Multipolar Pacing by Cardiac Resynchronization Therapy With a Defibrillator as Treatment in Type 2 Diabetes Mellitus Failing Heart Patients: Impact on Responders Rate, and Clinical Outcomes.

Introduction: Type 2 diabetes mellitus (T2DM) is a worldwide increasing disease, impacting on heart functions, and cardiac diseases, and outcomes. T2DM may lead to heart failure (HF) disease, and conditioning HF disease progression, and the response to treatments. In HF patients, cardiac resynchronization therapy with a defibrillator (CRT-d) is a well-established treatment to improve symptoms, quality of life, NYHA class, and clinical outcomes. T2DM may condition the CRT-d response. The advancement of CRT-d technology worked to reduce implant complications, phrenic nerve stimulation (PNS) events, and left ventricle (LV) catheter dislodgments, and to ameliorate the CRT-d responders rate, and clinical outcomes. The multipolar LV lead pacing represented one of the waited technological advancement in CRT-d technology, resulted in a stable and continuous CRT-d pacing. The stable and continuous CRT-d pacing may condition the prognosis, and CRT-d responders rate in failing heart patients. At our knowledge, there are not data investigating these effects in a population of T2DM failing heart subjects. In this study T2DM failing heart patients randomly received a CRT-d via multipolar LV lead and/or a CRT-d via bipolar LV lead. In these patients we evaluated, as primary study endpoints, PNS events, LV lead dislodgments, interventions for LV re-positioning, cardiac deaths, all cause deaths, stroke events, and hospitalizations for HF worsening. As secondary endpoints we evaluated arrhythmic events, strokes, and CRT-d responders rate. Our study hypothesis was that, in T2DM failing heart patients multipolar LV pacing may lead to a reduction of PNS episodes, LV leads dislodgments, and interventions to re-positioning LV leads, leading to a significant amelioration of the HF clinical status, and of the CRT-d responders rate. These effects induced by multipolar CRT-d pacing may reduce arrhythmic events, hospitalizations for HF worsening, and of cardiac deaths, and all cause deaths in T2DM patients.

Methods: From September 2012 to September 2015 we conducted a multicenter, prospective, randomized study at University of Campania Luigi Vanvitelli, Italy, Catholic University of Sacred Heart, Campobasso, Italy, and John Paul II Research and Care Foundation, Campobasso, Italy. We screened 213 consecutive T2DM patients with stable chronic HF, NYHA functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%), stable sinus rhythm, candidates to receive a CRT-d treatment according to the international guidelines. Exclusion criteria were: age <18 or >75 years, ejection fraction >35%, previous implantable cardioverter defibrillator (ICD), CRT-d and/or pacemaker implant, absence of informed patient consent, and any condition that would make survival for 1 year unlikely. 198 eligible patients were included in the study, and received a CRT-d treatment, and a traditional CRT-d ambulatory monitoring. The CRT-d has randomly undergone via multipolar left lead pacing (n 101) v/s bipolar left lead pacing (n 98). Study population was divided in Multipolar CRT-d group (multipolar LV pacing), v/s Bipolar CRT-d group (bipolar LV pacing), according to the LV lead stimulation catheter used, and implanted at enrolment. 99 patients in Multipolar CRT group v/s 96 patients in the Bipolar CRT group completed the follow up. All patients were informed about the study nature, and gave their written informed, and signed consent to participate in the study.

Study protocol: 199 patients received a CRT-d, then divided in multipolar CRT-d patients (n 101), and bipolar CRT-d patients (n 98). Before interventions, baseline laboratory studies, including HbA1c, lipid panel, and fibrinogen, were determined. Follow-up was concluded at 12 months after CRT-d implant. Responders patients to a CRT-d treatment were defined by evidence of LV reverse remodeling, 6 minutes-walk improvement and Minnesota Living with Heart Failure scale improvement. Enrolled patients were followed by clinical, instrumental assessment, and device telemetric control at follow up. During these visits we reported lead functionality parameters, and arrhythmic events in CRT-d recipients, PNS episodes, and CRT-d effect on clinical outcomes. This study was conducted from September 2012 to December 2015. The study was conducted in accordance with the Declaration of Helsinki. The Ethics Committees of all participating institutions approved the protocol.

Intervention phase: CRT-d implant procedure, and LV pacing leads positioning Experienced electrophysiologists performed CRT implant procedures, that were standardized. Right atrial catheters were all placed in right atrial appendage, right ventricular catheters in right ventricle apex, as indicated by antero-posterior, right anterior, and left anterior oblique views projections at radioscopic imaging. LV epicardial catheters were placed by percutaneous coronary sinus catheterization. In this case we have chosen, by previous described radioscopic projections and angiography, a lateral and/or posterior-lateral target vessel, according to international guidelines recommendations. We randomly chose a multipolar and/or a bipolar left ventricle pacing lead, as described before in the text. Implantation duration was defined as the time between skin incision until suture. Measurements were repeated within 24hours of implantation using the implanted pulse generator and pacemaker programmer, and then 10th days, 6th month, 12th month after discharge at follow up. The sensing and pacing LV configurations were defined by 10 bipolar configurations for multipolar LV pacing modality, and at least 4 different left ventricle pacing configurations (LV tip to either LV ring or right ventricular (RV) coil, and LV ring to either LV tip or RV coil) for the bipolar left ventricle pacing group. LV pacing leads were connected to an appropriate bipolar CRT-D device.

Follow up phase: