State of the science in women's cardiovascular disease: a Canadian perspective on the influence of sex and gender

Review Paper
Norris C, Yip C, Nerenberg K, Clavel MA, Pacheco C, Foulds H, Hardy M, Gonsalves C, Jaffer S, Parry M, Colella TJF, Dhukai A, Grewal J, Price J, Levinsson A, Hart D, Harvey P, Van Spall H, Sarfi H, Sedlak T, Ahmed S, Baer C, Coutinho T, Edwards J, Green C, Kirkham AA, Srivaratharajah K, Dumanski S, Keeping-Burke L, Lappa N, Reid R, Robert H, Smith G, Martin-Rhee M, Mulvagh S
Journal of the American Heart Association. 2020;9(4):e015634.

Cardiovascular disease (CVD) is the leading cause of premature death for women in Canada. Although it has long been recognized that estrogen impacts vascular responses in women, there is emerging evidence that physiologic and pathophysiologic cardiovascular responses are uniquely affected across the spectrum of a woman’s life. Despite a global understanding that manifestations and outcomes of CVD are known to differ between men and women, uptake of the recognition of sex and gender influences on the clinical care of women has been slow or absent.

To highlight the need for better research, diagnosis, treatment, awareness, and support of women with CVD in Canada, the Canadian Women’s Heart Health Alliance (CWHHA), supported by the University of Ottawa Heart Institute, and in collaboration with the Heart and Stroke Foundation of Canada (HSFC), undertook a comprehensive review of the evidence on sex‐ and gender‐specific differences in comorbidities, risk factors, disease awareness, presentation, diagnosis, and treatment across the entire spectrum of CVD. The intent of this review was not to directly compare women and men on epidemiological and outcome measures of CVD, but to synthesize the state of the evidence for CVD in women and identify significant knowledge gaps that hinder the transformation to clinical practice and care that is truly tailored for women, a significant health challenge that has only been recognized in Canada relatively recently. This review highlights the scarcity of Canadian data on CVD in women as part of the ongoing struggle to increase awareness of and improve outcomes for women with CVD. Because of a paucity of published Canada‐specific evidence, the purpose of this review is to provide an infrastructure to summarize world‐wide published evidence, including knowledge gaps that must be understood to then make effective recommendations to alleviate the glaring “unders” of CVD for women in Canada: under‐aware, under‐diagnosed and under‐treated, under‐researched, and under‐support.

Rehabilitation needs in anti-cancer treatment-related cardiotoxicity

Review Paper
Pituskin E, Kirkham AA, Cox-Kennett N, Dimitry R, Dimitry J, Paterson DI, Gyenes G
Seminars in Oncology Nursing 2020;36(1):doi.org/10.1016/j.soncn.2020.150986

Objectives: To examine and summarize current international guidelines regarding cardiovascular risk reduction before and during cancer therapy, and to discuss the emerging role of cardio-oncology as a subspecialty in cancer care and the role of cardio-oncology rehabilitation.

Data sources: Published articles and guidelines.

Conclusion: With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number of individuals now survive a cancer diagnosis. However, for some the cost is high – many survivors are now at higher risk of death from cardiovascular disease than from recurrent cancer. Cardiovascular morbidity and mortality are common and associated with common cancer therapies serially administered in adult oncology care.

Implications for nursing practice: Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and support the patient within the family and community.

Curing breast cancer and killing the heart: A novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer

Review Paper
Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ
Progress in Cardiovascular Diseases 2019;62(2):116-26

Due to advances in prevention, early detection and treatment, early breast cancer mortality has decreased by nearly 40% during the last four decades. Yet, the risk of cardiovascular disease (CVD) mortality is significantly elevated following a breast cancer diagnosis, and it is a leading cause of death in this population. This review will discuss the most recent evidence for risks, pathology, mechanisms, and prevention of CVD morbidity and mortality in women with breast cancer. This evidence will be synthesized into a new model ‘the compounding risk and protection model.’ This model proposes that the balance between risk factors (i.e., older age, pre-existing traditional CVD risk factors and shared biologic pathways for CVD and cancer such as inflammation, as well as treatment-related and lifestyle toxicity) and potential protection factors (i.e., lifelong non-smoking, regular physical activity, a healthy diet rich in fruits and vegetables, and management of body weight and stress, heart failure therapy) determine the individual risk of CVD morbidity and mortality after diagnosis of early breast cancer.

