E/E′ Is a New Independent Predictor of Recovered Ejection Fraction in Patients With Systolic Heart Failure Undergoing Ablation for Atrial Fibrillation

Aims: Catheter ablation should be considered in patients with atrial fibrillation (AF) and with heart failure (HF) with reduced ejection fraction (EF; HFrEF) to improve survival and reduce heart failure hospitalization. Careful patient selection for AF ablation is key to achieving similar outcome benefits. However, limited data exist regarding predictors of recovered ejection fraction. We aimed to evaluate the predictors of recovered ejection fraction in consecutive patients with HF undergoing AF ablation.Methods and Results: A total of 156 patients [67.3% men, median age 63 (11)] with AF and HF underwent initial catheter ablation between September 2017 and October 2019 in the First Affiliated Hospital of Dalian Medical University. Overall, the percentage of recovered ejection fractions was 72.3%. Recovered EFs were associated with a 39% reduction in all-cause hospitalization compared to non-recovered EFs at the 1-year follow-up [23.8 vs. 62.8 (odds ratio) OR 2.09 (1.40–3.12), P < 0.001]. Univariate analysis for recovered EFs showed that diabetes (P = 0.083), prevalent HF (P = 0.014), prevalent AF (P = 0.051), LVEF (P = 0.022), and E/E′ (P = 0.001) were associated with EF improvement. Multivariate analysis showed that the only independent predictor of EF recovery was E/E′ [OR 1.13 (1.03–1.24); P = 0.011]. A receiver operating characteristic analysis determined that the suitable cut-off value for E/E′ was 15 (sensitivity 38.7%, specificity 89.2%, the area under curve 0.704).Conclusions: Ejection fraction (EF) recovery occurred in 72.3% of patients, associated with a 39% reduction in all-cause hospitalization compared to the non-recovered EFs in our cohort. The only independent predictor of recovered EF was E/E′ < 15 in our series.

Stimulant Drugs of Abuse and Cardiac Arrhythmias

Nonmedical use of prescription and nonprescription drugs is a worldwide epidemic, rapidly growing in magnitude with deaths because of overdose and chronic use. A vast majority of these drugs are stimulants that have various effects on the cardiovascular system including the cardiac rhythm. Drugs, like cocaine and methamphetamine, have measured effects on the conduction system and through several direct and indirect pathways, utilizing multiple second messenger systems, change the structural and electrical substrate of the heart, thereby promoting cardiac dysrhythmias. Substituted amphetamines and cocaine affect the expression and activation kinetics of multiple ion channels and calcium signaling proteins resulting in EKG changes, and atrial and ventricular brady and tachyarrhythmias. Preexisting conditions cause substrate changes in the heart, which decrease the threshold for such drug-induced cardiac arrhythmias. The treatment of cardiac arrhythmias in patients who take drugs of abuse may be specialized and will require an understanding of the unique underlying mechanisms and necessitates a multidisciplinary approach. The use of primary or secondary prevention defibrillators in drug abusers with chronic systolic heart failure is both sensitive and controversial. This review provides a broad overview of cardiac arrhythmias associated with stimulant substance abuse and their management.

Multi-Omics Approach Profiling Metabolic Remodeling in Early Systolic Dysfunction and in Overt Systolic Heart Failure

Metabolic remodeling plays an important role in the pathophysiology of heart failure (HF). We sought to characterize metabolic remodeling and implicated signaling pathways in two rat models of early systolic dysfunction (MOD), and overt systolic HF (SHF). Tandem mass tag-labeled shotgun proteomics, phospho-(p)-proteomics, and non-targeted metabolomics analyses were performed in left ventricular myocardium tissue from Sham, MOD, and SHF using liquid chromatography–mass spectrometry, n = 3 biological samples per group. Mitochondrial proteins were predominantly down-regulated in MOD (125) and SHF (328) vs. Sham. Of these, 82% (103/125) and 66% (218/328) were involved in metabolism and respiration. Oxidative phosphorylation, mitochondrial fatty acid β-oxidation, Krebs cycle, branched-chain amino acids, and amino acid (glutamine and tryptophan) degradation were highly enriched metabolic pathways that decreased in SHF > MOD. Glycogen and glucose degradation increased predominantly in MOD, whereas glycolysis and pyruvate metabolism decreased predominantly in SHF. PKA signaling at the endoplasmic reticulum–mt interface was attenuated in MOD, whereas overall PKA and AMPK cellular signaling were attenuated in SHF vs. Sham. In conclusion, metabolic remodeling plays an important role in myocardial remodeling. PKA and AMPK signaling crosstalk governs metabolic remodeling in progression to SHF.

Predictive value of electrophysiological study for risk stratification of ventricular tachyarrhythmias in patients with non-ischemic cardiomyopathy and chronic systolic heart failure

A systematic review and meta-analysis of studies providing information on the use of intracardiac electrophysiological study (EPS) to stratify the risk of ventricular tachyarrhythmia (VT) in patients with non-ischemic chronic heart failure with low left ventricle ejection fraction (HFrEF). Relevant publications were searched until 20.01.2021 by two independent researchers in major search engines, electronic archives of clinical research, and open access preservatives repository. The end point considered was an episode of sudden cardiac death or sustained paroxysm of VT, or an appropriate electrotherapy of an implanted cardiac defibrillator. Ten clinical trials with 608 relevant patients (mean age: 51.5 ± 12 years; mean left ventricle EF: 26.8±8.5%, NYHA class: I - 17.7%; II - 33.7%; III - 35.9%, IV - 12.7%) were selected. The end point was registered in 92 patients (15.1%): in 47 patients (43.9%) with previously induced VT during EPS and in 45 patients (8.9%) without VT. The diagnostic odds ratio was 5.57 (2.27-13.63). The combined sensitivity and specificity of the EPS were 42% (26-61%) and 88% (83-92%) respectively. The results indicate the potential of EPS to stratify the arrhythmic risk in patients with non-ischemic HFrEF.

