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The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects. Genome-wide analyses identify multiple loci associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and left ventricular (LV) traits. Cardiomyopathies exhibit strong genetic correlations with LV traits, with opposing effects in HCM and DCM.

With the development and advancement of next-generation sequencing (NGS), genetic analysis is becoming more accessible. High-throughput genetic studies using NGS have contributed to unraveling the association between cardiomyopathy and genetic background, as is the case with many other diseases. Rare variants have been shown to play major roles in the pathogenesis of cardiomyopathy, which was empirically recognized as a monogenic disease, and it has been elucidated that the clinical course of cardiomyopathy varies depending on the causative genes. These findings were not limited to dilated and hypertrophic cardiomyopathy; similar trends were reported one after another for peripartum cardiomyopathy (PPCM), cancer therapy-related cardiac dysfunction (CTRCD), and alcoholic cardiomyopathy (ACM). In addition, as the association between clinical phenotypes and the causative genes becomes clearer, progress is being made in elucidating the mechanisms and developing novel therapeutic agents. Recently, it has been suggested that not only rare variants but also common variants contribute to the development of cardiomyopathy. Cardiomyopathy and genetics are approaching a new era, which is summarized here in this overview.

BackgroundCardiac magnetic resonance imaging (CMRI) with late gadolinium enhancement (LGE) is increasingly used to quantify myocardial fibrosis in hypertrophic cardiomyopathy (HCM). This can assist in refining sudden cardiac death (SCD) risk stratification and guiding management. International guidelines differ in recommendations for incorporation of LGE burden in SCD risk stratification. This study reviews the reporting of LGE burden, and compares SCD risk from AHA and ESC calculators.MethodsRetrospectively reviewed data for 38 HCM patients from a tertiary centre out-patient clinic. CMRI reports reviewed, SCD risk factors (family history, syncope, ventricular arrhythmias, maximal LV wall thickness, LVOT gradient) were extracted, and ICD status was recorded. Data analysed using Microsoft Excel, mean values compared using paired t-test; association tested using the chi-square test.ResultsOf the 38 patients, 90% had a CMRI report available. Percentage LGE fibrosis was reported in four cases, LGE fibrosis was described as mild in 62% (n=20) of cases, and severe in 22% (n=7). Mean LV wall thickness was 18.5mm (95% CI 16.9;20.2mm). ICDs were implanted in 24% (n=9). Mean AHA and ESC 5-year SCD risk were 2.8% and 2.7% respectively, paired t-test demonstrated that the difference was not statistically significant (p=0.06). No cases of cardiac arrest were documented during follow-up; two patients with ICDs had appropriate therapies.ConclusionsIn this single-centre cohort, LGE fibrosis on CMRI was frequently reported, however the reporting of LGE as a percentage was less common. While LGE does not impact the AHA 5-year predicted SCD risk, the AHA 2024 guidelines would recommend consideration of an ICD in patients with extensive LGE (>15%). Our data demonstrates that current CMRI reporting without specific LGE percentages can make incorporating these recommendations challenging. These findings underscore the need for standardized LGE reporting, particularly if it is to be considered in risk stratification for ICD implantation.

Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5–67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6–57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.).

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes 1 . Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1 . Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer 2 . Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD. Single-nuclear transcriptomic and proteomic analyses identify molecular characteristics shared by multiple classes of congenital heart disease, including phenotypes associated with insulin resistance.

In this double-blind, placebo-controlled trial involving 2854 patients with Chagas' cardiomyopathy, no clinical benefit was found with 2 to 3 months of benznidazole therapy during 5 years of followup. Chagas’ disease is the third most common parasitic disease globally, after malaria and schistosomiasis. 1 Chagas’ cardiomyopathy is the most common form of nonischemic cardiomyopathy and one of the leading causes of complications and death in Latin America. 2 An estimated 6 million to 7 million persons are infected, and 36,800 new cases occur each year. Chagas’ cardiomyopathy develops in approximately 25% of patients infected with Trypanosoma cruzi . 3 – 5 Chagas’ disease has two phases: acute and chronic. Acute infection is usually a self-limited febrile illness. 6 In the chronic phase, cardiac or digestive complications develop in approximately one third of patients two . . .

Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown. We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index. A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and -1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups. Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.).

Background Potentially modifiable cardiovascular risk factors, including hypertension, diabetes, obesity, alcohol consumption, and smoking initiation, are associated with hypertrophic (HCM) and dilated (DCM) cardiomyopathies, representing promising targets for interventions. However, the causality and cross-ancestry generalizability of these associations remain uncertain. Methods Collecting summary-level data from genome-wide association studies for systolic (SBP) and diastolic (DBP) blood pressure, hypertension, type 2 diabetes, fasting glucose, glycated hemoglobin, body mass index (BMI), waist circumference (WC), alcohol consumption, smoking initiation, HCM, and DCM (sample size ranging from 38,288 to 1,812,017), we performed comprehensive two-sample univariable Mendelian randomization (MR) to evaluate the causal effect of each trait on HCM and DCM in both European and East Asian populations. We performed multivariable MR to investigate the independent effects of interrelated traits (SBP vs. DBP; BMI vs. WC). Results MR analyses identified reliable evidence of a causal effect of SBP on HCM (Europeans: odds ratio (OR) = 1.03, 95% confidence interval (CI) = 1.02–1.04; East Asians: OR = 1.06, 95% CI = 1.03–1.08). For DCM, reliable evidence of causal effects was identified for DBP (Europeans: OR = 1.04, 95% CI = 1.03–1.04; East Asians: OR = 1.07, 95% CI = 1.04–1.11), WC (Europeans: OR = 1.73, 95% CI = 1.58–1.89; East Asians: OR = 3.32, 95% CI = 1.22–9.03), and alcohol consumption (Europeans: OR = 1.50, 95% CI = 1.20–1.86; East Asians: OR = 1.32, 95% CI = 1.11–1.56). In Europeans, genetically predicted higher WC (OR = 1.75, 95% CI = 1.53–2.01) and smoking initiation (OR = 1.34, 95% CI = 1.16–1.56) specifically increased the risk of HCM and DCM, respectively, while genetically predicted higher alcohol consumption (OR = 1.68, 95% CI = 1.36–2.07) specifically increased the risk of HCM in East Asians. Conclusions This study provided reliable cross-ancestry genetic evidence supporting higher SBP as a causal risk factor for HCM and higher DBP, WC, and alcohol consumption as causal risk factors for DCM. These findings underscore the potential of precision prevention strategies targeting modifiable cardiovascular risk factors to reduce cardiomyopathy burden across populations.