Regression of cardiac hypertrophy in health and disease: mechanisms and therapeutic potential

Abstract

Left ventricular hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Although reverse ventricular remodelling was long thought to be irreversible, evidence from the past three decades indicates that this process is possible with many existing heart disease therapies. The regression of pathological hypertrophy is associated with improved cardiac function, quality of life and long-term health outcomes. However, less than 50% of patients respond favourably to most therapies, and the reversibility of remodelling is influenced by many factors, including age, sex, BMI and disease aetiology. Cardiac hypertrophy also occurs in physiological settings, including pregnancy and exercise, although in these cases, hypertrophy is associated with normal or improved ventricular function and is completely reversible postpartum or with cessation of training. Studies over the past decade have identified the molecular features of hypertrophy regression in health and disease settings, which include modulation of protein synthesis, microRNAs, metabolism and protein degradation pathways. In this Review, we summarize the evidence for hypertrophy regression in patients with current first-line pharmacological and surgical interventions. We further discuss the molecular features of reverse remodelling identified in cell and animal models, highlighting remaining knowledge gaps and the essential questions for future investigation towards the goal of designing specific therapies to promote regression of pathological hypertrophy.

Fig. 1 |. Cellular signalling pathways of physiological and pathological hypertrophy.

a, Cellular pathways of physiological hypertrophy. Insulin or insulin-like growth factor 1 (IGF1) bind to the insulin receptor or IGF1 receptor (IGF1R), respectively, and activate RAS–mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)–AKT pathways, which promote cell survival and growth and protein synthesis. The thyroid hormones triiodothyronine (T₃) or thyroxine (T₄) also trigger the PI3K–AKT pathway and cause increased transcription of MHY6 and SERCA2A. The PI3K–AKT pathway inhibits CCAAT/enhancer-binding protein-β (C/EBPβ), glycogen synthase kinase 3β (GSK3β), forkhead box protein O1 (FOXO1) and FOXO3, all of which are negative regulators of hypertrophy. b, Cellular pathways of pathological hypertrophy. Catecholamines, angiotensin II (Ang II) and endothelin 1 (ET-1) trigger pathways that promote maladaptive gene expression and growth. Catecholamines and Ang II–ET-1 activate the downstream effectors calcineurin and calcium–calmodulin-dependent protein kinase II (CaMKII), which stimulate the transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2A (MEF2A), responsible for pathological growth. G protein-coupled receptor kinases (GRKs) mediate adrenergic receptor (AR) desensitization and promote pathological hypertrophy by inhibiting histone deacetylases (HDACs). Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) typically inhibit NFAT, MEF2A and transient receptor potential canonical channel (TRPC) but in heart failure, their receptors become desensitized. Increased neprilysin activity in heart failure triggers degradation of circulating BNP levels, further repressing natriuresis. Additionally, phosphodiesterases (PDEs) inhibit cGMP production resulting in maladaptive gene expression. AC, adenylyl cyclase; AT1R, angiotensin II type 1 receptor; EPAC, exchange protein directly activated by cAMP; GC, guanylate cyclase; GRB2, growth factor receptor-bound protein 2; IRS, insulin receptor substrate; JNK, JUN N-terminal kinase; MEK, MAP/ERK kinase; mTOR, mechanistic target of rapamycin; NPR, natriuretic peptide receptor; PKA, protein kinase A; PKG, protein kinase G; PLC, phospholipase C; TLR, Toll-like receptor; TRIF, TIR domain-containing adapter molecule 1; TR, thyroid hormone receptor.

Fig. 2 |. Molecular features of hypertrophy regression with mechanical unloading.

Mechanical unloading induced by left ventricular (LV) assist device (LVAD) therapy alters cardiomyocyte metabolism, protein turnover, gene expression and contractility as well as immune responses. Before LVAD therapy (red boxes), hypertrophic cardiomyocytes have immature phenotypes, such as increased glucose metabolism and a fetal gene expression pattern. Heart failure also causes desensitization of β-adrenergic receptors (β-AR) in cardiomyocytes. After LVAD therapy (blue boxes), β-AR responsiveness is restored, resulting in increased contractility and transcription of genes encoding calcium-handling proteins. The pentose phosphate pathway (PPP), oxidative phosphorylation through the electron transport chain, and one-carbon metabolism increase with LVAD treatment, resulting in the generation of nicotinamide adenine dinucleotide (NADH), a by-product that participates in other metabolic pathways and protects against oxidative damage. The ubiquitin–proteasome system (UPS) as well as the calpain protein degradation pathways become upregulated after LVAD treatment; however, autophagy activation and gene expression have been observed either to increase or to decrease. Altogether, these molecular changes result in decreased fibrosis and LV mass and volume as well as increased ejection fraction and contractility. AC, adenylyl cyclase; G6P, glucose-6-phosphate; MMP, matrix metalloproteinase; PKA, protein kinase A; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Fig. 3 |. Molecular features of cardiac atrophy.

Atrophy can be initiated by an increase in the circulating levels of certain factors (such as myostatin, activin A and inflammatory cytokines) and/or increased cellular oxidative stress. Myostatin and activin A bind to the activin receptor type 2B (ACVR2B), which stimulates downstream SMAD2 and SMAD3 signalling. SMAD2 and SMAD3 inhibit pro-growth pathways (AKT and mechanistic target of rapamycin (mTOR) pathways) and activate FOXO transcription factors, which translocate to the nucleus and increase the expression of genes related to autophagy and the ubiquitin–proteasome system (UPS). Inflammatory cytokines (such as tumour necrosis factor) activate the p38 and JUN N-terminal kinase (JNK) MAP kinase pathways and nuclear factor-κB (NF-κB), which stimulate atrophic-related gene expression patterns and protein degradation. Increased intracellular levels of reactive oxygen species (ROS) act on similar pathways, while also causing the translocation of apoptosis regulator BAX and BH3-interacting domain death agonist (BID) to the mitochondria, leading to mitochondrial dysfunction and triggering apoptosis through apoptosis-inducing factor mitochondria associated 1 (AIFM1; also known as AIF) and cytochrome c–caspase 3 signalling. ROS also inhibit growth pathways and promote FOXO-dependent degradation by activating the E3 ubiquitin protein ligase CBL-B, which mediates insulin receptor substrate 1 (IRS1) degradation and thus represses downstream AKT signalling. Calpain activation owing to increased intracellular calcium levels in cardiac atrophy also triggers proteolysis, mitochondrial dysfunction and (in some instances; dashed line) apoptosis. ASK1, apoptosis signal-regulating kinase 1; GSK3β, glycogen synthase kinase 3β; IL-1R, IL-1 receptor; IκBα, NF-κB inhibitor-α; IKK, inhibitor of nuclear factor-κB kinase; TNFR, tumour necrosis factor receptor.