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Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM. Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy. Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7-20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason. Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train. The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066.

Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

Plasma acylcarnitines are biomarkers of β-oxidation and are useful in diagnosing several inborn errors of metabolism but have never been investigated systematically in patients with mitochondrial myopathy. We hypothesized that acylcarnitines can also be biomarkers of mitochondrial myopathy and sought to investigate the prevalence and pattern of elevated acylcarnitines. This was a prospective cohort study of patients with confirmed mitochondrial myopathy followed at Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark. We included 35 patients (44 ± 15 years, 15 women) with mitochondrial myopathy caused by single, large-scale deletions of mitochondrial DNA (n = 17), pathogenic variants in mitochondrial transfer RNA (n = 13), or in proteins of the respiratory chain complexes (n = 5).Concentrations of 35 acylcarnitines were measured using ultra-HPLC and tandem mass-spectrometry. Findings were compared with muscle mutation load in all patients and to respiratory chain activity in 26 patients. Prevalence of elevated concentrations of acylcarnitines related to acyl-coenzyme A (CoA) dehydrogenases in patients with mitochondrial myopathy and relation to genotypes/phenotypes. In total, 27 (77%) patients had elevated concentrations of acylcarnitines related to acyl-CoA dehydrogenases. Elevated concentrations of seven acylcarnitine species were more common in patients compared with a control cohort of >900 individuals, and a specific pattern involving hydroxylated long-chain acylcarnitines occurred in 22 (63%) patients. Severity of derangements was correlated with muscle mutation load and genotypes/phenotypes. In conclusion, elevated concentrations of acylcarnitines is common in patients with mitochondrial myopathy and shows a specific pattern affecting hydroxylated long-chain acylcarnitines, which can have implications for future diagnostic workup of patients.

We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2 and p.R534Q in F5 . We also document that F2 and F5 mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels). Genome-wide association analyses identify 93 risk loci for venous thromboembolism (VTE). A polygenic score derived from these results identifies individuals at increased VTE risk equivalent to monogenic forms of the disease.

BackgroundParticipation in regular exercise activities is recommended for patients with chronic heart failure. However, less is known about the effect of exercise in patients with genetic dilated cardiomyopathy (DCM). We sought to examine the effect of vigorousintensity training on physical capacity in patients with DCM caused by truncating titin variants (TTNtv).Trial designNon-randomised clinical pre-post trial of exercise training.MethodsIndividuals with DCM-TTNtv were included from outpatient clinics for inherited cardiac diseases. The trial consisted of 8 weeks of usual care followed by 8 weeks of regular vigorous-intensity cycling exercise, enclosed by three test days. The primary outcome was change in peak oxygen uptake (VO2). Secondary outcomes included change in blood volume, total haemoglobin mass, measures of systolic function and cardiac output/stroke volume during exercise.ResultsThirteen out of 14 included participants (43% women, age 48±11 years, body mass index: 30±6 kg/m2) completed the trial. In the exercise training period, peak VO2 increased by +1.9 mL/kg/min (95% CI +0.9 to +2.9, p=0.002). Compared with usual care, exercise training improved peak VO2 by +2.9 mL/kg/min (95% CI +1.2 to +4.5, p=0.002), corresponding to a 10% increase. Adaptations to exercise training included an increase in resting cardiac output (+0.8 L/min, p=0.042), total blood volume (+713 mL, p<0.001), total haemoglobin mass (+73 g, p<0.001), and improved left ventricular (LV) systolic function (LV ejection fraction: +3.2% (p=0.053) and global longitudinal strain: −2.0% (p=0.044)). No exercise-related adverse events or change in plasma biomarkers of cardiac or skeletal muscle damage were observed.ConclusionsOur study shows that vigorous intensity exercise training improved peak VO2 in patients with DCM-TTNtv. Exercise training was associated with improved LV systolic function and increased blood volume and oxygen carrying capacity. Future research should investigate the effect of long-term exercise in this group.Trial registration numberNCT05180188.

BackgroundTruncating variants in titin (TTNtv) are the most common cause of dilated cardiomyopathy (DCM). We evaluated the genotype-phenotype correlation in TTNtv-DCM, with a special focus on long-term outcomes, arrhythmias, response to treatment and sex-related presentation.MethodsData on patient characteristics and outcomes were collected retrospectively from electronic health records of patients genotyped at two Danish heart transplantation centres.ResultsWe included 115 patients (66% men). At diagnosis of DCM, mean age was 46±13 years and left ventricular ejection fraction (LVEF) was 28%±13%. During a median follow-up of 7.9 years, 26% reached a composite outcome of left ventricular assist device implantation, heart transplantation or death. In 20% an arrhythmia preceded the DCM diagnosis. In total, 43% had atrial fibrillation (AF) and 23% had ventricular arrhythmias. Long-term left ventricular reverse remodelling (LVRR; LVEF increase ≥10% points or normalisation) was achieved in 58% and occurred more frequently in women (72% vs 51%, p=0.042).In multivariable proportional hazards analyses, occurrence of LVRR was a strong independent negative predictor of the composite outcome (HR: 0.05 (95% CI 0.02 to 0.14); p<0.001). Female sex independently predicted lower rates of ventricular arrhythmias (HR: 0.33 (95% CI 0.11 to 0.99); p=0.05), while the location of the TTNtv was not associated with cardiovascular outcomes.ConclusionDCM caused by TTNtv presented in midlife and was associated with a high burden of AF and ventricular arrhythmias, which often preceded DCM diagnosis. Furthermore, LVRR occurred in a high proportion of patients and was a strong negative predictor of the composite outcome. Female sex was positively associated with occurrence of LVRR and longer event-free survival.

To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P = .4). With the exception of tissue Doppler systolic (s’) velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.

BackgroundTreatment with implantable cardioverter-defibrillators (ICDs) effectively prevents sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). Identifying patients most likely to benefit from a primary prevention ICD remains challenging. We aimed to investigate the long-term incidence of ICD therapy in patients with HCM according to SCD-risk at baseline.MethodsThe study retrospectively included all patients with HCM treated with an ICD for primary or secondary prevention between 1995 and 2022 in Eastern Denmark. Medical records for each patient were evaluated. Patients were stratified into risk groups according to the European Society of Cardiology HCM Risk-SCD score.ResultsWe included 208 patients (66% male) with HCM and an ICD for primary (78%) or secondary prevention (22%). During a median 10-year follow-up, 66 patients (32%) received appropriate ICD therapy (antitachycardia pacing and/or shock), while 20 (10%) received inappropriate therapy. Patients with an ICD implanted for secondary prevention were almost twice as likely to receive appropriate therapy compared with patients with an ICD implanted for primary prevention (47% vs 28%, p=0.02). The 5-year cumulative incidences of appropriate shock therapy were 17% in patients with a high HCM Risk-SCD score, 16% in patients with an intermediate-risk score and 6% in patients with a low-risk score. A high-risk score was associated with higher cumulative incidence of appropriate shock therapy (p=0.012).ConclusionOne-third of patients with HCM treated with an ICD experienced appropriate ICD therapy. The HCM-Risk SCD score adequately distinguished between low-risk and high-risk patients among those who underwent ICD implantation. Further improvements of risk-tools are needed to identify a larger proportion of the two-thirds of patients who did not benefit from ICD implantation after 10 years of observation.