Babken Asatryan

Phenotypic Spectrum of HCN4 Mutations: A Clinical Case

The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation (Na+/K+) currents (If/Ih) are generated by 4 members of the channel family (HCN1–4).1 These currents contribute to the pacemaker function2 in heart and brain.3 The HCN4 current is known to play a crucial role in the automaticity of the sinus node through the generation of a slow diastolic depolarization during the phase 4 of the cardiac action potential.4 Thus, it is a crucial channel for appropriate pacemaker activity and conduction system function because it facilitates rapid repolarization. Interestingly, HCN4 has been shown to be expressed in essentially the entire heart tissue.5 Mutations in HCN4 have been associated mainly with sick sinus syndrome phenotype6; however, in recent years, a broad spectrum of phenotypes has been reported, including sinus bradycardia,7 inappropriate sinus tachycardia,8 early-onset atrial fibrillation,9,10 atrio-ventricular block,11,12 idiopathic ventricular tachycardia,13 left ventricular noncompaction (LVNC),14–17 dilation of the aorta, and mood and anxiety disorders.19 In the present study, we report a case with sick sinus syndrome, LVNC, mood and anxiety disorders, and ventricular fibrillation (VF) hosting 2 novel HCN4 -pore mutations. The index patient was a 36-year-old man, who presented initially with mood and anxiety disorders characterized by important depressive episodes. Previous clinical records revealed a slightly impaired left ventricular function, paroxysmal atrial fibrillation, frequent premature ventricular complexes, and nonsustained tachycardia originating from the right ventricle. Therapy with β-blocker was initiated but discontinued shortly because of profound sinus bradycardia, which did not resume after washout. A cardiac magnetic resonance imaging excluded a right ventricular cardiomyopathy. The left ventricle showed an uncommon hypertrabeculation; however, the criteria for an LVNC were not fulfilled at that time. Eight years later, the patient was hospitalized because of heart failure and …

Sports-related sudden cardiac deaths in the young population of Switzerland

Background In Switzerland, ECG screening was first recommended for national squad athletes in 1998. Since 2001 it has become mandatory in selected high-risk professional sports. Its impact on the rates of sports-related sudden cardiac death (SCD) is unknown. Objective We aimed to study the incidence, causes and time trends of sports-related SCD in comparison to SCD unrelated to exercise in Switzerland. Methods We reviewed all forensic reports of SCDs of the German-speaking region of Switzerland in the age group of 10 to 39 years, occurring between 1999 and 2010. Cases were classified into three categories based on whether or not deaths were associated with sports: no sports (NONE), recreational sports (REC), and competitive sports (COMP). Results Over the 12-year study period, 349 SCD cases were recorded (mean age 30±7 years, 76.5% male); 297 cases were categorized as NONE, 31 as REC, and 21 as COMP. Incidences of SCD per 100,000 person-years [mean (95% CI)] were the lowest in REC [0.43 (0.35–0.56)], followed by COMP [1.19 (0.89–1.60)] and NONE [2.46 (2.27–2.66)]. In all three categories, coronary artery disease (CAD) with or without acute myocardial infarction (MI) was the most common cause of SCD. Three professional athletes were identified in COMP category which all had SCD due to acute MI. There were no time trends, neither in overall, nor in cause-specific incidences of SCD. Conclusions The incidence of SCD in young individuals in Switzerland is low, both related and unrelated to sports. In regions, like Switzerland, where CAD is the leading cause of SCD associated with competitions, screening for cardiovascular risk factors in addition to the current PPS recommendations might be indicated to improve detection of silent CAD and further decrease the incidence of SCD.

Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects for Swiss practice

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased persons privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives.

Translating emerging molecular genetic insights into clinical practice in inherited cardiomyopathies

Cardiomyopathies are primarily genetic disorders of the myocardium associated with higher risk of life-threatening cardiac arrhythmias, heart failure, and sudden cardiac death. The evolving knowledge in genomic medicine during the last decade has reshaped our understanding of cardiomyopathies as diseases of multifactorial nature and complex pathophysiology. Genetic testing in cardiomyopathies has subsequently grown from primarily a research tool into an essential clinical evaluation piece with important clinical implications for patients and their families. The purpose of this review is to provide with a contemporary insight into the implications of genetic testing in diagnosis, therapy, and prognosis of patients with inherited cardiomyopathies. Here, we summarize the contemporary knowledge on genotype-phenotype correlations in inherited cardiomyopathies and highlight the recent significant achievements in the field of translational cardiovascular genetics.

The association between endurance training and heart rate variability: the confounding role of heart rate.

Heart rate variability (HRV) is a widely used marker of cardiac autonomic nervous activity (CANA). Changes in HRV with exercise training have often been interpreted as increases in vagal activity. HRV is strongly associated with heart rate, which in turn, is associated with heart size. There is strong evidence from basic studies that lower heart rate in response to exercise training is caused by morphological and electrical remodeling of the heart. In a cross-sectional study in participants of a 10 mile race, we investigated the influence of endurance exercise on HRV parameters independently of heart size and heart rate. One-hundred-and-seventy-two runners (52 females and 120 males) ranging from novice runners with a first participation to an endurance event to highly trained runners, with up to 15 h of training per week, were included in the analysis. R-R intervals were recorded by electrocardiography over 24 h. Left ventricular end diastolic volume indexed to body surface area (LVEDVI) was assessed by transthoracic echocardiography and peak oxygen consumption (VO2peak) by cardiopulmonary exercise testing. Exercise was quantified by VO2peak, training volume, and race performance. HRV was determined during deep sleep. HRV markers of vagal activity were moderately associated with exercise variables (standardized β = 0.28–0.40, all p < 0.01). These associations disappeared when controlling for heart rate and LVEDVI. Due to the intrinsic association between heart rate and HRV, conclusions based on HRV parameters do not necessarily reflect differences in CANA. Based on current evidence, we discourage the use of HRV as a marker of CANA when measuring the effect of chronic exercise.

Unexplained Cardiac Arrest in an Apparently Healthy Young Woman: What Is the Underlying Substrate of the Arrhythmia?

An 18-year-old woman with a history of anorexia nervosa and multiple episodes of dizziness and syncope of unknown cause was transferred to the emergency department by ambulance 1 hour after starting to feel palpitations, dizziness, tightness in the chest, and presyncope at school. At the time of presentation, she was hemodynamically stable, but the symptoms persisted. The ECG recorded at admission is shown in Figure 1A. A supraventricular tachycardia with aberrancy was suspected. Conversion attempts first with vagal maneuvers (carotid sinus massage and Valsalva maneuver) followed by adenosine (6 mg IV) were unsuccessful, but the ventricular rate and the QRS duration normalized gradually within 12 hours. The full cardiovascular and laboratory workup showed unremarkable findings, and the patient was discharged with prescription of metoprolol 25 mg/d. Figure 1. ECG obtained at the time of initial admission and readmission to the emergency department. A , The ECG recorded at initial admission shows regular wide-QRS complex tachycardia with right bundle-branch block morphology and a ventricular rate of 120 bpm, no identifiable P waves, and no atrioventricular dissociation. B , The ECG recorded at readmission shows agonal heart rhythm with …

Late-onset severe long QT syndrome.

We report a case of torsades de pointes arrhythmia as the first manifestation of congenital Long QT syndrome in a 77‐year‐old man with family history of sudden unexplained death. This case illustrates the importance of vigilant clinical assessment and genetic counseling in families with sudden death in order to identify properly asymptomatic relatives at risk for cardiac events. It also demonstrates that Long QT syndrome can still manifest with potentially fatal arrhythmias late in life in previously asymptomatic elderly patients.