review authors. Page 20, Line 13 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. Appendix C; Code Available Upon Request 106 Appendix B Systematic Review Search Terms Search Strategy for OVID - Medline (R)/EMBASE/Web of Science/Cochrane Register of Controlled Trials/Cochrane Database of Systematic Reviews/Native Health Database (Alberta, 2022). Search # Search Keyword or Phrase 1 Atherosclerosis/ or Cholesterol, LDL/ or Hypercholesterolemia/ or Coronary Artery Disease/ 2 Hyperlipoproteinemia Type II 3 Hypercholesterol?emia.mp. 4 Hypercholesterolemia/ or hypercholesterolemia.mp. 5 familial hypercholesterolemia.mp. 6 familial hypercholesterolaemia.mp. 7 FH.mp. 8 Coronary Artery Disease.mp. 9 LDL cholesterol.mp. 10 PCSK9.mp. 11 (APOB or LDLR).mp. 12 Dyslipidemias/ 13 hyperlipidemia.mp 14 dyslipidemia.mp. 15 low-density lipoprotein cholesterol.mp. 16 Cholesterol, LDL/ 107 17 indigenous.mp. 18 (exp Indians, North American/ or exp Inuits/ or exp Health Services, Indigenous/ or exp Ethnopharmacology/ or Athapaskan.mp. or Saulteaux.mp. or Wakashan.mp. or Cree.mp. or Dene.mp. or Inuit.mp. or Inuk.mp. or Inuvialuit*.mp. or Haida.mp. or Ktunaxa.mp. or Tsimshian.mp. or Gitsxan.mp. or Nisga'a.mp. or Haisla.mp. or Heiltsuk.mp. or Oweenkeno.mp. or Kwakwaka'wakw.mp. or Nuu chah nulth.mp. or Tsilhqot'in.mp. or Dakelh.mp. or Wet'suwet'en.mp. or Sekani.mp. or Dunne-za.mp. or Dene.mp. or Tahltan.mp. or Kaska.mp. or Tagish.mp. or Tutchone.mp. or Nuxalk.mp. or Salish.mp. or Stl'atlimc.mp. or Nlaka'pamux.mp. or Okanagan.mp. or Sec wepmc.mp. or Tlingit.mp. or Anishinaabe.mp. or Blackfoot.mp. or Nakoda.mp. or Tasttine.mp. or Tsuu T'inia.mp. or Gwich'in.mp. or Han.mp. or Tagish.mp. or Tutchone.mp. or Algonquin.mp. or Nipissing.mp. or Ojibwa.mp. or Potawatomi.mp. or Innu.mp. or Maliseet.mp. or Mi'kmaq.mp. or Micmac.mp. or Passamaquoddy.mp. or Haudenosaunee.mp. or Cayuga.mp. or Mohawk.mp. or Oneida.mp. or Onodaga.mp. or Seneca.mp. or Tuscarora.mp. or Wyandot.mp. or Aboriginal*.mp. or Indigenous*.mp. or Metis.mp. or red road.mp. or "on reserve".mp. or off-reserve.mp. or First Nation.mp. or First Nations.mp. or Amerindian.mp. or (urban adj3 (Indian* or Native* or Aboriginal*)).mp. or ethnomedicine.mp. or country food*.mp. or residential school*.mp. or ((exp Medicine, Traditional/ or traditional medicine*.mp.) not Chinese.mp.) or exp Shamanism/ or shaman*.mp. or traditional heal*.mp. or traditional food*.mp. or medicine man.mp. or medicine woman.mp. or autochtone*.mp. or (Native* adj1 (man or men or women or woman or boy* or girl* or adolescent* or youth or youths or person* or adult or people* or Indian* or Nation or tribe* or tribal or band or bands)).mp.) and (exp Canada/ or (Canad* or British Columbia or Columbie Britannique or Alberta or Saskatchewan or Manitoba or Ontario or Quebec or Nova Scotia or New Brunswick or Newfoundland or Labrador or Prince Edward Island or Yukon Territory or NWT or Northwest Territories or Nunavut or Nunavik or Nunatsiavut or NunatuKavut).mp.) 19 (((Indians, North American/ or Inuits/) and (Alaska/ or Alaska*.mp.)) or (((Anvik or Barrow or Bethel or Buckland or Cantwell or Chilcoot or Clarkes Point or Cordova or