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Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

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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.

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Figure 1: Mid-systolic drop in ejection velocities.
Figure 2: Left ventricular ejection velocities in early systole and mid-systole in obstructive HCM.
Figure 3: ECG, invasively-measured LVOT pressure gradient, and TDI velocity trace from the basal septum.
Figure 4: Apical aneurysm in mid-LV obstruction.
Figure 5: Acute heart failure and shock.
Figure 6: Postoperative echocardiogram performed 4 months later.
Figure 7: Three proposed central pathophysiological pathways for development of hypertrophic cardiomyopathy phenotype in genetic hypertrophic heart disease.

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Authors and Affiliations

  1. Julian O. M. Ormerod is at the Oxford Heart Centre, Oxford University Hospitals, Headley Way, Oxford, OX3 9DU, UK.,

    Julian O. M. Ormerod

  2. Michael P. Frenneaux is at the Norwich Medical School, University of East Anglia, James Watson Road, Norwich, NR4 7UQ, UK.,

    Michael P. Frenneaux

  3. Mark V. Sherrid is at New York University School of Medicine, Skirball 9N, 530 First Avenue, New York City, New York 10543, USA.,

    Mark V. Sherrid

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All the authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

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M.P.F. is the inventor of method of use patents for perhexiline in heart muscle diseases; these patents are owned by Heart Metabolics in which he has no financial interest. M.V.S. has provided protocol consultation to Heart Metabolics. J.O.M.O. declares no competing interests.

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Ormerod, J., Frenneaux, M. & Sherrid, M. Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy. Nat Rev Cardiol 13, 677–687 (2016). https://doi.org/10.1038/nrcardio.2016.98

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