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In this comparative-effectiveness trial, biventricular pacing prevented the reduction in left ventricular ejection fraction that is seen with right ventricular pacing. The deleterious effect of nonphysiologic right ventricular apical pacing on left ventricular systolic function has been recognized since the 1920s. 1 In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, the unexpected increased rates of death and hospital admission for heart failure among patients who were randomly assigned to the dual-chamber, rate-adaptive (DDDR) mode were purportedly due to the adverse effect of right ventricular apical pacing on left ventricular structural remodeling. 2 Results of subsequent trials have supported the notion that right ventricular apical pacing might lead to adverse clinical outcomes in patients with standard pacing indications. 3 – 7 Nevertheless, right ventricular . . .

Anthracycline (ANT) is a topoisomerase-interacting agent that is used in most malignancy treatments. We investigated the efficacy of enalapril (angiotensin-converting enzyme inhibitor) in the prevention of ANT-induced cardiomyopathy. In this randomized, single-blind, and placebo-controlled study, 69 patients with a newly diagnosed malignancy for which ANT therapy was planned were randomly assigned to either a group receiving enalapril ( n  = 34) or placebo ( n  = 35). Echocardiography studies were performed before chemotherapy and at 6 months after randomization. Additionally, troponin I and creatinine kinase-MB (CK-MB) were measured 1 month after the initiation of chemotherapy. In the enalapril group, the mean left ventricular ejection fraction (LVEF) ( p  = 0.58) was the same at baseline and 6 months after randomization. Conversely, LVEF significantly decreased in the control group ( p  < 0.001). Additionally, LV end systolic volume and left atrial diameter were significantly increased compared with the baseline measures in the control group. According to the tissue Doppler study, the mitral annuli early diastolic ( e ′) and peak systolic ( s ′) velocities were significantly reduced, and the E (the peak early diastolic velocity)/ e ′ ratio was significantly increased in the control group. Furthermore, the TnI and CK-MB levels were significantly higher in the control group than in the enalapril group. Enalapril appears efficacious in preserving systolic and diastolic function in cancer patients treated with ANTs.

Background Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. Methods/Design The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m 2 ) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability. Discussion When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. Trial registration ClinicalTrials.gov; NCT02717507

Right ventricular (RV) pacing has been linked with lead-induced tricuspid regurgitation (TR), left ventricular (LV) dysfunction, and dyssynchrony, but the effect of pacing on RV function is unclear. We sought to investigate the effect of pacing on RV synchrony, RV function, and TR, and their association with LV function. In this substudy of the PROTECT-PACE (Protection of left ventricular function during right ventricular pacing) study of the effects of RV pacing in patients with preserved ejection fraction, 145 patients (76 RV apex and 69 non-RV apex pacing) had measurable RV parameters. We assessed tricuspid annular plane systolic excursion (TAPSE), time difference between peak TAPSE and peak mitral annular plane systolic excursion (TM-APSE-dif), global LV longitudinal strain, E/e’, TR vena contracta, and TR peak gradient. Echocardiography was performed just after implantation and at 2 years. TR parameters significantly worsened after 2 years, but pacing site was not associated with changes in RV and TR parameters. No temporal change in TAPSE and TM-APSE-dif was observed overall, but worsening of TM-APSE-dif was associated with worsening TAPSE. Global longitudinal strain and E/e’ both deteriorated over 2 years; these changes were significantly associated. In a multivariate regression, worsening global longitudinal strain and worsening TM-APSE-dif were significantly associated with deterioration of TAPSE. Furthermore, increased E/e’ and its deterioration were associated with worsening TR vena contracta and TR peak gradient, respectively. Decreased TAPSE was also associated with deterioration of TR vena contracta. In conclusion, RV pacing appears to worsen TR, an effect which might be caused by elevated LV filling pressure due to LV dysfunction. In this study, RV pacing did not affect RV function during 2-year follow-up, but such an effect might occur if RV dyssynchrony or LV dysfunction occurred after pacing. The effect of RV pacing site on RV and TR mechanics was minor.

Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and β-blockers (BBs) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate–extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of ≥10% at follow-up or an absolute decrease of ≥5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function.

Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes. A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity. Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p<0.01), improved LV function (LV ejection fraction +3.09% [95% confidence interval (CI) 0.48 to 5.70%; p = 0.02]) and LV dimensions (LV end systolic volume indexed to body surface area -2.99mL/m2 [95% CI -5.69 to -0.29; p = 0.03]). Intervention also preserved battery longevity by approximately 5 months (+0.38 years [95% CI 0.14 to 0.62; p<0.01)) with no evidence of an effect on quality of life (+0.19, [95% CI -0.25 to 0.62; p = 0.402]). Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients. ClinicalTrials.gov identifier: NCT03627585.

Purpose Patients with ischemic cardiomyopathy (ICM) are prone to scar-related ventricular tachycardia (VT). The success of VT ablation depends on accurate arrhythmogenic substrate localization, followed by optimal delivery of energy provided by constant electrode-tissue contact. Current manual and remote magnetic navigation (RMN)-guided ablation strategies aim to identify a reentry circuit and to target a critical isthmus through activation and entrainment mapping during ongoing tachycardia. The MAGNETIC VT trial will assess if VT ablation using the Niobe™ ES magnetic navigation system results in superior outcomes compared to a manual approach in subjects with ischemic scar VT and low ejection fraction. Methods and results This is a randomized, single-blind, prospective, multicenter post-market study. A total of 386 subjects (193 per group) will be enrolled and randomized 1:1 between treatment with the Niobe ES system and treatment via a manual procedure at up to 20 sites. The study population will consist of patients with ischemic cardiomyopathy with left ventricular ejection fraction (LVEF) of ≤35% and implantable cardioverter defibrillator (ICD) who have sustained monomorphic VT. The primary study endpoint is freedom from any recurrence of VT through 12 months. The secondary endpoints are acute success; freedom from any VT at 1 year in a large-scar subpopulation; procedure-related major adverse events; and mortality rate through 12-month follow-up. Follow-up will consist of visits at 3, 6, 9, and 12 months, all of which will include ICD interrogation. Conclusions The MAGNETIC VT trial will help determine whether substrate-based ablation of VT with RMN has clinical advantages over manual catheter manipulation. Trial registration Clinicaltrials.gov identifier: NCT02637947

Diastolic dysfunction is an important predictor of poor outcome after myocardial infarction. Metformin treatment improved diastolic function in animal models and patients with diabetes. Whether metformin improves diastolic function in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unknown. The GIPS-III trial randomized STEMI patients, without known diabetes, to metformin or placebo initiated directly after PCI. The previously reported primary endpoint was left ventricular ejection fraction at 4 months, which was unaffected by metformin treatment. This is a predefined substudy to determine an effect of metformin on diastolic function. For this substudy trans-thoracic echocardiography was performed during hospitalization and after 4 months. Diastolic dysfunction was defined as having the combination of a functional alteration (i.e. decreased tissue velocity: mean of septal e' and lateral e') and a structural alteration (i.e. increased left atrial volume index (LAVI)). In addition, left ventricular mass index and transmitral flow velocity (E) to mean e' ratio (E/e') were measured to determine an effect of metformin on individual echocardiographic markers of diastolic function. In 237 (63%) patients included in the GIPS-III trial diastolic function was measured during hospitalization as well as at 4 months. Diastolic dysfunction was present in 11 (9%) of patients on metformin and 11 (9%) patients on placebo treatment (P = 0.98) during hospitalization. After 4 months 22 (19%) of patients with metformin and 18 (15%) patients with placebo (P = 0.47) had diastolic dysfunction. In addition, metformin did not improve any of the individual echocardiographic markers of diastolic function. In contrast to experimental and observational data, our randomized placebo controlled trial did not suggest a beneficial effect of short-term metformin treatment on diastolic function in STEMI patients.