Craig or Crooked Creek or Deering or Dot Lake or Douglas or Eagle or Eek Elim or English Bay or Evansville or False Pass or Galena or Louden or Gambel or Georgetown or (Haida not (Haida Gwaii or Skidegate or Charlotte or Canada)) or Haines or Hamilton 108 or Healy Lake or Holy Cross or Hughes or Kake or King Island or King Salmon or Kotlik or Kwethluik or Marshall or McGrath or Minto or Nome or Northway or Old Harbor or Oscarville or Sheldon's Point or Perryville or (Petersburg not St Petersburg) or Pilot Point or Pilot Station or Point Hope or Point lay or Port Graham or Port Heiden or Port Lions or Pribilof* or St Paul Island or St George Island* or Sand Point or Rampart or Red Devil or Ruby or Saxman or Saint Michael or Stebbins or Stevens or Stony River or twin Hills) adj3 (Eskimo or Indian or community or Native or traditional or Indigenous or tribe or tribes or tribal or elder or elders or people or peoples)) or ((Native Village and Alaska*) or ((Native adj2 Alaska*) not species) or "Indians/alaska" or Afognak or Agdaagux or Akhiok or Akiachak or Akiak or Akutan or Alakanuk or Alatna or Aleknagik or Algaaciq or Allakaket or Anaktuvuk or Andreafski or Angoon Community or Aniak or Arctic Village or Venetie or Asa'carsarmiut or Atka or Atmautluak or Atqasuk or Atkasook or "beaver village" or "Bill Moore* Slough" or Belkofski or Birch Creek Tribe or Brevig Mission or Chenega or Chanega or Chalkyitsik or Cheesh-Na Chistochina or Chefornak or Chevak or Chickaloon or Chignik or Chilkat or Copper Center Village or Klukwan or Chinik or Golovin or Chitina or Chuathbaluk or Kuskokwim or Chuloonawick or Curyung or Diomede or Inalik or Egegik or Eklutna or Ekuk or Ekwok or Emmonak or Bettles Field or Fort Yukon or Gakona or Goodnews Bay or Holikachuk or Gulkana or Hoonah or Hooper Bay or Huslia or Hydaburg or Igiugig or Iliamna or Inupiat or Inupiaq or Arctic Slope or Iqurmuit or Ivanoff Bay or Kaguyak or Kaktovik or Barter Island or Kalskag or Kaltag or Kanatak or Karluk or Kasaan or Kasigluk or Elders Council or Kasigluk or Kenaitze or Ketchikan or Kiana or Kipnuk or Kivalina or Klawock or Kluti Kaah or Knik Tribe or Kobuk or Kokhanok or Kongiganak or Kotlik or Kotzebue or Koyuk or Koyukuk or Kwethluk or Kwigillingok or Kwinhagak or Quinhagak or Larsen Bay or Levelock or Lesnoi or Kalskag or Manley Hot Springs or Manokotak or Fortuna Ledge or Mary's Igloo or Mekoryuk or Mentasta or Metlakatla or Annette Island Reserve or Naknek or Nanwalek or Napaimute or Napakiak or Napaskiak or Nelson Lagoon or Nenana or Koliganek or Stuyahok or Newhalen Village or Newtok Village or Nightmute or Nikolski or Ninilchik or Noatak or Nondalton Village or Noorvik or Nuiqsut or Nooiksut or Nulato or Nunakauyarmiut or Toksook or Nunam Iqua or Nunapitchuk or Ohogamiut or Orutsararmuit or Ouzinkie or Paimiut or Pauloff or Pedro Bay or Pitka's Point or Portage Creek or Ohgsenakale or Aleut or Aleuts or Qagan Tayagungin or Qawalangin or Unalaska or Salamatoff or Savoonga or Scammon Bay or Selawik or Seldovia or Shageluk or Shaktoolik or 109 Shishmaref or Shungnak or (Sitka not spruce) or Skagway Village or Sleetmute or Naknek or Sun'aq or (Kodiak not bear*) or