Myofilament dysfunction as an emerging mechanism of volume overload heart failure

Abstract

Two main hemodynamic overload mechanisms [i.e., volume and pressure overload (VO and PO, respectively] result in heart failure (HF), and these two mechanisms have divergent pathologic alterations and different pathophysiological mechanisms. Extensive evidence from animal models and human studies of PO demonstrate a clear association with alterations in Ca(2+) homeostasis. By contrast, emerging evidence from animal models and patients with regurgitant valve disease and dilated cardiomyopathy point toward a more prominent role of myofilament dysfunction. With respect to VO HF, key features of excitation-contraction coupling defects, myofilament dysfunction, and extracellular matrix composition will be discussed.

Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes

“…In pressure-overload activation of the Akt/mTOR signaling cascade is enhanced with hyperglycemia (Hernandez et al, 2013), but this pathway was not found to be upregulated in highfructose aortic regurgitation (Bouchard-Thomassin et al, 2011). However, aortic-regurgitation does not produce pure volumeoverload (Wilson and Lucchesi, 2014), and others have reported that activation of Akt/mTORC1 pathway has a central role in promoting eccentric hypertrophy in aorto-caval shunts with the level of pathway activation being a function of LV end-diastolic stress (Ikeda et al, 2015) (Figure 4).…”

“…The extracellular matrix (ECM) regulates contractile performance via direct manipulation of myocardial stiffness as well as by coordinating myocardial remodeling (Baharvand et al, 2005). In volume-overload, ECM is degraded with reductions in collagen fractional volume, and increases in elastin (Ryan et al, 2007;Wilson and Lucchesi, 2014;Hutchinson et al, 2015). Collagen reductions occur due to increased matrix metalloproteinases (MMPs) activity and a concurrent decrease in their inhibitors, tissue inhibitors of MMPs (TIMPs) (Levick et al, 2008;Wilson and Lucchesi, 2014).…”

“…In volume-overload, ECM is degraded with reductions in collagen fractional volume, and increases in elastin (Ryan et al, 2007;Wilson and Lucchesi, 2014;Hutchinson et al, 2015). Collagen reductions occur due to increased matrix metalloproteinases (MMPs) activity and a concurrent decrease in their inhibitors, tissue inhibitors of MMPs (TIMPs) (Levick et al, 2008;Wilson and Lucchesi, 2014). This is in stark contrast to pressure-overload, whereby increased collage synthesis occurs (Bishop et al, 1994) and is associated with perivascular fibrosis (Toischer et al, 2010).…”

The contributions of cardiac myosin binding protein C and troponin I phosphorylation to β‐adrenergic enhancement of in vivo cardiac function

“…A central feature of heart failure (HF) is contractile dysfunction (either systolic or diastolic) accompanied by ventricular wall remodelling (Hamdani et al . ; van der Velden, ; Wilson & Lucchesi, ) and impaired β‐adrenergic signalling that disrupts downstream protein phosphorylation (Post et al . ).…”

Remodelamento das proteínas contráteis cardíacas na transição da hipertrofia compensada para falência cardíaca

“…A seguir, a cabeça da miosina de cadeia pesada (MCP) liga-se ao ATP e ao sofrer hidrólise (ADP+Pi), a miosina adquire grande afinidade pela actina, deslizando pelo filamento fino, o que causa a contração do miocárdio. Após a liberação do Pi, um novo ciclo de pontes cruzadas é formado (Boron;Boulpaep, 2008;Wilson;Lucchesi, 2014).…”