sacubitril and Arrhythmias--Cardiac

Sacubitril/valsartan, the first angiotensin receptor neprilysin inhibitor approved by the Food and Drug Administration for marketing, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in patients with chronic heart failure with a reduced ejection fraction. However, some researchers have also found that sacubitril/valsartan has an antiarrhythmic effect. The mechanism by which sacubitril/valsartan reduces the mortality associated with malignant ventricular arrhythmias is not precise. Many studies have concluded that ventricular arrhythmia is associated with a reduction in myocardial fibrosis. This article reviews the current understanding of the effects of sacubitril/valsartan on the reduction of ventricular arrhythmia and explains its possible mechanisms. The results of this study suggest that sacubitril/valsartan reduces the occurrence of appropriate implantable cardioverter-defibrillator shocks. Meanwhile, sacubitril/valsartan may reduce the occurrence of ventricular arrhythmias by affecting 3 pathways of B-type natriuretic peptide, Angiotensin II, and Bradykinin. The conclusion of this study is that sacubitril/valsartan reduces the number of implantable cardioverter-defibrillator shocks and ventricular arrhythmias in heart failure with reduced ejection fraction patients.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Neprilysin; Stroke Volume; Tetrazoles; Valsartan; Ventricular Dysfunction, Left

Heart failure (HF) is a major cause of morbidity and mortality, with nearly half of all HF-related deaths resulting from sudden cardiac death (SCD), most often from an arrhythmic event. The pathophysiologic changes that occur in response to the hemodynamic stress of HF may lead to increased arrhythmogenesis. Theoretically, medications that block these arrhythmogenic substrates would decrease the risk of SCD. The combined angiotensin receptor and neprilysin inhibitor (ARNi; tradename Entresto) is the newest commercially available medication for the treatment of heart failure.. We reviewed and synthesized the available literature regarding sacubitril/valsartan and its effects on cardiac rhythm. ARNi has been shown to decrease cardiovascular mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF). Emerging evidence suggests that ARNi also may play a role in reducing arrhythmogenesis and thereby SCD.. This review summarizes the current data regarding this ARNi and its potential antiarrhythmic effects.

Topics: Angiotensin Receptor Antagonists; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Heart Failure; Humans; Neprilysin; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan

Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM-HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias.. Adverse event reports related to ventricular arrhythmias were examined in PARADIGM-HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time-updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy-defibrillator (CRT-D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62-0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65-0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT-D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71-1.21) versus 0.53 (95% CI 0.37-0.78) in those without an ischaemic aetiology (p for interaction = 0.020).. Sacubitril/valsartan reduced the incidence of investigator-reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non-ischaemic aetiology.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Stroke Volume; Tetrazoles; Valsartan

Conflicting results have been reported in the literature on the potential antiarrhythmic effect of sacubitril/valsartan in heart failure patients with reduced ejection fraction (HFrEF). The objectives of this study were: 1- to evaluate the long term effects of sacubitril/valsartan on arrhythmic burden in HFrEF patients; 2- to evaluate the correlation between the reduction of premature ventricular complexes during f-up and reverse remodelling.. We identified 255 consecutive HFrEF patients treated with sacubitril/valsartan between March 2017 and May 2020 and followed by the Heart Failure and Cardiac Transplant Unit of IRCCS San Matteo Hospital in Pavia (Italy). Within this subgroup, 153 patients underwent 24 h-Holter-ECG or implantable cardioverter defibrillators (ICD) interrogation at baseline, at 12 months (t1) and at 24 months (t2) and transthoracic echocardiography at baseline and after 12 months after the beginning of sacubitril/valsartan. Cardiac-related hospitalizations were analyzed in the 12 months preceding and during 24 months following the drug starting date.. Global burden of 24-h premature ventricular complexes (PVC) was significantly reduced at 12 months (t1) and at 24 months (t2) as compared to the same period before treatment (1043 [304-3360] vs 768 [82-2784] at t1 vs 114 [9-333] at t2, P = 0.000). In the subgroup of patients implanted with biventricular ICD (n = 30), the percentage of biventricular pacing increased significantly (96% [94-99] vs 98% [96-99] at t1 vs 98%[97-100] at t2; P = 0.027). The burden of non-sustained ventricular tachycardia and sustained ventricular tachycardia did not change from baseline to t1 and t2, but a reduction of patients with at least one ICD appropriate shock was reported. The correlations between reduction in 24 h PVC and reduction in LV-ESVi or improvement in LVEF were not statistically significant (respectively R = 0.144, P = 0.197 and R = -0.190, P = 0.074). Heart failure related hospitalizations decreased during follow up (11.1% in the year before treatment vs 4.6% at t1 and 4.6% at t2; P = 0.040).. Sacubitril/valsartan reduced the number of premature ventricular complexes and increased the percentage of biventricular pacing in a cohort of HFrEF patients already on optimal medical therapy. PVC reduction did not correlate with reverse left ventricular remodelling. Whether sacubitril/valsartan has any direct antiarrhythmic effects is an issue to be better explored in future studies.