Shoonaq' or Takotna or Tanacross or Tanana or Tangirnaq or Tatitlek or Tazlina or Telida Village or Tetlin or Tlingit or Haida or Togiak or Tuluksak or Tuntutuliak or Tununak or Tyonek or Ugashik or Umkumiute or Unalakleet or (Village adj3 (Grayling or Circle or Lime or Nikolai or Wales or Platinum or Wainwright or Ambler or Unga or Teller or White Mountain)) or Wrangell or Yakutat or Yupiit or Yup'ik)).mp.) not (geolog* or thermokarst* or seismic* or geomorphology).mp. [mp=ti, ab, hw, tx, kw, ct, tn, ot, dm, mf, dv, kf, fx, dq, bt, nm, ox, px, rx, ui, sy] 20 first nation*.mp. 21 exp Indigenous Peoples/ 22 aboriginal.mp. 23 (aboriginal* or aborigine*).mp. 24 indigenous people.mp. 25 Indians, North American/ or First Nation.mp. 26 Indigenous Peoples/ or Health Services, Indigenous/ or indigenous.mp. 27 torres strait.mp. 28 maori.mp. 29 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 30 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 31 29 and 30 110 Appendix C Included Studies Reporting Indigenous Patients with Hypercholesterolemia and Elevated LDL-C NR = not reported, LDL-C = low-density lipoprotein cholesterol. Study Study Name for Indigenous Population Study Design Country Relative Location of Study Number of Cases Sample Number Reported Prevalence (%) Percent with Diabetes Classification of Hyper-cholesterolemia Molina et al., 1991 Yaqui Indians Cross-sectional United States of America Suburban 2 42 4.8 40.5 Fasting Plasma Cholesterol ≥ 6.21 mmol/L (240mg/dl) Campos-outcalt et al., 1995 Native American (Pascua Yaqui Indians) Cross-sectional United States of America Urban 37 230 16.18 37.39 Total Cholesterol ≥ 6.21 (240 mg/dL) OR LDL-C ≥ 4.14 mmol/L (160 mg/dL) OR taking cholesterol lowering medication Rowley et al., 2000 Aboriginal Australian Prospective Australia Rural 143 424 33.7 8.6 Plasma Cholesterol ≥ 5.5 mmol/L (212 mg/dL) Thommasen et al., 2004 Bella-Coola Aboriginal Retrospective Canada Rural 47 717 6.56 9.76 Previous Physician Diagnosis Oster et al., 2010 Alberta First Nations Cross-sectional Canada On-reserve 926 2102 44.1 100 Total Cholesterol ≥ 5.2 mmol/L (201 mg/dL) Balabanski et al., 2020 Australia Aboriginal Patients Retrospective Australia Rural 51 74 68.9 70.3 Medical Records Kataoka-Yahiro et al., 2020 Native Hawaiians Cross-sectional United States of America Mix 118 350 33.7 26.9 Self-reported DiabetPrev. et al., 2000 American Indians Prospective United States of America Mix 25 171 14.62 NR History of High Cholesterol Montour et al., 1989 Mohawks of Kahnawake Cross-sectional Canada On-reserve 13 82 15.85 100 Blood Cholesterol ≥ 7.5mmol/L 111 (290mg/dL) in the past 5 years Leonard et al., 2002 Torres Strait Islander People Prospective Australia Rural 194 592 32.8 26 Fasting Total Cholesterol ≥ 5.5 mmol/L (212 mg/dL) Lopez et al., 2014 American Indians Retrospective United States of America Mix 68 114 59.7 100 History of High Cholesterol Hodge et al., 2011 Aboriginal Australian & Torres Strait Islanders Cross-sectional Australia Urban 312 897 34.78 17.95 Total Cholesterol ≥ 5.5 mmol/L (212mg/dL) OR Self-reported Use of Cholesterol Lowering Medication D'Souza et al., 2005 New South Wales (NSW) Indigenous Population (Prison) Cross-sectional Australia Mix 89 239 37.3 5 Serum Cholesterol ≥ 5.5 mmol/L (212mg/dL) Campbell et al., 2012 Aboriginal Australian & Torres Strait Islanders Women Cross-sectional Australia Rural 144 961 15 9.5 Elevated Cholesterol ≥ 5.5mmol/L (212mg/dL) Boyko et al., 2004 American Indian/Native Alaskan (Native American) Cross-sectional United States of America Mix 128 253 50.7 100 Self-reported diagnosis of high cholesterol Gault et al., 1996 Aboriginal Community in Central Australia (Isolated) Cross-sectional Australia Rural 228 437 52.17 9 Total Cholesterol ≥ 5.5 mmol/L (212mg/dL) Kejriwal et al., 2004 Australia Aboriginal Cross-sectional Australia Mix 40 45 88.9 66.7 Previous Diagnosis Rudkowska et al., 2013 Inuit Population Cross-sectional Canada Rural 43 553 7.78 NR Previous Diagnosis Dahl et al., 1996 Chippewa Indian reservations in Northern Cross-sectional United States of America On-reserve 329 609 54 100 Total Cholesterol ≥ 5.17 mmol/L (200 mg/dL ) 112 Minnesota (American Indian) Study Study Name for Indigenous Population Study Design Country Relative Location of Study Number of Cases Sample Number Reported Prevalence (%) Percent with Diabetes Classification of Elevated LDL-Cholesterol Howard et al., 2009 Alaskan Eskimos (Inupiat Eskimos) Prospective United States of America Suburban 141 499 28.26 5.81 LDL-C ≥ 4.14 mmol/L (160 mg/dL) OR taking lipid lowering medication Calabria et al., 2018 Australian Aboriginal and Torres Strait Islander Cross-sectional Australia Mix 671 2820 23.8 10.7 LDL-C ≥ 3.5mmol/L (135 mg/dL) Hopkins et al., 2014 Yup'ik and Inupiat Indigenous Groups (Western Alaska Native People) Cross-sectional Canada, United States of America Rural 1633 3985 40.98 NR LDL-C ≥ 3.36 mmol/L (130 mg/dL) OR taking lipid lowering medication Kelly et al., 2019 Ontario First Nations Retrospective Canada Rural 1313 1859 70.6 71.6 LDL-C ≥ 2.0mmol/L (77.3 mg/dL) OR taking lipid lowering medication Clough et al., 2004 Australia Aboriginal (Arnhem Land in Northern Territory) Cross-sectional Australia On-reserve 38 98 38.4 NR LDL-C ≥ 3.4 mmol/L (132 mg/dL) Bhattacharyya et al., 2010 Oji-Cree reserves in Sioux Lookout Zone, Ontario Controlled Before-After Canada Rural 154 302 51 100 LDL-C ≥ 2.5mmol/L (96.7 mg/dL) Redwood et al., 2010 Alaska Native and American Indian People, EARTH Study (from Alaska) Prospective Canada, United States of America Mix 991 3822 25.93 NR LDL-C ≥ 3.36 mmol/L (130mg/dL) Singh et al., 2018 Canadian Inuit Cross-sectional Canada Rural 719 2191 32.82 NR LDL-C ≥ 3.4 mmol/L (132 mg/dL) OR taking cholesterol lowering medication 113 Harris et al., 2011 Canadian First Nations Communities (CIRCLE Study) Retrospective Canada Mix 691 835 82.8 100 LDL-C > 2.5 mmol/L (96.7 mg/dL) OR lipid-lowering medication Proust et al., 2016 Cree (Eeyouch) of Northern Québec Retrospective Canada Suburban 17 829 2 17.3 LDL-C ≥ 4.5 mmol/L (174 mg/dL) Green et al., 2020 Ontario First Nations Retrospective Canada Mix 1755 14755 11.9 100 LDL-C ≥ 3.0 mmol/L (116 mg/dL) Delisle et al., 1995 Algonquin communities of Quebec (Canada) Cross-sectional Canada Rural 89 299 29.77 24.41 LDL-C ≥ 4.14 mmol/L (160 mg/dL) Lee et al., 2006 Arizona ( Pima/Mari- Copa/Papago Indians), Oklahoma (Apache, Caddo, Comanche, Delaware, Fort Sill Apache, Kiowa, and Wichita), North/South Dakota ( Oglala and Cheyenne River Sioux) Prospective United States of America Mix 436 4274 10.2 45 LDL-C ≥ 4.14 mmol/L (160 mg/dL) Mendlein et al., 1997 Navajo Indians Prospective United States of America On-reserve 70 788 8.88 21.9 LDL-C ≥ 4.14 mmol/L (160 mg/dL) Dubé et al., 2015 Alaska Canada and Greenland Inuit Population Retrospective Canada, United States of America Rural 200 3043 6.57 NR LDL-C ≥ 5.0mmol/L (193 mg/dL) 114 Appendix D Results of Meta-Regression Analyses CI, Confidence interval; NA, not applicable; R2, coefficient of determination (Schwarzer, 2007). Independent Variable Number of Studies β coefficient (95% CI) P-value R2 (%) Sample Size 34 -1.02 x10-4 (-2.69 x104 to 6.67 x10-5) 0.23 19.61 Age 24 4.40 x10-2 (-1.76 x10-2 to 1.06 x10-1 ) 0.15 0.00 Sex 31 -2.17 x10-2 (-5.38 x10-2 to 1.04 x10-2 ) 0.18 1.57 Diabetes 27 1.55 x10-2 (2.39 x10-3 to 2.86 x10-2 ) 0.022 0.00 Publication Year 34 NA 0.39 0.00 115 Appendix E Sensitivity Analysis Sensitivity analysis using the Freeman-Tukey transformation to estimate the pooled prevalence of hypercholesterolemia across Indigenous populations (3). Article citations listed in appendix references. (4-37). 116 Appendix F Regression Plots Regression plots of treatment effect by percentage of females (A), study population age (B), sample size (C), and percentage with diabetes (D). Treatment effect is measured in logit transformed proportion. 117 118 Appendix G Funnel Plot of Logit Transformed Prevalence in Relation to Standard Error. The 95% confidence intervals are indicated (Schwarzer, 2007). 119 Appendix H Sensitivity analysis omitting examining the influence of single studies on pooled prevalence estimate. 120 Appendix I Funnel plot of trim-and-fill analysis. The plot depicts logit transformed prevalence in relation to standard error with 95% confidence intervals are indicated. 121 Appendix J Appendix References 1. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 2021;10:89. 2. Alberta U of. University of Alberta, Library Health Sciences Search Filters. 2022. Available at: https://guides.library.ualberta.ca/health-sciences-search-filters/indigenous-peoples. Accessed May 18, 2022. 3. Schwarzer G. meta: An R Package for Meta-Analysis. 2007;7:40–45. 4. Balabanski AH, Goldsmith K, Giarola B, et al. Stroke incidence and subtypes in Aboriginal people in remote Australia: a healthcare network population-based study. BMJ Open 2020;10:e039533. 5. Bhattacharyya O, Harris S, Zwarenstein M, Barnsley J. Controlled trial of an intervention to improve cholesterol management in diabetes patients in remote Aboriginal communities. Int J Circumpolar Health 2010;69:333–343. 6. McNeely MJ, Boyko EJ. Diabetes-related comorbidities in Asian Americans. J Diabetes Complications 2005;19:101–106. 7. Calabria B, Korda RJ, Lovett RW, et al. Absolute cardiovascular disease risk and lipid‐lowering therapy among Aboriginal and Torres Strait Islander Australians. Med J Aust 2018;209:35–41. 