Maintenance of protein quality control is a critical function of the ubiquitin proteasome system (UPS). Evidence is rapidly mounting to link proteasome dysfunction with a multitude of cardiac ...diseases, including ischemia, reperfusion, atherosclerosis, hypertrophy, heart failure, and cardiomyopathies. Recent studies have demonstrated a remarkable level of complexity in the regulation of the UPS in the heart and suggest that our understanding of how UPS dysfunction might contribute to the pathophysiology of such a wide range of cardiac afflictions is still very limited. Whereas experimental systems, including animal models, are invaluable for exploring mechanisms and establishing pathogenicity of UPS dysfunction in cardiac disease, studies using human heart tissue provide a vital adjunct for establishing clinical relevance of experimental findings and promoting new hypotheses. Accordingly, this review will focus on UPS dysfunction in human dilated and hypertrophic cardiomyopathies and highlight areas rich for further study in this expanding field.
Myosin modulators are a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardiomyopathies. The therapeutic goal of these drugs is to target cardiac ...myosins directly to modulate contractility and cardiac power output to alleviate symptoms that lead to heart failure and arrhythmias, without altering calcium signaling. In this Review, we discuss two classes of drugs that have been developed to either activate (omecamtiv mecarbil) or inhibit (mavacamten) cardiac contractility by binding to β-cardiac myosin (MYH7). We discuss progress in understanding the mechanisms by which the drugs alter myosin mechanochemistry, and we provide an appraisal of the results from clinical trials of these drugs, with consideration for the importance of disease heterogeneity and genetic etiology for predicting treatment benefit.
BACKGROUND:Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart ...and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.
METHODS:We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias.
RESULTS:Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM.
CONCLUSIONS:Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.
AIMThis executive summary of the hypertrophic cardiomyopathy clinical practice guideline provides recommendations and algorithms for clinicians to diagnose and manage hypertrophic cardiomyopathy in ...adult and pediatric patients as well as supporting documentation to encourage their use.
METHODSA comprehensive literature search was conducted from January 1, 2010, to April 30, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases.
STRUCTUREMany recommendations from the earlier hypertrophic cardiomyopathy guidelines have been updated with new evidence or a better understanding of earlier evidence. This summary operationalizes the recommendations from the full guideline and presents a combination of diagnostic work-up, genetic and family screening, risk stratification approaches, lifestyle modifications, surgical and catheter interventions, and medications that constitute components of guideline directed medical therapy. For both guideline-directed medical therapy and other recommended drug treatment regimens, the reader is advised to follow dosing, contraindications and drug-drug interactions based on product insert materials.
BACKGROUND:A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient ...management and outcomes. The SHaRe registry (Sarcomeric Human Cardiomyopathy Registry) was established to provide the scale of data required to address these issues, aggregating longitudinal data sets curated by 8 international HCM specialty centers.
METHODS:Data on 4591 patients with HCM (2763 genotyped) followed up for a mean of 5.4±6.9 years (24 791 patient-years; median, 2.9 years; interquartile range, 0.3–7.9 years) were analyzed for cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association functional class III/IV symptoms (all making up the overall composite end point), and left ventricular ejection fraction <35%. Outcomes were analyzed individually and as composite end points.
RESULTS:Median age at diagnosis was 45.8 (interquartile range, 30.9–58.1) years, and 37% of patients were female. Age at diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% (95% CI, 72–80) cumulative incidence of the overall composite outcome by 60 years of age compared with 32% (95% CI, 29–36) by 70 years of age for patients diagnosed at >60 years old. Young patients with HCM (age, 20–29 years) had 4-fold higher mortality than the general US population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had a 2-fold greater risk for adverse outcomes compared with patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% (95% CI, 23–40) of patients <40 years of age at diagnosis but in 1% (95% CI, 1–2) of those >60 years old at diagnosis.
CONCLUSIONS:The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years after diagnosis. Young age at diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.
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