The French hypertrophic cardiomyopathy gene register: A systematic large gene screening for hypertrophic cardiomyopathy.

BACKGROUND: Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. AIMS: The performance of this approach was tested in GEREMY, a HCM prospective observational French register. METHODS: Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used. RESULTS: A 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis. CONCLUSIONS: Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach.

Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. OBJECTIVES: To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6 weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6 months (late MACE). RESULTS: Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6 weeks and 6 months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6 months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. CONCLUSIONS: Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Very Low Residual Dystrophin Quantity Is Associated with Milder Dystrophinopathy.

OBJECTIVE: This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations. METHODS: We performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database-DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death. RESULTS: Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty-two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty-four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001). INTERPRETATION: Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280-292.

The French national protocol for Kennedy's disease (SBMA): consensus diagnostic and management recommendations.

BACKGROUND: Kennedy's disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. RESULTS: The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. CONCLUSION: The French national Kennedy's disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.

X-linked Emery-Dreifuss muscular dystrophy manifesting with adult onset axial weakness, camptocormia, and minimal joint contractures.

Emery-Dreifuss muscular dystrophy is an early-onset, slowly progressive myopathy characterized by the development of multiple contractures, muscle weakness and cardiac dysfunction. We present here the case of a 65-year-old male patient with a 20 year history of slowly progressive camptocormia, bradycardia and shortness of breath. Examination showed severe spine extensor and neck flexor muscle weakness with slight upper limb proximal weakness. Cardiologic assessment revealed slow atrial fibrillation. Whole body MRI demonstrated adipose substitution of the paravertebral, limb girdle and peroneal muscles as well as the tongue. Emerin immunohistochemistry on patient muscle biopsy revealed the absence of nuclear envelope labeling confirmed by Western Blot. Genetic analysis showed a hemizygous duplication of 5 bases in exon 6 of the EMD, emerin, gene on the X chromosome. This is an unusual presentation of X-linked Emery-Dreifuss muscular dystrophy with adult onset, predominant axial muscles involvement and minimal joint contractures. Diagnosis was prompted by the analysis of emerin on muscle biopsy.

Lamin and the heart.

Lamins A and C are intermediate filament nuclear envelope proteins encoded by the LMNA gene. Mutations in LMNA cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an LMNA mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for LMNA, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude LMNA mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our LMNA knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.

Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care.

Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA-related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.

Brugada syndrome and abnormal splicing of SCN5A in myotonic dystrophy type 1.

BACKGROUND: In patients with myotonic dystrophy type 1 (DM1), the mechanisms underlying sudden cardiac death, which occurs in up to 1/3 of patients, are unclear. AIMS: To study the potential role of Brugada syndrome in ventricular tachyarrhythmias and sudden death in DM1 patients. METHODS: We screened 914 adult patients included in the DM1 Heart Registry during 2000-2009 for the presence of type 1 Brugada pattern on electrocardiogram (ECG). We also performed direct sequencing of SCN5A in patients with Brugada pattern. Further, we analysed SCN5A splicing on ventricular myocardial specimens harvested during cardiac transplantation in a 45-year-old patient with DM1 and three controls with inherited dilated cardiomyopathy. RESULTS: A type 1 Brugada pattern was present on the ECG of seven of 914 patients (0.8%), including five with a history of sustained ventricular tachyarrhythmia or sudden death, who fulfilled the criteria for Brugada syndrome. SCN5A sequencing was normal in all patients. Ventricular myocardial specimen analysis displayed abnormal splicing of SCN5A exon 6, characterized by over-expression of the 'neonatal' isoform, called exon 6A, in the patient with DM1, but not from the controls. CONCLUSION: Our findings suggest a potential implication of Brugada syndrome in sudden death in DM1, which may be related to missplicing of SCN5A. Our findings provide a new insight into the pathophysiology of heart disease in DM1.

Blood glutathione decrease in subjects carrying lamin A/C gene mutations is an early marker of cardiac involvement.

Dominant inherited Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B are due to mutations in the LMNA gene encoding lamin A/C and present similar life-threatening cardiac disease, the early diagnosis of which lacks reliable biomarkers. Glutathione depletion characterizes subjects with cardiac diseases of non-genetic aetiology. We examined blood glutathione in 22 LMNA-mutated subjects without altered left ventricular ejection fraction (LVEF>40%) measured by conventional echocardiography. Left and right ventricular (LV/RV) contractility was evaluated using echocardiography implemented with tissue-Doppler echography. Blood glutathione was positively correlated with LV and RV contractility (p<0.05), and was decreased by 23% in subjects with reduced LV/RV contractility compared to subjects with normal contractility. ROC analysis showed that blood glutathione reliably detected reduced LV/RV contractility (AUC-95% CI: 0.90 [0.76-1.04]; p=0.01). Blood glutathione decrease may allow the detection of reduced contractility in muscular dystrophic LMNA-mutated patients with still preserved LVEF.