8. Campbell SK, Lynch J, Esterman A, McDermott R. Pre-Pregnancy Predictors of Diabetes in Pregnancy Among Aboriginal and Torres Strait Islander Women in North Queensland, Australia. Matern Child Health J 2012;16:1284–1292. 122 9. Campos-Outcalt D, Ellis J, Aickin M, Valencia J, Wunsch M, Steele L. Prevalence of cardiovascular disease risk factors in a southwestern Native American tribe. Public Health Rep 1995;110:742–748. 10. Clough AR, Rowley K, O’Dea K. Kava use, dyslipidaemia and biomarkers of dietary quality in Aboriginal people in Arnhem Land in the Northern Territory (NT), Australia. Eur J Clin Nutr 2004;58:1090–1093. 11. Hirata-Dulas CA, Rith-Najarian SJ, McIntyre MC, et al. Risk factors for nephropathy and cardiovascular disease in diabetic Northern Minnesota American Indians. Clin Nephrol 1996;46:92–98. 12. Delisle HF, Rivard M, Ekoé J-M. Prevalence Estimates of Diabetes and of Other Cardiovascular Risk Factors in the Two Largest Algonquin Communities of Quebec. Diabetes Care 1995;18:1255–1259. 13. The Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. The Diabetes Prevention Program Research Group. Diabetes Care 2000;23:1619–1629. 14. D’Souza RM, Butler T, Petrovsky N. Assessment of cardiovascular disease risk factors and diabetes mellitus in Australian prisons: is the prisoner population unhealthier than the rest of the Australian population? Aust N Z J Public Health 2005;29:318–323. 15. Dubé JB, Wang J, Cao H, et al. Common low-density lipoprotein receptor p.G116S variant has a large effect on plasma low-density lipoprotein cholesterol in circumpolar inuit populations. Circ Cardiovasc Genet 2015;8:100–105. 123 16. Gault A, O’Dea K, Rowley KG, McLeay T, Traianedes K. Abnormal Glucose Tolerance and Other Coronary Heart Disease Risk Factors in an Isolated Aboriginal Community in Central Australia. Diabetes Care 1996;19:1269–1273. 17. Green ME, Shah BR, Slater M, Khan S, Jones CR, Walker JD. Monitoring, treatment and control of blood glucose and lipids in Ontario First Nations people with diabetes. CMAJ 2020;192:E937–E945. 18. Harris SB, Naqshbandi M, Bhattacharyya O, Hanley AJG, Esler JG, Zinman B. Major gaps in diabetes clinical care among Canada’s First Nations: Results of the CIRCLE study. Diabetes Res Clin Pract 2011;92:272–279. 19. Hodge A, Cunningham J, Maple-Brown L, Dunbar T, O’Dea K. Plasma carotenoids are associated with socioeconomic status in an urban Indigenous population: an observational study. BMC Public Health 2011;11:76. 20. Hopkins SE, Austin MA, Metzger JS, et al. Sex differences in obesity prevalence and cardiometabolic factors among Western Alaska Native people. Nutr Metab Cardiovasc Dis 2015;25:312–318. 21. Howard BV, Comuzzie A, Devereux RB, et al. Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos. Nutr Metab Cardiovasc Dis 2010;20:350–358. 22. Kataoka-Yahiro MR, Davis J, Rhee CM, Wong L, Hayashida G. Racial/Ethnic Differences in Early Detection and Screening for Chronic Kidney Disease Among Adults in Hawaii: A 10-Year Population Health Study. Prev Chronic Dis. 2020;17:200011. 23. Kejriwal NK, Tan JTH, Vasudevan A, Ong M, Newman MAJ, Alvarez JM. Follow-up of Australian Aboriginal Patients Following Open-Heart Surgery in Western Australia. Heart, Lung Circ 2004;13:70–73. 