Molecular mechanisms of heart failure progression associated with implantable cardioverter-defibrillator shocks for ventricular tachyarrhythmias

Implantable cardioverter-defibrillators (ICDs) are highly effective in reducing mortality related to ventricular tachyarrhythmias (VTAs). Despite this benefit, the occurrence of ICD shocks for VTAs in patients with heart failure (HF) and depressed left ventricular function has been associated with adverse outcomes. Patients with shocked VTAs are at an elevated risk of HF and death. While VTAs may be markers for high-risk patients, it is possible that the harmful effects of electrical shocks and VTAs are involved in HF progression and associated mortality. Some investigators have speculated that shocked VTAs may activate signaling pathways in the molecular cascade of HF. We recently reported in an experimental model of ventricular fibrillation storm that multiple ICD shocks for recurrent ventricular fibrillation caused striking activation of Ca2+/calmodulin-dependent protein kinase II, a validated signaling molecule for HF. This review article describes the harmful effects of shocks and VTAs and proposes that Ca2+/calmodulin-dependent protein kinase II could connect shocked VTAs to adverse outcomes

Normal dose of pilsicainide showed marked negative inotropic effects in a patient who had no underlying heart disease

We report the case of an otherwise healthy 64-year-old female who developed cardiopulmonary arrest after the administration of pilsicainide for treatment of paroxysmal atrial fibrillation. She had had an episode of paroxysmal atrial fibrillation, but no liver dysfunction, renal dysfunction, or echocardiographic abnormality before her admission. On the day of admission and the following day, 50 mg of pilsicainide was administered intravenously over 10 min (total 100 mg). Shortly after the second injection, she developed marked bradycardia and hypotension and eventually fell into a state of pulseless electrical activity. Immediate cardiopulmonary resuscitation was started. Although application of a temporary pacemaker restored her heart rate, echocardiography revealed no left ventricular contraction. We started percutaneous cardiopulmonary support (PCPS) and intra-aortic balloon pumping (IABP). Her cardiac contraction gradually recovered and returned to completely normality 3 days after the onset. The patient was discharged in an ambulatory condition

A rare KCNE1 polymorphism, D85N, as a genetic modifier of long QT syndrome

Background: The gene KCNE1 encodes the β-subunit of cardiac voltage-gated K+ channels and causes long QT syndrome (LQTS). LQTS is characterized by the prolongation of QT interval and lethal arrhythmias such as torsade de pointes (TdP). A KCNE1 polymorphism, D85N, has been shown to modify the phenotype of LQTS through a loss-of-function effect on both KCNQ1 and KCNH2 channels when co-expressed and reconstituted in a heterologous expression system. Methods: A screening for the D85N polymorphism was performed in 355 LQTS families with mutations in KCNQ1, KCNH2, or SCN5A. Among the probands who had a heterozygous status with the polymorphism, we focused on a family with a KCNH2 mutation (E58K), a N-terminal missense mutation, and examined the clinical significance of this polymorphism. We also conducted biophysical assays to analyze the effect of the polymorphism in mammalian cells. Results: In 355 probands, we found 14 probands (3.9%) who had a heterozygous compound status with the D85N polymorphism. In the family with a KCNE1-D85N polymorphism and a KCNH2-E58K mutation, the proband and her daughter carried both the KCNH2 mutation and the KCNE1-D85N polymorphism. They experienced repetitive syncope and TdP. Two sons of the proband had either KCNH2-E58K mutation or KCNE1-D85N, but were asymptomatic. Biophysical assays of KCNE1-D85N with KCNH2-E58K variants produced a larger reduction in the reconstituted IKr currents compared to co-expression with wild-type KCNE1. Conclusions: The KCNE1-D85N polymorphism modified the clinical features of LQTS patients

Variable phenotype expression with a frameshift mutation of the cardiac sodium channel gene SCN5A

Loss-of-function mutations in the cardiac sodium channel α-subunit gene SCN5A result in multiple inherited arrhythmic syndromes. This case report describes 2 unrelated probands carrying an identical SCN5A frameshift mutation, V1764fsX1786, who exhibited distinct clinical manifestations: progressive cardiac conduction defect (PCCD)/Brugada syndrome (patient #1) and idiopathic ventricular fibrillation (IVF) (patient #2). Using a whole-cell patch clamp technique, cells expressing V1764fsX1786 showed no observable Na+ current. Therefore, a significant phenotypic overlap was found between IVF and PCCD/Brugada syndrome in the 2 probands with the V1764fsX1786, loss-of-function frameshift mutation of the cardiac sodium channel gene SCN5A