Women’s cardiovascular health – the cardio-oncologic jigsaw

Abstract

Improvements in cancer care have led to an exponential increase in cancer survival. This is particularly the case for breast cancer, where 5-year survival in Australia exceeds 90%. Cardiovascular disease (CVD) has emerged as one of the competing causes of morbidity and mortality among cancer survivors, both as a complication of cancer therapies and because the risk factors for cancer are shared with those for CVD. In this review we cover the key aspects of cardiovascular care for women throughout their cancer journey: the need for baseline cardiovascular risk assessment and management, a crucial component of the cardiovascular care; the importance of long-term surveillance for ongoing maintenance of cardiovascular health; and strong evidence for the beneficial effects of physical exercise to improve both cancer and cardiovascular outcomes. There is general disparity in cardiovascular outcomes for women, which is further exacerbated when both CVD and cancer co-exist. Collaboration between oncology and cardiac services, with an emergence of the whole field of cardio-oncology, allows for expedited investigation and treatment for these patients. This collaboration as well as a holistic approach to patient care and key role of patients’ general practitioners are essential to ensure long-term health of people living with, during and beyond cancer.

摘要

癌症治疗的进步导致癌症患者生存率呈指数增加。这种情况对于乳腺癌患者尤为显著, 在澳大利亚, 乳腺癌的5年生存率超过90%。心血管疾病（CVD）已经成为癌症幸存者中发病率和死亡率上升的主要原因之一, 它既作为癌症治疗的并发症, 也因为和癌症有一些相同的危险因素。在这篇综述中, 包括女性在整个癌症治疗中心血管护理的几个关键方面：进行基线心血管风险评估和管理的必要性, 这是心血管护理的重要组成部分；长期监测以持续维护心血管健康的重要性；以及体育锻炼对改善癌症和心血管结果的有力证据。对于女性, 心血管结果存在普遍的不平等, 当CVD和癌症共存时, 情况更为严重。肿瘤学和心脏学之间的合作, 以及心脏肿瘤学领域的出现, 可以增加对这些患者的调查和治疗。这种学科合作以及对患者整体护理、患者全科医生的重要角色, 都是对患者在患有、在癌症期间和癌症之后保持长期健康的有力保障。

Keywords:

• Cardio-oncology
• cardiovascular disease
• cancer
• risk factor management
• lifestyle factors

Introduction

Cardiovascular disease (CVD) poses the greatest threat to the health of women, and is the leading cause of death amongst women globally, followed closely by cancer [1–3]. Every hour one Australian woman will die from heart disease, and CVD accounts for more than one-third of all female deaths globally [3,4]. This burden of disease carries a huge cost to the health-care system and patients. Although rates of female death and hospitalization from CVD over the last decade have improved, CVD remains a leading cause of premature death and healthy life years lost for postmenopausal women [1]. Unfortunately, significant differences in the care received by men and women persist; women with coronary disease are less likely than men to undergo invasive angiography, and less likely to receive guideline directed therapy or attend cardiac rehabilitation [1,4,5]. This treatment gap is amplified when considering the intersection of cancer on cardiovascular outcomes for women. Like CVD, cancer has a critical influence on survival, premature death and healthy life lost in women. In women, breast cancer followed by melanoma, colorectal cancer and lung cancer account for most new cancer diagnoses, with lung cancer having the highest mortality [6].

We now have cancer and CVD, two seemingly separate disease states, that are the leading causes of mortality and morbidity in our society [7]. Yet they share risk factors (e.g. obesity and smoking) and recognized pathophysiological mechanisms (e.g. inflammation and redox stress) [8]. Due to their high background prevalence they frequently co-exist, but each disease also increases the risk for the development of the other, with cancer survivors being 40% more likely to die from CVD than the general population, making CVD the second leading cause of death in people with cancer [9]. Similarly, patients with CVD have a higher risk of developing cancer compared with the general population [10]. The cumulative effect of these twin morbidities is even more profound for people living in regional and rural areas [11].

This complex overlap has given rise to the new field of cardio-oncology, with the broad aims of improving the cardiovascular health of people living with, through and beyond cancer [12]. Cardio-oncology aims to provide specific pathways for physicians and patients to navigate the complexities of managing cancer whilst preventing, mitigating and addressing CVD and balancing the risk of cardiovascular complications against the benefits of cancer treatment [13–15]. This demands a tailored, personalized approach given the broad range of cancer types, their prognoses and the background risk factor profiles of patients undergoing cancer therapy. This review aims to highlight the complex interplay of traditional and novel cardiovascular risk factors and their role in both the pathogenesis of cancer and the influence on approaches to treatment with respect to CVD. The oncology journey is rarely straightforward; thus cardio-oncology requires a proactive and flexible approach to optimize cardiovascular health of patients through cancer treatment and beyond.