124 24. Kelly L, Matsumoto C, Schreiber Y, et al. Prevalence of chronic kidney disease and cardiovascular comorbidities in adults in First Nations communities in northwest Ontario: a retrospective observational study. CMAJO 2019;7:E568–E572. 25. Lee ET, Howard BV, Wang W, et al. Prediction of Coronary Heart Disease in a Population With High Prevalence of Diabetes and Albuminuria: The Strong Heart Study. Circ 2006;113:2897–2905. 26. Leonard D, McDermott R, O’Dea K, et al. Measuring Prevalence: Obesity, diabetes and associated cardiovascular risk factors among Torres Strait Islander people. Aust N Z J Public Health 2002;26:144–149. 27. Lopez JMS, Bailey RA, Rupnow MFT, Annunziata K. Characterization of Type 2 Diabetes Mellitus Burden by Age and Ethnic Groups Based on a Nationwide Survey. Clin Ther 2014;36:494–506. 28. Mendlein JM, Freedman DS, Peter DG, et al. Risk Factors for Coronary Heart Disease among Navajo Indians: Findings from the Navajo Health and Nutrition Survey. J Nutr 1997;127:2099S-2105S. 29. Molina J, Campos-Outcalt D. CORONARY ARTERY DISEASERS FACTORS IN YAQUI INDIANS MEXICAN AMERICANS. J NAT MED ASSOC 1991;83:6. 30. Oster RT, Shade S, Strong D, Toth EL. Improvements in Indicators of Diabetes-related Health Status Among First Nations Individuals Enrolled in a Community-driven Diabetes Complications Mobile Screening Program in Alberta, Canada. Can J Public Health 2010;101:410–414. 125 31. Proust F, Drescher O, Laouan-Sidi EA, Robinson E, Lucas M, Dewailly É. Omega-3 polyunsaturated fatty acid profiles and relationship with cardiometabolic risk factors in Cree ( Eeyouch ) of Northern Québec. Int J Circumpolar Health 2016;75:30361. 32. Redwood DG, Lanier AP, Johnston JM, Asay ED, Slattery ML. Chronic Disease Risk Factors Among Alaska Native and American Indian People, Alaska, 2004-2006. 2010;7:10. 33. Rowley KG, Gault A, McDermott R, Knight S, McLeay T, O’Dea K. Reduced prevalence of impaired glucose tolerance and no change in prevalence of diabetes despite increasing BMI among Aboriginal people from a group of remote homeland communities. Diabetes Care 2000;23:898–904. 34. Rudkowska I, Dewailly E, Hegele RA, et al. Gene–diet interactions on plasma lipid levels in the Inuit population. Br J Nutr 2013;109:953–961. 35. Montour LT, Macaulay AC, Adelson N. Diabetes mellitus in Mohawks of Kahnawake, PQ: a clinical and epidemiologic description. CMAJ 1989;141:549–552. 36. Singh K, Chan HM. Association of blood polychlorinated biphenyls and cholesterol levels among Canadian Inuit. Environ Res 2018;160:298–305. 37. Thommasen HV, Patenaude J, Anderson N, Mc Arthur A, Tildesley H. Differences in diabetic co-morbidity between Aboriginal and non-Aboriginal people living in Bella Coola, Canada. Rural Remote Health 2004;4:319. 126 Appendix K Indigenous Patient Assessment Survey 127 128 129 130 131 132 133 134 135 136 137 138 139 Appendix L Data Aggregate for Indigenous Patients FRONT 140 BACK
Thesis/Dissertation
eng
Experimental Medicine
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Brunham, Liam
Indigenous cardiovascular health : assessing disease, risk factors, and patient care
Text