The role of regenerative therapy in the treatment of right ventricular failure: a literature review

Abstract

Right ventricular (RV) failure is a commonly encountered problem in patients with congenital heart disease but can also be a consequence of left ventricular disease, primary pulmonary hypertension, or RV-specific cardiomyopathies. Improved survival of the aforementioned pathologies has led to increasing numbers of patients suffering from RV dysfunction, making it a key contributor to morbidity and mortality in this population. Currently available therapies for heart failure were developed for the left ventricle (LV), and there is clear evidence that LV-specific strategies are insufficient or inadequate for the RV. New therapeutic strategies are needed to address this growing clinical problem, and stem cells show significant promise. However, to properly evaluate the prospects of a potential stem cell-based therapy for RV failure, one needs to understand the unique pathophysiology of RV dysfunction and carefully consider available data from animal models and human clinical trials. In this review, we provide a comprehensive overview of the molecular mechanisms involved in RV failure such as hypertrophy, fibrosis, inflammation, changes in energy metabolism, calcium handling, decreasing RV contractility, and apoptosis. We also summarize the available preclinical and clinical experience with RV-specific stem cell therapies, covering the broad spectrum of stem cell sources used to date. We describe two different scientific rationales for stem cell transplantation, one of which seeks to add contractile units to the failing myocardium, while the other aims to augment endogenous repair mechanisms and/or attenuate harmful remodeling. We emphasize the limitations and challenges of regenerative strategies, but also highlight the characteristics of the failing RV myocardium that make it a promising target for stem cell therapy.

Autologous skeletal myoblast patch implantation prevents the deterioration of myocardial ischemia and right heart dysfunction in a pressure-overloaded right heart porcine model

“…However, the MVO 2 was increased by hypertrophic changes in the ventricular cardiomyocytes in a pressure-overloaded right heart [43,[49][50][51]. Under these conditions, the RV cardiomyocytes, which were originally poorly resistant to ischemia [8,12,13], were in seriously ischemic conditions. The metabolic remodeling in cardiomyocytes owing to increased oxidative stress, due to the ischemic conditions of a pressure-overloaded RV, can cause various reactions, such as inflammation, apoptosis, and fibrosis, leading to RV dysfunction [8,12,13].…”

“…Under these conditions, the RV cardiomyocytes, which were originally poorly resistant to ischemia [8,12,13], were in seriously ischemic conditions. The metabolic remodeling in cardiomyocytes owing to increased oxidative stress, due to the ischemic conditions of a pressure-overloaded RV, can cause various reactions, such as inflammation, apoptosis, and fibrosis, leading to RV dysfunction [8,12,13]. Based on these conditions of the pressure-overloaded RV myocardium, the main therapeutic mechanism in autologous skeletal myoblast patch implantation therapy-angiogenesis-may be effective for pressure-overloaded right heart failure.…”

“…In the initial stage of pressure-overloaded right heart failure, compensatory mechanisms such as volume dilatation and hypertrophic change work to maintain the RV function in a hyperdynamic state [8,12,13]. In this stage, the myocardial oxidative metabolism improves, and coronary flow reserve can be secured [43,[49][50][51]58,59].…”

“…In this stage, the myocardial oxidative metabolism improves, and coronary flow reserve can be secured [43,[49][50][51]58,59]. However, the prolonged pressure overload advances the metabolic remodeling of cardiomyocytes, owing to persistent mechanical stress on the myocardium and severe ischemic conditions [8,12,13,19,20]. Eventually, the right heart failure progresses to a decompensated stage with impaired RV function due to the reduction in cardiac reserve [13,[60][61][62].…”

“…However, long-term cardiac overload owing to anatomical features and residual lesions after repair leads to heart failure [4][5][6], especially right heart failure [7,8], which is also known to be a predictor for poor outcomes [4,[8][9][10][11]. Myocardial ischemia is primarily associated with right ventricular dysfunction, causing right heart failure in patients with CHD [4,8,[12][13][14][15][16][17][18][19][20]. Thus, myocardial ischemia could be a potential therapeutic target for right heart failure.…”