Search

Over the past three decades numerous disease-causing genes have been linked to the pathogenesis of heritable cardiomyopathies, but many causal genes are yet to be identified. Next-generation sequencing (NGS) platforms have revolutionised clinical testing capacity in familial cardiomyopathy. In this review, we summarise how NGS technologies have advanced our understanding of genetic non-syndromic cardiomyopathy over the last decade. First, 26 putative new disease-causing genes have been identified to date, mostly from whole-exome sequencing, and some of which (FLNC, MTO1, HCN4) have had a considerable clinical impact and are now included in routine diagnostic gene panels. Second, we consider challenges in variant interpretation and the importance of large-scale NGS population control cohorts for this purpose. Third, an emerging role of common variation in some forms of genetic cardiomyopathy is being elucidated through recent studies which have illustrated an additive effect of numerous polymorphic loci on cardiac parameters; this may explain phenotypic variability and low rates of genetic diagnosis from sequencing studies. Finally, we discuss the clinical utility of genetic testing in cardiomyopathy in Western settings, where NGS panel testing of core disease genes is currently recommended with possible implications for patient management. Given the findings of recent studies, whole-exome or whole-genome sequencing should be considered in patients of non-European ancestry with clearly familial disease, or severe paediatric disease, when no result is obtained on panel sequencing. The clinical utility of polygenic risk assessment needs to be investigated further in patients with unexplained dilated cardiomyopathy and hypertrophic cardiomyopathy in whom a pathogenic variant is not identified. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterised by fibrofatty replacement of predominantly the right ventricle and high risk of ventricular arrhythmias and sudden cardiac death (SCD). Early diagnosis and accurate risk assessment are challenging yet essential for SCD prevention. This manuscript summarises the current state of the art on ARVC diagnosis and risk stratification. Improving the 2010 diagnostic criteria is an ongoing discussion. Several studies suggest that early diagnosis may be facilitated by including deformation imaging ('strain') for objective assessment of wall motion abnormalities, which was shown to have high sensitivity for preclinical disease. Adding fibrofatty replacement detected by late gadolinium enhancement or T1 mapping in cardiac MRI as criterion for diagnosis is increasingly suggested but requires more supporting evidence from consecutive patient cohorts. In addition to the traditional right-dominant ARVC, standard criteria for arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic left ventricular cardiomyopathy (ALVC) are on the horizon. After diagnosis confirmation, the primary management goal is SCD prevention, for which an implantable cardioverter-defibrillator is the only proven therapy. Prior studies determined that younger age, male sex, previous (non-) sustained ventricular tachycardia, syncope, extent of T-wave inversion, frequent premature ectopic beats and lower biventricular ejection fraction are risk factors for subsequent events. Previous implantable cardioverter-defibrillator indication guidelines were however limited to three expert-opinion flow charts stratifying patients in risk groups. Now, two multivariable risk prediction models (arvcrisk.com) combine the abovementioned risk factors to estimate individual risks. Of note, both the flow charts and prediction models require clinical validation studies to determine which should be recommended. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the role of the ECG in the differential diagnosis between Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM).Methods: In this multicentre retrospective study, 111 AFD patients with left ventricular hypertrophy were compared with 111 patients with HCM, matched for sex, age and maximal wall thickness by propensity score. Independent ECG predictors of AFD were identified by multivariate analysis, and a multiparametric ECG score-based algorithm for differential diagnosis was developed.Results: Short PR interval, prolonged QRS duration, right bundle branch block (RBBB), R in augmented vector left (aVL) ≥1.1 mV and inferior ST depression independently predicted AFD diagnosis. A point-by-point ECG score was then derived with the following diagnostic performances: c-statistic 0.80 (95% CI 0.74 to 0.86) for discrimination, the Hosmel-Lemeshow χ2 6.14 (p=0.189) for calibration, sensitivity 69%, specificity 84%, positive predictive value 82% and negative predictive value 72%. After bootstrap resampling, the mean optimism was 0.025, and the internal validated c-statistic for the score was 0.78.Conclusions: Standard ECG can help to differentiate AFD from HCM while investigating unexplained left ventricular hypertrophy. Short PR interval, prolonged QRS duration, RBBB, R in aVL ≥1.1 mV and inferior ST depression independently predicted AFD. Their systematic evaluation and the integration in a multiparametric ECG score can support AFD diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To compare mortality and serious morbidity rates between outborn and inborn livebirths at 22-27 weeks' gestation.Design: Population-based cohort study.Setting: Victoria, Australia.Patients: Livebirths at 22-27 weeks' gestation free of major malformations in 2010-2011.Interventions: Outcome data for outborn (born outside a tertiary perinatal centre) infants compared with inborn (born in a tertiary perinatal centre) infants were analysed by logistic regression, adjusted for gestational age, birth weight and sex.Main Outcome Measures: Infant mortality and serious morbidity rates to hospital discharge.Results: 541 livebirths