Figure 2: Compounding risk and protection model

Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors

Review Paper
Kirkham AA, Bland K, Sayyari S, Campbell KL, Davis M
Current Oncology Reports 2016;18(2):12

Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors.

Utility of equations to estimate peak oxygen uptake and work rate from a sixminute walk test in patients with COPD in a clinical setting.

Original Research PaperReview Paper
Kirkham AA, Pauhl KE, Elliot RM, Scott JA, Doria SC, Davidson HK, Campbell KL, Camp PG
Journal of Cardiopulmonary Rehabilitation and Prevention 2015;35(6):431-8.

PURPOSE:

To determine the utility of equations that use the 6-minute walk test (6MWT) results to estimate peak oxygen uptake ((Equation is included in full-text article.)o2) and peak work rate with chronic obstructive pulmonary disease (COPD) patients in a clinical setting.

METHODS:

This study included a systematic review to identify published equations estimating peak (Equation is included in full-text article.)o2 and peak work rate in watts in COPD patients and a retrospective chart review of data from a hospital-based pulmonary rehabilitation program. The following variables were abstracted from the records of 42 consecutively enrolled COPD patients: measured peak (Equation is included in full-text article.)o2 and peak work rate achieved during a cycle ergometer cardiopulmonary exercise test, 6MWT distance, age, sex, weight, height, forced expiratory volume in 1 second, forced vital capacity, and lung diffusion capacity. Estimated peak (Equation is included in full-text article.)o2 and peak work rate were estimated from 6MWT distance using published equations. The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work to prescribe aerobic exercise intensities of 60% and 80% was calculated.

RESULTS:

Eleven equations from 6 studies were identified. Agreement between estimated and measured values was poor to moderate (intraclass correlation coefficients = 0.11-0.63). The error associated with using estimated peak (Equation is included in full-text article.)o2 or peak work rate to prescribe exercise intensities of 60% and 80% of measured values ranged from mean differences of 12 to 35 and 16 to 47 percentage points, respectively.

CONCLUSIONS:

There is poor to moderate agreement between measured peak (Equation is included in full-text article.)o2 and peak work rate and estimations from equations that use 6MWT distance, and the use of the estimated values for prescription of aerobic exercise intensity would result in large error. Equations estimating peak (Equation is included in full-text article.)o2 and peak work rate are of low utility for prescribing exercise intensity in pulmonary rehabilitation programs.

The utility of cardiac stress testing for detection of cardiovascular disease in breast cancer survivors: A systematic review

Review Paper
Kirkham AA, Virani SA, Campbell KL
International Journal of Women’s Health 2015;7:127-140.

Abstract

BACKGROUND:

Heart function tests performed with myocardial stress, or “cardiac stress tests”, may be beneficial for detection of cardiovascular disease. Women who have been diagnosed with breast cancer are more likely to develop cardiovascular diseases than the general population, in part due to the direct toxic effects of cancer treatment on the cardiovascular system. The aim of this review was to determine the utility of cardiac stress tests for the detection of cardiovascular disease after cardiotoxic breast cancer treatment.

DESIGN:

Systematic review.

METHODS:

Medline and Embase were searched for studies utilizing heart function tests in breast cancer survivors. Studies utilizing a cardiac stress test and a heart function test performed at rest were included to determine whether stress provided added benefit to identifying cardiac abnormalities that were undetected at rest within each study.

