Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and defined by unexplained isolated progressive myocardial hypertrophy, systolic and diastolic ventricular dysfunction, arrhythmias, sudden cardiac death and histopathologic changes, such as myocyte disarray and myocardial fibrosis. Mutations in genes encoding for proteins of the contractile apparatus of the cardiomyocyte, such as β-myosin heavy chain and myosin binding protein C, have been identified as cause of the disease. Disease is caused by altered biophysical properties of the cardiomyocyte, disturbed calcium handling, and abnormal cellular metabolism. Mutations in sarcomere genes can also activate other signaling pathways via transcriptional activation and can influence non-cardiac cells, such as fibroblasts. Additional environmental, genetic and epigenetic factors result in heterogeneous disease expression. The clinical course of the disease varies greatly with some patients presenting during childhood while others remain asymptomatic until late in life. Patients can present with either heart failure symptoms or the first symptom can be sudden death due to malignant ventricular arrhythmias. The morphological and pathological heterogeneity results in prognosis uncertainty and makes patient management challenging. Current standard therapeutic measures include the prevention of sudden death by prohibition of competitive sport participation and the implantation of cardioverter-defibrillators if indicated, as well as symptomatic heart failure therapies or cardiac transplantation. There exists no causal therapy for this monogenic autosomal-dominant inherited disorder, so that the focus of current management is on early identification of asymptomatic patients at risk through molecular diagnostic and clinical cascade screening of family members, optimal sudden death risk stratification, and timely initiation of preventative therapies to avoid disease progression to the irreversible adverse myocardial remodeling stage. Genetic diagnosis allowing identification of asymptomatic affected patients prior to clinical disease onset, new imaging technologies, and the establishment of international guidelines have optimized treatment and sudden death risk stratification lowering mortality dramatically within the last decade. However, a thorough understanding of underlying disease pathogenesis, regular clinical follow-up, family counseling, and preventative treatment is required to minimize morbidity and mortality of affected patients. This review summarizes current knowledge about molecular genetics and pathogenesis of HCM secondary to mutations in the sarcomere and provides an overview about current evidence and guidelines in clinical patient management. The overview will focus on clinical staging based on disease mechanism allowing timely initiation of preventative measures. An outlook about so far experimental treatments and potential for future therapies will be provided.

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations inCasz1,Dnajc18,Pde4dip,Rnf38orTmem161bgenes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of theDNAJC18gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.

Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator. Number and percentages of patients with CALM variants and LQTS, CPVT, LQTS/CPVT overlap, IVF, UD, and SCD are reported in the upper left part of the graphical abstract together with two examples of LQTS and CPVT electrocardiograms. In the upper right part, it is shown a graphical representation of the reduction of all cardiac events and SCD between the original cohort (up to 2019) and the cases enrolled between 2019 and 2023. In the lower part, it is reported the number or percentage of CALM patients with cardiomyopathies, congenital heart defects, and neurological features. CALM, calmodulin; LQTS, long QT syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; ICD, implantable cardioverter–defibrillator; IVF, idiopathic ventricular fibrillation; UD, uncertain diagnosis; SCD, sudden cardiac death.

Background: To compare outcome and cardiac pathology between patients with Noonan syndrome (N-HCM) and sarcomere protein-associated (S-HCM) childhood onset hypertrophic cardiomyopathy (HCM). Methods: Clinical data were recorded from medical charts. Primary endpoint was survival. Secondary endpoints were survival without hospitalization, without intervention or without arrhythmic events. Functional clinical status and results from genetic testing, imaging, electrocardiographic (ECG) studies, cardiopulmonary exercise testing (CPET) and histopathology were compared between groups. Results: Childhood HCM was diagnosed in 29 N-HCM and 34 S-HCM patients. Follow-up time was greater than 10 years in more than half of all patients. Mortality was below 7% and not different between groups. Children with N-HCM presented at a younger age and there was less time of survival without hospitalization for heart failure or intervention in N-HCM compared to S-HCM patients. Clinical functional status improved over time in N-HCM patients. On long-term follow-up, left ventricular posterior wall thickness indexed to body surface area decreased in N-HCM and increased in S-HCM patients. There was a trend to lower risk for severe arrhythmic events in N-HCM patients and only S-HCM individuals received an implantable cardioverter-defibrillator. There were no differences between groups in ventricular function, ECG and CPET parameters. Myocardial fibrosis as assessed by histopathology of myocardial specimens and cardiovascular magnetic resonance with late gadolinium enhancement or T1 mapping was present in both groups. Conclusions: When compared to S-HCM patients, children with N-HCM have increased morbidity during early disease course, but favorable long-term outcome with low mortality, stagnation of myocardial hypertrophy, and low risk for malignant arrhythmias.

Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11^N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

Surgical septal myectomy is performed to relieve left ventricular outflow tract narrowing in severe drug-refractory obstructive hypertrophic cardiomyopathy. The objective of this study was to assess the perioperative and long-term clinical outcome of this procedure performed during infancy. Clinical, transthoracic echocardiographic, electrocardiographic, 24-h Holter, cardiopulmonary exercise test and genetic data were extracted by medical record review. A subset of patients underwent additional prospective detailed clinical evaluation including cardiac magnetic resonance imaging with contrast. Surgery was performed in 23 paediatric patients between 1978 and 2015 at the German Heart Centre Munich. Twelve patients had undergone surgery during infancy (≤ 1 year) (Group A), 11 between 1 and 18 years of age (Group B). The underlying genetic diagnosis was Noonan syndrome spectrum and non-syndromic hypertrophic cardiomyopathy. As compared to Group B, patients in Group A showed more concomitant cardiac procedures and received more homologous transfusions. One perioperative death occurred in Group A, and none in Group B. Two patients in Group A but no patient in Group B required redo septal myectomy. The long-term clinical outcome was similar between the 2 groups. One patient in Group B required cardioverter–defibrillator/pacemaker implantation for higher degree atrioventricular block and none in Group A. There was no evidence of differences in myocardial fibrosis between groups on long-term follow-up magnetic resonance imaging. Surgical septal myectomy can be performed safely during infancy with favourable perioperative and long-term clinical outcome but with a trend towards a higher reoperation rate later in life.