The Canadian Women’s Heart Health Alliance ATLAS on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 8: Knowledge Gaps and Status of Existing Research Programs in Canada

Despite significant progress in medical research and public health efforts, gaps in knowledge of women’s heart health remain across epidemiology, presentation, management, outcomes, education, research, and publications. Historically, heart disease was viewed primarily as a condition in men and male individuals, leading to limited understanding of the unique risks and symptoms that women experience. These knowledge gaps are particularly problematic because globally heart disease is the leading cause of death for women. Until recently, sex and gender have not been addressed in cardiovascular research, including in preclinical and clinical research. Recruitment was often limited to male participants and individuals identifying as men, and data analysis according to sex or gender was not conducted, leading to a lack of data on how treatments and interventions might affect female patients and individuals who identify as women differently. This lack of data has led to suboptimal treatment and limitations in our understanding of the underlying mechanisms of heart disease in women, and is directly related to limited awareness and knowledge gaps in professional training and public education. Women are often unaware of their risk factors for heart disease or symptoms they might experience, leading to delays in diagnosis and treatments. Additionally, health care providers might not receive adequate training to diagnose and treat heart disease in women, leading to misdiagnosis or undertreatment. Addressing these knowledge gaps requires a multipronged approach, including education and policy change, built on evidence-based research. In this chapter we review the current state of existing cardiovascular research in Canada with a specific focus on women.

across cardiovascular (CV) conditions, women and female participants remain under-represented in research.2][3][4][5] Of note, female and male are used in this review when referring to sex particularities, whereas the use of men and women are associated with gender.
Regulatory and funding agencies have highlighted the importance of adequate inclusion of women and female participants in research studies, and have implemented policies requiring sex-and gender-specific analyses but little progress has been made in this regard. 4,6There remain large knowledge gaps in (1) unique CV conditions that affecting only female individuals (2) CV conditions that affect primarily women and female individuals; (3) CV treatments in pregnant or lactating women; and (4) CV conditions that present, progress, or respond to treatment differently in women and female patients.Individuals who have the potential to become pregnant or who are pregnant or lactating remain largely excluded from research because of outdated protection by exclusion ideologies. 5The net result is that there are limited safety and efficacy data to inform treatment decisions in female individuals and those who identify as women.The role of gender in health and disease is largely unknown, although is being increasingly explored.Women living with CV disease (CVD) in Canada are generally older than men, face related problems such as cognitive dysfunction and frailty, experience health care disparities, might have poorer quality of life, and might benefit more than men from certain health care resources. 7,8Large gaps in knowledge exist most acutely for transgender individuals, who are marginalized in clinical care and might be at higher CV risk and have poorer CV outcomes due to social, as well as biological factors such as genderaffirming hormone therapy.Closing the gaps in knowledge might facilitate better care as well as the development of sexand gender-specific guidelines for women and gender-diverse individuals living with CVD.
Gaps in sex-and gender-specific knowledge, care, and research representation are pervasive and could be circumvented through dedicated women-and female-led training programs, clinical centres, and research networks.0][11] The landscape for such training programs, services, and networks in Canada is currently unknown.The aim of this review is to define knowledge gaps, map existing resources, and identify areas for growth opportunities in women's CV research in Canada.Figure 1 summarizes this chapter's key concepts.
research, and publications.Historically, heart disease was viewed primarily as a condition in men and male individuals, leading to limited understanding of the unique risks and symptoms that women experience.These knowledge gaps are particularly problematic because globally heart disease is the leading cause of death for women.Until recently, sex and gender have not been addressed in cardiovascular research, including in preclinical and clinical research.Recruitment was often limited to male participants and individuals identifying as men, and data analysis according to sex or gender was not conducted, leading to a lack of data on how treatments and interventions might affect female patients and individuals who identify as women differently.This lack of data has led to suboptimal treatment and limitations in our understanding of the underlying mechanisms of heart disease in women, and is directly related to limited awareness and knowledge gaps in professional training and public education.Women are often unaware of their risk factors for heart disease or symptoms they might experience, leading to delays in diagnosis and treatments.Additionally, health care providers might not receive adequate training to diagnose and treat heart disease in women, leading to misdiagnosis or undertreatment.Addressing these knowledge gaps requires a multipronged approach, including education and policy change, built on evidencebased research.In this chapter we review the current state of existing cardiovascular research in Canada with a specific focus on women.tableau clinique, de la prise en charge, des r esultats, de l' education, de la recherche et des publications.Du point de vue historique, la cardiopathie a d'abord et e perçue comme une maladie qui touchait les hommes et les individus de sexe masculin.De ce fait, la compr ehension des risques particuliers et des symptômes qu' eprouvent les femmes est limit ee.Ces lacunes dans les connaissances posent particulièrement problème puisqu'à l' echelle mondiale la cardiopathie est la cause principale de d ecès chez les femmes.Jusqu'à r ecemment, la recherche en cardiologie, notamment la recherche pr eclinique et clinique, ne portait pas sur le sexe et le genre.Le recrutement souvent limit e aux participants masculins et aux individus dont l'identit e de genre correspond au sexe masculin et l'absence d'analyses de donn ees en fonction du sexe ou du genre ont eu pour cons equence un manque de donn ees sur la façon dont les traitements et les interventions nuisent aux patientes f eminines et aux individus dont l'identit e de genre correspond au sexe f eminin, et ce, de façon diff erente.Cette absence de donn ees a men e à un traitement sousoptimal et à des limites de notre compr ehension des m ecanismes sous-jacents de la cardiopathie chez les femmes, et est directement reli ee à nos connaissances limit ees, et à nos lacunes en formation professionnelle et en education du public.Le fait que les femmes ne connaissent souvent pas leurs facteurs de risque de maladies du coeur ou les symptômes qu'elles peuvent eprouver entraîne des retards de diagnostic et de traitements.De plus, le fait que les prestataires de soins de sant e ne reçoivent pas la formation ad equate pour poser le diagnostic et traiter la cardiopathie chez les femmes les mène à poser un mauvais diagnostic ou à ne pas traiter suffisamment.Pour pallier ces lacunes de connaissances, il faut une approche à plusieurs volets, qui porte notamment sur l' education et les changements dans les politiques, et qui repose sur la recherche fond ee sur des donn ees probantes.Dans ce chapitre, nous passons en revue l' etat actuel de la recherche existante sur les maladies cardiovasculaires au Canada, plus particulièrement chez les femmes.

