Pramod Deshmukh

Direct His-bundle pacing: present and future.

Direct His‐bundle pacing (DHBP) produces rapid sequential multisite synchronous ventricular activation and, therefore, would be an ideal alternative to right ventricular apical (RVA) pacing. In 54 patients with cardiomyopathy, ejection fraction (EF) 0.23 ± 0.11, persistent atrial fibrillation, and normal QRS < 120 ms. DHBP was attempted. This was successful in 39 patients. In seven patients, the effect of increasing heart rate on contractility (Treppe effect) was investigated. Twelve patients who also received a RVA lead underwent cardiopulmonary testing. After a mean follow‐up of 42 months, 29 patients are still alive with EF improving from 0.23 ± 0.11 to 0.33 ± 0.15. Functional class improved from 3.5 to 2.2. DP/dt increased at each pacing site (P < 0.05) as the heart rate increased to 60, 100, and 120 beats/min. Rise in dP/dt by DHBP pacing at 120 beats/min was at least 170 ± mmHg/s, greater than any other site in the ventricle (P < 0.05). Cardiopulmonary testing revealed longer exercise time (RVA 255 ± 110 s) (His 280 ± 104 s) (P < 0.05), higher O2 uptake (RVA 15 ± 4 mL/kg per minute) (His 16 ± 4 mL/kg minute) (P < 0.05), and later anaerobic threshold (RVA 126 ± 71 s) (His 145 ± 74 s) (P < 0.05) with DHBP compared to RVA pacing. Long‐term DHBP is safe and effective in humans. DHBP is associated with a superior Treppe effect and increased cardiopulmonary reserve when compared to RVA pacing. (PACE 2004; 27[Pt. II]:862–870)

Mutations in SCN10A Are Responsible for a Large Fraction of Cases of Brugada Syndrome

BACKGROUND BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart. OBJECTIVES The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

The role of silent ischemia, the arrhythmic substrate and the short-long sequence in the genesis of sudden cardiac death

To study the role of silent ischemia and the arrhythmic substrate in the genesis of sudden cardiac death, 67 patients were studied (mean age 62 +/- 12 years). Of these, 14 patients (Group 1) had an in-hospital episode of ventricular tachycardia or fibrillation while wearing a 24 h Holter ambulatory electrocardiographic (ECG) monitor, 33 (Group II) had a documented episode of sustained ventricular tachycardia or fibrillation, or both, and 20 (Group III) had angina pectoris but no ventricular tachycardia or fibrillation. Eight Group I survivors underwent programmed electrical stimulation or ECG signal averaging, or both. All Group II patients underwent 24 h Holter monitoring and ECG signal averaging to detect late potentials before programmed electrical stimulation. Group III patients underwent both 24 h Holter recording and coronary angiography. The 24 h ECG tapes were analyzed for ST segment changes, prematurity index and characteristics of ventricular premature depolarizations. Any ST depression greater than or equal to 1 mm for greater than 30 s was considered to be a reflection of silent ischemia, and the induction of ventricular tachycardia or fibrillation by programmed electrical stimulation or the presence of late potentials, or both, was considered to be a reflection of the arrhythmia substrate. Silent ischemia preceded ventricular tachycardia in only 2 (14%) of the 14 Group I patients. The prematurity index was less than 1 in only 18% of ventricular tachycardia episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.

BACKGROUND Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K(+) channel (I(K-ATP)), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. METHODS AND RESULTS Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC₅₀ that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC₅₀ from 8.5 ± 2 mM to 13.4 ± 5 μM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by -18.0 mV (p<0.01) and increased late I(Na) from 0.14% to 2.01% of peak I(Na) (p<0.01). CONCLUSION Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in I(K-ATP) when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.

Riata lead failure with normal electrical lead parameters and normal fluoroscopic appearance

Recently, insulation breach of the Riata lead raised a big concern. Management of these externalized leads has been addressed by professional organizations. However, what to do in patients with Riata leads without manifested failure is an ongoing clinical dilemma. Here, we present two clinical scenarios where the implantable cardioverter defibrillator system failed to deliver shock therapy in spite of having a new ICD generator and “appropriately functioning leads” as revealed by lead interrogation.

His bundle pacing: Initial experience and lessons learned

Direct His bundle pacing provides the most physiologic means of artificial pacing of the ventricles with a preserved His-Purkinje system and may play a role in patients with a diseased intrinsic conduction system. We describe our initial motivations and experience with permanent direct His bundle pacing and important lessons learned since that time.

His Bundle Pacing: Concept to Reality

This article summarizes the initial experience with permanent His bundle pacing, the lessons learned, and the concepts that have been developed in the subsequent decade of experience with His bundle pacing. This article also addresses the advancements in technology, which have allowed His bundle pacing to be more widely adopted and used in various clinical situations.

Hemodynamics of His Bundle Pacing

In addition to the His bundle, numerous other sites have been evaluated as more physiologic alternatives to pacing at the right ventricular apex. Several hemodynamic studies have shown the benefit of His bundle pacing and septal pacing in comparison with right ventricular apical pacing. This article summarizes this literature and presents acute hemodynamic data in an intrapatient study examining His bundle pacing, right ventricular septal pacing, and right ventricular apical pacing.