RESULTS:

Fourteen studies were identified. Overall, there was a benefit to utilizing stress tests over tests at rest in identifying evidence of cardiovascular disease in five studies, a possible benefit in five studies, and no benefit in four studies. The most common type of stress test was myocardial perfusion imaging, where reversible perfusion defects were detected under stress in individuals who had no defects at rest, in five of seven studies of long-term follow-up. Two studies demonstrated the benefit of stress echocardiography over resting echocardiography for detecting left ventricular dysfunction in anthracycline-treated breast cancer survivors. There was no benefit of stress cardiac magnetic resonance imaging in one study. Two studies showed a potential benefit of stress electrocardiography, whereas three others did not.

CONCLUSION:

The use of cardiac stress with myocardial perfusion imaging and echocardiography may provide added benefit to tests performed at rest for detection of cardiovascular disease in breast cancer survivors, and merits further research.

Exercise prevention of cardiovascular disease in breast cancer survivors

Review Paper
Kirkham AA, Davis MK
Journal of Oncology special issue: “Cancer and Cardiovascular Disease: The Complex Labyrinth” 2015; Article ID 917606, in press


ABSTRACT
Thanks to increasingly effective treatment, breast cancer mortality rates have significantly declined over the past few decades. Following the increase in life expectancy of women diagnosed with breast cancer, it has been recognized that these women are at an elevated risk for cardiovascular disease due in part to the cardiotoxic side effects of treatment. This paper reviews evidence for the role of exercise in prevention of cardiovascular toxicity associated with chemotherapy used in breast cancer, and in modifying cardiovascular risk factors in breast cancer survivors. There is growing evidence indicating that the primary mechanism for this protective effect appears to be improved antioxidant capacity in the heart and vasculature and subsequent reduction of treatment-related oxidative stress in these structures. Further clinical research is needed to determine whether exercise is a feasible and effective nonpharmacological treatment to reduce cardiovascular morbidity and mortality in breast cancer survivors, to identify the cancer therapies for which it is effective, and to determine the optimal exercise dose. Safe and noninvasive measures that are sensitive to changes in cardiovascular function are required to answer these questions in patient populations. Cardiac strain, endothelial function, and cardiac biomarkers are suggested outcome measures for clinical research in this field.

Aerobic capacity and upper limb strength are reduced in women diagnosed with breast cancer: A systematic review

Review Paper
• Neil SE, Kirkham AA, Hung SH, Niksirat N, Nishikawa K, Campbell KL
Journal of Physiotherapy 2014;60(4):189-200

Question: What are typical values of physical function for women diagnosed with breast cancer and how do these compare to normative data? Design: Systematic review with meta-analysis. Participants: Women diagnosed with breast cancer who were before, during or after treatment. Outcome measures: Physical function was divided into three categories: aerobic capacity, upper and lower extremity muscular fitness, and mobility. Measures of aerobic capacity included field tests (6-minute walk test, 12- minute walk tests, Rockport 1-mile test, and 2-km walk time) and submaximal/maximal exercise tests on a treadmill or cycle ergometer. Measures of upper and lower extremity muscular fitness included grip strength, one repetition maximum (bench, chest or leg press), muscle endurance tests, and chair stands. The only measure of mobility was the Timed Up and Go test. Results: Of the 1978 studies identified, 85 were eligible for inclusion. Wide ranges of values were reported, reflecting the range of ages, disease severity, treatment type and time since treatment of participants. Aerobic fitness values were generally below average, although 6-minute walk time was closer to population norms. Upper and lower extremity strength was lower than population norms for women who were currently receiving cancer treatment. Lower extremity strength was above population norms for women who had completed treatment. Conclusion: Aerobic capacity and upper extremity strength in women diagnosed with breast cancer are generally lower than population norms. Assessment of values for lower extremity strength is less conclusive. As more research is published, expected values for sub-groups by age, treatment, and co- morbidities should be developed.