Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Abstract

Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

Hypertrophic cardiomyopathy with dynamic obstruction and high left ventricular outflow gradients associated with paradoxical apical ballooning

“…A spectrum of dynamic systolic dysfunction with varying severity has been demonstrated in obstructive HCM patients even in patients with normal or high ejection fractions. 4,[8][9][10][11][12][13] In patients with LVOT gradients ≥60 mm Hg, there is a ubiquitous midsystolic drop in Doppler velocities and flow of LV ejection that can be demonstrated with pulsed Doppler interrogation of the LV cavity before entry into the LVOT. [8][9][10][11]13 Others demonstrated a mid-systolic drop in descending aortic velocities.…”

“…1,2 Obstruction may be spontaneously labile. 4,5 Cardiomyocyte energy depletion, shown by phosphorus-31 cardiac magnetic resonance imaging, occurs in HCM patients irrespective of obstruction and is also present in genotype-positive, phenotype-negative patients before the development of hypertrophy. 2 The systolic pressure gradients across the LVOT cause symptoms due to increased LV pressure and work, coronary hypoperfusion, supply demand ischemia, 3 an instantaneous drop in ejection velocities and flow caused by obstruction, mitral regurgitation, tensionmediated diastolic dysfunction, inability to increase cardiac output with exercise, and occasionally frank hypotension.…”

“…4,[8][9][10][11][12][13] It is most commonly manifest as a reversible mid-systolic drop in pulsed Doppler mid-LV ejection velocities and flow in patients with LVOT gradients >60 mm Hg; its characteristic spectral Doppler appearance has fostered the term the "lobster claw" abnormality. 4,[8][9][10][11][12][13] It is most commonly manifest as a reversible mid-systolic drop in pulsed Doppler mid-LV ejection velocities and flow in patients with LVOT gradients >60 mm Hg; its characteristic spectral Doppler appearance has fostered the term the "lobster claw" abnormality.…”

“…Moreover, the cardiomyocytes of HCM patients often demonstrate genetically determined inefficient energy utilization, and consequent depletion of high-energy phosphate moieties. 4,5 Cardiomyocyte energy depletion, shown by phosphorus-31 cardiac magnetic resonance imaging, occurs in HCM patients irrespective of obstruction and is also present in genotype-positive, phenotype-negative patients before the development of hypertrophy. 6 Obstruction in HCM additionally exacerbates energy depletion by dint of the increased work.…”

“…We have termed this phenomenon "dynamic systolic dysfunction due to LVOT obstruction." 4,[8][9][10][11][12][13] It is most commonly manifest as a reversible mid-systolic drop in pulsed Doppler mid-LV ejection velocities and flow in patients with LVOT gradients >60 mm Hg; its characteristic spectral Doppler appearance has fostered the term the "lobster claw" abnormality. 8,9 This flow abnormality is caused by a premature termination of longitudinal LV contraction.…”