Did you know? Is there a reserve in myocardial work via the Frank‐Starling mechanism in healthy humans?

The human heart—as for any mechanical device—must have a maximum working capacity beyond which failure or damage occurs. This capacity is routinely tested by incremental exercise protocols supposedly reaching maximal myocardial work in 6–10 min.1 Notwithstanding the high prognostic strength of myocardial work capacity,1 the doubt remains: is myocardial work truly maximal or there is a reserve not mobilized by exercise? If there were no reserve in myocardial work at the point of exhaustion during incremental exercise, its prognostic relevance could not, in principle, be enhanced. On the contrary, if such a reserve exists, current exercise protocols should be modified or combined with other interventions to provide unequivocal information, that is, truly maximal myocardial work capacity, plausibly entailing the strongest predictor of cardiac function and overall health. A previous experimental study combining exercise and atrial pacing stated, but did not provide evidence of, a reserve in myocardial work capacity during incremental exercise in healthy young individuals.2 Among the limitations of the supraphysiological increase in heart rate via atrial pacing during exercise at high intensity, the physiological match of the timing of atrial contraction, ventricular relaxation, and filling is unlikely to occur, leading to increased atrial pressure, reduced ventricular filling, and stroke volume.2, 3 In this regard, the human heart demonstrates the largest functional enhancement with regular stimuli such as endurance training, which increases ventricular filling and stroke volume but not heart rate.4 Accordingly, the question remains to be addressed via the manipulation of the physiological principle governing myocardial work capacity, the Frank-Starling mechanism, known as the “Law of the Heart.” Healthy young individuals (n = 11, 28 ± 7 years, 55% ♀) were recruited via online and printed advertisements in the medical campus of the University of Hong Kong. Inclusion criteria comprised healthy status according to clinical questionnaires and resting echocardiography/ECG screening, absence of current medical symptoms and medication, and no history of major disease. The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority West Cluster (UW 21-401). The participants reported three times to the laboratory for testing. In the initial testing session, blood volume (BV) was determined via the carbon monoxide (CO) rebreathing technique, as previously detailed.5 The testing protocol of the experimental testing sessions was identical except for the intravenous (antecubital) infusion condition: (i) placebo (PBO-sham) via saline infusion (10 mL of 0.9% NaCl, BD) or (ii) BV expansion (BVexp) via albumin (Albumin 20%, CSL Behring infusion) eliciting a 10% increment in BV. The experimental procedure was blinded to the participant via a blackout curtain with a small incision for the cannulated arm. Due to the potentially long total half-life of albumin in the human body (up to 19 days), the order of testing sessions was not randomized (1st day: PBO-sham, 2nd day: BVexp) in order to prevent confounding carryover effects. General methodological details of cardiac, hemodynamic and hematological measurements as well as the characteristics of the incremental exercise protocol have been previously reported.6 Specifically, in the present study myocardial work was comprehensively determined by the product of the following factors: (i) myocardial contraction coefficient (heart rate × stoke volume/left ventricular (LV) mass), (ii) afterload (represented by systolic blood pressure at the heart height level), (iii) wall stress (the product of systolic blood pressure (SBP) and LV end-systolic volume diameter/LV wall thickness averaged from septal and left-lateral walls); (iv) LV strain (end-systolic LV global radial strain averaged from mitral and apex myocardial levels) and myocardial torsion (comprising longitudinal and circumferential strain components). Wall stress and strain respectively represents force and distance, the product of which yields work. Statistical analyses (SPSS 26.0, IBM) comprised two-way ANOVA with repeated measures with intravenous infusion condition (PBO-sham, BVexp) and exercise (rest, exercise) as within-subject factors, along with their interaction. All individuals were healthy, non-smokers, non-obese (body mass index = 21.9 ± 1.9 kg/m2), and moderately physically active (3.8 ± 2.0 h of aerobic exercise per week). The resting cardiac phenotype conformed to normative values according to age, sex, and ethnicity.7 The effects of the intravenous infusion and exercise on myocardial work and its underlying functional components are presented in Figure 1. Exercise increased stroke volume, heart rate, cardiac output, SBP, and LV radial strain (p ≤ 0.018), whereas LV end-systolic volume was reduced (p = 0.006). An interaction was found between intravenous infusion and exercise (p = 0.039), BVexp increasing exercise stroke volume to a greater degree than PBO-sham. No other interaction was detected. Myocardial work was largely increased by exercise (p < 0.001) but not affected by the intravenous infusion condition (p = 0.423). This study reveals a ceiling in myocardial work during incremental exercise in healthy individuals. Despite the effect of exercise on stroke volume was enhanced by BVexp through the Frank-Starling mechanism, myocardial work capacity remained unaltered. In fact, cardiac output did not differ between BVexp and PBO-sham, suggesting a counterbalancing effect of hypervolemia and elevated cardiac filling on the increase in heart rate with exercise. Herein, the baroreceptor reflex, additionally activated by BVexp via increased stroke volume, may have limited the increment in heart rate thus preserving cardiac output.8 Similarly, cardiac output remained unaltered at high exercise intensities in previous experiments in that heart rate was increased to supraphysiological levels, denoting the inverse adaptive relationship between stroke volume and heart rate.2 Such a study,2 despite claiming a reserve in myocardial work, did not comprehensively define it, not including LV mass, wall stress, strain, and torsion in the algorithm. Provided that further studies using sound algorithms corroborate the non-existence of a reserve in myocardial work during incremental exercise, renewed questions in cardiac physiology will arise. In healthy individuals, the extremely low absolute risk of myocardial infarction or fatal cardiac events associated with vigorous physical exertion (e.g., 1 sudden cardiac death (SCD) per 1.51 million episodes of vigorous exercise)9 implies a robust, yet to be established, mechanism preventing maximal myocardial work to exceed the threshold of myocardial damage—even when the presumed major determinant of myocardial work, that is, ventricular filling, is acutely enhanced. Such a mechanism, possibly extrinsic to the heart, must be able to regulate myocardial work independently of the Frank-Starling mechanism.6, 10 Alternatively, the structure of the heart might be overdeveloped in relation to the maximal functional demand that can be exerted on it (without the activation of negative feedback loops); hence, the heart would be conservatively protected during exercise. In other respects, if increased ventricular filling per se does not increase maximal myocardial work, what adaptations to endurance training explain the augmented myocardial work capacity, which however seem to be lost when blood volume expansion and increased venous return are negated by phlebotomy?4, 11 Addressing these uncertainties may not only advance our understanding of cardiac physiology, but open new lines of research into the pathophysiology and treatment of cardiovascular disease. In conclusion, the present experimental evidence denotes the absence of a reserve in myocardial work in response to its utmost physiological stressor, that is, exercise, in humans, notwithstanding the “Law of the heart.” Hence, incremental exercise may generally elicit truly maximal myocardial work capacity under “standard” (healthy) physiological conditions. Meihan Guo: Investigation; methodology; writing – review and editing. David Montero: Investigation; funding acquisition; writing – original draft; conceptualization; methodology; validation; writing – review and editing; formal analysis; supervision. The authors declare that they have no competing interests. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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