Women, cancer and CVD

There is well-established evidence for cardiac adverse effects of cancer treatments used in many female-dominated cancers such as breast and gynecological malignancies [13,16–19]. The classic example is the large body of evidence linking anthracycline chemotherapy use in breast cancer with short-term and long-term adverse effects on cardiac function, leading to the development of asymptomatic and symptomatic heart failure [15,20,21]. Women may be particularly susceptible to these adverse effects: despite overall similar lifetime odds of developing invasive cancer, female as compared to male childhood cancer survivors have a greater risk of developing cardio-toxicity and heart failure following anthracycline therapy, highlighting key gender differences, the mechanisms of which are poorly understood [22,23].

Left ventricular dysfunction and clinical heart failure are also seen (albeit less frequently) with the use of human epidermal growth factor receptor-2 (HER2) targeted therapies, which are commonly used in breast cancers and tumors of the female reproductive tract overexpressing HER2 [24]. Targeted anti-HER2 therapies, such as trastuzumab, can lead to left ventricular dysfunction, heart failure and cardiac arrythmias [24,25], with combination therapies, especially with anthracyclines, increasing CVD risk exponentially [26]. Fortunately, alternative regimens continue to emerge for HER2-positive breast cancers, avoiding anthracyclines and their toxicity [16,27].

Other treatments associated with cardiac risks include endocrine therapy (selective estrogen receptor modulators and aromatase inhibitors) and radiation therapy – both contribute to increased rates of coronary artery disease, due to acceleration of atherosclerosis, increased thrombosis and with variable metabolic effects [15,28]. Compared to tamoxifen, aromatase inhibitors increase risk for both ischemic events and heart failure. The explanation for this discrepancy may be a protective effect of tamoxifen (via cholesterol lowering) offsetting the pro-thrombotic effects [29,30]. Inflammatory cardiac disease (myocarditis) is a growing issue resulting from the expanding role of immunotherapies and other targeted cancer treatments, including tyrosine kinase inhibitors, also contributing to an observed increase in cardiac dysfunction and heart failure [31,32]. Figure 1 summarizes the pathophysiology and mechanisms of action for a broad range of breast cancer therapies that have been shown to cause cardiotoxicity.

Figure 1. Schematic diagram summarizing the pathophysiology and mechanisms of action for a broad range of breast cancer therapies that have been shown to cause cardiotoxicity. HER2, human epidermal growth factor receptor-2. Reproduced with permission from Chen et al. [26].

In addition to gender differences regarding cancer types and treatments, female gender differences exist in patterns of heart failure [24,33]. Conclusive data demonstrate a significantly higher prevalence of heart failure with preserved ejection fraction (HFpEF) in women as compared to men, whereby heart failure with reduced ejection fraction secondary to ischemia is more common in men [34]. Another example of gender discrepancy within heart failure is seen in takotsubo cardiomyopathy found predominantly in women: this complex syndrome is also poorly understood. A hypothesized pathophysiology suggests that a drop in estrogen during menopause may increase sensitivity of cardiac tissue to catecholamines leading to acute cardiac failure [35].

Menopause marks a clear transition in cardiac risk for women. Early menopause may be an intentional goal (estrogen-sensitive cancers) or unintended consequence of cancer treatment. Chemotherapy, radiation therapy, targeted hormone suppression or surgery (bilateral oophorectomy) can all result in early menopause, and are associated with an increase in cardiovascular risk [36]. Younger age at menopause is associated with higher risks of coronary artery disease and heart failure, surgical menopause being a higher risk than early natural menopause [37]. Data on the specific effects of early menopause from other cancer treatments is lacking. Due to these risks (as well as negative effects on bone health), significant effort is made to prevent early menopause when possible [38].

Despite clear gender differences in heart failure, our understanding of why this occurs and what genetic and phenotypic factors may be driving the underlying pathology remains in its infancy. Furthermore, guidelines often fail to articulate these gender differences and this is reflected in a lack of gender-based guideline recommendations [33]. This is in part due to a lack of evidence for treatments in diagnostic subgroups (e.g. in HFpEF), which may stem from underrepresentation of women in heart failure trials [33,39]. Acknowledging the sex-related differences in cardiac disease, cancer and treatment-related adverse outcomes will guide more personalized cardio-oncology care, and likely improve patient outcomes [33].

