Exercising caution: is there a role for exercise testing in the hypertrophic cardiomyopathy population?

It is well established that engaging in regular physical activity effectively reduces all-cause mortality. Notwithstanding, high intensity physical activity has been associated with sudden cardiac death (SCD) due to malignant cardiac arrhythmias, particularly in individuals with hypertrophic cardiomyopathy (HCM). Although most cases of SCD typically occur outside of the physical activity setting, individuals with HCM often purposefully limit their exercise participation, which can lead to secondary health complications arising from a sedentary lifestyle. Presently, there is no existing data that describe an ‘optimal’ dose of exercise that mitigates risk of arrhythmia for HCM patients. Therefore, investigation into the exercise intensities appropriate for this population is particularly important. In a recent issue of The Journal of Physiology, Shah et al. (2019) explored the relationship between exercise intensity and catecholamine levels, known pro-arrhythmic factors, in men (29 ± 8 years) diagnosed with mild non-obstructive HCM (n = 9) and age-matched healthy controls (n = 5). It was hypothesized that levels of adrenaline (epinephrine) and noradrenaline (norepinephrine) would remain stable at low-to-moderate exercise intensities, followed by an exponential rise at intensities progressing above the blood lactate threshold (LT) and ventilatory threshold (VT). Participants attended two visits in which the first comprised a resting echocardiograph to assess cardiac function, and a maximal effort cardiopulmonary exercise test on a cycle ergometer to determine the VT. During the second visit, participants completed a submaximal incremental exercise test that consisted of eight successive 3-min stages with intensities increasing by 20 W. Exercise intensities were individualized to each participant, which was an important addition in the methodology. This ensured participants would reach their VT by stage six. Capillary earlobe lactate and venous blood sampling from an intravenous catheter were acquired from each participant after every 3-min stage. Shah et al. (2019) demonstrated that exercise parameters, including maximal rate of oxygen consumption (), VT and LT, were similar between patients with non-obstructive HCM and healthy controls. Plasma concentrations of adrenaline and noradrenaline did not differ between groups at rest or at any intensity during submaximal exercise. Both groups had similar catecholamine concentrations, in which levels remained stable up to low-to-moderate intensities, upon which concentrations rapidly increased at exercise intensities above the LT and VT. Importantly, the authors demonstrate that the catecholamine threshold occurs at an intensity that is higher than both the VT and LT. Based on their findings, the authors recommend personalized exercise prescriptions, safely developed through identification of each patient's VT or LT. The current study provides an important contribution to the limited body of literature surrounding the relationship between exercise intensity, catecholamine kinetics, and the risk of arrhythmia in HCM patients. The authors were cognizant of the small sample size and of the possibility that catecholamine kinetics may also vary based upon the frequency or duration of exercise, which was not assessed. The authors should be commended for their work, as their results provide a foundational framework for future studies. However, the following factors should be considered when interpreting the findings: (i) the characteristics of the HCM population that was evaluated, (ii) the limited inclusion of post-exercise assessments, and (iii) the lack of female participants. The authors report no differences in the catecholamine response to exercise between HCM patients and healthy controls. In addition to being matched for age, HCM participants and healthy controls did not differ in most physiological measures including heart rate, VT, LT and cardiorespiratory fitness. While this may be a strength in the study design, this may also be perceived as a limitation that prevented any meaningful distinctions from being found between cohorts. Participants were recruited on the basis of having mild non-obstructive HCM, and were excluded if they presented with an obstructive form of HCM, an ejection fraction < 50%, a history of ventricular tachycardia, or any use of medications that interfered with the sympathetic nervous system. The authors report that patients with HCM were accumulating less than 5 h of aerobic exercise weekly, which is still a significant amount of activity, without participating in any form of competitive exercise in the past 12 months. Interestingly, the maximal cardiorespiratory fitness () of some HCM participants was well above the 80th percentile for their age (Wang et al. 2010), suggesting the HCM cohort was quite active. Perhaps the inclusion of patients with moderate-to-severe forms of HCM would have allowed for a more distinguishing comparison. Furthermore, patients with complicated forms of HCM may have benefitted to a