free of major malformations were recorded. By 1 year, 49 (58%) outborns and 140 (31%) inborns died (adjusted OR (aOR) 2.78, 95% CI 1.52 to 5.09, p=0.001). In total, 445 infants were admitted to neonatal intensive care unit (NICU); 93 died by 1 year (14/49 outborns and 79/396 inborns), (aOR 1.75, 95% CI 0.87 to 3.55, p=0.12). There were no significant differences in rates of necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia (BPD) or the combined outcome of death or BPD in outborn infants compared with inborn infants. Outborns had an increased risk of cystic periventricular leukomalacia (cPVL) compared with inborns (12.2% vs 2.8%, respectively; aOR 5.34, 95% CI 1.84 to 15.54, p=0.002).Conclusions: Mortality rates remained higher for outborn livebirths at 22-27 weeks' gestation compared with inborn peers in 2010-2011. Outborn infants admitted to NICU did not have substantially different rates of mortality or serious morbidity compared with inborns, with the exception of cPVL. Longer-term health consequences of outborn birth before 28 weeks' gestation need to be determined. [ABSTRACT FROM AUTHOR]

Cardiac disease is now the leading cause of death in Duchenne muscular dystrophy (DMD). Clinical evaluations over time have demonstrated asymptomatic cardiac troponin elevations and acute elevations are associated with symptoms and cardiac dysfunction in DMD. Clinicians require a better understanding of the relationship of symptoms, troponin levels and progression of cardiac disease in DMD. As clinical trials begin to assess novel cardiac therapeutics in DMD, troponin levels in DMD are important for safety monitoring and outcome measures. The Parent Project Muscular Dystrophy convened an expert panel of cardiologists, scientists, and regulatory and industry specialists on 16 December 2019 in Silver Spring, Maryland and reviewed published and unpublished data from their institutions. The panel recommended retrospective troponin data analyses, prospective longitudinal troponin collection using high-sensitivity cardiac troponin I assays, inclusion of troponin in future clinical trial outcomes and future development of clinical guidelines for monitoring and treating troponin elevations in DMD., Competing Interests: Competing interests: DA: consultant to PPMD/I-ACT for Children, no relevant conflicts. LC: employee and shareholder of Pfizer, Inc. NK and J-MS: Critical Path Institute is supported by the Food and Drug Administration (FDA) of the US Department of Health and Human Services (HHS) and is 62% funded by FDA/HHS totalling $14 448 917 and 28% funded by non-government source(s) totalling $8 669 646. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the US Government. EM: consultant to AstraZeneca, Amgen, Avidity, 4D Molecular Therapeutics, Pfizer, Janssen, Cytokinetics, Exonics and Invitae; grant support from NIH and Department of Defense., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite advances in our understanding of the genetic causes of hypertrophic cardiomyopathy (HCM), a large portion of this patient population do not carry sarcomere gene mutations when screened. It remains largely unknown why patients without sarcomere mutations develop asymmetric myocardial hypertrophy., Methods: We performed a retrospective analysis of probands with HCM who underwent genetic testing to determine if clinical phenotypes were different depending on sarcomere mutation status. A medical history, three generation family history and clinical phenotyping were performed on 127 probands with HCM. Genetic screening was performed using clinically available HCM genetic testing panels., Results: We found that probands with HCM with pathogenic sarcomere mutations were over three times more likely to have a family history of HCM (66% vs 17%, p<0.0001) and were diagnosed with HCM at a much younger age (32 vs 51 years old, p<0.0001). In contrast, probands with HCM without sarcomere mutations were significantly more obese (body surface area p=0.003, body mass index p=0.04 adjusted for age) and were more likely to present with left ventricular outflow tract obstruction (p=0.0483)., Conclusion: Patients with sarcomere mutation negative HCM present at an older age and are more obese compared with patients with sarcomere mutation positive HCM. The role of ageing and obesity in asymmetric myocardial hypertrophy warrants further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT)., Methods and Results: Consecutive patients referred for aetiological workup of LVH, beginning at 12 mm of LVWT were retrospectively included in this tertiary single-centred observational study. Patients presenting with severe aortic stenosis were excluded. Aetiological workup was reviewed for each subject and aetiologies were adjudicated by expert consensus.Among 591 patients referred for LVH aetiological workup, 41% had a maximal LVWT below 15 mm. LVH aetiologies were led by cardiac amyloidosis (CA, 34.3%), followed by sarcomeric hypertrophic cardiomyopathy (S-HCM, 32.1%), hypertensive cardiomyopathy (21.7%), unknown aetiology (7.6%) and other (4.2%), including Anderson-Fabry's disease (1.7%). CA and S-HCM affected over 50% of patients with mild LVH (12-14 mm); the prevalence of these aetiologies rose with LVH severity. Among patients with Anderson-Fabry's disease, 4 (40%) had a maximal LVWT <15 mm., Conclusions: Mild LVH (ie, 12-14 mm) conceals multiple aetiologies that can lead to specific treatment, cascade family screening and specific follow-up. Overall, CA is nowadays the leading cause of LVH in tertiary centers., Competing Interests: Competing interests: Olivier Lairez received research support and personal compensation for consulting, serving on a scientific advisory board, speaking or other activities with Alnylam, Amicus, Genzyme, Pfizer and Shire-Takeda. Eve Cariou received personal compensation for speaking with Pfizer., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)