Pathological cardiac hypertrophy is a leading risk factor for cardiovascular morbidity and mortality and is associated with increased fibrosis and apoptosis that lead to ventricular stiffness, risk of arrhythmia and impaired cardiac function. 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. In this Review, we summarize the evidence for hypertrophy regression in patients with current first-line pharmacological and surgical interventions. 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. 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. 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. The regression of pathological hypertrophy is associated with improved cardiac function, quality of life and long-term health outcomes. 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. GPCR – G-protein-coupled receptor RTK – receptor tyrosine kinase MAPKKs – mitogen-activated protein kinase kinases ROS – reactive oxygen species RyR – Ryanodine receptor PI3K – phosphoinositide-3 kinase JNK – c-Jun N-terminal kinase NFκB – nuclear factor kappa B PKC – protein kinase C Cam – calmodulin CnA – calcineurin A CnB – calcineurin B NFAT – nuclear factor of activated T-cell Akt – protein kinase B (PKB) mTOR – mammalian target of rapamycin LPS – lipopolysaccharide.Left ventricular hypertrophy is a leading risk factor for cardiovascular morbidity and mortality. Growth hormones induced by physiological cues, such as exercise or pregnancy, bind to and activate downstream signaling of RTKs, which, on the other hand, leads to adaptive hypertrophic growth. Stress signals can trigger the activation MAP kinase cascades, which activate a number of downstream targets such as JNK, finally leading to transcriptional activation. Inflammatory stimuli can exacerbate the disease condition by inducing interstitial inflammatory cell infiltration and fibrosis. ROS can contribute to hypertrophy by direct interaction with cellular proteins and subsequent changes in cellular contraction and/or induction of apoptosis, or by activation of NFκB-mediated gene transcription. Calcineurin in turn dephosphorylates NFAT transcription factor, leading to its nuclear translocation, where it activates gene transcription. Elevated calcium ion levels downstream of GPCRs, either through activation of voltage-gated calcium channels or from intracellular stores, is sensed by calmodulin, which activates calcineurin. Diagrammatic representation of main intracellular signaling pathways regulating cardiac hypertrophy.
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