Cardiorespiratory fitness, conventionally measured using cardiopulmonary exercise testing, is a physiologic marker of cardiovascular and respiratory health and has an incrementally greater predictive value for cardiovascular mortality compared with traditional risk factors such as hypertension and diabetes mellitus.^1,2 The associations between low cardiorespiratory fitness and worse cardiovascular and overall mortality outcomes are consistent across various populations, including younger and older individuals of either gender.^1,3 Cardiorespiratory fitness has therefore been proposed by the American Heart Association as a "clinical vital sign."¹

The clinical associations between high cardiorespiratory fitness and cardiovascular health are diverse and likely stem from cardiorespiratory fitness's beneficial effects on metabolic, endocrine, and immune processes.⁴ In addition, cardiorespiratory fitness has favorable health associations with muscular strength and bone density.⁵ Not surprisingly, individuals with high cardiorespiratory fitness have a lower prevalence of cardiovascular disease (CVD) risk factors.⁶ In an analysis of a large cohort of low-risk, middle-age men and women, higher levels of cardiorespiratory fitness were associated with a lower likelihood of clinically relevant coronary heart disease risk factors, including obesity, dyslipidemia, and hyperglycemia.⁶ Higher cardiorespiratory fitness has also been linked to improved insulin sensitivity and reductions in lipoprotein synthesis.^7,8 Positive implications of regular exercise also include lower resting heart rate and ambulatory blood pressure values.⁹ In addition, exercise training is associated with improved psychological metrics, including emotional stress and behavioral anxiety levels.¹⁰

The inverse associations between cardiorespiratory fitness and CVD and all-cause mortality follow a dose-response relationship. In a systematic analysis of 33 studies evaluating exercise and cardiovascular events, individuals with maximal aerobic capacity lower than 7.9 MET had higher rates of all-cause mortality (hazard ratio [HR] 1.70; confidence interval [CI] 1.51-1.92) and coronary heart disease/CVD (HR 1.56; CI 1.39-1.75) compared with individuals with a mean aerobic capacity greater than 10.9 MET.¹¹ When added to traditional risk assessment models, cardiorespiratory fitness enhances risk prediction of both short- and long-term cardiovascular outcomes.¹² Furthermore, cardiorespiratory fitness correlates not only with the above-mentioned end-points but also with incident myocardial infarction, diabetes, atrial fibrillation, and stroke.^2,13

In patients with cancer, physical endurance is similarly associated with a more favorable cardiovascular health profile. A recent prospective analysis of the Women's Health Initiative demonstrated that physical activity prior to the diagnosis of breast cancer was associated with a graded reduction in subsequent cardiovascular events.¹⁴ In this study, 4,015 female patients with breast cancer completed a baseline questionnaire regarding leisure-time physical activity. At a median follow-up of 12.7 years, the incidence of a broad composite of cardiovascular events decreased with higher total MET performance categories. Compared with individuals performing less than 2.5 weekly MET, those achieving 2.5-8.5 MET had a 20% lower CVD event rate, and patients exceeding 18 weekly MET experienced a 37% reduced CVD rate. In addition to its favorable cardiovascular effects, physical activity has important cancer-specific benefits. A large prospective evaluation in the Nurses' Health Study showed that more intense physical activity regimens correlate with the adjusted relative risk (RR) of death from breast cancer (RR 0.80 for 3-8.9 MET hour per week, RR 0.50 for 9-14.9 MET hour per week; 1.0 defined as <3 MET hours per week).¹⁵ The mechanisms underlying improved breast cancer outcomes with exercise include lower body weight, which has an independent association with lower cancer recurrence, as well as lower circulating estrogen.¹⁵ Additional postulated mechanisms include improvements in insulin sensitivity, lower systemic inflammation and oxidative stress, and enhanced immune function.¹⁶

The influence of cancer treatments on the cardiopulmonary functions of patients with cancer is increasingly recognized. A systematic analysis of 27 studies of patients with breast cancer receiving adjuvant therapies demonstrated a 10% (-2.4 mL/kg/min) lower maximum rate of oxygen consumption following completion of chemotherapy relative to the pre-treatment baseline.¹⁷ Compared with healthy, sedentary women, patients who had received adjuvant therapy had a 25% lower maximum rate of oxygen consumption. This and other investigations have opened the door to dedicated research of exercise physiology aberrations in patients with cancer and suggested that nontraditional measures of cardiovascular function and oxygen delivery may be perturbed in patients with cancer who undergo treatment, independent of cancer interventions with established pulmonary or cardiac toxicities.