Knowledge Gaps
Gaps of knowledge threaten women's heart health: approaches to prevention, diagnosis, treatment, and care do not consider the unique female physiology, or gender roles and identities, which might vary across the life span.
Hormonal and other biological differences between male and female individuals require adequate representation of both sexes in cardiology research.There is a misconception that CVD occurs almost exclusively in men, likely driven by the exclusion of female representation in many studies and historically driven by a desire to reduce variability within research.From cell cultures that are most often derived from cells from male patients, to preclinical studies using primarily male animal models, the female sex is highly underrepresented in CV research.Even when included in clinical trials, at best only approximately one-third of participants are women. 4Therefore, major knowledge gaps continue to exist.
Despite a net improvement since the early 1990s, propelled primarily by federal mandates in the United States of America, major research in women's CV health is still lagging and urgently requires additional support to achieve parity.Risk factors for CVD are modulated by sex and gender.Indeed, untreated stage 1 hypertension causes more endothelial dysfunction in female compared with male patients. 12he effect of smoking is 2 times higher in women (even greater in younger women) than in men. 13Hypertriglyceridemia and diabetes are associated with worse outcomes in women compared with that in men. 14nfortunately, the pathophysiological understanding of many of these differences is still lacking.Similarly, disorders occurring with sex-unique physiologic states, such as pregnancy, polycystic ovarian disease, and menopause, have been observed to be associated with increased CV risk, but they are under-researched and mechanisms have not yet been elucidated.
Despite well-known sex differences in cardiac remodelling, 15,16 the sex-specific pathophysiology of CVD is not adequately explained.][19] It is well known that compared with men, women with ACS have delayed presentation and referral. 20,213][24] Unfortunately, sex and gender effects on CVD diagnosis and prognosis are not yet fully understood.
Moreover, we have only recently become aware that cardiac biomarkers such as troponin and natriuretic peptides used in the diagnosis of cardiac disease have sex-specific thresholds for normative values, which are not consistently implemented. 25,26The underlying physiological explanations for these differences are unknown but might be related to differences in how female hearts respond to pressure and volume.Higher rates of atypical causes of ACS have been observed in women requiring assessment of specific biomarkers, which are rarely drawn.For example, in a female patient with an allergic history who presents with ACS and is shown to have no evidence of obstructive coronary artery disease (CAD), it is imperative for the tryptase enzyme to be checked promptly for the evaluation of allergic/anaphylactic coronary (Kounis) syndrome. 27Unfortunately, this enzyme is rarely drawn, or is drawn too late to be valid.
Although it has been observed that noninvasive and invasive diagnostic testing might have sex-specific variation in accuracy, 19 no diagnostic strategy has been tested specifically in women.
9][30] These variations are not fully understood, and results remain controversial.Medical therapies have been studied almost exclusively in men.Thus, the efficacy and adverse events specific to women are not clearly defined.Moreover, even when therapy has been proven effective and safe in women, it will be used less or at suboptimal implementation compared with that used in men.Fortunately, over the past decade, focused research programs in Canada have begun to emerge to address such knowledge gaps.

Research Programs in Canada
Coincident with new directives from Canadian granting agencies requiring applications to address sex and gender as biological and social variables, progress has been made over the past decade in the development of research studies and programs dedicated to women's heart health.However, this focus is yet evolving, and far from sufficient.Moreover, sexand gender-based analysis and reporting are yet to become mandatory for all research published in journals.
Canada is a leader in CV research and is home to many expert scientists and clinicians studying CVD and related areas of health.Women-specific heart health research has been emerging over the past few decades, as evidenced by the establishment of focused programs within Canadian academic institutions and clinical centres of excellence.To evaluate the extent of women's heart health research across Canada, the Canadian Women's Heart Health Alliance (CWHHA) distributed a brief survey titled: "National survey: knowledge gaps and status of existing cardiac and/or stroke-focused research programs that incorporate sex and gender in Canada" to assess the depth, breadth, and current status of this research.
The survey was created by the CWHHA Knowledge Translation and Mobilization Working Group using the Research Electronic Data Capture (REDCap) database and distributed electronically in April 2022 using the CWHHA, the Canadian Institute of Health Research (CIHR), the Heart and Stroke Foundation of Canada (HSFC), and Canadian universities e-mail distribution lists.A total of 109 responses, representing the Canadian provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, Nova Scotia, and Newfoundland and Labrador, were received.Response results were reviewed and categorized according to the scientific area of research, study/laboratory name, primary investigator, and institution.Although not an exhaustive list of current programs of research, these results provided a snapshot of current CV research in women in Canada (Table 1).The results of this survey highlight the gaps in geographical representation and areas of research currently being conducted, thereby creating opportunities for future research directions, knowledge translation strategies, and collaborations to further develop and strengthen women's heart health research initiatives across Canada.
These findings support the need to amplify the number of research programs and studies focused on women's heart health while simultaneously training future generations of scientists and clinicians promoting the use of a sex and gender lens.