Mechanical left ventricular dyssynchrony (MLVD) might contribute in the therapeutic decision-making in patients with heart failure (HF) prior to cardiac resynchronization therapy (CRT). Our aim was to assess MLVD in patients with HF prior to implantable cardioverter-defibrillator (ICD) compared to patients with CRT-D. In a prospective study, patients with LVEF ≤ 35% who were scheduled for ICD or CRT-D, underwent gated SPECT myocardial perfusion imaging with technetium 99m sestamibi within 3 months prior procedure. MLVD was measured by phase analysis. The study cohort consisted of 143 patients, 71 with ICD and 72 with CRT-D. Age 68.3 ± 11 and LVEF 24 ± 6%. Phase standard deviation (SD) was 62.5 ± 18 and 59.7 ± 20 (P = NS), respectively. During follow-up of 23.7 ± 12.1 months, there were 10 vs 14 cardiac death in ICD and CRT-D, respectively (P = NS), hospitalization for HF, in 34 vs 53 (P < .001). In multivariate analysis, Phase SD was the independent predictor for cardiac death [HR 2.66 (95% CI 1.046-6.768), P = .04]. Kaplan-Meier curves of phase SD of 60° significantly identified ICD patients with and without cardiac deaths and hospitalization for HF exacerbation. MLVD by phase SD can identify patients with cardiac events and predict cardiac death in patients treated with ICD.

Background Enhancement of myocardial glucose uptake may reduce fatty acid oxidation and improve tolerance to ischemia. Hyperglycemia, in association with hyperinsulinemia, stimulates this metabolic change but may have deleterious effects on left ventricular (LV) function. The incretin hormone, glucagon-like peptide-1 (GLP-1), also has favorable cardiovascular effects, and has emerged as an alternative method of altering myocardial substrate utilization. In patients with coronary artery disease (CAD), we investigated: (1) the effect of a hyperinsulinemic hyperglycemic clamp (HHC) on myocardial performance during dobutamine stress echocardiography (DSE), and (2) whether an infusion of GLP-1(7-36) at the time of HHC protects against ischemic LV dysfunction during DSE in patients with type 2 diabetes mellitus (T2DM). Methods In study 1, twelve patients underwent two DSEs with tissue Doppler imaging (TDI)—one during the steady-state phase of a HHC. In study 2, ten patients with T2DM underwent two DSEs with TDI during the steady-state phase of a HHC. GLP-1(7-36) was infused intravenously at 1.2 pmol/kg/min during one of the scans. In both studies, global LV function was assessed by ejection fraction and mitral annular systolic velocity, and regional wall LV function was assessed using peak systolic velocity, strain and strain rate from 12 paired non-apical segments. Results In study 1, the HHC (compared with control) increased glucose (13.0 ± 1.9 versus 4.8 ± 0.5 mmol/l, p < 0.0001) and insulin (1,212 ± 514 versus 114 ± 47 pmol/l, p = 0.01) concentrations, and reduced FFA levels (249 ± 175 versus 1,001 ± 333 μmol/l, p < 0.0001), but had no net effect on either global or regional LV function. In study 2, GLP-1 enhanced both global (ejection fraction, 77.5 ± 5.0 versus 71.3 ± 4.3%, p = 0.004) and regional (peak systolic strain −18.1 ± 6.6 versus −15.5 ± 5.4%, p < 0.0001) myocardial performance at peak stress and at 30 min recovery. These effects were predominantly driven by a reduction in contractile dysfunction in regions subject to demand ischemia. Conclusions In patients with CAD, hyperinsulinemic hyperglycemia has a neutral effect on LV function during DSE. However, GLP-1 at the time of hyperglycemia improves myocardial tolerance to demand ischemia in patients with T2DM. Trial Registration: http://www.isrctn.org . Unique identifier ISRCTN69686930