Belinda Gray

Natural history of genotype positive–phenotype negative patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a primary disorder of the myocardium characterised by hypertrophy, usually of the left ventricle, in the absence of other loading conditions such as hypertension [1,2]. HCM affects 1 in 500 (0.2%) of the general population, and importantly remains the commonest structural cause of sudden cardiac death (SCD) in individuals aged less than 35 years, including competitive athletes [3,4]. HCM is a clinically heterogeneous disease, with patients experiencing a range of symptoms from mild dyspnoea and palpitations, to the most tragic outcome of SCD [1,5]. To date, mutations in at least 14 genes have been identified to cause HCM [1,6]. A genetic diagnosis in a proband does not currently have prognostic or therapeutic value, but subsequent predictive genetic testing of asymptomatic family members has significant benefit. Increased availability of commercial genetic testing for HCM has led to the emergence of a novel patient subset within the vast and everexpanding HCM spectrum, that is the genotype positive–phenotype negative (G+P−) individual [7,8]. These patients carry the causative gene mutation, but appear to have no clinical or morphological evidence of the disease, with no evidence of left ventricular hypertrophy on echocardiography. There is currently no data regarding the natural history and long-term risk profile of G+P− HCM patients. This study sought to investigate the natural history of G+P− HCM patients presenting at all ages. From 2000 to 2009, patients were identified through the HCM Clinic at Royal Prince Alfred Hospital, Sydney, Australia [9]. Individuals who tested positive for a pathogenic gene mutation and without any evidence of hypertrophy on 2D echocardiography (i.e. G+P−) at their first visit were included. Data were recorded at first visit (Table 1) and patients were followed for a minimum of 12 months, either in the HCM Clinic, or by their referring cardiologist. Clinical characteristics evaluated included basic demographics, family history, clinical history including previous syncope and New York Heart Association (NYHA) functional class, and genetic diagnosis. Electrocardiographic (ECG) data included corrected QT interval (QTc), LV hypertrophy, ST segment changes and rhythm abnormalities. Echocardiographic data included measurement of left ventricular (LV) wall thickness and LV outflow tract obstruction. Statistical analysis was carried out using Prism 5.0, and patients were analysed in two groups, i.e. those aged ≤18 years and N18 years at the first visit, using paired t-tests and Fishers exact test. A total of 32 G+P− patients were identified (n=16 aged ≤18 years, n=16 aged N18 years) from 19 families. Mean age at first visit was 23±15 years and the majority of the patients were female (62%). Most patients (69%) had a family history of sudden cardiac death. None of the cohort had developed previous syncope. The underlying mutations were identified in MYBPC3 (63%), MYH7 (19%), TNNI3 (4%) and ACTN2 (2%) genes, and one patient carried two mutations. ECG analysis showed all patients were in sinus rhythm, with a mean QT interval of 406±17 ms, which was independent of age. An abnormal ECG was reported in 13% of individuals, all of which were non-specific ST segment changes. During the mean follow-up period of 4.1±2.8 years, no patients developed new symptoms. Serial echocardiography showed a small increase in LV wall thickness in those aged ≤18 years (7.4±1.8 to 8.9±2.5 mm; p=0.02; Fig. 1A) which was consistent with normal physiological cardiac growth [5]. No increase was observed in those aged N18 years (9.7±1.1 to 10.0±1.0 mm; p=0.50; Fig. 1B). In the combined group of all 32 patients, a small increase in LV wall thickness was present (8.5±1.5 mm to 9.4±2.0 mm; p=0.01; Fig. 1C). Only one patient of the cohort developed clinical HCM during follow-up. This patient, a boy aged 7 years at first visit, developed clinical HCM by age 16 years (increase in LV wall thickness from 8 to 16 mm), and required insertion of an implantable cardioverter defibrillator (ICD) for primary prevention. Genetic testing in HCM has had a major impact on both understanding the molecular processes underpinning HCM, as well as providing a key diagnostic tool in screening at-risk familymembers. Widespread genetic testing has also led to the identification of a new subgroup of HCM patients, i.e. G+P− patients. As seen in the current cohort, these patients are usually asymptomatic, have no signs of a hypertrophic phenotype, and can present at all ages. It is currently unclear if these G+P− patients will develop disease later in life. In addition, children who are G+P− may simply be at the pre-clinical

Brugada Syndrome: A Heterogeneous Disease with a Common ECG Phenotype?

Our understanding of Brugada syndrome (BrS) has evolved since the syndrome was first described in 1992. BrS is considered to be a primary inherited channelopathy often involving the inward sodium current and the diagnosis has traditionally required the exclusion of overt structural heart disease.

A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form. OBJECTIVE The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT. METHODS Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms. RESULTS Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism. CONCLUSION We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.

New Insights Into the Genetic Basis of Inherited Arrhythmia Syndromes

Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3 Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype. This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship. ### Long QT Syndrome Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …

Social determinants of health in the setting of hypertrophic cardiomyopathy

INTRODUCTION Social determinants of health play an important role in explaining poor health outcomes across many chronic disease states. The impact of the social gradient in the setting of an inherited heart disease, hypertrophic cardiomyopathy (HCM), has not been investigated. This study sought to profile the socioeconomic status of patients attending a specialized multidisciplinary clinic and to determine the impact on clinical factors, psychosocial wellbeing and adherence to medical advice. METHODS Patients with HCM and at-risk relatives attending a specialized multidisciplinary clinic in Sydney Australia between 2011 and 2013 were included. Clinical, socioeconomic, geographic remoteness and adherence data were available. A broader clinic and registry-based group completed a survey including psychological wellbeing, health-related quality of life, Morisky Medication Adherence Scale and individual-level socioeconomic information. RESULTS Over a 3-year period, 486 patients were seen in the specialized clinic. There was an over-representation of patients from socioeconomically advantaged and the least geographically remote areas. Socioeconomic disadvantage was associated with comorbidities, poor psychological wellbeing and health-related quality of life, lower understanding of HCM and more complex clinical management issues such as NYHA class, atrial fibrillation and left ventricular outflow tract obstruction. Approximately 10% of patients were non-adherent to medical advice, and poor medication adherence was seen in 30% of HCM patients with associated factors being younger age, minority ethnicity, anxiety and poor mental quality of life. CONCLUSIONS Of all the patients attending a specialized cardiac genetic clinic, there is an overrepresentation of patients from very advantaged and major metropolitan areas and suggests that those most in need of a multidisciplinary approach to care are not accessing it.

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.

Cardiovascular Effects of Energy Drinks in Familial Long QT Syndrome: A Randomized Cross-Over Study

BACKGROUND Caffeinated energy drinks may trigger serious cardiac effects. The aim of this study was to determine the cardiovascular effects of caffeinated energy drink consumption in patients with familial long QT syndrome (LQTS). METHODS AND RESULTS From 2014-2016, 24 LQTS patients aged 16-50 years were recruited to a randomized, double-blind, cross-over study of energy drink (ED) versus control (CD) with participants acting as their own controls (one week washout). The primary study outcome was an increase in corrected QT interval (QTc) by >20ms. Secondary outcomes were changes in systolic and diastolic blood pressure. In 24 patients with LQTS (no dropout), mean age was 29±9 years, 13/24 (54%) were female, and 8/24 (33%) were probands. Intention to treat analysis revealed no significant change in QTc with ED compared with CD (12±28ms vs 16±27ms, 3% vs 4%, p=0.71). The systolic and diastolic blood pressure significantly increased with ED compared to CD (peak change 7±16mmHg vs 1±16mmHg, 6% vs 0.8%, p=0.046 and 8±10 vs 2±9mmHg, 11% vs 3% p=0.01 respectively). These changes correlated with significant increases in serum caffeine (14.6±11.3 vs 0.5±0.1μmol/L, p<0.001) and serum taurine (737±199 vs -59±22μmol/L, p<0.001). There were three patients with dangerous QTc prolongation of ≥50ms following energy drink consumption. CONCLUSION Caffeinated energy drinks have significant haemodynamic effects in patients with LQTS, especifically an acute increase in blood pressure. Since dangerous QTc prolongation was seen in some LQTS patients, we recommend caution in young patients with LQTS consuming energy drinks.

Late positive flecainide challenge test for Brugada syndrome

Belinda Gray, BSc(Med), MBBS, Mark McGuire, MBBS, PhD, Christopher Semsarian, MBBS, PhD, FHRS, Caroline Medi, BMed, PhD From the Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia, and Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, New South Wales, Australia.

NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy

The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM.

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

Objective To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome‐wide focus. Study design A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole‐exome sequencing. Exome‐wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic‐matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St Georges University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole‐exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinics Medical Genome Facility, Rochester, Minnesota. Results Although no exome‐wide significant (P < 2.5 × 10−6) difference in burden of ultra‐rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra‐rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). Conclusions The lack of exome‐wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence‐based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS‐associated biological pathway for future SIDS investigative research.