Research Training
It is essential that instruction in sex-and gender-based research techniques be required in all research training programs, along with compliance and competency-based assessments of implementation.
Recent mandates issued from our major Canadian sources for research funding, CIHR and HSFC, require that applications include sex and gender considerations in research design, data analysis, and reporting.Thus, it is essential that research trainees receive education to implement these skills early in their careers.Principal investigators (PIs) and research supervisors play a critical role in the development of our next generation of scientists and clinicians, to ensure that appropriate methods are used to address sex and gender considerations in every study and in every research subject.
In the CWHHA National Research Survey (distributed electronically in April 2022 and representing the Canadian provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, Nova Scotia, and Newfoundland and Labrador), we explored the integration of sex and gender training into existing research training programs through questions directed to current postdoctoral students as well as those in MSc or PhD programs.According to our results, 18 (35%) of 51 trainee respondents reported that their academic or research institution included sex and gender content in their course content, which was delivered by 32  Very few respondents reported that their institution had requirements to integrate sex and gender considerations into theses or dissertations (n ¼ 4; 8%).One  respondent noted that trainees were assessed on sex and gender integration at every committee meeting and their thesis defense.The reported barriers to the implementation of policies requiring integration of sex and gender into research training included departmental, faculty, and/or institutional lack of necessary time (n ¼ 8), lack of funding (n ¼ 7), paucity of trained research faculty (n ¼ 6), lack of perception regarding the requirement for funding success (n ¼ 5), inadequate resources for local research team (n ¼ 5), and disinterest or disinclination by researchers (n ¼ 4).Specific to requirements to consider sex and gender in theses and dissertations, one specific barrier mentioned was that dissertation formatting requirements are instituted centrally by the University, not within individual programs.Although such policies are critical for ensuring inclusion, diversity, equity, and access in health-related and biomedical research in cells, animals, or humans, they would not apply to several other research disciplines and graduate programs.
We recommend that, at a minimum, all health research trainees complete the CIHR sex and gender module and access available workshops and seminars (eg, The Libin Cardiovascular Institute's Research is Better with Sex and Gender Symposium, Canadian Women's Heart Health Summit).Frequently, new updates to sex and gender training resources for trainees such as in the recently funded CIHR training programs (https://cihr-irsc.gc.ca/e/52854.html)and the CIHR chronic disease networks (https://cihr-irsc.gc.ca/e/ 45854.html)and these can be accessed by visiting the Web site of each training platform.Through the expansion and diversity of training offers, more trainees will have access to these courses and achieve up to date knowledge.Time and funding constraints might limit the scope and size of student-led projects such that the projects cannot be adequately powered to probe for sex differences.However, PIs should encourage their trainees to consider the possible effect of sex on results, interpretations, and conclusions as the minimum requirements of the Sex And Gender Equity in Research (SAGER) guidelines.Furthermore, senior research trainees will benefit from cowriting the sex and gender consideration sections of operating grant applications with their mentors.An initiative that individual departments or faculty could undertake to reduce funding barriers and enhance uptake by supervisors and trainees would be to offer small internal grants for student-led projects focused on sex and gender considerations.

Intersectionality and Research in Women
CVD and their risk factors are increasing among Indigenous and racialized women, while research and literature are sorely limited.

Indigenous women's experiences of CVD
While women's specific experiences of cardiac health outcomes are becoming more evident, a comprehensive understanding of Indigenous women's experience of CVD in Canada is sorely lacking.CVD and risk factors continue to increase among Indigenous women.Undermining a clear understanding of Indigenous women's experiences is the fact that most research is limited to general estimates of CVD or risk factors (Table 2).The historic marginalization, research ethical breaches, colonial mindsets, and lack of cultural competence in health care delivery and research involving Indigenous peoples has limited the trust and engagement of Indigenous peoples in the health research enterprise. 31he limited literature around Indigenous women's experiences of CVD represent incomplete assessments across Indigenous identities.Although broad terms such as Indigenous and Aboriginal are often used, these terms obscure significant diversity across hundreds of Indigenous communities representing more than 60 distinct Indigenous languages (https://www12.statcan.gc.ca/census-recensement/2021/dppd/dv-vd/language-langue/index-en.html).
Considerable diversity exists across Indigenous communities, including diversity of health outcomes and CVD risk factors. 32Approximately 28% of this diversity in risk factors and health outcomes can be attributed to socioeconomic status, access to health care, access to affordable prescription medications, educational opportunities, social supports, and community cohesion. 33Further compounding the lack of data available is the inconsistent accuracy and reporting of identity.5][36][37][38][39] Addressing gaps in the literature of Indigenous women's experiences of CVD will require greater understanding of experiences of Indigenous women from diverse Indigenous nations with clear and accurate descriptions of identity, and requires individual reporting of data according to identity or nation.Moreover, improving environmental conditions would be of major importance to improve health in remote communities. 40