greater extent from this type of investigation due to the likelihood that they are less active. The confirmation of safe exercise intensities may have helped encourage this population to increase their activity levels. The authors also suggest that future exercise prescriptions should be dealt with case-by-case. However, a larger and more heterogeneous sample size that includes patients across the spectrum of HCM may have produced observations with a broader relevance to a larger proportion of the HCM population and thus eliminate the need for time-consuming individualized tests. Participation in the present study involved two separate sessions that occurred within 1–2 weeks following the first visit. This design element minimized potential confounds of health status or exertional tolerance discrepancies between data collection sessions. The inclusion of a resting echocardiograph was another strong design element that provided a thorough characterization of cardiac function. Catecholamine kinetics was characterized throughout the eight stages of exercise; however, there was no assessment of catecholamines or cardiac function post exercise. As Shah et al. (2019) describe, most episodes of SCD typically do not occur during physical activity. Therefore, an important opportunity to assess the recovery period following vigorous exercise was missed. A study by Dimsdale and colleagues (1984) assessed the catecholamine levels of healthy young men during incremental cycling exercise to maximal effort and for 6 min into recovery. As expected, noradrenaline and adrenaline levels increased with intensity. However, noradrenaline levels continued to rise significantly during recovery, suggesting there is the possibility of an increased risk of cardiac arrhythmias in the period after exercise (Dimsdale et al. 1984). It should be acknowledged that Dimsdale and colleagues (1984) assessed participants up to maximal effort, which was not the case in the present study. Nevertheless, their work demonstrates the critical importance of monitoring HCM patients’ responses following a bout of exercise. It is possible that HCM participants, especially those with moderate-to-severe symptoms, may demonstrate post-exercise catecholamine kinetics that increase their susceptibility to arrhythmic events in the recovery period. Future work should incorporate prolonged measurements into recovery in order to further elucidate appropriate exercise loads that mitigate risk for the HCM population. In the present study, careful selection criteria were used to identify patients eligible to participate. Interestingly, only male patients with HCM were included in the study despite the fact that females comprise ∼43% of the cases of diagnosed HCM (Maron et al. 2016). It is recognized that the work by Shah et al. (2019) is pilot work with a small sample size, and the inclusion of females with HCM and healthy female controls may have considerably lengthened the study timeline. However, at a time where female participation in sport and physical activity is on the rise, it is increasingly relevant to be considering their physiological responses to exercise. Moreover, there are sex differences in the catecholamine response to exercise, which may limit the applicability of the present study to females with HCM. At rest, and in response to moderate and vigorous intensity submaximal cycling intensities, healthy young females demonstrate lower levels of adrenaline and noradrenaline compared to age-matched males (Wheatley et al. 2014), which may be attributed to the lower sympathetic system activation that is typically observed pre-menopause. Therefore, it is insufficient to exclude half of the HCM population, especially given the likelihood that females will respond to exercise differently from males. It is critical for future work to explore the catecholamine kinetics of both male and female HCM patients, and confirm whether exercise intensities should be tailored differently based on sex. In conclusion, Shah et al. (2019) have shed light on an important and complex relationship that exists around vigorous exercise and the risk of arrhythmia. By exploring the catecholamine response to progressive exercise, this study has made an effort to determine safe exercise intensities that preserve the possibility of HCM patients engaging in exercise, which is an essential lifestyle practice for well-being. The present study has demonstrated that patients with mild non-obstructive HCM show similar rates of peak oxygen consumption, VT, LT and plasma catecholamine kinetics to healthy controls in response to exercise. While these results suggest exercise testing may be useful for developing exercise prescriptions that are catecholamine sparing, it is important to consider the complete response to exercise, which includes the recovery period. Future work should focus on extending these observations to a broader population including females with HCM and those with moderate-to-severe diagnoses. None declared. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. No funding was obtained for this review.

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