Distal Ventricular Pacing for Drug-Refractory Mid-Cavity Obstructive Hypertrophic Cardiomyopathy: A Randomized, Placebo-Controlled Trial of Personalized Pacing

Abstract

BackgroundPatients with refractory symptomatic left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy (HCM) have few therapeutic options. Right ventricular (RV) pacing is associated with modest hemodynamic and symptomatic improvement, and LV pacing pilot data suggest therapeutic potential. We hypothesized site-specific-pacing would reduce LVMCO gradients and improve symptoms.MethodsPatients with symptomatic-drug-refractory LVMCO were recruited for a randomized blinded trial of personalized prescription of pacing (PPoP). Multiple LV and apical RV pacing sites were assessed during invasive hemodynamic study of multisite pacing. Patient-specific pacing-site and atrioventricular (AV) delays, defining PPoP, were selected on basis of LVMCO gradient reduction and acceptable pacing parameters. Patients were randomized to 6-months of active PPoP or back-up pacing in a cross-over design. The primary outcome examined invasive gradient change with best-site pacing. Secondary outcomes assessed quality of life and exercise following randomization to PPoP.ResultsA total of 17 patients were recruited; 16 of whom met primary endpoints. Baseline NYHA was 3±0.6 despite optimal medical therapy. Hemodynamic effects were assessed during pacing at the RV apex and at a mean of 8 LV sites. The gradients in all 16 patients fell with pacing, with maximum gradient reduction achieved via LV pacing in 14 (88%) patients and RV apex in 2. The mean baseline gradient of 80±29 mmHg, fell to 31±21 mmHg with best-site pacing, a 60% reduction (p<0.0001). One cardiac vein perforation occurred in one case, and 15 subjects entered cross-over; 2 withdrawals occurred during cross-over. Of the 13 completing cross-over, 9 (69%) chose active pacing in PPoP configuration as preferred setting. PPoP was associated with improved 6-minute walking test performance (328.5±99.9 vs 285.8±105.5 meters, p=0.018); other outcome measures also indicated benefit with PPoP.ConclusionsIn a randomized placebo-controlled trial, LV pacing reduces obstruction and improves exercise performance in severely symptomatic LVMCO patients.RegistrationNCT03450252.Clinical PerspectiveWhat is Known?Patients with refractory, symptomatic LVMCO present a significant challenge for clinical management, with very few treatment options.Data on the use of right ventricular (RV) pacing in patients with refractory, symptomatic LVMCO indicate suboptimal therapeutic responses whilst pilot data indicate a potential therapeutic role for LV pacing.What the Study Adds?Personalized prescription of pacing (PPoP) therapy guided by invasive hemodynamics significantly reduced LVMCO gradients and improved exercise performance in the first randomized, placebo-controlled trial in symptomatic LVMCO.This study provides the basis for a multicenter trial of PPoP for LVMCO and for the use of site-specific pacing in managing other forms of HCM.Graphical Abstract