Racialized women's experiences of CVD
The 2021 Statistics Canada census data on race and ethnicity indicates that the total racialized peoples population in Canada comprises 26.5% of the overall population, the largest group being of South Asian origin, followed by Chinese and Black populations.Each racialized group includes approximately 50% women (https://www12.statcan.gc.ca/ census-recensement/2021/dp-pd/prof/index.cfm?Lang%20¼ %20E).The confluence of identifying as racialized and as a woman represents a particularly under-represented group in CVD research.Within Canada, comprehensive understandings of the experiences of CVD among racialized communities, including African descent, East Asian, and South Asian individuals are sparse.Amidst the limited literature in this area, very few report results specific to the experiences of women.
Across different ethnic identities, racialized women's experiences of CVD vary widely (Table 3).2][43] Conversely, women of Filipina descent experience greater risks of hypertension than East Asian women and women of European descent. 44The experiences of women of African descent are much more varied, particularly in comparison with women of European descent, with women of African descent having lower rates of CAD 42 and stroke, 41 and higher rates of hypertension. 41,43,45The sparse literature of South Asian women's specific experiences identifies a higher rate of CAD mortality and incidence of acute myocardial infarction, compared with women of European descent in Canada. 46Immigrating to Canada affects racialized women's experiences of CVD, with increases in experiences of hypertension with immigration, when women of African descent, and South Asian women experience the greatest increases in hypertension, whereas women of European descent and Chinese women experience minimal changes in hypertension prevalence with immigration to Canada. 41acialized women present different risk profiles and experiences of CVD compared with women of European descent in Canada.Understanding, managing, and treating CVD among racialized women requires understanding and evidence specific to their needs and experiences.Although a clear gap in literature of the CVD experiences among racialized women is evident, solutions require evidence specific to them, and reporting of women-specific data within studies including racialized men and women.Funding Agencies: Grants, Scholarships, and Awards Federal granting agencies now require integration of sex and gender as variables in all applications, or in lieu of this, presentation of a strong rationale as to why it is not required.Provincial and local granting agencies do not consistently have this requirement, and policy change to require the integration of sex and gender into all funding applications is recommended.Numerous funding opportunities exist to enhance the integration of sex and gender in research supported by federal granting agencies.
In cellular mechanistic studies, it has been identified that sex specificity exists; indeed, "every cell has a sex" has been the mantra of the National Institute of Health since 2016, when a new policy was enacted requiring that preclinical research also consider sex as an important biological variable in vertebrate animal and human studies.This policy served as a complement to the inclusion policy requiring reporting analyses of sex, gender, racial, and ethnic differences in clinical trials established in 2001.These efforts have expanded the consideration of sex in research designs, analyses, and reporting across the research continuum, from preclinical studies to clinical randomized controlled trials.
The CIHR Institute of Gender and Health (IGH) has implemented multiple initiatives to increase sex-and genderbased analysis (SGBA; SGBA Plus [SGBAþ]) in health research.These include IGH-specific initiatives and crosscutting initiatives performed in collaboration with other government agencies.These programs are meant to promote the application of sex and gender outcomes in the current health research landscape (http://www.cihr-irsc.gc.ca/e/ 51310.html).Several societies and grant foundations also recognize the importance of integrating SGBA (HSFC, Canadian Cancer Society) and applying promotional strategies (www.heartandstroke.ca/women).In this section, we outline the current Canadian initiatives to fund and promote SGBAþ in health research.

SGBAD health research policy partnerships competition
The integration of sex and gender into the health policy process is complex and requires a deep understanding of the scientific literature, including how to apply SGBAþ in a way that is informed by the best available evidence.Recognizing this gap in knowledge, the IGH and Health Canada's Gender and Health Unit collaborated to fund the SGBAþ Research Policy Partnerships competition in 2017.This funding opportunity aims to support SGBAþ research and facilitate its transfer into health policy development and practice.The total amount available for the SGBAþ Research Policy competition is $150,000 to fund 2 projects per year, with a maximum funding per grant of $75,000.To date, there have been 7 awardees (https://cihr-irsc.gc.ca/e/51192.html).
Other organizations have also provided specific funding for SGBAþ in CV research per se or through other specialties.The HSFC has committed to advancing SGBAþ and improving health for all and requires applicants to integrate SGBA in all research designs (https://www.heartandstroke.ca/what-we-do/research/strategy/funding-excellence).Also, the Women's Xchange at Women's College Hospital (https:// womensxchange.womensresearch.ca/challenge/previously-fun

CIHR Planning and Dissemination grants
The CIHR Planning and Dissemination grants aim to support the planning and creation of events that contribute to the advancement of health research.To meet the needs of their respective communities and support their mandates, each of the participating CIHR institutes has tailored the specific requirements of this funding opportunity.Specifically, the IGH currently provides $40,000 to fund 2 Planning and Dissemination grants focused on facilitating the uptake of sex and gender considerations into health research and policy.The event must take place in Canada and the presenter list must reflect diversity and gender parity.In addition, the nominated Principal Applicant must have completed 1 of the sex-and gender-based analysis online training modules through the CIHR IGH and submit a Certificate of Completion.Overall, the success of this funding opportunity will increase the number of knowledge translation events that focus on SGBAþ in health research.

Sex and gender research chairs
As the field of sex and gender science continues to grow, CIHR recognized the need for discipline-specific chairs to increase visibility and promote innovation.The Sex and Gender Science Chairs funding opportunity aims to support research into the sex-and gender-related mechanisms that underlie risk, incidence, and response of various disease processes.The maximum amount of funds available per chair is $175,000 per year for a total of 4 years.To be eligible for this opportunity, researchers must have completed 1 of the sex-and gender-based analysis online training modules developed by the CIHR IGH and submit a Certificate of Completion (https://cihr-irsc.gc.ca/e/51596.html).
The HSFC has been instrumental in providing funding to advance knowledge in women's CV health, funding chair and professorship positions for early and midcareer investigators, early career chair positions for Indigenous women's heart and brain health, and most recently IMPACT awards linking heart and brain health (including heart disease, stroke, and vascular cognitive impairment).

Women's Health Clinical Mentorship Grant
The Women's Health Clinical Mentorship Grant was developed to advance women's health research and provide mentorship for trainees interested in improving clinical care for women.Each trainee/mentor pair can apply for funding for a 1-year research project.This funding opportunity includes $600,000 total funding for 12 mentorship grants ($50,000 each).To be eligible for this grant, both applicants must have successfully completed 1 of the sex-and genderbased analysis training modules developed by the CIHR IGH and submit a Certificate of Completion.This award opportunity has had considerable uptake in the field of CV research since its inception in 2019.It is expected that the Women's Health Clinical Mentorship Grant will continue to position Canadian researchers at the forefront of women's health studies (https://cihr-irsc.gc.ca/e/51599.html).

Indigenous gender and wellness initiative
The importance of gender is often overlooked in Indigenous health and wellness.The Indigenous Gender and Wellness (IGW) Initiative is a 3-phase program that aims to improve health and wellness for Indigenous peoples from a gendered perspective.Implemented in 2019, the first phase of this initiative distributed travel awards to bring interested Indigenous peoples and researchers to attend an idea fair and learning circle on Indigenous gender and wellness.The event facilitated collaboration between Indigenous peoples and allies and lent itself to the second phase of this initiative, the Indigenous Gender and Wellness Development grants.These grants are intended to support idea fair attendees to continue working on their projects.This funding opportunity offered $1,680,000 to support > 22 grants up to $75,000.The IGW Team grant funding opportunity is the third phase of the IGW Initiative and provides funding of $7,000,000 for 14 grants to be awarded to Indigenous-led projects relating to gender and holistic health (https://cihr-irsc.gc.ca/e/51988.html).

