Left Bundle Branch Area Defibrillator (LBBAD): A First-in-Human Feasibility Study.

BACKGROUND: Left bundle branch area (LBBA) pacing is a promising pacing technique. LBBA implantable cardioverter-defibrillator (ICD) lead implantation reduces the number of leads in patients with both pacing and ICD indications, reducing cost and potentially increasing safety. LBBA positioning of ICD leads has not previously been described. OBJECTIVES: The goal of this study was to evaluate the safety and feasibility of implanting an LBBA ICD lead. METHODS: This prospective, single-center, feasibility study was conducted in patients with an ICD indication. LBBA ICD lead implantation was attempted. Acute pacing parameters and paced electrocardiography data were collected, and defibrillation testing was performed. RESULTS: LBBA defibrillator (LBBAD) implantation was attempted in 5 patients (mean age 57 ± 16.5 years; 20% female) and achieved in 3 (60%). Mean procedural and fluoroscopy duration were 170.0 ± 17.3 minutes and 28.8 ± 16.1 minutes, respectively. Left bundle capture was achieved in 2 patients (66%) and left septal capture in 1 patient. LBBA pacing exhibited a mean QRS duration and V6 R-wave peak time of 121.3 ± 8.3 milliseconds and 86.1 ± 10.0 milliseconds. In all 3 patients, defibrillation testing was successful with mean time to adequate shock delivery of 8.6 ± 2.6 seconds. Acute LBBA pacing threshold and R-wave amplitudes were 0.80 ± 0.60 V at 0.4 milliseconds and 7.0 ± 2.7 mV. No LBBA lead-related complications occurred. CONCLUSIONS: This first-in-human evaluation showed the feasibility of LBBAD implantation in a small cohort of patients. With current tools, implantation remains complex and time-consuming. Considering the feasibility reported and the potential benefits, further technological development in this field is warranted with evaluation of long-term safety and performance.

Ventricular arrhythmia during ajmaline challenge for the Brugada syndrome.

The Brugada syndrome is a genetic disease characterized by an abnormal electrocardiogram (ECG) and an elevated risk of sudden cardiac death. Sodium channel blockers (SCBs), such as ajmaline, are used to unmask the characteristic type 1 Brugada electrocardiographic pattern. We review the literature on the incidence of ventricular arrhythmia (VA) during SCB challenge. We evaluate the clinical and electrocardiographic characteristics of these patients as well as their prognosis. All articles published from January 2000 until August 2015, in which the incidence and predictors of VAs during SCB challenge were reported, are reviewed. The occurrence of VA during SCB challenge ranges from 0 to 17.8%. The weighted average for induction of any VA during sodium blocking challenge is 2.4%; for non-sustained ventricular tachycardia (VT), it is 0.34% and for sustained VT 0.59%. No fatal cases were reported. Predictors may be young age, conduction disturbance at baseline ECG, and mutations in the SCN5A gene. All other clinical and electrocardiographic characteristics failed to be consistent predictors. Life-threatening arrhythmias during SCB challenge are not an exceptional event. Therefore, provocation testing must necessarily be performed in an appropriate environment in which advanced life support facilities are present. Patients who have a higher risk for induced arrhythmias might be those who display a conduction disturbance at baseline ECG or have certain SCN5A mutations or are of a younger age. However, survivors of these induced arrhythmias do not seem to suffer from a worse prognosis.

Nitric oxide donor molsidomine favors features of atherosclerotic plaque stability during cholesterol lowering in rabbits.

Rupture-prone atherosclerotic plaques are characterized by a thin fibrous cap containing numerous macrophage-derived foam cells and few smooth muscle cells (SMC). Decreasing the ratio between macrophages and SMC might favor plaque stabilization. Macrophages expressing inducible nitric oxide (NO) synthase become hypersensitive to killing by exogenous NO donors. Therefore, we investigated in cholesterol-fed rabbits (20 weeks 0.3% cholesterol) the effect of 4 weeks cholesterol withdrawal alone and in combination with the NO donor molsidomine on plaque size, cell composition, superoxide production and extracellular superoxide dismutase (ecSOD) mRNA expression in the atherosclerotic plaques in the aorta. Cholesterol withdrawal alone did not alter atherosclerotic plaque size, the increased superoxide production or the decreased ecSOD mRNA, but led to the formation of a thin subendothelial macrophage-free layer and reduced both vascular cell adhesion molecule-1 expression and cell replication in the luminal part of the plaques. Treatment with molsidomine (1 mg/kg/day) during cholesterol withdrawal did not affect plaque size but increased the thickness of the subendothelial macrophage-free layer consisting of SMC, and normalized both superoxide production and ecSOD mRNA expression. The latter findings demonstrate that molsidomine, when combined with cholesterol lowering, decreases signs of oxidative stress and increases features of stable atherosclerotic plaques.

Platelet phagocytosis and processing of beta-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis.

In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, beta-amyloid peptide (Abeta, cleaved from APP), and platelets (CD9), along with inducible NO synthase (iNOS) and cyclooxygenase-2, two markers of macrophage activation, around microvessels in advanced human carotid artery plaques (n=18). Abeta colocalized with iNOS-expressing macrophages that were often surrounded by platelets. In vitro, murine J774 and human THP-1 macrophages were incubated with or without washed human platelets. Coincubation of macrophages and platelets led to platelet phagocytosis (electron and confocal microscopy) and formation of lipid-, APP-, and Abeta-containing foam cells. These expressed iNOS mRNA (reverse transcription-polymerase chain reaction) and protein and produced nitrite and tumor necrosis factor-alpha (ELISA). Macrophage pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride, a protease inhibitor, reduced APP processing and inhibited NO biosynthesis induced by platelet phagocytosis but not by lipopolysaccharides. Human atherosclerotic plaques and J774 and THP-1 macrophages contained mRNA of the APP-cleaving enzyme beta-secretase. This is the first demonstration of Abeta, a peptide extensively studied in Alzheimer's disease, in human atherosclerotic plaques. It was present in activated iNOS-expressing perivascular macrophages that had phagocytized platelets. In vitro studies indicate that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Abeta, resulting in iNOS induction. This represents a novel mechanism for macrophage activation in atherosclerosis.