The Impact of Angiotensin Receptor-Neprilysin Inhibitors on Arrhythmias in Patients with Heart Failure: A Systematic Review and Meta-analysis.

Angiotensin receptor-neprilysin inhibitor (ARNI) use has become increasingly popular. Current guidelines recommend using ARNI therapy for heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). As therapies become more widely available, heart failure-associated burdens such as ventricular arrhythmias and sudden cardiac death (SCD) will become increasingly prevalent. We conducted a systematic review and meta-analysis to assess the impact of ARNI therapy on HFrEF and HFpEF pertaining to arrhythmogenesis and SCD. We performed a search of MEDLINE (PubMed), the Cochrane Library, and ClinicalTrials.gov for relevant studies. The odds ratios (ORs) of SCD, ventricular tachycardia (VT), ventricular fibrillation (VF), atrial fibrillation/flutter (AF), supraventricular tachycardia (SVT), and implantable cardioverter-defibrillator (ICD) shocks were calculated. A total of 10 studies, including 6 randomized controlled trials and 4 observational studies, were included in the analysis. A total of 18,548 patients from all studies were included, with 9,328 patients in the ARNI arm and 9,220 patients in the angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) arm, with a median follow-up time of 15 months. There was a significant reduction in the composite outcomes of SCD and ventricular arrhythmias in patients treated with ARNIs compared to those treated with ACEIs/ARBs (OR, 0.71; 95% confidence interval, 0.54-0.93; P = .01; I2 = 17%; P = .29). ARNI therapy was also associated with a significant reduction in ICD shocks. There was no significant reduction in the VT, VF, AF, or SVT incidence rate in the ARNI group compared to the ACEI/ARB group. In conclusion, the use of ARNIs confers a reduction in composite outcomes of SCD and ventricular arrhythmias among patients with heart failure. These outcomes were mainly driven by SCD reduction in patients treated with ARNIs.

The CADILLAC risk score accurately identifies patients at low risk for in-hospital mortality and adverse cardiovascular events following ST elevation myocardial infarction.

BACKGROUND: The CADILLAC risk score was developed to identify patients at low risk for adverse cardiovascular events following ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI). METHODS: We performed a single center retrospective review of STEMI hospitalizations treated with PPCI from 2014 to 2018. Patients were stratified using the CADILLAC risk score into low risk, intermediate risk and high risk groups. Patients presenting with cardiac arrest or cardiogenic shock were excluded from the study. The primary outcome was adverse clinical events during initial hospitalization. Secondary outcomes were adverse clinical events at 30 days and 1 year following index hospitalization. RESULTS: The study included 341 patients. Compared to patients with a low CADILLAC score, adverse clinical events were similar in the intermediate risk group during hospitalization (OR 1.23, CI 0.37-4.05, p 0.733) and at 30 days (OR 2.27, CI 0.93-5.56, p 0.0733) while adverse clinical events were significantly elevated in the high risk group during hospitalization (OR 4.75, CI 1.91-11.84, p 0.0008) and at 30 days (OR 8.73, CI 4.02-18.96, p < 0.0001). At 1 year follow-up, compared to the low risk CADILLAC group (9.4% adverse clinical event rate), cumulative adverse clinical events were significantly higher in the intermediate risk group (22.9% event rate, OR 2.86, CI 1.39-5.89, p 0.0044) and in the elevated risk group (58.6% event rate, OR 13.67, CI 6.81-27.43, p < 0.0001). The mortality rate was 0% for patients defined at low risk by CADILLAC score during hospitalization, as well up to 1 year follow up. On receiver operating curve analysis, discrimination of in-hospital adverse clinical events was fair using CADILLAC (C = 0.66, odds ratio 1.18; 95% CI 1.04-1.33; p = 0.0064) with somewhat better discrimination at 30-day follow-up (C = 0.719) and 1-year follow-up (C = 0.715). CONCLUSION: Patients defined as low risk by the CADILLAC score following a STEMI were associated with lower mortality and adverse clinical event rates during hospitalization and up to 1 year following STEMI when compared to those with an intermediate or high CADILLAC score.