Journal Publications
Reporting results disaggregated according to sex/gender should be mandatory for all published articles.Indeed sexand gender-specific reporting of study results is required to understand the therapeutic efficacy and side effects of pharmacologic, device, and lifestyle interventions for women and men, as well as the understanding of unique physiologic responses.Sex-and gender-specific findings in a published evidence base is required to enable the development of appropriate recommendations in CV guideline documents, which currently are sorely lacking.
Publication of research findings reporting sex-or genderspecific experiences of cardiac health outcomes are an important component of understanding women's experiences of CVD.Specific to women during pregnancy, the Canadian Cardiovascular Society (CCS) recently published a clinical practice update on the management of CVD for pregnant patients. 47This update provides recommendations on the use of medications along with preconception and pregnancy counselling for various CVDs, including arrhythmias, hypertension, cardiomyopathies, valvular heart disease, congenital heart disease, and pulmonary hypertension during pregnancy.Most of the past CCS guidelines or consensus documents, apart from those focused on pregnancy-related conditions, have not reported sex-specific recommendations because of a lack of published data.The guidelines on antiplatelet therapy in CAD attempted to evaluate sex-based data and showed extensive reporting gaps such that formal recommendations could not be made.There is a concerted effort by the CCS Guidelines Committee asking that such data be identified and where available and feasible, to be used to formulate sex-specific recommendations.

Sex and gender equity in journal publications
9][50][51][52][53][54] Despite these regular calls for understanding women-specific experiences of CVD, advances in research and reporting of women-specific experiences remain low. 51urther, sex-specific data reporting remains low among randomized clinical trials of pharmacological interventions for CVD. 55he importance of sex-specific reporting of CVD research has been highlighted in many international society statements, including the European Society for Cardiology, 52 American Heart Association, 53 and the CCS, 56 specifically calling for sex-specific reporting of clinical trial findings.In response to a critical deficiency in reporting sex-and gender-disaggregating data, the SAGER guidelines were developed.8][59] Accordingly, the SAGER guidelines have now been translated into 6 languages and their use is encouraged by large funding agencies such as the CIHR. 59he endorsement of these guidelines by journal publications supports identifying and recognizing sex-specific experiences.However, none of the endorsing organizations of these guidelines are cardiology journals.
A recent bibliometric analysis of all CV publications, including Canada and international, identified only 13% of more than 189,000 publications from 2006-2015 reporting experiences specific to women or female participants. 51lthough there has been a small increase (3.4%) in the proportion of research articles reporting women-specific experiences, there has not been an increase in the proportion of clinical trials, meta analyses, or review articles reporting women-specific experiences. 51,60Further, a review of randomized controlled trials of pharmacological interventions for CVD has not shown an increase in sex-specific reporting of results since guidelines calling for sex-specific reporting have been published. 55lthough recognition of the importance of researching, identifying, and reporting women-specific experiences of and treatments for CVD have been recognized, the proportion of published research evaluating and reporting women-specific experiences continues to remain low.With increased awareness and understanding of the unique experiences of CVD among women and the risks/consequences of overlooking these sex and gender differences, the inclusion of women and sex-specific CVD research remains a high priority.

Guideline publication
The lack of progress in researching, identifying, and reporting women-specific experiences of and treatments for CVD still limits the available evidence to support guidelines and recommendations specific to the treatment and management of CVD for women.This lack of knowledge is evident in the lack of a comprehensive women-specific guideline on CVD in Canada, with infrequent and inconsistent comments in existing guidelines addressing women as a "special population." 7Within guidelines for familial hypercholesterolemia, the only guidelines specific to women are pregnancy-related. 61anadian guidelines around antiplatelet therapy do not mention women or any specific similarities or differences in experiences between men and women. 62Guidelines for anemia, biomarkers, and therapeutic trial implications also do not include any specific recommendations or guidelines for women. 63Guidelines for valvular heart diseases introduced the sex-specific thresholds for identifying severe aortic valve calcification although they did not provide any other womenspecific recommendation, 64 except for concomitant or expected pregnancy.Overall, a greater understanding of women's specific experiences and treatments of CVD are needed.

Publication on CVD and pregnancy
Among women in Canada who have heart disease, pregnancy is associated with significant morbidity. 47,65Women in Canada who experience hypertensive disorders during pregnancy, including preeclampsia and pregnancy-induced hypertension, are at high risk for premature CVD, with markedly reduced 30-year survival rates and vascular events beginning at an average age of 38 years. 66,67Sufficient publications on the experiences of hypertension during pregnancy among women (almost only non-Hispanic white women) in Canada are available to support guidelines for management of hypertension during pregnancy. 67,68Within Canada, the incidence of myocardial infarction during pregnancy is 1.15/100,000 pregnancies, well below experiences in the United States, as well as low rates of maternal mortality of 0.06/100,000 pregnancies. 69Numerous adverse events of pregnancy have been linked to increased hemorrhage with blood transfusion and other severe maternal morbidities. 70Severe to mild events during pregnancy, such as preterm birth, stillbirth, placental abruption, gestational diabetes, low birth weight, etc, are risk factors for future CVD.Further, a woman's future risk of CVD after adverse pregnancy events is affected by socioeconomic status, race, and ethnicity, highlighting the importance of evaluating diverse women's experiences. 70Assessments of oral contraception risks of myocardial infarction and cerebrovascular accidents have also been assessed in Canada. 71

Publication on women and myocardial infarction
Canadian guidelines on ST-elevation myocardial infarction acknowledge the need for more research and publications regarding the experiences of women. 72Similarly, guidelines for ischemic heart disease do not include any specific recommendations for women. 73Canadian guidelines on revascularization of multivessel CAD also lack any specific recommendations or guidelines for women. 74These guidelines highlight this significant gap in understanding and treatment of myocardial infarction for women and a clear need for more research and publications on women's specific experiences and treatment of CVD.

