Cardiomyocyte Stiffness in Diastolic Heart Failure

Abstract

Background-Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. Methods and Results-DHF patients (nϭ12) had an LVEF of 71Ϯ11%, an LV end-diastolic pressure (LVEDP) of 28Ϯ4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5Ϯ4.0%, PϽ0.05) than did controls (nϭ8, 3.8Ϯ2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.

Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation

“…This in turn may strengthen the interaction between cardiac troponin C and the switch peptide domain of cTnI, thereby inducing a reduction in myofilament Ca 2ϩ sensitivity and at the same time weaken the interaction between the IP domain and actin. PKA treatment resulted in a reduction of passive force, as has been described previously (17,51). The passive force is believed to originate from titin strain that is reduced upon PKA (or protein kinase G)-mediated phosphorylation.…”

Differential contribution of cardiac sarcomeric proteins in the myofibrillar force response to stretch

“…In general, high LDA is correlated with a high level of passive tension. This is true within the same cardiac tissue in which passive tension has been modified either by changing the pre-history of stretch before activation [12], by phosphorylation of titin with PKA [3,19], high and low passive tension between atrium and ventricle [19], or between myocytes isolated from various places of the ventricle with various cellular passive stiffness ( [9], present study). Differential titin isoform expression across the LV wall have been found in pig [6] but not in goat [37] and rat [9].…”

Roles of SIRT3 in heart failure: from bench to bedside

“…In patients with HF with preserved ejection fraction (HFPEF), the left ventricular volume is normal but the wall is thickened and the myocardial stiffness is increased (Ohtani et al, 2012). However, in patients with HF with reduced ejection fraction (HFREF), the left ventricular is dilated and its thickness is either normal or reduced (Borbely et al, 2005). Notably, it has been demonstrated that the deletion of cardiomyocytes ultimately leads to HF (Olivetti et al, 1997).…”