Myosin Cross-Bridge Dynamics in Patients With Hypertension and Concentric Left Ventricular Remodeling

Abstract

Background Hypertension (HTN) causes concentric left ventricular (LV) remodeling, defined as an increased relative wall thickness or overt LV hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction (EF). It is not known if the myofilament contributes to diastolic dysfunction in patients with concentric remodeling. Methods and Results Intra-operative myocardial biopsies were obtained in 15 male patients undergoing coronary bypass grafting (CBG), all with normal LV EF and wall motion. Eight patients had a history of HTN and concentric remodeling. Seven without HTN or remodeling served as controls. Myocardial strips were dissected and demembranated with detergent. Isometric tension was measured and sinusoidal length perturbation analysis performed at sarcomere length 2.2μm and pCa 8 –4.5. Sinusoidal analysis provides estimates of cross-bridge dynamics, including rate constants of attachment and detachment and cross-bridge attachment time (ton). The normalized isometric tension-pCa relation was similar in HTN and controls. However, ton was significantly prolonged at submaximal [Ca2+] (pCa ≥ 6.5) in HTN patients. Analysis of protein phosphorylation revealed ~25% reduction in phosphorylation of troponin I in HTN patients (P < 0.05). Conclusions Compared with controls, patients with HTN and concentric remodeling display prolonged ton at submaximal [Ca2+] without a change in the tension-pCa relation. Prolonged ton implicates altered cross-bridge dynamics as a cause of slowed relaxation in these patients. This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism.

Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

“…Along with Copeland et al 12 and our report, 15 their results support the idea that changes in MyBP-C phosphorylation play a significant role in DCM and HFpEF. Understanding MyBP-C as a phosphorylation-dependent regulator of human diastolic function is important because acto-myosin cross-bridges are never fully disengaged in human myocardium during diastole.…”

“…It is important to note that our measurements of MyBP-C and TnI phosphorylation in human myocardium 15 from patients with LVH were not site-specific. If reduced MyBP-C phosphorylation plays a significant role in impaired inotropic responses and slowed/incomplete relaxation in human DCM and HFpEF, it will be important to quantify sitespecific phosphorylation in larger numbers of patients and attempt to establish cause and effect.…”

“…As in DCM, changes in titin isoforms and phosphorylation result in opposite effects on titin's stiffness, but in this case, changes in phosphorylation of titin's PKA/ PKG, as well as its PKC-α sites, are dominant and play a key role in markedly increased cardiomyocyte and myocardial passive stiffness. 7,13,14 Using permeabilized strips of human myocardium obtained from patients with hypertension and LVH and control subjects undergoing coronary bypass grafting, 15 all with normal EF, we recently reported that the crossbridge dissociation rate constant is slowed and its inverse, the cross-bridge on-time (time the cross-bridge is attached and generating force), is prolonged at submaximal [Ca 2+ ] in patients with hypertension+LVH compared with control subjects. These changes in acto-myosin dynamics serve to slow left ventricular relaxation.…”

Pro‐Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction

“…Concentric left ventricular remodeling and associated increased diastolic chamber stiffness and slowed relaxation are the rule, while increased systolic chamber and arterial stiffness are common. At the level of the myocardium, altered calcium handling,47 increased collagen content and cross‐linking48, 49 and alterations in phosphorylation of contractile proteins50 and titin29, 49 cause increased passive stiffness and slowed and incomplete myofilament relaxation. These advances in understanding the pathophysiology of HFpEF have led to attempts to more precisely phenotype the syndrome44 in an effort to better guide treatment.…”

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“…This finding was associated with reduced phosphorylation of troponin I, suggesting decreased phosphorylation of protein kinase A/G sites as a mechanism. 27 …”