Publication on women and atrial fibrillation
The CCS guidelines for management of atrial fibrillation include recognition of the importance of sex, with greater ageadjusted incidence among men, but greater numbers of female patients. 75Literature around women's experiences of atrial fibrillation have identified differences in presentation, effects, mortality, and stroke experiences. 75Available research also identifies inappropriate underutilization or underdosing of medications for women experiencing atrial fibrillation or with associated complications and poorer outcomes. 75Although guidelines on the assessment and management of syncope recognize greater incidence and prevalence among women, sex-specific recommendations are not available.Additional research is required to further identify experiences, complications, and treatments of arrhythmias specific to women.

Publication on women and heart failure
Evidence around women's experiences of heart failure in Canada is limited.Guidelines from the CCS for a pharmacological standard of care for heart failure do not consider womenspecific experiences. 76In recent clinical trials, sex differences in benefits of some heart failure treatments have been recognized, 8,77 though limited sex-specific recommendations have yet to emerge. 1,4,76,78Position statements on the evaluation and management of patients with cardiac amyloidosis do not address women-specific experiences or treatments, likely due to a lack of available evidence. 79Specific recommendations and guidelines around heart failure specific to women in Canada are limited to pregnancy-related recommendations and guidelines. 80blication on women, cancer, and CVD The CCS guidelines around complications of cancer therapy identify women as being at high risk of asymptomatic left ventricular dysfunction and anthracycline-induced heart failure. 81However, there are no Canadian guidelines or recommendations for CV complications of cancer specific to women. 81

Publication on women and valvular heart diseases
Several publications have reported sex specificity in valvular heart disease, 82,83 especially in aortic stenosis 17,[84][85][86] and mitral regurgitation. 87,88These articles report many differences in pathophysiology, diagnosis, management, and/or outcomes; however, guidelines provide only 1 sex-specific recommendation, which is the sex-specific thresholds for identification of severe aortic stenosis using calcification measured using computed tomography. 64Nevertheless, the Heart Valve Voice Canada highlighted in their patient journey report that "the patient's care journey is often different for women." 89

Authors, Editorial Boards, and Reviewers
Studies across several published sciences, including medicine, showed that women are less likely than men to be first or last authors, members of the editorial boards, or reviewers especially in high impact factor journals.This under-representation might partly explain the shortage of women at the top ranks of academic positions.
To enhance the reporting of sex-based findings and experiences, it is important first to understand the current state of affairs when it comes to the vast under-representation of women across the CV sciences, surgery, and medicine within Canada.
The necessity of publication in research is well known and is often summarized as "publish or perish."In addition, the coauthor position is important, especially first author for trainees and last/senior author for PIs.The representation of women as scientific authors in cardiology has historically been low. 90Despite an increase in female authorship, 90,91 there is still a deficit of women as first and last authors, especially in high impact journals, in original research and editorials.Women are also under-represented as leaders of CV randomized controlled trials, representing 1 in 10 lead authors of CV trials published in high impact journals. 11Some publications tried to explain why women were less productive (ie, greater family responsibility, less welcoming work environment, etc), but recently it was suggested that this is not a matter of productivity, but rather, that their work is undervalued. 92his lack of women as leading authors in publication is also reflected in the few female authors in most of the cardiology guidelines.Interestingly, having a female as the senior author in cardiology publications can improve the quality, visibility, and sex/gender sensitivity of the research. 93,94he Canadian Journal of Cardiology (CJC), CJC Open, and CJC Pediatric & Congenital Heart Disease are the main CV journals espoused by the CCS.Although past editorial board membership has been largely men, there has been an increase over time in the number of women (CJC 11%, CJC Open 37%) and women trainees (45%) as members of the editorial board and mentorship program, respectively. 95CJC Open is also being led by a female editor-in-chief since its inception in 2019.In comparison, cardiac surgery journals report 10% of female representation collectively on their editorial boards, ranging from 0 to 30% for an individual journal. 96The statistically significant positive correlation identified between percentage of women on cardiac surgery journal editorial boards and the journal impact factor (r ¼ 0.8; P < 0.001) underscores the value of this diversity. 96emale representation in reviewers' teams and editorial boards of cardiology journals is low, but there have been efforts to increase gender diversity in recent years.Recent studies have shown that the proportion of female editors-inchief increased from 0% in 2005 to 20% in 2015 or 21% in 2019 among more than 20 cardiology journals. 97,98owever, there is still need for continued improvement, because less than 25% of editorial board members are female. 97,98lthough there has been progress in increasing gender diversity in editorial boards of cardiology journals, there is still work to be done to address sex disparities and promote equity in leadership roles.Increasing female representation in editorial boards can help to promote diversity of perspectives and ensure that the needs of all members of the scientific community are represented.

