Myocardial Recovery

Abstract

In this paper, the feasibility of myocardial recovery is analyzed through a literature review. First, the phenomena of remodeling and reverse remodeling are analyzed, approached through the physics of elastic bodies, and the terms myocardial depression and myocardial recovery are defined. Continuing, potential biochemical, molecular, and imaging markers of myocardial recovery are reviewed. Then, the work focuses on therapeutic techniques that can facilitate the reverse remodeling of the myocardium. Left ventricular assist device (LVAD) systems are one of the main ways to promote cardiac recovery. The changes that take place in cardiac hypertrophy, extracellular matrix, cell populations and their structural elements, β-receptors, energetics, and several biological processes, are reviewed. The attempt to wean the patients who experienced cardiac recovery from cardiac assist device systems is also discussed. The characteristics of the patients who will benefit from LVAD are presented and the heterogeneity of the studies performed in terms of patient populations included, diagnostic tests performed, and their results are addressed. The experience with cardiac resynchronization therapy (CRT) as another way to promote reverse remodeling is also reviewed. Myocardial recovery is a phenomenon that presents with a continuous spectrum of phenotypes. There is a need for algorithms to screen suitable patients who may benefit and identify specific ways to enhance this phenomenon in order to help combat the heart failure epidemic.

Keywords: cardiac resynchronization therapy; left ventricular assist devices; markers; recovery; remodeling.

Figure 1

(A) A material, when an increasing stress is applied to it, can increase its length up to a certain point and, when the applied stress is stopped, it can return to its original state without affecting its structure (elastic deformation). From this point onwards, the material will partially return to its original state as permanent structural changes are created in its structure (plastic deformation). (B,C) Myocardial tissue shows a similar behavior. When tension is exerted on the myocardial wall, the damage it will suffer can be either permanent or reversible, in whole or in part, depending on the damage and its duration. (D) The three factors that will determine the evolution of myocardial functionality are (1) its macroscopic geometry, (2) the cardiomyocyte and (3) the extracellular matrix. The clinical impact that the degree of remodeling will have concerns two possible outcomes, myocardial remission and myocardial recovery. Abbreviations: C, cardiac myocyte; M, extracellular matrix; LV, left ventricle. Reprinted with permission from Mann DL, et al., (2012), Copyright © 2012, American College of Cardiology Foundation. Published by Elsevier Inc. Ref. [1].

Figure 2

(A,B): The changes in the mRNAs of COLIAN1, TGF1β, in which no statistical difference is observed before and after the removal of the LVAD. (C,D): The changes in the mRNAs of THY1 and TIMP4, where there is a statistically significant difference between the patients who recovered and those who did not. (E–H): mRNA expression of COL1A1, COL3A1, FN and THY1 after LVAD removal was negatively correlated with ejection fraction. Reprinted with permission from Felkin LE, et al., (2009), Copyright © 2009 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. Ref. [19].

Figure 3

After LVAD placement (A): cell size and (B): capacitance (an index of cell surface area), tend to return to normal donor values, indicating reversal of hypertrophy. (C): No increase in the contraction-frequency-dependent relationship was observed in patient cells with or after LVAD use in contrast to donor cells. As a result, the researchers hypothesized the involvement of calcium transport mechanisms as responsible for the improvement in contraction. (D): LVAD-implanted HF patients show reduced calcium current amplitude compared to LVAD-removal patients and no-difference compared to donors. After LVAD removal there is an increase in the amount of calcium observed compared to heart failure patients and donors. The LVAD increases the amplitude of the calcium current and its quantity, improving the excitation-contraction relationship of the cardiomyocyte, being a mechanism for promoting cardiac recovery. * p < 0.05; ** p < 0.01; LVAD core: left ventricular tissue taken at LVAD implant; post LVAD: left ventricular tissue taken at LVAD removal. Reprinted with permission from Terracciano CMN, et al., (2003), Copyright © 2003, Oxford University Press [27].

Figure 4

Extrapolating the lessons learned from patients with ventricular assist devices to the broader heart failure population. Reprinted with permission from Taleb I, et al., (2022), Copyright © 2022, Wolters Kluwer Health [65].

Figure 5

Heart failure (HF) is a spectrum of phenotypes. Each HF phenotype is the result of a patient-specific trajectory wherein the heart remodels towards concentric hypertrophy, eccentric hypertrophy or a combination of both. The way of entry and the subsequent path of the trajectory depend on the patient’s risk factors, comorbidities and disease modifiers (genome, proteome, metabolome). Both pharmaceutical treatment (i.e., β-blocker, ARNI/ACE-i/ARB, MRA, SGLT-2 inhibitor, diuretic) and device therapy (i.e., cardiac resynchronization therapy, left ventricular assist devices) may lead to reverse remodeling. Abbreviations: ARNI, angiotensin receptor-neprilysin inhibitor; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; MRA, mineralocorticoid receptor antagonists; SGLT2-inhibitor, sodium-glucose Cotransporter 2-nhibitor; CRT, cardiac resynchronization therapy; GDMT, guideline medical therapy.