Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy: The BRAVO Trial.

OBJECTIVES: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method. BACKGROUND: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform. METHODS: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro-B-type natriuretic peptide. RESULTS: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro-B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms. CONCLUSIONS: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829).

A randomized comparison of triple-site versus dual-site ventricular stimulation in patients with congestive heart failure.

OBJECTIVES: We compared the effects of triple-site versus dual-site biventricular stimulation in candidates for cardiac resynchronization therapy. BACKGROUND: Conventional biventricular stimulation with a single right ventricular (RV) and a single left ventricular (LV) lead is associated with persistence of cardiac dyssynchrony in up to 30% of patients. METHODS: This multicenter, single-blind, crossover study enrolled 40 patients (mean age 70 +/- 9 years) with moderate-to-severe heart failure despite optimal drug treatment, a mean LV ejection fraction of 26 +/- 11%, and permanent atrial fibrillation requiring cardiac pacing for slow ventricular rate. A cardiac resynchronization therapy device connected to 1 RV and 2 LV leads, inserted in 2 separate coronary sinus tributaries, was successfully implanted in 34 patients. After 3 months of biventricular stimulation, the patients were randomly assigned to stimulation for 3 months with either 1 RV and 2 LV leads (3-V) or to conventional stimulation with 1 RV and 1 LV lead (2-V), then crossed over for 3 months to the alternate configuration. The primary study end point was quality of ventricular resynchronization (Z ratio). Secondary end points included reverse LV remodeling, quality of life, distance covered during 6-min hall walk, and procedure-related morbidity and mortality. Data from the 6- and 9-month visits were combined to compare end points associated with 2-V versus 3-V. RESULTS: Data eligible for protocol-defined analyses were available in 26 patients. No significant difference in Z ratio, quality of life, and 6-min hall walk was observed between 2-V and 3-V. However, a significantly higher LV ejection fraction (27 +/- 11% vs. 35 +/- 11%; p = 0.001) and smaller LV end-systolic volume (157 +/- 69 cm(3) vs. 134 +/- 75 cm(3); p = 0.02) and diameter (57 +/- 12 mm vs. 54 +/- 10 mm; p = 0.02) were observed with 3-V than with 2-V. There was a single minor procedure-related complication. CONCLUSIONS: Cardiac resynchronization therapy with 1 RV and 2 LV leads was safe and associated with significantly more LV reverse remodeling than conventional biventricular stimulation.

NO metabolite flux across the human coronary circulation.

OBJECTIVES: The theory of a red blood cell derived nitric oxide (NO) reserve conserving NO bioactivity and delivering NO as a function of oxygen demand has been the subject of much interest. We identified the human coronary circulation as an ideal model system in which to analyse NO metabolites because of its large physiological oxygen gradient. Our objective was to identify whether oxygen drove apportion between various NO metabolite species across a single vascular bed. METHODS: Plasma and red blood cell NO metabolites were assessed from the left main coronary artery, coronary sinus and pulmonary artery (providing cross heart and cross pulmonary analysis) of healthy subjects under resting conditions and following administration of an inhibitor of NO biosynthesis. Physiological parameters and angiographic data were monitored throughout the study. RESULTS: Under baseline conditions we observed significant metabolite flux upon the transit of blood across the coronary and pulmonary vascular beds. Whilst there was no net loss of NO through the coronary circulation (p=0.0759), plasma nitrite/protein NO (excluding nitrate) (p=0.0279) and red blood cell sulphanilamide labile signal (p=0.0143) decreased whereas haemoglobin-bound NO increased three-fold (p=0.005). These changes across the coronary circulation were reversed through the pulmonary circuit with red blood cell sulphanilamide labile signal (p=0.0143) and plasma nitrite/protein NO (p=0.0279) increasing and haemoglobin-bound NO decreasing. Blockade of NO synthesis increased mean arterial blood pressure (p<0.01) and reduced coronary artery diameter (p<0.05), however we observed similar apportion of NO metabolites across the heart and lung with no net loss or gain in total NO metabolites. CONCLUSIONS: For the first time in human subjects across the resting coronary circulation we reveal significant re-apportionment of NO between metabolite species which correlate with haemoglobin oxygen saturation. These changes occur even within the transit time of blood across this single vascular bed. We demonstrate no net loss/gain of NO from the total metabolite pool across the coronary circulation even where NO biosynthesis is inhibited.

A new endocardial "over-the-wire" or stylet-driven left ventricular lead: first clinical experience.

Transvenous left ventricular (LV) leads are primarily inserted "over-the-wire" (OTW). However, a stylet-driven (SD) approach may be a helpful alternative. A new polyurethane-coated, unipolar LV lead can be placed either by a stylet or a guide wire, which can be inserted into the lead body from both ends. The multicenter OVID study evaluates the clinical performance of this new steroid- and nonsteroid eluting lead. The primary endpoint is the LV lead implant success rate after identification of the coronary sinus (CS). Secondary endpoints include complication rate, short- and long-term lead characteristics, overall procedure and LV lead placement duration, total fluoroscopy time, and lead handling characteristics ratings. To date, 96 patients with heart failure (68 +/- 9 years old, 76% men) are enrolled. The CS was identified in 95 patients and, in 85 (88.5%), the LV lead was successfully implanted. The final lead positioning was lateral in 41%, posterolateral in 35%, anterolateral in 18%, and great cardiac vein in 6% of patients. In 70%, the 85 successful implantations, both stylet-driven and guide-wire techniques were used, a stylet only was used in 22%, and a guide wire only in 8%. Mean overall duration of 85 successful procedures was 112 +/- 40 minutes, total fluoroscopy time 28 +/- 15 minutes, and the duration of LV lead placement was 35 +/- 29 minutes. During a 3-month follow-up, the loss of LV capture occurred in three and phrenic nerve stimulation in six patients. The mean long-term pacing threshold is 0.8 V/0.5 ms and pacing impedance is 550 Omega. The OVID data suggest that these new leads are safe and effective. The choice of both OTW and SD techniques during lead implantation offers greater procedural flexibility.