Considerations at the initiation of cancer treatment

Baseline cardiovascular risk stratification is an integral part of cardio-oncologic work-up ideally performed at the time of cancer diagnosis and before initiation of treatment [15,40,41]. This assessment allows the patient, oncologist and cardiologist to appreciate the patients’ individualized risks and to assist planning for cancer therapy type, intensity and duration whilst also highlighting required cardiac pre-optimization strategies [40]. Risk stratification will guide initial cardiovascular investigations and provide a roadmap for ongoing surveillance and management throughout and after cancer treatment [40]. An inclusive approach with the patient provides an opportunity to discuss cardiac toxicity risk and may improve patients’ understanding and self-care [15,40]. Common risk stratification components include age, existing co-morbidity associated with CVD risk (hypertension and renal disease), modifiable lifestyle risk factors (e.g. smoking and dyslipidemia), previous CVD events, cardiopulmonary exercise test results, cardiac biomarkers and past and current cancer history [14,15,40]. The European Society of Cardiology Heart Failure Association – International Cardio-Oncology Society (HFA–ICOS) risk assessment tool is recommended in the 2022 European Society of Cardiology cardio-oncology guidelines with previous validation in breast cancer populations [15,42]. Indeed, baseline cardiovascular risk assessment is one of the key internationally agreed-upon quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment [14]. Figure 2 summarizes the components of this baseline cardiovascular risk assessment.

Figure 2. Different risk factors which contribute to baseline cardiovascular (CV) risk in a cancer patient scheduled to receive a cardiotoxic cancer treatment, and a checklist of the clinical history and investigations required at baseline prior to starting a cardiotoxic cancer therapy. *Cardiac biomarkers (troponin and natriuretic peptides) should be measured where available. BNP, brain natriuretic peptide; ECG, electrocardiogram; HbA1c, glycated hemoglobin; NT-proBNP, N-terminal pro-brain natriuretic peptide. Reproduced with permission from Lyon et al. [40].

Given the overlap in modifiable risk factors for both CVD and cancer, and their high prevalence within the cancer population, there is significant potential for common preventative strategies. More than 90% of Australian women have at least one modifiable risk factor for CVD and over the last two decades the proportion of women who are overweight or obese (60%), are considered sedentary (59%), have elevated blood pressure (20%) or have elevated blood lipids (63%) has increased [1,43]. Concerningly, the only behavioral risk factor which has declined over the past two decades has been smoking, from 24% down to 11% [1]. Recent statistics from the Australian Institute of Health and Welfare (AIHW) demonstrate that almost half (42%) of the cancer burden may be attributable to modifiable risk factors (such as obesity and smoking) [6], thus there is significant potential to address these shared modifiable behavioral and environmental risk factors to impact both CVD and cancer. Strategies including weight loss, smoking cessation, restricting alcohol consumption and exercise programs aimed at improving cardiovascular fitness have been emphasized in cardio-oncology guidelines and will be outlined in further detail in the following [15,44].

Considerations throughout cancer treatment

Cancer, its treatment and the patient’s risk profile interact in complex ways, predisposing to the wide spectrum of CVD including heart failure, arrythmias, coronary artery disease, valvular heart disease, thromboembolism and cardiomyopathy [45,46]. This risk is present at the start of the cancer journey (baseline cardiovascular risk), may increase over time (as a combination of effects of cancer therapies and their interaction with patient’s risk factors) and persists for at least two decades after treatment is completed [15,40,46].

In patients at high/very high risk, according to baseline cardiovascular assessment [40], receiving anthracyclines and/or HER2 therapies for breast cancer (age >65 years, renal failure, accompanying radiotherapy, known hypertension, valvular heart disease and higher cumulative dose), the latest guideline indicates that angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists and beta-blockade therapy could be considered for prevention of cardiac dysfunction [15,47,48]. Small trials of these agents in patients receiving anthracyclines have shown less decline in left ventricular ejection fraction, likely by promoting positive remodeling after myocardial injury, although reductions in overt heart failure have not been conclusively demonstrated [49]. Studies on the use of spironolactone and eplerenone have not yielded positive results as preventative therapy; however, they are indicated when left ventricular systolic dysfunction is identified. HMG CoA reductase inhibitors (statins) have also been shown, albeit with variable success, to reduce the risks of anthracyclines and trastuzumab-mediated cardiotoxicity, with ongoing randomized studies supporting the role of these agents in reducing left ventricular dysfunction, potentially reflecting the role of statin therapy in reducing inflammation. Ongoing randomized trials may shed further light on the role of these agents [50].

