Esperanza García-Molina

Insights into genotype–phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3

Background Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype–phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. Methods 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. Results 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. Conclusions The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile.

Penetrance and risk profile in inherited cardiac diseases studied in a dedicated screening clinic.

Genetically transmitted cardiomyopathies can affect several members in a family. Identification of high-risk patients could lead to a preventive treatment. We report the results of a 5-year experience of a dedicated clinic. Family screening was offered to 493 consecutive unrelated patients; 2,328 subjects (40 +/- 19 years old, 52% men) were evaluated (mean 4.4 relatives/family). Electrocardiography and echocardiography were performed in all cases; additional tests were indicated depending on the disease. Familial study was recommended because of a proband with hypertrophic cardiomyopathy (HC) in 57%, idiopathic dilated cardiomyopathy (IDC) in 14%, arrhythmogenic right ventricular cardiomyopathy (ARVC) in 2%, left ventricular noncompaction in 2%, Brugada syndrome (BS) in 15%, long QT syndrome (LQTS) in 3%, and other conditions in 6%. Familial disease was confirmed in 164 (39%); 43% with HC, 47% with IDC, 25% with ARVC, 33% with left ventricular noncompaction, 28% with BS, and 30% with LQTS. Two hundred twenty-two (44 +/- 20 years old, 60% men) affected relatives were identified (129 of whom were newly diagnosed). Sixty-four patients were newly diagnosed with HC, 40 with IDC, 2 with ARVC, 5 with left ventricular noncompaction, 14 with BS, and 2 with LQTS, in whom appropriate risk stratification and medication, if needed, were initiated (specific medication in 40, 31.0%). Cardioverter-defibrillator implantation was indicated in 4 relatives for primary prevention. Ninety-two (18.7%) had a family history of sudden death (FHSCD). Consanguinity was rare but significantly associated to a higher percentage of family disease (75.0% vs 38.3%, p = 0.003) and family history of sudden death (42.1% vs 17.8, p <0.001). In conclusion, the prevalence of familial disease in inherited cardiac conditions is high. Systematic familial study identified many asymptomatic affected patients who could benefit from early treatment to prevent complications. Dedicated clinics and multidisciplinary teams are needed for proper screening programs.

Unclassifiable arrhythmic cardiomyopathy associated with Emery–Dreifuss caused by a mutation in FHL1

Emery–Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non‐dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL‐1 disorder in X‐linked cardiomyopathy.

Heat stroke, an unusual trigger of Brugada electrocardiogram

A young male individual with diagnosis of heat stroke was admitted unconscious to hospital. Electrocardiogram (ECG) at admission demonstrated typical right bundle branch block and ST-segment elevation in V1 and V2 (coved morphology) diagnostic of Brugada syndrome. Maximal creatine kinase was 10,131 (IU/L); creatine kinase-MB, 15 (IU/L); troponin T, 0.039 ng/mL; and creatinine 1.6, mg/dL. Patient recovered from coma on day 6. Electrocardiogram normalized within the first 24 hours; no arrhythmias were documented. Echocardiogram before discharge was normal. Brugada ECG pattern can express intermittently, and challenge tests with a sodium channel blocker are often required for diagnosis. Ventricular arrhythmias and sudden death occur typically at night or during enhanced vagal activity. Fever has been related to polymorphic ventricular tachycardia particularly in children; nevertheless, prevalence is higher within males in their fourth to fifth decade. Mutations in SCN5A gene encoding a sodium channel can be found in up to 30% of cases. This sodium channel is sensitive to temperature changes. Sequencing of the gene failed to find any abnormality in our patient. A possible role of heat shock proteins in ion channels trafficking to cell membrane has been recently described. Despite diffuse ST-T deviations having been described in patients with heat stroke, localized right precordial leads ST elevation consistent with Brugada syndrome have not been reported. Recognition of typical ECG pattern is of importance because this syndrome is associated to an increased risk of sudden cardiac death.

