-
Nature Reviews. Cardiology Jun 2022Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated... (Review)
Review
Variants in >12 genes encoding sarcomeric proteins can cause various cardiomyopathies. The two most common are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Current therapeutics do not target the root causes of these diseases, but attempt to prevent disease progression and/or to manage symptoms. Accordingly, novel approaches are being developed to treat the cardiac muscle dysfunction directly. Challenges to developing therapeutics for these diseases include the diverse mechanisms of pathogenesis, some of which are still being debated and defined. Four small molecules that modulate the myosin motor protein in the cardiac sarcomere have shown great promise in the settings of HCM and DCM, regardless of the underlying genetic pathogenesis, and similar approaches are being developed to target other components of the sarcomere. In the setting of HCM, mavacamten and aficamten bind to the myosin motor and decrease the ATPase activity of myosin. In the setting of DCM, omecamtiv mecarbil and danicamtiv increase myosin activity in cardiac muscle (but omecamtiv mecarbil decreases myosin activity in vitro). In this Review, we discuss the therapeutic strategies to alter sarcomere contractile activity and summarize the data indicating that targeting one protein in the sarcomere can be effective in treating patients with genetic variants in other sarcomeric proteins, as well as in patients with non-sarcomere-based disease.
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Mutation; Myocardium; Myosins; Sarcomeres
PubMed: 35304599
DOI: 10.1038/s41569-022-00682-0 -
European Heart Journal Nov 2019Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive...
Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.
Topics: Acute Disease; Animals; Antioxidants; Calcium; Cardiotonic Agents; Case-Control Studies; Catecholamines; Clinical Trials as Topic; Diastole; Dobutamine; Dogs; Energy Metabolism; Excitation Contraction Coupling; Heart Failure; Humans; Mitochondria; Models, Animal; Myocardial Contraction; Nitrogen Oxides; Oxidation-Reduction; Phosphodiesterase Inhibitors; Placebos; Receptors, Adrenergic; Sarcomeres; Shock, Cardiogenic; Simendan; Swine; Systole; Urea
PubMed: 30295807
DOI: 10.1093/eurheartj/ehy600 -
Neuromuscular Disorders : NMD Oct 2021The nemaline myopathies constitute a large proportion of the congenital or structural myopathies. Common to all patients is muscle weakness and the presence in the... (Review)
Review
The nemaline myopathies constitute a large proportion of the congenital or structural myopathies. Common to all patients is muscle weakness and the presence in the muscle biopsy of nemaline rods. The causative genes are at least twelve, encoding structural or regulatory proteins of the thin filament, and the clinical picture as well as the histological appearance on muscle biopsy vary widely. Here, we suggest a renewed clinical classification to replace the original one, summarise what is known about the pathogenesis from mutations in each causative gene to the forms of nemaline myopathy described to date, and provide perspectives on pathogenetic mechanisms possibly open to therapeutic modalities.
Topics: Actins; Biopsy; Humans; Muscle Proteins; Muscle Weakness; Muscle, Skeletal; Mutation; Myopathies, Nemaline; Sarcomeres
PubMed: 34561123
DOI: 10.1016/j.nmd.2021.07.012 -
Nature Genetics Feb 2021Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic...
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.
Topics: Adolescent; Adult; Aged; Blood Pressure; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Carrier Proteins; Case-Control Studies; Formins; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Humans; Middle Aged; Myosin Heavy Chains; Polymorphism, Single Nucleotide; Risk Factors; Sarcomeres; Young Adult
PubMed: 33495597
DOI: 10.1038/s41588-020-00764-0 -
Circulation Research May 2021Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction....
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetrical, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray, and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. and , encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ≈40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ≈5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category, PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years, the yield of the genetic testing is expected to be improved and the so-called missing causal gene be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.
Topics: Calcium; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Carrier Proteins; Death, Sudden, Cardiac; Genetic Testing; Homeostasis; Humans; Hypertrophy, Left Ventricular; Mutation; Myosin Heavy Chains; Myosin Light Chains; Penetrance; Phenotype; Sarcomeres; Stroke Volume; Ventricular Outflow Obstruction
PubMed: 33983830
DOI: 10.1161/CIRCRESAHA.121.318346 -
Cell Apr 2021Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health...
Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing. Structures of myosin, tropomyosin, and actin at ~10 Å further reveal two conformations of the "double-head" myosin, where the flexible orientation of the lever arm and light chains enable myosin not only to interact with the same actin filament, but also to split between two actin filaments. Our results provide unexpected insights into the fundamental organization of vertebrate skeletal muscle and serve as a strong foundation for future investigations of muscle diseases.