Ongoing cardiovascular surveillance represents an important component of patient management during and after therapy. During treatment, patients will ideally undergo clinical assessment, cardiac biomarker measurement and cardiac imaging, depending on the anti-cancer treatment and baseline cardiovascular risk, to identify and help mitigate cardiovascular adverse effects. Surveillance strategies are tailored to the patients and therapies to match the expected risk of CVD. Standard transthoracic echocardiography forms the basis of baseline and ongoing assessment with changes in left ventricular function traditionally used to identify patients that may require initiation of medical therapy and consideration of alternative cancer treatment regimens [48]. More sophisticated approaches to serial assessment include the use of cardiac strain imaging which, like natriuretic peptides, may identify early subclinical changes in ventricular function. Patients with persisting elevated troponin levels are noted to be at higher risk of cardiotoxicity and would warrant closer observation during follow-up [51]. Given the myriad of cardiovascular issues complicating cancer and its treatment, it is important to acknowledge that biomarkers are sensitive, but lack specificity [52]. There is also an increasing emphasis on so-called ‘permissive cardiotoxicity’ [53] – the practice of accepting and managing cardiovascular adverse effects by the multidisciplinary team without interrupting anti-cancer therapy.

Considerations after cancer treatment: long term follow-up and survivorship

Accordingly, there is now an emphasis on identifying and managing cardiovascular risk throughout the cancer journey – before, during and after treatment – whilst acknowledging that cancer therapies contribute to this risk. The aim is to provide the maximal benefits of cancer therapy (allowing appropriate dosing and completion of treatment cycles) while minimizing CVD risk during cancer treatment [15,54]. The recognition of late adverse events has led to a focus on addressing relevant predisposing factors at the time of cancer diagnosis with a view to optimizing survival beyond cancer therapy [13,40]. With survival rates for all cancers, and particularly breast cancer, improving with early detection and effective treatments, CVD is now the second leading cause of mortality amongst survivors after cancer itself [55]. While the effects of anthracycline chemotherapy and trastuzumab on the risk of developing both early and late left ventricular dysfunction are well established, the risk of developing subsequent coronary artery disease is similarly important, with increased rates of incident coronary disease seen in cancer survivors, particularly those treated with chest radiotherapy [56].

While the risk of coronary artery disease in cancer survivors is clear, approaches to risk stratification and modification are less well established. Initiatives outlined in guidelines that address hypertension, blood glucose, physical activity, weight, diet, smoking and dyslipidemia to reduce incident cancer are likely to improve CVD risk and are increasingly important in ensuring longevity after cancer diagnosis [15,40]. This imperative to minimize future vascular risk is highlighted by guidelines designed to establish CVD risk at the time of diagnosis and focus on treating risk factors. Importantly, however, traditional guidelines designed to estimate risk and guide primary prevention cannot necessarily incorporate all of the aspects of risk associated with each specific cancer type, subsequent therapy and individual response [57]. Nonetheless, recognizing risk factors (such as age, presence of modifiable cardiac risk factors, previous cardiac history, elevated cardiac biomarkers, current and previous cancer treatments) and utilizing specific risk scores which incorporate cancer diagnosis can identify high-risk patients suitable for cardio-oncology clinic review, while patients at lower risk can continue with usual care, and cardiology review as needed [12,41].

After shepherding patients through the cancer treatment journey, the next aim is identifying patients who warrant ongoing cardiovascular follow-up beyond the first 12 months post treatment [58,59]. Annual cardiovascular risk assessment is recommended in all cancer survivors [15,45]. To better inform ongoing prevention therapies, computed tomography calcium scoring and computed tomography coronary angiography are emerging techniques [60]. Specific high-risk groups include those receiving radiation therapy where the cardiac silhouette is included in the radiation field. These patients typically developed accelerated coronary disease 5–10 years post treatment with the incidence of CAD and heart failure six-fold higher in some groups, such as those with lymphoma and lung cancer [56]. Cancer survivorship also adds other complications to future cardiac care. For example, cardiac surgery may be more complex given impaired wound healing and radiation-induced damaged to the potential donor arteries (left internal mammary artery or right internal mammary artery), while radiation-induced esophageal injury may preclude adequate valvular assessment with trans-esophageal echocardiography.