Acute coronary syndrome in human immunodeficiency virus-infected patients: characteristics and 1 year prognosis.

AIMS: Natural history and prognosis of acute coronary syndrome (ACS) in HIV-infected patients remain to be determined. We sought to compare coronary risk factors, angiographic features, acute results of percutaneous coronary intervention, in-hospital outcomes, and pre-specified 1 year prognosis of HIV-infected and HIV-uninfected patients with ACS. METHODS AND RESULTS: HIV-infected and HIV-uninfected patients with a first episode of ACS were matched for age (±5 years), sex, and type of ACS. The primary endpoint was the rate of major adverse cardiac and cerebral events (MACCE), comprising cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke. Overall, 103 HIV-infected and 195 HIV-uninfected patients were enrolled (mean age 49.0 ± 9.4 years, 94% men). Coronary risk factors were well balanced, but HIV-infected patients more frequently used illicit drugs (23 vs. 6%, P = 0.001) and had higher triglyceride concentrations (246 ± 189 vs. 170 ± 139 mg/dL, P = 0.002) compared with HIV-uninfected patients. Angiographic features of coronary artery disease were similar (multivessel disease 41 vs. 39%, P = 0.96; ACC/AHA type culprit lesion ≥B2, both 77%, P = 0.83). At 1 year, the rate of occurrence of first MACCE did not differ between groups [hazard ratio (HR) 1.4, 95% CI 0.6-3.0]. Recurrent ACS was more frequent in HIV-infected patients (HR 6.5, 95% CI 1.7-23.9) with no difference in the rate of clinical restenosis. CONCLUSIONS: These results suggest that the acute management of ACS in HIV-infected patients can routinely be the same as that of HIV-uninfected patients, but that specific secondary prevention measures are needed to alleviate the increased risk of recurrent ACS.

Delayed cardiomyopathy in dystrophin deficient mdx mice relies on intrinsic glutathione resource.

Oxidative stress contributes to the pathogenesis of Duchenne muscular dystrophy (DMD). Although they have been a model for DMD, mdx mice exhibit slowly developing cardiomyopathy. We hypothesized that disease process was delayed owing to the development of an adaptive mechanism against oxidative stress, involving glutathione synthesis. At 15 to 20 weeks of age, mdx mice displayed a 33% increase in blood glutathione levels compared with age-matched C57BL/6 mice. In contrast, cardiac glutathione content was similar in mdx and C57BL/6 mice as a result of the balanced increased expression of glutamate cysteine ligase catalytic and regulatory subunits ensuring glutathione synthesis in the mdx mouse heart, as well as increased glutathione peroxidase-1 using glutathione. Oral administration from 10 weeks of age of the glutamate cysteine ligase inhibitor, l-buthionine(S,R)-sulfoximine (BSO, 5 mmol/L), led to a 33% and 50% drop in blood and cardiac glutathione, respectively, in 15- to 20-week-old mdx mice. Moreover, 20-week-old BSO-treated mdx mice displayed left ventricular hypertrophy associated with diastolic dysfunction, discontinuities in beta-dystroglycan expression, micronecrosis and microangiopathic injuries. Examination of the glutathione status in four DMD patients showed that three displayed systemic glutathione deficiency as well. In conclusion, low glutathione resource hastens the onset of cardiomyopathy linked to a defect in dystrophin in mdx mice. This is relevant to the glutathione deficiency that DMD patients may suffer.

Left ventricular dysfunction and cardiac arrhythmias are frequent in type 2 myotonic dystrophy: a case control study.

In contrast with Steinert's disease (DM1), type 2 muscular dystrophy (DM2) is not known to be associated with a high prevalence of cardiac involvement. Our objective was to compare the results of detailed cardiac investigations in populations of DM2 and DM1 patients, and in controls. Thirty-eight DM2 patients (17 males; age=57.1+/-15.2years) were investigated for possible heart involvement, and their results compared with 76 age-sex matched DM1 patients and 76 controls. Cardiac abnormalities were present in 15 DM2 patients, including conductive defects in 14, systolic dysfunction in 6, supraventricular arrhythmias in 6 and stroke in 5 patients and were significantly more frequent than in controls. When compared to DM1 patients, conductive defects were less frequent, supraventricular arrhythmias had similar prevalence and there was a trend towards more frequent left ventricular dysfunction in DM2 patients. Our study suggests that systematic cardiac investigations should be recommended in these patients.