Topics: Actin Cytoskeleton; Actinin; Actomyosin; Animals; Cryoelectron Microscopy; Female; Mice; Mice, Inbred BALB C; Models, Molecular; Muscle, Skeletal; Protein Binding; Sarcomeres; Tropomyosin
PubMed: 33765442
DOI: 10.1016/j.cell.2021.02.047 -
Journal of the American Heart... Jan 2022Background Pediatric dilated cardiomyopathy (DCM) is a well-known clinical entity; however, phenotype-genotype correlations are inadequately described. Our objective was...
Background Pediatric dilated cardiomyopathy (DCM) is a well-known clinical entity; however, phenotype-genotype correlations are inadequately described. Our objective was to provide genotype associations with life-threatening cardiac outcomes in pediatric DCM probands. Methods and Results We performed a retrospective review of children with DCM at a large pediatric referral center (2007-2016), excluding syndromic, chemotherapy-induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life-threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, =0.21). truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, =0.01), but life-threatening cardiac outcomes occurred in both infants and teenagers with these variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with variants between amino acids 1 and 600. Conclusions Sarcomeric variants were common in pediatric DCM. We demonstrated genotype-specific associations with age of diagnosis and cardiac outcomes. In particular, had domain-specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.
Topics: Adolescent; Cardiomyopathy, Dilated; Child; Genetic Association Studies; Genetic Testing; Genotype; Humans; Mutation; Sarcomeres
PubMed: 34935411
DOI: 10.1161/JAHA.121.022854 -
Circulation Mar 2020Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy...
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.
Topics: Adenosine Triphosphatases; Animals; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Cells, Cultured; Energy Metabolism; Humans; Induced Pluripotent Stem Cells; Mice; Molecular Dynamics Simulation; Muscle Relaxation; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Myosin Heavy Chains; Protein Conformation; Sarcomeres
PubMed: 31983222
DOI: 10.1161/CIRCULATIONAHA.119.042339 -
International Journal of Molecular... Nov 2019Muscular contraction is a fundamental phenomenon in all animals; without it life as we know it would be impossible. The basic mechanism in muscle, including heart... (Review)
Review
Muscular contraction is a fundamental phenomenon in all animals; without it life as we know it would be impossible. The basic mechanism in muscle, including heart muscle, involves the interaction of the protein filaments myosin and actin. Motility in all cells is also partly based on similar interactions of actin filaments with non-muscle myosins. Early studies of muscle contraction have informed later studies of these cellular actin-myosin systems. In muscles, projections on the myosin filaments, the so-called myosin heads or cross-bridges, interact with the nearby actin filaments and, in a mechanism powered by ATP-hydrolysis, they move the actin filaments past them in a kind of cyclic rowing action to produce the macroscopic muscular movements of which we are all aware. In this special issue the papers and reviews address different aspects of the actin-myosin interaction in muscle as studied by a plethora of complementary techniques. The present overview provides a brief and elementary introduction to muscle structure and function and the techniques used to study it. It goes on to give more detailed descriptions of what is known about muscle components and the cross-bridge cycle using structural biology techniques, particularly protein crystallography, electron microscopy and X-ray diffraction. It then has a quick look at muscle mechanics and it summarises what can be learnt about how muscle works based on the other studies covered in the different papers in the special issue. A picture emerges of the main molecular steps involved in the force-producing process; steps that are also likely to be seen in non-muscle myosin interactions with cellular actin filaments. Finally, the remarkable advances made in studying the effects of mutations in the contractile assembly in causing specific muscle diseases, particularly those in heart muscle, are outlined and discussed.
Topics: Actins; Animals; Humans; Models, Biological; Muscle Contraction; Muscle, Striated; Muscles; Myosins; Protein Binding; Sarcomeres; Structure-Activity Relationship
PubMed: 31739584
DOI: 10.3390/ijms20225715 -
Cell Reports May 2022Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that is characterized by unexplained segmental hypertrophy that is usually most pronounced in the septum....
Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that is characterized by unexplained segmental hypertrophy that is usually most pronounced in the septum. While sarcomeric gene mutations are often the genetic basis for HCM, the mechanistic origin for the heterogeneous remodeling remains largely unknown. A better understanding of the gene networks driving the cardiomyocyte (CM) hypertrophy is required to improve therapeutic strategies. Patients suffering from HCM often receive a septal myectomy surgery to relieve outflow tract obstruction due to hypertrophy. Using single-cell RNA sequencing (scRNA-seq) on septal myectomy samples from patients with HCM, we identify functional links between genes, transcription factors, and cell size relevant for HCM. The data show the utility of using scRNA-seq on the human hypertrophic heart, highlight CM heterogeneity, and provide a wealth of insights into molecular events involved in HCM that can eventually contribute to the development of enhanced therapies.
Topics: Cardiomyopathy, Hypertrophic; Heart Defects, Congenital; Humans; Hypertrophy; Sarcomeres; Transcriptome
PubMed: 35545053
DOI: 10.1016/j.celrep.2022.110809