It is also important to highlight another disparity among patients living beyond cancer – they seem to be consistently undertreated for their cardiovascular risk factors [47,61]. Lack of use of routine cardiovascular therapies, such as statins for management of dyslipidemia, is associated with more cardiovascular admissions among cancer patients [62]. In this context, it is important to note that while patients encounter many health-care providers during their cancer journey, the focus of care should be patient-centered and primary care providers/general practitioners play an integral part in patient care and can facilitate and manage many cardiovascular risk factors and other health concerns in collaboration with tertiary care clinicians [63]. General practitioners can effectively screen and manage cardiovascular risk factors before, during and after cancer therapy, and in particular can support long-term survivorship care and ensure people living beyond cancer treatment are appropriately managed for all their non-oncological comorbidities, including hypertension, hyperlipidemia and diabetes.

Ongoing controversies include when to initiate survivorship screening strategies, especially in the context of radiotherapy, given that an increased risk of coronary events is seen within 2 years of treatment completion; as well as who is best positioned to provide such long-term surveillance, given complexities of cancer treatment regimens.

Heart health at all stages

Optimizing cardiovascular risk factors and ensuring a healthy lifestyle are crucial at any stage of the cancer journey, especially for patients at high cardiovascular risk [15]. Smoking cessation, restricting alcohol consumption to a maximum of 100 g per week and maintaining adequate physical activity are all proven, non-pharmacological steps to optimal cardiac health.

Physical inactivity and poor fitness are clearly associated with worse cancer and cardiovascular outcomes, although most data are in men [64–66]. Breast cancer patients suffer from reduced cardiorespiratory fitness (as measured by VO₂) in comparison to healthy patients, which may reflect treatment toxicity or reduced physical activity during treatment. In one study, 50-year-old female breast cancer survivors had cardiorespiratory fitness comparable to 60-year-old healthy populations [67]. To combat this loss of a decade of fitness, physical activity during and post cancer is crucial, and is strongly recommended by numerous professional societies [68].

One explanation for this loss of fitness is a high prevalence of HFpEF in postmenopausal women. The hallmarks of HFpEF are increased ventricular stiffness and inability of the left ventricle to relax. Through increasing vascular stiffness and impairing diastolic function, cancer and cancer therapies promote HFpEF, which may be more common than heart failure with reduced ejection fraction in cancer survivors [69–71]. HFpEF is increasingly being considered a disease of physical inactivity, with lifestyle factors (obesity and smoking) being predictors of HFpEF in cancer survivors [71–73].

Contrary to most areas, research on the role of exercise during and after cancer has predominately focused on women (specifically those with breast cancer) [74,75]. Clinicians and patients may harbor concerns that exercise training is ineffective or too strenuous, but exercise prescription including high-intensity interval training and moderate-intensity continuous training is tolerable and improves VO₂ in cancer patients and survivors [68]. Australian data in breast cancer patients receiving anthracycline chemotherapy showed that exercise improved VO₂, but did not attenuate functional disability [76]. Beyond the cardiovascular benefits of exercise, the various other issues faced by cancer survivors – including muscle strength and falls, osteoporosis, obesity, anxiety, depression and body image – all benefit from physical activity.

Conclusion

Cardio-oncology is a growing specialty focused on the prevention, early detection, management and long-term surveillance of CVD during a patient’s cancer journey. The nexus between carcinogenesis and CVD relates to the shared risk factors, bidirectional increases in relative risk of development of either disease state, effects of cancer therapies on the cardiovascular system and patient-specific factors. These issues may disproportionately affect women due to the high prevalence of cardiotoxicity observed in female-specific cancer treatments and pre-existing disparities in cardiovascular outcomes. The collaborative nature of cardio-oncology promotes interventions focused on shared care and a patient-centric approach. The need to consider CVD risk and implement appropriate diagnostic, surveillance and preventative strategies is clear. While guidelines outline principles of management, the need for personalized approaches incorporating the underlying diagnosis, cancer treatment and CVD risk with a view for optimal long-term outcomes is essential [15]. Future directions should include research aiming to identify those at highest risk who would benefit from specific cardioprotective therapies as well as best ways of implementing guideline-recommended approaches into routine clinical practice.

Potential conflict of interest

No potential conflict of interest was reported by the authors.

Acknowledgements

The funders had no role in the preparation of the manuscript or its content.

Additional information

Funding

A. L. Sverdlov is supported by the National Heart Foundation of Australia Future Leader Fellowship [Award ID 106025]; D. T. M. Ngo is supported by the National Heart Foundation of Australia Future Leader Fellowship [Award ID 104814]; this work is supported in part by the NSW Health Cardiovascular Research Capacity Program Early-Mid Career Researcher Grant (to A. L. Sverdlov and D. T. M. Ngo) and Department of Health and Aged Care Medical Research Future Fund [MRF2017053] (to A. L. Sverdlov and D. T. M. Ngo). The funders had no role in the preparation of the manuscript or its content.