Meetings and Conferences
Women's heart health research is less likely to be presented at conferences, or relegated to categories described as a subset of "special populations," which can perpetuate the knowledge gap in women with heart disease.Addressing this issue requires increasing the representation of women's heart health topics in scientific conferences and providing more opportunities for women scientists to lead investigative trials and present their work.
Within Canada, the CV community convenes at the Canadian Cardiovascular Congress (CCC) on an annual basis.The CCS recently forged a "One Heart Team" model of partnership with its affiliates that represent cardiac surgery and other disciplines (eg, cardiac imaging and echocardiography, critical care cardiology, adult congenital cardiology, heart failure and transplant cardiology, interventional cardiology, pediatric cardiology, etc).Each of these affiliates are represented at the CCC, but have their own annual meetings or events.Although many journals and funding agencies are beginning to use the SAGER framework to encourage reporting of sex-based data, there is no formal requirement to use this for research or symposia presentations at the CCC or CCS affiliate meetings.Over the past 2 years, however, the CCC has incorporated a dedicated research session and award within their programming in which trainees present sex-based research studies.A similar trend has been variably incorporated within the CCS affiliate meetings.
The only environmental scan of the annual CCC meetings highlighted several interesting trends around female representation including 95 : (1) few women (n ¼ 4) served as Scientific Program Committee chairs, and only after 2016; and (2) 30% or fewer women were members of the Scientific Program Committee (23%) or served as major symposia panelists (30%) at the CCC between 2014 and 2018.
Importantly, with a targeted effort to solicit diversity including 50% women through workshop proposal submissions, there has been an increase in the number of women as planning committee members, session chairs, and speakers.
An analysis of the Canadian Association of Thoracic Surgeons annual meetings from 1997 to 2020 revealed that most lecturers (88%) and invited speakers (67%) were white men. 99he Canadian Women's Heart Health Summit was launched in 2016 and is cohosted by the University of Ottawa Heart Institute and HSFC.The Canadian Women's Heart Health Summit is a biannual, multiday conference that focuses exclusively on sex-and gender-specific evidence related to heart, brain, and vascular health.Its objectives are to: (1) bring together national and international leaders, knowledge users, and women with lived experience to develop and disseminate strategies to improve heart, brain, and vascular health among women; (2) identify emerging areas of research and clinical practice related to heart, brain, and vascular conditions affecting women across their life span; (3) address gaps in research and clinical practice for heart, brain, and vascular disease in women, improving risk stratification, diagnosis, and therapy from a sex and gender perspective; and, (4) promote networking among clinicians, scientists, policy-makers, trainees, and women with lived experience, facilitating translation of knowledge that will ultimately improve the health of women.
The Canadian Organization for Gender and Sex (COGS) research was launched in 2019 and had its first meeting in 2020.The COGS mission is to forge a transformative, transdisciplinary field of sex and gender science.Its objectives are to: integrate sex and gender in research, bolster sex and gender science with transformative new methods, measures, and technologies, promote the transdisciplinary field of sex and gender science, build strong networks among policy makers, service providers, the technology community, funders, and the public to advance sex and gender science, and train the next generation in the field of sex and gender scientists.
These data altogether highlight that editorial boards and conference leadership disparities might lead to slower academic advancement of under-represented groups and fewer publications or leadership roles related to less inclusive review processes or engagement.To address this critical underrepresentation of women and racialized peoples within the CV community, the Canadian Association of Thoracic Surgeons and the CCS have established equity, diversity, and inclusion task forces and the CJC family of journals has actively sought to enhance opportunities for women.Additional methods to enhance female representation at conferences include the evolving use of social media, promotional media campaigns, and allyship through the formation of women's alliances to amplify gender equality activism and foster the advancement of women to these opportunities.

Translation of Research Knowledge into Clinician Training/Knowledge
Effective knowledge translation and accurate guidelines/ knowledge application improve patient outcomes and reduce health care costs.It is particularly important to identify and reduce barriers to improve knowledge translation and guideline adherence in women's heart health.
There is universal agreement that clinical guidelines and patient care should follow the best up to date evidence.Patients rely on health care professionals to provide them with the most recent, transparent, safe, and effective health care for their families and society.][102] The guideline recommendations are followed on average, in 67% of clinical decisions, but there is a significant variation among physicians and the guidelines. 103here are various barriers that could lead to the failure of the implementation of clinical guidelines, and some of the barriers are related to the sex and gender of the physician and/or the patient.A meta-analysis on guidelines adherence reveal that patient's sex is a major predictor of decreased guidelines adherence in CVD.Women experiencing myocardial infarction received fewer coronary angiography examinations, and were less often prescribed bblockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or lipid-lowering therapy. 104Interestingly, the physician's sex was of less importance, with only a difference in bblocker prescriptions (higher in female physicians).All of these differences are less important (or absent) in large centres with cardiology departments.The differences in CVD in women might explain a part of these differences in treatment adherence.However, these differences have been described and should be known.Barriers in knowledge transmission appear to also be worse for women (see the paragraphs on journals and conferences), who are also more inclined to report sex-specific results.
Although change might take time, failure to implement and translate research knowledge into practice not only contributes to suboptimal care for patients but also affects health care organizations and society by missing out on the benefits of innovation and potential financial value gained on research investment. 105Knowledge translation is not linear and involves many processes, systems, and interactions between all stake holders and knowledge users.

Recommendations
Despite action to improve understanding of women's heart health at the federal or provincial levels (Table 4), more action is still required (Table 5).Although the inclusion of women in CV clinical trials has improved, it still remains an important priority, and the inclusion of women who identify as Indigenous and/or racialized is a key demographic.We should add ethnic/ethnicity and Indigenous to all of the sex and gender approaches in this section to be genuinely inclusive as authors of this publication.

Trainees (education)
To improve the inclusion of sex-and gender-based analyses in CVD research, improving the education of trainees is essential.The 5 major points to implement would be: Emphasize the importance of sex and gender considerations in CVD research.Provide training on sex and gender concepts and methods.Encourage the use of sex and gender analysis tools.Facilitate collaboration with sex and gender CVD experts.Foster a culture of inclusivity, diversity, equity, and accessibility to encourage trainees to maintain this culture in their future career which will likely involve mentorship.

Faculty/scientists/researchers
Faculty, scientists, and researchers must recognize that sex and gender play a critical role in shaping CVD health outcomes and that incorporating these factors into research can lead to more accurate and comprehensive results.They thus should (Table 5): Foster a culture of inclusivity, diversity, equality, and accessibility that applies to their studies and research training environment.Prioritize education and training on sex and gender concepts in women's heart health and methods for trainees and staff.Encourage interdisciplinary collaboration.Use sex and gender analysis tools and resources.Publish and disseminate research findings that account for sex and gender in women's heart health.