Usefulness of Glucagon-Like Peptide-1 Receptor Agonists to Reduce Adverse Cardiovascular Disease Events in Patients with Type 2 Diabetes Mellitus.

Evidence suggests glucagon-like peptide-1 receptor agonists (GLP-1 RA) reduce cardiovascular disease (CVD) events. The objective of this study was to analyze randomized controlled trials (RCT) testing GLP-1 RA's effect on CVD events among participants with type 2 diabetes (T2DM). RCTs comparing GLP-1 RA versus placebo were identified using the PubMed and Cochrane databases. The endpoints in this study included major adverse cardiovascular events (MACE; a composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke), and the individual components of MACE. The primary analysis calculated risk ratios (RR) and 95% confidence intervals (CI) for each endpoint. Heterogeneity for each endpoint was calculated using Chi2 and I2 tests. For any endpoint with significant heterogeneity, a meta-regression was performed using mean baseline hemoglobin A1C (A1C) as the moderator and a R2 value was calculated. Seven RCTs (N = 56,004) were identified with 174,163 patient-years of follow-up. GLP-1 RA reduced MACE [RR 0.89, 95% CI 0.83 to 0.95], cardiovascular death [RR 0.88, 95% CI 0.81 to 0.95], and nonfatal stroke [RR 0.85, 95% CI 0.77 to 0.95]. There was no statistically significant heterogeneity among these RCTs. GLP-1 RA did not reduce nonfatal MI [RR 0.91, 95% CI 0.81 to 1.02]. However, there was significant heterogeneity among these RCTs (Chi2 = 12.68, p = 0.05, I2 = 53%). When accounting for baseline A1C in the regression model, there was no longer significant heterogeneity for this endpoint (p = 0.23, I2 = 27%). A potential linear relationship between baseline A1C and GLP-1 RA's effect on nonfatal MI (R2 = 0.64) was observed. In conclusion, GLP-1 RA reduced MACE, cardiovascular death, and nonfatal stroke; GLP-1 RA did not reduce nonfatal MI, however there may be a linear association between baseline A1C and GLP-1 RA's effect on nonfatal MI.

A Comparison of Rate Control Agents for the Treatment of Atrial Fibrillation: Follow-Up Investigation of the AFFIRM Study.

There are limited data from randomized controlled trials comparing rate control agents in atrial fibrillation. Patient-level data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was used to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline. The rate control agents used were beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin. The independent variable for this analysis was the initial study drug used and the dependent variables were time to first hospitalization and time to death from any cause. We analyzed 1,144 out of 2,027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. There were 485 (42.5%) participants in the beta-blocker group, 344 (30%) in the calcium channel blocker group, and 315 (27.5%) in the digoxin group. All hospitalization and all-cause mortality occurred in 55.9% and 12.5% of those in the beta-blocker group, 58.4% and 16.7% in the calcium channel blocker group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group. In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with atrial fibrillation.

Redox regulation of hormone sensitive lipase: Potential role in the mechanism of MEHP-induced stimulation of basal steroid synthesis in MA-10 Leydig cells.

Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a plasticizer with endocrine disruptor activity that has been shown to stimulate basal steroid biosynthesis in Leydig cells. The mechanism by which it does so is unknown. Using MA-10 mouse tumor Leydig cells, we assessed the effects of MEHP on reactive oxygen species (ROS) levels, and on the signal transduction pathways that mobilize cholesterol. Exposure to 0-300 µM MEHP stimulated basal progesterone production in a dose-dependent manner. Progesterone stimulation was correlated with increases in the phosphorylation of hormone-sensitive lipase (HSL; aka cholesteryl ester hydrolase), which is involved in the production of free cholesterol, and of steroidogenic acute regulatory (STAR) protein expression. Co-treating MA-10 cells with MEHP and the ROS scavenger N-acetyl cysteine (NAC) blocked the activation of HSL, blunted MEHP-induced STAR, and reduced basal progesterone formation. These observations suggest that ROS generation by MEHP leads to activation of HSL and increase in STAR which, together, result in increased free-cholesterol bioavailability and progesterone formation.