The cardiovascular effects of chemotherapy and hormonal therapy in patients with breast cancer have been traditionally evaluated using echocardiographic imaging studies given that clinical heart failure is the most serious complication of such treatments in that population. The incidence of clinical heart failure in patients who receive anti-HER2 therapies, a viable treatment option in 15% of all patients with breast cancer, is in the range of 1-4%.¹⁸ The development of left ventricular dysfunction, however, is a more commonly encountered phenomenon and occurs in as many as 10% of patients.¹⁸ Although recovery of left ventricular ejection fraction (LVEF) can be expected upon discontinuation of the offending agent and/or initiation of goal-directed medical therapy, some patients may experience permanent reductions in LVEF, implying that residual cardiopulmonary injury may persist either secondary to drug-related myocardial trauma or due to non-myocardial pathologies that are not captured with standard echocardiographic imaging. Such toxicities may lead to increased symptom burden and the development of overt CVD over time and are therefore essential to understand.

In a recently published case-control study, Yu et al. evaluated the long-term cardiopulmonary consequences of asymptomatic declines in LVEF in a cohort of patients with breast cancer treated with trastuzumab and with a prior anthracycline exposure (~90% of patients).¹⁹ This was a single-center, cross-sectional investigation of 42 women with non-metastatic, HER2-positive breast cancer who had completed trastuzumab-based therapy at least 2 years prior to enrollment. At a median of 7 years after completion of HER2-directed therapy, mean LVEF was lower in the cardiotoxicity cohort compared with the non-cardiotoxicity cohort (56.9% vs. 65.3%; p < 0.001), and the mean global longitudinal strain was slightly worse in the cardiotoxicity group (-17.8% vs. -19.8%; p = 0.005). The post-exercise mean peak oxygen consumption was 15% lower in the cardiotoxicity arm (22.9 ml/Kg/min) compared with the non-cardiotoxicity (27.0 ml/Kg/min) and healthy cohorts (30.5 ml/Kg/min; p < 0.001). In addition, post-exercise LVEF and contractile reserve were decreased in patients with prior cardiotoxicity (LVEF 65.6%, 74.5%, 75.6%; contractile reserve 3.3 L/min/m2, 4.0 L/min/m², 4.4 L/min/m²; p = 0.03). There were no differences in the arteriovenous oxygen content difference.

Several methodological pitfalls should be mentioned. First, patients had numerous cardiotoxic drug exposures (doxorubicin, trastuzumab, and non-anthracycline cytotoxics) that could have induced a trastuzumab-independent cardiac dysfunction via a variety of mechanisms. For example, 90% of the patients had received anthracycline-based regimens, and 30% underwent left breast radiation therapy. It is therefore possible that radiation-associated cardiac abnormalities—early pericarditis and myocarditis or late coronary artery disease or conduction system defects that were not described in the manuscript—contributed to the left ventricular dysfunction or the oxygenation derangements. Secondly, pre-chemotherapy cardiopulmonary exercise testing was not performed; therefore, it is possible that patients who sustained a drop in their LVEF during treatment had a lower baseline peak oxygen consumption secondary to subclinical cardiac dysfunction (or other confounders) that might have predisposed them to develop cardiotoxicity. In that case, the post-exercise oxygenation derangement could have been a marker rather than the result of the cardiotoxicity. In addition, the lack of physician blinding could have affected the interpretation of the results.

