Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Indications and utility of cardiac genetic testing in athletes.

Sports Cardiology practice commonly involves the evaluation of athletes for genetically determined cardiac conditions that may predispose to malignant arrhythmias, heart failure, and sudden cardiac death. High-level exercise can lead to electrical and structural cardiac remodelling which mimics inherited cardiac conditions (ICCs). Differentiation between 'athlete's heart' and pathology can be challenging and often requires the whole armamentarium of available investigations. Genetic studies over the last 30 years have identified many of the genetic variants that underpin ICCs and technological advances have transformed genetic testing to a more readily available and affordable clinical tool which may aid diagnosis, management, and prognosis. The role of genetic testing in the evaluation and management of athletes with suspected cardiac conditions is often unclear beyond the context of specialist cardio-genetics centres. This document is aimed at physicians, nurses, and allied health professionals involved in the athlete's care. With the expanding role and availability of genetic testing in mind, this document was created to address the needs of the broader sports cardiology community, most of whom work outside specialized cardio-genetics centres, when faced with the evaluation and management of athletes with suspected ICC. The first part of the document provides an overview of basic terminology and principles and offers guidance on the appropriate use of genetic testing in the assessment of such athletes. It outlines key considerations when contemplating genetic testing, highlighting the potential benefits and pitfalls, and offers a roadmap to genetic testing. The second part of the document presents common clinical scenarios in Sports Cardiology practice, outlining the diagnostic, prognostic, and therapeutic implications of genetic testing, including impact on exercise recommendations. The scope of this document does not extend to a comprehensive description of the genetic basis, investigation, or management of ICCs.

Andersen-Tawil syndrome: deep phenotyping reveals significant cardiac and neuromuscular morbidity.

Andersen-Tawil syndrome is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterized by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multisystem phenotype is not well described. In-depth, multisystem phenotyping is required to inform diagnosis and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognized, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fat accumulation on MRI and tubular aggregates on muscle biopsy, emphasizing the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing was not reliable in predicting neuromuscular symptoms. A normal long exercise test was seen in five patients, of whom four had episodic weakness. Sixty-seven per cent of patients treated with acetazolamide reported a good neuromuscular response. Thirteen per cent of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but Holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal Holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature; however, 8% of patients did not have dysmorphic features and one-third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that Andersen-Tawil syndrome is not benign. We report marked neuromuscular morbidity and cardiac risk with multisystem involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of Andersen-Tawil syndrome patients have no (or few) dysmorphic features or negative long exercise test. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population.

BACKGROUND: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown. METHODS: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases. Allele frequencies of all TRDN null variants identified in the cardiac-specific isoform of TRDN in the Genome Aggregation Database were used to determine the estimated prevalence and ethnic distribution of TKOS. RESULTS: No triadin null individuals were identified in 599 sudden infant death syndrome and 258 sudden unexplained death in the young exomes. Using the Genome Aggregation Database, we estimate the overall prevalence of TKOS to be ≈1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (≈1:4.1 million). CONCLUSIONS: TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either sudden infant death syndrome or sudden unexplained death in the young. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research to better care for these patients.

Accuracy of the 2017 international recommendations for clinicians who interpret adolescent athletes' ECGs: a cohort study of 11 168 British white and black soccer players.

AIM: To investigate the accuracy of the recently published international recommendations for ECG interpretation in young athletes in a large cohort of white and black adolescent soccer players. METHODS: 11 168 soccer players (mean age 16.4±1.2 years) were evaluated with a health questionnaire, ECG and echocardiogram; 10 581 (95%) of the players were male and 10 163 (91%) were white. ECGs were retrospectively analysed according to (1) the 2010 European Society of Cardiology (ESC) recommendations, (2) Seattle criteria, (3) refined criteria and (4) the international recommendations for ECG interpretation in young athletes. RESULTS: The ESC recommendations resulted in a higher number of abnormal ECGs compared with the Seattle, refined and international criteria (13.2%, 4.3%, 2.9% and 1.8%, respectively). All four criteria were associated with a higher prevalence of abnormal ECGs in black athletes compared with white athletes (ESC: 16.2% vs 12.9%; Seattle: 5.9% vs 4.2%; refined: 3.8% vs 2.8%; international 3.6% vs 1.6%; p<0.001 each). Compared with ESC recommendations, the Seattle, refined and international criteria identified a lower number of abnormal ECGs-by 67%, 78% and 86%, respectively. All four criteria identified 36 (86%) of 42 athletes with serious cardiac pathology. Compared with ESC recommendations, the Seattle criteria improved specificity from 87% to 96% in white athletes and 84% to 94% in black athletes. The international recommendations demonstrated the highest specificity for white (99%) and black (97%) athletes and a sensitivity of 86%. CONCLUSIONS: The 2017 international recommendations for ECG interpretation in young athletes can be applied to adolescent athletes to detect serious cardiac disease. These recommendations perform more effectively than previous ECG criteria in both white and black adolescent soccer players.

Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. CONCLUSIONS: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.

Radiation exposure during cardiac catheterisation is similar for both femoral and radial approaches.

OBJECTIVES: Radial approach invasive coronary angiography has been shown to be superior to the femoral approach in terms of reducing vascular access complications and improving patient comfort. However, one major limitation has been the perception of higher patient radiation exposure, with guidelines recommending 7mSv as an appropriate average effective dose (E) for routine coronary angiography. Therefore, we sought here to assess differences in radiation exposure between the femoral and radial access routes in patients undergoing diagnostic coronary angiography with or without angioplasty (CA +/- PCI), as performed by two operators, experienced in both techniques. METHODS: Consecutive patients (n=870) from July 2011-December 2012, undergoing routine CA +/- PCI at Royal Prince Alfred Hospital, Sydney by two experienced interventional cardiologists were identified. Radiation doses were automatically recorded as dose area products (DAPs) at procedure time and converted into E using a conversion factor of 0.18 mSv/(Gycm2), as validated by the National Radiological Protection Board (NRPB). RESULTS: Of the 870 patients, 598 underwent diagnostic CA (347 femoral, 251 radial); and 272 underwent CA+ PCI (179 femoral, 93 radial). The mean age of the patients was 65±12 years and the majority (n=617, 71%) were male. Both groups were well matched with respect to baseline demographics, clinical presentation and angiographic characteristics, though there was an excess of patients with a history of coronary grafts in the femoral group, due to operator preference. In the patients who underwent diagnostic CA, there was no significant difference in the average effective radiation dose for femoral versus radial arterial access (E=7.9±8.2 vs. 8.3±10.6mSv; p=0.66). Similarly, there was also no difference in average effective radiation dose for femoral versus radial arterial access in patients undergoing CA+PCI (E=13.2±8.1 vs E=14.4±8.3 mSv; p=0.26). CONCLUSION: In our high volume cardiac catheterisation laboratory, radiation doses for routine angiography were near UNSC targets. Patient radiation exposure was comparable between femoral and radial approaches, for both CA and CA +/- PCI. Thus, our results allay concerns that radial cardiac catheterisation might be associated with greater radiation exposure.

Comparison of conventional autopsy and magnetic resonance imaging in determining the cause of sudden death in the young.

BACKGROUND: Sudden death in the young is a tragic complication of a number of medical diseases. There is limited data regarding the utility of post-mortem Magnetic Resonance (MR) imaging and Computer Tomography (CT) scanning in determining the cause of sudden death. This study sought to compare the accuracy of post-mortem cross-sectional imaging (MR and CT) with the conventional autopsy in determining the cause of sudden death in the young. METHODS: Consecutive patients from 2010 to 2012 (aged 1-35 years) who had sudden death were included. Patients were scanned by CT and 1.5 T MR imaging prior to the conventional autopsy being performed. The primary outcome was diagnostic congruence between imaging and conventional autopsy. RESULTS: In 17 patients studied, the mean age at death was 23 ± 11 years, with a male predominance (n = 12; 71%). The most common cause of death was a primary cardiac pathology (n = 8; 47%), including ARVC (24%) and ischemic heart disease (12%). Non-cardiac causes identified included pulmonary embolism (6%), and aortic dissection (6%). MR imaging correctly identified the diagnosis in 12 patients who subsequently had positive findings at conventional autopsy, while the diagnosis in the remaining 5 cases remained unexplained. MR imaging was found to be highly sensitive (100%) with a high negative (100%) and positive (80%) predictive value. CONCLUSIONS: Dedicated post-mortem MR imaging of the heart and brain is a useful modality in determining the cause of sudden death in children and young adults, particularly in situations where a conventional autopsy cannot be performed for logistic, cultural or personal reasons.