Manipulation of sarcoplasmic reticulum Ca²⁺ release in heart failure through mechanical intervention

Abstract

Left ventricular assist devices (LVADs) were developed as a means of temporary circulatory support, but the mechanical unloading they offer also results in significant reverse remodelling. In selected patients, these improvements are sufficient to allow ultimate device explantation without requiring transplantation; this represents a fundamental shift in our understanding of heart failure. Like heart failure itself, LVADs influence multiple biological systems. The transverse tubules are a system of membrane invaginations in ventricular cardiomyocytes which allow rapid propagation of the action potential throughout the cell. Through their dense concentration of L-type Ca 2+ channels in close proximity to intracellular ryanodine receptors, the t-tubules enable synchronous Ca 2+ release throughout the cell. The t-tubules' structure appears to be specifically regulated by mechanical load, such that either the overload of heart failure (or the spontaneously hypertensive rat model) or the profound unloading in a chronically unloaded heart result in impaired t-tubule structure, with ineffective Ca 2+ release. While there are multiple molecular pathways which underpin t-tubule regulation, Telethonin (Tcap) appears to be important in regulating the effect of altered loading on the t-tubule system.

Isovolumic loading of the failing heart by intraventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation

“…First, they support our main thesis that cardiac atrophy is the most serious harmful effect of prolonged mechanical unloading which, even in the face of the sound evidence on molecular and structural ‘reverse remodeling’ after LVAD application [ 4 , 6 , 11 , 15 , 30 ], could limit successful outcomes of such treatment in terms of functional cardiac recovery and possible weaning from LVAD treatment.…”

“…Unfortunately, prolonged LVAD support was reported to induce cardiac atrophy, probably the main harmful effect in such treated patients. Most probably, cardiac atrophy underlies the lack of significant myocardial function improvement in LVAD patients, even though their hearts exhibit molecular, functional, and structural signs of reverse remodeling [ 4 , 6 , 11–15 ]. None of the approaches aimed at minimizing this detrimental effect proved successful.…”

Effects of Increased Myocardial Tissue Concentration of Myristic, Palmitic and Palmitoleic Acids on the Course of Cardiac atrophy of the Failing Heart Unloaded by Heterotopic Transplantation

“…In addition, we found that the diet-induced increases in myocardial concentration of myristic, palmitic and palmitoleic acids did not alter the pattern of the LV gene expression, similarly in healthy and failing hearts after HT x . This is important because, initially, after the discovery that the remodeling process of the atrophied or hypertrophied heart includes a return to the "fetal gene program" (Depre et al 1998, Depre et al 1999, Taegtmeyer et al 2010, the dominant view has been that a return to the fetal gene program is detrimental and a hallmark of progressive deterioration in cardiac functions (Bloomekatz et al 2016, Ibrahim et al 2015, Soppa et al 2008. In accordance with this claim it was even distinguished between "physiological" and "pathological" hypertrophy (Dorn 2007, Lee et al 2016.…”

“…in patients with advanced HF waiting for cardiac transplantation (Braunwald 2015, Drakos et al 2016, McLarty 2015. Until recently it was believed that adverse cellular, structural and functional changes in the myocardium of patients with HF ("remodeling process"), are progressive and irreversible (Braunwald 2015, Ibrahim et al 2015. However, this belief has been shown to be inaccurate, Vol.…”

“…However, this belief has been shown to be inaccurate, Vol. 67 because some clinical studies in HF patients after LVAD implantation indicated that long-term unloading leads to near-normalization of almost all structural and functional abnormalities of the failing myocardium, a process termed reverse remodeling (Biks 2013, Drakos et al 2016, Chaggar et al 2016, Ibrahim et al 2015. Therefore, several groups have proposed that LVAD could be used as a "bridge to recovery" in the sense that patients with advanced HF after some period of LVAD support should show significant improvement of cardiac function, which would eventually make it possible to withdraw LVAD support (Drakos et al 2016, Chaggar et al 2016, McLarty 2015.…”