Perhexiline Therapy in Patients with Type 2 Diabetes: Dissociation Between Potentiation of Nitric Oxide Signalling and Changes in Insulin Resistance

Purpose: Perhexiline (Px) has previously been utilized primarily in the treatment of otherwise refractory angina pectoris and/or systolic heart failure. In recent years, Px has also shown increasing promise as a potential chemotherapeutic agent. Px inhibits carnitine palmitoyltransferases 1 and 2 (CPT1, CPT2), which control uptake of long-chain fatty acids into mitochondria and thus represent the rate-limiting steps in their metabolism. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may parallel insulin sensitization. No previous studies have examined either the effect of Px on insulin sensitivity, or the relationship of such putative changes with effects on NO signalling. We therefore sought to examine these relationships in patients with stable T2D and cardiovascular disease.Methods: In 30 patients with concomitant T2D and cardiovascular disease, Px was initiated, and dosage was titrated to reach therapeutic range and to prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP), as well as other markers of inflammation and modulators of NO signaling.Results: Px substantially potentiated inhibition of ADP-induced platelet aggregation by SNP (from 16.7±3.0 to 27.3±3.7%; p=0.005). Px did not change fasting blood glucose concentrations and reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p=0.028), via increasing fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L: p=0.014). Increases in SNP responses tended (r=-0.30; p=0.11) to be reciprocally related to increases in HOMA-IR. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px.Conclusions: In patients with stable T2D and cardiovascular disease, Px is not an insulin sensitizer, and does not normally induce hypoglycaemia. These results effectively dissociate the NO-sensitizing effect of Px from variability in insulin signaling.

Long-term Follow-up of the The Danish Study to Assess theEfficacy of ICDs in Patients with Non-ischemic Systolic HeartFailure on Mortality (DANISH)

Background: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICDs) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure during a median follow-up of 5.6 years, though there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional four years of follow-up data from DANISH. Methods: In DANISH, 556 patients with non-ischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years). Results: During a median follow-up of 9.5 years (25 th -75 th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (HR 0.89 [95%CI,0.74-1.08]; P=0.24). In patients ≤70 years (n=829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] vs 158/440 [36%]; HR 0.78 [95%CI,0.61-0.99]; P=0.04), whereas in patients >70 years (n=287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] vs 68/120 [57%]; HR 0.92 [95%CI,0.67-1.28]; P=0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] vs 164/560 [29%], HR 0.87 [95%CI,0,70-1.09], P=0.20; ≤70 years, 87/389 [22%] vs 122/440 [28%], HR 0.75 [95%CI,0.57-0.98], P=0.04; >70 years, 60/167 [36%] vs 42/120 [35%], HR 0.97 [95%CI,0.65-1.45], P=0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] vs 57/560 [10%]; HR 0.60 [95%CI,0.40-0.92]; P=0.02) and in patients ≤70 years (19/389 [5%] vs 49/440 [11%]; HR 0.42 [95%CI,0.24-0.71]; P=0.0008), but not in patients >70 years (16/167 [10%] vs 8/120 [7%]; HR 1.34 [95%CI,0.56-3.19]; P=0.39). Conclusions: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.

Effect of Mineralocorticoid Receptor Antagonists on the Prognosis of Patients with Ventricular Tachyarrhythmias

<b><i>Introduction:</i></b> The study sought to assess the effect of treatment with mineralocorticoid receptor antagonists (MRAs) on long-term prognosis of patients with systolic heart failure (HF) surviving index episodes of ventricular tachyarrhythmias. <b><i>Methods:</i></b> A large retrospective registry was used including consecutive HF patients with left ventricular ejection fraction &#x3c;45% and index episodes of ventricular tachyarrhythmias from 2002 to 2015. The primary endpoint was all-cause mortality at 3 years and secondary endpoints were rehospitalization, as well as the composite endpoint consisting of recurrent ventricular tachyarrhythmias, sudden cardiac death and appropriate implantabe cardioverter defibrillator (ICD) therapies at 3 years. <b><i>Results:</i></b> 748 patients were included, 20% treated with MRA and 80% without. At 3 years, treatment with MRA was not associated with improved all-cause mortality (22% vs. 24%, log-rank <i>p</i> = 0.968; hazard ratio (HR) = 1.008; 95% CI 0.690–1.472; <i>p</i> = 0.968). Accordingly, risk of the composite endpoint (28% vs. 27%; HR = 1.131; 95% CI 0.806–1.589; <i>p</i> = 0.476) and first cardiac rehospitalization (24% vs. 22%; HR = 1.139; 95% CI 0.788–1.648; <i>p</i> = 0.489) were not affected by treatment with MRA. <b><i>Conclusion:</i></b> In patients with ventricular tachyarrhythmias, treatment with MRA was not associated with improved all-cause mortality at 3 years. The therapeutic effect of MRA treatment in patients with ventricular tachyarrhythmias needs to be reinvestigated within further randomized controlled trials.