There are several important questions related to the long-term effects of chemotherapy in patients with breast cancer. Some of these questions pertain to the predictive role of cardiopulmonary exercise testing in patients with breast cancer, and others relate to the potential benefits of exercise in improving outcomes. First, what is the long-term effect of specific breast cancer regimens on various cardiopulmonary exercise parameters? For example, are dose-dense anthracycline-containing regimens (i.e., doxorubicin and cyclophosphamide, administered every 2 weeks), non-dose-dense regimens (administered every 3 weeks), or non-anthracycline-containing regimens, each followed by HER-2-directed therapy, associated with a distinct toxicity profile? Secondly, would a longer interval between anthracycline and trastuzumab therapies lead to attenuation of cardiopulmonary exercise impairments? Studies have shown a lower cardiotoxicity incidence with sequential (rather than concomitant) use of anthracycline and trastuzumab and with longer intervals between the two, so it would be important to assess the cardiopulmonary function of patients with varying treatment intervals. Next, does baseline cardiorespiratory fitness predict subsequent cardiopulmonary exercise abnormalities in patients treated with HER-2 blockers or other cancer drugs? What are the clinical implications of decreased cardiorespiratory fitness in breast cancer survivors in terms of future overt CVD (i.e., acute coronary syndrome, heart failure, and stroke) as well as its associated patient-reported outcomes? Lastly, and pertaining to the impact of cardiorespiratory fitness upon clinical outcomes, could physical activity regimes, implemented before or during chemotherapy, ameliorate some of the cardiopulmonary effects of particular chemotherapy combinations? A caveat to the latter is the possibility that regularly exercised individuals may show better exercise testing results, which may reflect conditioning and musculoskeletal capacity and not merely cardiopulmonary functions.

The study by Yu et al. augments our comprehension of exercise intolerance as an objective and chronic, treatment-related cardiopulmonary impairment in patients treated for breast cancer. As the survival outcomes of patients with breast cancer continue to improve, it will be particularly relevant to learn more about these emerging exercise-specific pathological derangements. It will be equally important to correlate these exercise abnormalities with long-term cardiovascular outcomes and determine which early cardiopulmonary changes are likely to result in long-term clinical impairments with associated morbidity and mortality. Learning about the predictive value of cardiac biomarkers, magnetic resonance imaging-detectable myocardial fibrosis or scar, and left ventricular function for the development of clinical cardiovascular conditions in patients with breast cancer will further our understanding of these events. Collection of long-term data regarding downstream cardiovascular events, patient-reported functioning, and quality-of-life measures should be performed and would help fill the knowledge gaps of cancer treatment toxicity in patients with breast cancer. In addition, studies that would assess cardiopulmonary performance aspects in patients with breast cancer who are treated with specific anti-cancer regimens are urgently needed. One such ongoing research endeavor is the UPBEAT (Understanding and Predicting Breast Cancer Events After Treatment) trial, a National Institutes of Health-sponsored interventional study designed to evaluate the impact of anthracycline- and non-anthracycline-based chemotherapies on maximal (peak oxygen uptake) and submaximal (6-minute walk) exercise capacity in women with breast cancer.²⁰ The results of that trial will shed light on the spectrum and natural history of exercise abnormalities in patients with breast cancer and are likely to emphasize the need for routine exercise training in these patients. Clinical trials should also investigate the effect of exercise fitness training on patients' outcomes, in particular evaluating whether different exercise-based protocols result in better tolerance and higher completion rates of cancer treatments and improved cardio-oncologic outcomes. Positive results are likely to prompt the creation of cancer exercise training programs as a form of cardio-oncology rehabilitation. This could become the standard of care equivalent to contemporary cardiac rehabilitation programs for patients with CVD.

References

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Clinical Topics: Arrhythmias and Clinical EP, Cardio-Oncology, Sports and Exercise Cardiology, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Cardiotoxicity, Cardio-oncology, Risk Factors, Cross-Sectional Studies, Physical Endurance, Cardiovascular Diseases, Incidence, Insulin Resistance, Case-Control Studies, Atrial Fibrillation, Confidence Intervals, Breast Neoplasms, Stroke Volume

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