Jason T. Jacobson

Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis

The remodeling of ventricular gap junctions, as defined by changes in size, distribution, or function, is a prominent feature of diseased myocardium. However, the regulation of assembly and maintenance of gap junctions remains poorly understood. To investigate N-cadherin function in the adult myocardium, we used a floxed N-cadherin gene in conjunction with a cardiac-specific tamoxifen-inducible Cre transgene. The mutant animals appeared active and healthy until their sudden death ≈2 months after deleting N-cadherin from the heart. Electrophysiologic analysis revealed abnormal conduction in the ventricles of mutant animals, including diminished QRS complex amplitude consistent with loss of electrical coupling in the myocardium. A significant decrease in the gap junction proteins, connexin-43 and connexin-40, was observed in N-cadherin–depleted myocytes. Perturbation of connexin function resulted in decreased ventricular conduction velocity, as determined by optical mapping. Our data suggest that perturbation of the N-cadherin/catenin complex in heart disease may be an underlying cause, leading to the establishment of the arrythmogenic substrate by destabilizing gap junctions at the cell surface.

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers.

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias.

A Novel Method for Sinus Node Modification and Phrenic Nerve Protection in Resistant Cases

This is a case report of inappropriate sinus tachycardia in a patient who had a previous unsuccessful endocardial ablation, which had been limited due to concerns of phrenic nerve injury. The patient required a repeat ablation that utilized a novel combined epicardial and endocardial approach for sinus node modification and simultaneous protection of the phrenic nerve via an epicardial balloon.

Assessing patients for catheter ablation during hospitalization for acute heart failure

Heart rhythm problems are common among patients who are hospitalized with acute heart failure (HF). Although it is often difficult to determine whether a tachyarrhythmia is the major contributor to an acute HF decompensation or merely a consequence of the decompensation, both issues usually need to be addressed. There is also a subset of patients with HF who have a tachycardia-induced cardiomyopathy (TIC), where the sole cause of the ventricular dysfunction is the heart rhythm problem. In most cases, the management of a tachyarrhythmia in a patient with acute HF is not significantly different than the management of a heart rhythm problem in any patient, but there are several special clinical scenarios and important considerations. These considerations include the time urgency for an intervention, the usual need to be more aggressive and definitive, the need to stabilize a patient to allow for a heart rhythm intervention, such as catheter ablation to be performed safely, and the limitations of antiarrhythmic drugs in patients with ventricular dysfunction. Catheter ablation is a highly effective treatment option for many patients with supraventricular or ventricular tachycardias who are hospitalized with HF. This review will discuss the different types of tachyarrhythmias that can be associated with acute HF and are amenable to catheter ablation, and the assessment that needs to take place in potentially eligible patients to determine when catheter ablation is appropriate.

Effect of Underlying Heart Disease on the Frequency Content of Ventricular Fibrillation in the Dog Heart

Although prior studies have examined the frequency content of heal electro‐gram characteristics during fibrillation, little is know about the effects of underlying heart disease on these parameters. This study was designed to compare the frequency content of local electrograms during VF in canine models of acute ischemia, subacute infarction, and chronic myocardial infarction (MI) to those in control animals to test the hypothesis that underlying heart disease can alter the basic characteristics of VF. VF was induced using burst pacing in three groups of mongrel dogs. Five dogs were evaluated 8 weeks after LAD occlusion MI, five were evaluated 5 days after experimental MI, and 5 had VF induced before (control) and immediately after LAD occlusion (ischemia). During VF, unipolar electrograms were recorded from 112 sites on the anterior LV and electrograms were evaluated 15 and 30 seconds after VF initiation in each group. Electrograms were analyzed by fast Fourier transform. No significant time dependent changes in VF characteristics were noted. The peak frequency was highest in control animals and 8‐week MI, intermediate in 5‐day MI, and lowest in acute ischemia (P < 0.01 for pairwise comparisons). In contrast, the fractional of energy within a bandwidth of 25% peak amplitude was highest in acute ischemia, (P < 0.001) and similar in the other three groups. Infarction decreased total energy by approximately 50%. In conclusion, the pressure of ischemia or infarction alters the frequency content of VF in a complex fashion. In addition to decreasing the peak frequency, the shape of the power spectral curve is altered in models of structural heart disease. These results suggest that the electrophysiological changes produced by infarction or ischemia alter the structural organization of ventricular fibrillation.

Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes

Diabetes and other metabolic conditions characterized by elevated blood glucose constitute important risk factors for cardiovascular disease. Hyperglycemia targets myocardial cells rendering ineffective mechanical properties of the heart, but cellular alterations dictating the progressive deterioration of cardiac function with metabolic disorders remain to be clarified. In the current study, we examined the effects of hyperglycemia on cardiac function and myocyte physiology by employing mice with high blood glucose induced by administration of streptozotocin, a compound toxic to insulin-producing β-cells. We found that hyperglycemia initially delayed the electrical recovery of the heart, whereas cardiac function became defective only after ~2 mo with this condition and gradually worsened with time. Prolonged hyperglycemia was associated with increased chamber dilation, thinning of the left ventricle (LV), and myocyte loss. Cardiomyocytes from hyperglycemic mice exhibited defective Ca2+ transients before the appearance of LV systolic defects. Alterations in Ca2+ transients involved enhanced spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca2+ clearance, and declined SR Ca2+ load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca2+ homeostasis in cardiomyocytes, hindering contractile activity and contributing to the manifestation of the diabetic cardiomyopathy. NEW & NOTEWORTHY We have investigated the effects of hyperglycemia on cardiomyocyte physiology and ventricular function. Our results indicate that defective Ca2+ handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.

Short QT Syndrome in Current Clinical Practice.

Short QT syndrome is a rare inherited autosomal dominant cardiac channelopathy associated with malignant ventricular and atrial arrhythmias. A shortened corrected QT interval is a marker for risk of malignant arrhythmias, which are secondary to increased transmural dispersion of repolarization. The underlying gain of function mutations in the potassium channels are most common but genetic testing remains low yield. This review discusses the cellular mechanisms, genetic involvement, clinical presentation, and current recommended management of patients with short QT syndrome relevant to current clinical practice.

Management of ventricular arrhythmias in structural heart disease

Abstract Ventricular arrhythmias (VA) are a source of significant morbidity and mortality in patients with structural heart disease (SHD). The advent of the implantable cardiac defibrillator (ICD) has had a positive effect on mortality, but the associated morbidity remains a significant problem. Modern treatment of VA has advanced far beyond medical therapy and includes strategies as simple as intelligent ICD programming and as complex as catheter ablation (CA). In these pages, the spectrum of management strategies will be discussed; from anti-arrhythmic drugs and ICD implantation and programming to CA and autonomic modulation. The focus of this review will be on strategies for secondary prevention of VA in patients with SHD, supported by clinical evidence for their utilization.

Radiofrequency ablation of atrioventricular nodal reentrant tachycardia in an orthotopic heart transplantation patient

Atrioventricular nodal reentrant tachycardia (AVNRT) after orthotropic heart transplant (OHT) is rare, in absence of rejection.

Notch Signaling Modulates the Electrical Behavior of Cardiomyocytes

Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+ Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+ currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a γ-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents. NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+ Kv currents, critical determinants of the electrical repolarization of myocytes.