Value of the “Standing Test” in the Diagnosis and Evaluation of Beta-blocker Therapy Response in Long QT Syndrome

INTRODUCTION AND OBJECTIVES Patients with congenital long QT syndrome (LQTS) have an abnormal QT adaptation to sudden changes in heart rate provoked by standing. The present study sought to evaluate the standing test in a cohort of LQTS patients and to assess if this QT maladaptation phenomenon is ameliorated by beta-blocker therapy. METHODS Electrographic assessments were performed at baseline and immediately after standing in 36 LQTS patients (6 LQT1 [17%], 20 LQT2 [56%], 3 LQT7 [8%], 7 unidentified-genotype patients [19%]) and 41 controls. The corrected QT interval (QTc) was measured at baseline (QTcsupine) and immediately after standing (QTcstanding); the QTc change from baseline (ΔQTc) was calculated as QTcstanding - QTcsupine. The test was repeated in 26 patients receiving beta-blocker therapy. RESULTS Both QTcstanding and ΔQTc were significantly higher in the LQTS group than in controls (QTcstanding, 528 ± 46ms vs 420 ± 15ms, P < .0001; ΔQTc, 78 ± 40ms vs 8 ± 13ms, P < .0001). No significant differences were noted between LQT1 and LQT2 patients. Typical ST-T wave patterns appeared after standing in LQTS patients. Receiver operating characteristic curves of QTcstanding and ΔQTc showed a significant increase in diagnostic value compared with the QTcsupine (area under the curve for both, 0.99 vs 0.85; P < .001). Beta-blockers attenuated the response to standing in LQTS patients (QTcstanding, 440 ± 32ms, P < .0001; ΔQTc, 14 ± 16ms, P < .0001). CONCLUSIONS Evaluation of the QTc after the simple maneuver of standing shows a high diagnostic performance and could be important for monitoring the effects of beta-blocker therapy in LQTS patients.

Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing.

INTRODUCTION AND OBJECTIVES Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. METHODS We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. RESULTS The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. CONCLUSIONS Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment.

