Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

Abstract

Pharmacotherapy has been serving as an effective treatment for HFs to improve symptom, functional capacity, quality of life, and to reduce the frequency of hospitalizations. [8] However, it differs in each HF subtype. Traditionally, angiotensin converting enzyme inhibitors (ACEIs), mineralocorticoid receptor antagonists (MRAs), and β-blockers are typical treatments for HFrEF. Since many hospitalizations and deaths in HFpEF patients are due to noncardiovascular causes, pharmacotherapy mainly focus on relieving of symptoms and easing comorbidities for HFpEF patients.HFpEF with a prevalence range from 31% to 55% has received most attention recently from the clinical and research field [4,9,10] due to lack of effective pharmacological treatment options. Although cardiac regenerative therapeutics have been widely studied in the past two decades [11] for treating both HFrEF and HFpEF, the treatment mechanisms and associated intrinsic cardiac remodeling process are nonspecific to each HF subtype. Besides, additional mechanisms such as metabolic disorders, proinflammatory conditions, and immunologic remodeling also influenced the prognosis of different HFs. [12] In this review, we summarized pathological cardiac remodeling, associated immune reactions, and signaling pathways for HF in general, and discussed the challenges that hamper clinical translation of regenerative therapeutics which holds diagnostic and therapeutic potential. This review helps to reveal the underlying mechanisms that may lead us to generate new clinical-feasible treatment for HFpEF in the future. [13][14][15][16][17][18] Signaling during HF Progression HF ProgressionThe growth of cardiomyocytes occurs in both physiological and pathological hypertrophy. [19] Physiologically, hemodynamic load stimulates normal, postnatal, pregnancy, and exercise-induced cardiac growth. [19] Pathologically, the stimulation from HF risk factors increases heart size, mass, or geometry. In the progression of HF, multiple molecular mechanisms associated with cardiomyocyte survival, death, energy metabolism, oxidative stress, inflammation, calcium transport and neurohormonal activation led to loss of functional cardiomyocytes, development of fibrosis, left ventricular remodeling, and HF prognosis. [20] Heart failure (HF) is one of the leading causes for hospital admissions worldwide. HF patients are classified based on the chronic changes in left ventricular ejection fraction (LVEF) as preserved (LVEF ≥ 50%), reduced (LVEF ≤ 40%), or mid-ranged (40% < LVEF < 50%) HFs. Treatments nowadays can prevent HFrEF progress, whereas only a few of the treatments have been proven to be effective in improving the survival of HFpEF. In this review, numerous mediators involved in the pathogenesis of HF are summarized. The regional upstream signaling and their diagnostic and therapeutic potential are also discussed. Additionally, the recent challenges and development in cardiac regenerative therapy that hold opportunities for future research and clinical translation are discussed.