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

Background: Patients 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. Methods: Patients 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. Results: A total of 17 patients were recruited; 16 of whom met primary endpoints. Baseline NYHA was 30±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 310±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 (328.50±99.9 vs 285.80±105.5 meters, p=0.018); other outcome measures also indicated benefit with PPoP. Conclusions: In a randomized placebo-controlled trial, LV pacing reduces obstruction and improves exercise performance in severely symptomatic LVMCO patients. Registration: [NCT03450252][1]. ### Competing Interest Statement SEP provides Consultancy to Circle Cardiovascular Imaging Inc., Calgary, Alberta, Canada. LL has received speaker fees from Sanofi, Alnylam and Bristol Myers Squibb (BMS); and received a grant from BMS. ### Clinical Trial NCT03450252 ### Funding Statement J.W. Malcolmson is funded by a National Institute for Health and Care Research Clinical Doctoral Research Fellowship (ICACDRF-2016-02-068). R.K. Hughes is supported by the British Heart Foundation (grant number FS/17/82/33222). This work acknowledges the support of the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330); a delivery partnership of Barts Health NHS Trust, Queen Mary University of London, St George?s University Hospitals NHS Foundation Trust and St George?s University of London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was granted by the National Research Ethics Service, City Road and Hampstead, London (Reference: 17/LO/1725). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data is available on reasonable request to corresponding author [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03450252&atom=%2Fmedrxiv%2Fearly%2F2023%2F12%2F20%2F2023.12.18.23300178.atom