Short QT and dilated cardiomyopathy. A phenotype with a good prognosis

A 36 year-old male with palpitations was referred to our cardiac outpatient clinic for evaluation in 1998. ECG demonstrated sinus bradycardia, normal QRS complex and repolarization abnormalities consistent with an early repolarization pattern, together with unusual peaked T waves up to 20 mV high in the precordial leads. The patient had similar ECGs at annual follow-up visits (QTc range: 342–385 ms) (Fig. 1). No arrhythmias were found using Holter ECG monitoring. Based on the peculiar repolarization appearance, a procainamide drug challenge test was then performed with no ECG changes suggestive of Brugada syndrome. During the drug challenge test QTc went from 342 ms to 405 ms. An echocardiogram demonstrated a normal heart. Repeated 24 h and 7 days ambulatory Holters failed to demonstrate any arrhythmia. An ECG from a previous cholesteatoma surgery performed 10 years earlier (1988) had shown similar findings. The patient was admitted to hospital with acute myocardial infarction in 2005 (when hewas 43 years old). The ECG showed up to 3 mm ST elevation in II, III and aVF, together with a mild ST segment depression in V1–V2. The T waves seemed to have normalized (a maximum of 6 mV in V3 was measured) while the QTc interval remained short (380 ms) (Fig. 2C). After primary angioplasty of an occluded right coronary artery, the clinical coursewas unremarkable. Despite a rise in cardiacmarkers (max CK 2219 IU/L), ECGwas normal at hospital discharge. The echocardiogram revealed limited basal inferior wall akinesis. Smoking cessation, betablockers and statins were recommended. An exercise test performed 6 months after myocardial infarction demonstrated no signs of ischaemia or arrhythmia. QTc atmaximal exercise test was365 ms(Fig. 2E). Thepatient remainedasymptomatic onhis last visit in 2010 (46 years old). He enjoys regular exercise 3 days a week, with good tolerance. The patient complained of occasional atypical chest pain and palpitations but, notably, he did not report any syncopal or presyncopal episodes. Familial and genetic testings were performed. His father, aged 75, was diagnosed with dilated cardiomyopathy. The fathers echocardiogram showed a left ventricular ejection fraction of 45% (LVEF), a left ventricular end diastolic diameter of 65 mm (LVEDD) and left ventricular hypertrophy of 13 mm (LVH). He had a history of paroxysmal atrial fibrillation, smoking, and no other cardiovascular risk factors. ECG showed RBBB with relatively short QTc (QTc 390 ms for a QRS complex duration of 150 ms). A 41 year-old sister had a history of paroxysmal supraventricular tachycardia which was successfully ablated and paroxysmal atrial fibrillation. She had mild dilatation (LVEDD of 56 mm) with normal LVEF in the echocardiogram. QTc measured from the sisters ECG was 365 ms. There were no peaked T waves seen in either the fathers or the sisters ECGs. A younger brother, aged 39, had QTc 350 ms with borderline LV diameters and ventricular function. A 48 year-old brother had both a normal ECG and echocardiogram. The eldest brother, aged 50, had dilated LV with regional wall motion abnormalities (LVEF 45%, LVEDD 61 mm) secondary to a prior inferoposterior myocardial infarction. There was no family history of sudden cardiac death. The sequencing of genes encoding ion channels related to QT syndromes and conduction disease was performed. Only two known polymorphism in KCNH2 (K897T) and KCNE1 (S38G) were identified, with normal SCN5A, KCNJ2 and KCNE2. Short QT syndrome has been related to a high risk of ventricular arrhythmia and sudden cardiac death [1,2]. This association is based on a few series with small populations and case reports [2]. Atrial fibrillation has also been described as part of the syndrome [2]. Mutations in potassium channels have been identified as cause of short QT syndrome [3–5]. Although an isolated case of dilated cardiomyopathy with short QT has already been published [6], this is the first reported case of a familial short QT syndrome with dilated cardiomyopathy. In keeping with a Finnish epidemiological study, a short QT interval is consistent with a long life expectancy [7]. In contrast, a recent review reported this syndrome accounted for 19/61 (41%) cases of sudden death mortality/cardiac arrest [2]. Despite most cases with severe events having a very short QT interval, patients with QTc of around 350 ms were not free from fatal complications. This case illustrates QTc interval behavior in a patient followed up for over 20 years, including measurements of changes in ischaemia, exercise and procainamide. ECG variations in short QT patients in different settings are mostly unknown [2]. Multiple Holter studies in our patient have failed to demonstrate any malignant arrhythmia. Severe forms are often described in early descriptions of similar diseases such as long QT, Brugada syndrome, hypertrophic cardiomyopathy and left ventricular non-compaction, etc. Later publications on these conditions have evidenced a more benign and broader phenotypic expression. There is an increasing interest in risk stratification in channelopathies. A short J point–T peak interval has been associated with a poor prognosis. A cut-off point of 120 ms has been suggested as a marker of prognosis. According to this paper, our patients QTc [342 ms], Jp–Tp [130 ms] interval and a QT interval index of 80% are in keeping with a relatively good prognosis. Some authors have suggested that structural cardiac abnormalities can be seen in patients with channelopathies [8]. In particular, SCN5A mutations can cause a variety of conditions such as short and long QT and Brugada syndromes, conduction disease and dilated cardiomyopathy. Despite the weakness of the evidence we have provided, our findings are in keepingwith the observation that channelopathies and cardiomyopathies might be caused by the same genetic abnormality. The patients father and sister both had atrial fibrillation and features of idiopathic dilated cardiomyopathy. Another brother had short QTc and borderline LV diameters and function. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).