Funding agencies
Most federal funding agencies have developed guidelines and policies that require researchers to consider sex and gender factors in their research design, analysis, and reporting.These guidelines must also be used in provincial and local funding agencies.In addition, the funding agency should (Table 5): Provide targeted funding opportunities for sex and gender CVD research.Encourage interdisciplinary collaboration across fields and disciplines.Foster a culture of inclusivity, diversity, equality, and accessibility.Monitor and evaluate the integration of sex and gender considerations in CVD research projects they fund.

Journal and conferences
Scientific journals, learned societies, and scientific conferences should develop and enforce editorial policies that require the reporting of sex and gender considerations.Every clinical trial, animal model, or basic study should be obligated to report results disaggregated according to sex.Thus, journals, societies, and conferences should (Table 5): Provide guidance to authors on how to incorporate sex and gender considerations into their CVD research.Actively encourage the publication of CVD research that incorporates sex and gender considerations.Require the use of appropriate sex and gender terminology in all CVD research reporting to ensure clarity and accuracy.Evaluate the integration of sex and gender considerations in all submitted CVD manuscripts and abstracts.Promote a culture that values diverse perspectives.

Patients and public
The patients and public should advocate for the incorporation of sex and gender considerations in CVD research.Thus, they need to (Table 5): Educate themselves on the importance of sex and gender considerations in CVD research Engage with CVD researchers, health care providers, and policy-makers Participate in sex and gender CVD research studies Share their experiences and perspectives.

Conclusions
There are major gaps in knowledge regarding the epidemiology, presentation, diagnosis, management, and outcomes in women's CVD.Women have unique risk factors for CVD that are often not recognized or addressed by health care providers, leading to poorer health outcomes compared with men.Additionally, there is a lack of sex-and gender-based analysis in research studies, which hinders our understanding of the underlying mechanisms of CVD in women.Addressing these gaps of knowledge requires a multifaceted approach, including improving medical education and training on women's CV health, increasing sex-and genderbased analysis in research studies, and promoting a culture of inclusivity, diversity, equality, and accessibility in health care.The call to action to improve sex-and gender-based analyses should emphasize the importance of integrating sex and gender considerations into all aspects of research design, execution, and reporting, and provide the necessary support and resources to achieve this goal.By doing so, the research community can contribute to a more equitable and effective research environment that benefits everyone.

Figure 1 .
Figure 1.Summary of knowledge gaps and existing research programs in Canada.Modified with permission from the Canadian Women's Heart Health Alliance.
CI, confidence interval; CVD, cardiovascular disease; HELLP, hemolysis, elevated liver enzymes and low platelets; IMT, intima-media thickness; LQTS, long QT syndrome; LLVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; PWV, pulse wave velocity.Health equity grants include applications that address the broad range of personal, social, and economic factors that determine individual and population health, including sex and gender.One of the mandates of the Arthritis Society Canada's research program is to promote the best treatments and care for those living with arthritis.They offer a host of funding opportunities that include Ignite Innovation grants, Strategic Operating grants, Stars Career Development awards, Postdoctoral Fellowships, and PhD salary awards (https://arthritis.ca/researchers/competition-results).

Table 3 .
Publications reporting sex-differences or sex-specific experiences of cardiac outcomes among nonwhite women and men in Canada: 2001-2022
Canadian Institutes of Health Research; EDI, equity, diversity, and inclusion; GBAþ, Gender-Based Analysis Plus; HSRF, Health System Research Fund; IGH, Institute of Gender and Health; N/A, not applicable; NRC, National Research Council; NSERC, Natural Sciences and Engineering Research Council of Canada; PHAC, Public Health Agency of Canada; SAGER, Sex And Gender Equity in Research; SGBA, sex and gender-based analysis; SSHRC, Social Sciences and Humanities Research Council; STEM, sciences, technology, engineering and mathematics; SWAN, Scientific Women's Academic Network.

Table 5 .
Call for actiondrecommendations Emphasize the importance of sex and gender considerations in research Research trainees should understand that sex and gender play a crucial role in shaping health outcomes and that ignoring these factors can lead to incomplete or inaccurate conclusions Provide training on sex and gender concepts and methods Trainees should receive training on the differences between sex and gender, how to incorporate these concepts into research design and analysis, and how to collect and analyze data that accounts for sex and gender Encourage the use of SGBAþ tools Trainees should be provided with tools such as SGBAþ checklists to ensure they have considered these factors in all aspects of their research Facilitate collaboration with sex and gender experts Trainees should be encouraged to collaborate with experts in sex and gender research, either within their own institution or through external partnerships, to improve the quality of their research Foster a culture of inclusivity and diversity Trainees should be taught to respect and value diverse perspectives, and to consider how social, cultural, and historical factors influence sex and gender dynamics in research Faculty/scientists/researchers Foster a culture of inclusivity and diversity Faculty, scientists, and researchers should actively work to promote a culture that values diverse perspectives and recognizes the importance of considering social, cultural, and historical factors that influence sex and gender dynamics in research Provide ongoing education and training on sex and gender concepts and methods Faculty, scientists, and researchers should provide ongoing training to their colleagues and trainees on how to incorporate sex and gender considerations into research design, analysis, and reporting.This can include workshops, seminars, and other educational opportunities Encourage interdisciplinary collaboration Faculty, scientists, and researchers should encourage collaboration across disciplines and with experts in sex and gender research to improve the quality of their research Use SGBAþ tools and resources Faculty, scientists, and researchers should use SGBAþ checklists and other resources to ensure that they have considered these factors in all aspects of their research Publish and disseminate research findings that account for sex and gender Faculty, scientists, and researchers should make a concerted effort to publish research findings that account for sex and gender, and to disseminate this information to the broader scientific community and to the public