Topics: Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Stroke Volume; Tachycardia, Ventricular; Tetrazoles; Treatment Outcome; Valsartan; Ventricular Function, Left; Ventricular Remodeling

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Echocardiography; Heart Failure; Humans; Incidence; Stroke Volume; Tetrazoles; Valsartan

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Arrhythmias, Cardiac; Biphenyl Compounds; Drug Combinations; Echocardiography; Heart Failure; Humans; Incidence; Stroke Volume; Tetrazoles; Valsartan

Fabry disease (FD) is a rare, X-linked lysosomal deposition disease characterized by multi-system symptoms. The accumulation of globotriaosylceramide in various organs, such as the kidneys and heart, as well as the nervous system, has been speculated to be the mechanism involved in tissue damage, including vascular impairment with thrombotic events.. Here, we describe a 72-year-old male patient diagnosed with FD, who first presented with acute myocardial infarction, left ventricular thrombosis, and pericardial effusion, accompanied by cardiac hypertrophy.. A physical examination showed that he was hemodynamically stable and an electrocardiogram showed ventricular tachycardia (Fig. 1A). The single obvious abnormality was an ST segment depression with a preterminal negative T wave in leads I and aVL (Fig. 1B). Coronary angiography revealed regular findings (Fig. 2). Echocardiogram conducted at our hospital revealed hypertrophy, ejection fraction 40%, pericardial effusion (Fig. 3). Speckle tracking two-dimensional echocardiography strain analysis technology confirmed left ventricular thrombosis, and also revealed decreased movement of the inferior and posterior walls, the basal segment of the posterior wall was locally fibrotic (Fig. 4A and B). Further, myocardial contrast echocardiography confirmed left ventricular thrombosis (Fig. 4C). Cardiovascular magnetic resonance imaging indicated biventricular uneven hypertrophy, which was considered metabolic cardiomyopathy, with diffuse fibrosis of biventricular walls, apical thrombosis, and ischemic cardiomyopathy in the basal segment of the left ventricular lateral wall and left ventricular anterior wall (Fig. 5). Serum alpha-galactosidase concentration was 0.7 nmol/h/mgPr (normal range, 29.0-64.4 nmol/h/mgPr). Subsequent genetic testing revealed that he was hemizygous for a previously reported missense mutation (c.902G>A) inexon 6 of the GLA gene,[1] which induce p.R301Q (p.Arg301Gln), confirming a diagnosis of FD (Fig. 6).. Orally administered drugs included rivaroxaban, sacubitril valsartan, beta blockers, dapagliflozin, and mineralocorticoid receptor antagonist. Cardiac resynchronization therapy with an implanted defibrillator was implemented to prevent sudden death.. At present, he is still in follow-up and there have been no adverse events.. Our case suggests that clinicians should consider the possibility of FD in patients with acute myocardial infarction and cardiomyopathy. A detailed analysis of subtle historical clues would help promote earlier diagnosis of FD.

Topics: Aged; Aminobutyrates; Arrhythmias, Cardiac; Biphenyl Compounds; Cardiomegaly; Fabry Disease; Humans; Male; Myocardial Infarction; Pericardial Effusion; Thrombosis

Sacubitril/valsartan (SAC/VAL) has been used in patients with heart failure and reduced ejection fraction (HFrEF), and cardiac resynchronization therapy (CRT) could benefit the HFrEF patients with wide QRS durations. This study aimed to evaluate the clinical impacts of SAC/VAL on reverse cardiac remodelling in CRT-eligible and CRT-ineligible HFrEF patients with different QRS durations.. The TAROT-HF study was a multicentre, observational study enrolling patients who initiated SAC/VAL from 10 hospitals since 2017. Patients with baseline left ventricular ejection fraction (LVEF) ≤ 35% were classified into two groups: (i) Group 1: CRT-eligible group, patients with left bundle branch block (LBBB) morphology plus QRS duration ≥130 ms or non-LBBB morphology plus QRS duration ≥150 ms; and (ii) Group 2: CRT-ineligible group. Propensity score matching was performed to adjust for confounders, and 1168 patients were analysed. Baseline characteristics were comparable between the two groups. The improvements in LVEF and left ventricular end-systolic volume index (LVESVi) were more significant in Group 2 than in Group 1 after 1 year SAC/VAL treatment (LVEF: 8.4% ± 11.3% vs. 4.5% ± 8.1%, P < 0.001; change percentages in LVESVi: -14.4% ± 25.9% vs. -9.6% ± 23.1%, P = 0.004). LVEF improving to ≥50% in Groups 1 and 2 constituted 5.2% and 20.2% after 1 year SAC/VAL treatment (P < 0.001). Multivariate analyses showed that wide QRS durations were negatively associated with the reverse cardiac remodelling in these HFrEF patients with SAC/VAL treatment.. Despite SAC/VAL treatment, wide QRS durations are associated with lower degrees of left ventricular improvement than narrow ones in the HFrEF patients. Optimal intervention timing for the CRT-eligible patients requires further investigation.

Topics: Arrhythmias, Cardiac; Bundle-Branch Block; Cardiac Resynchronization Therapy; Electrocardiography; Heart Failure; Humans; Stroke Volume; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS).. A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate.. Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension.. Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Topics: Adverse Drug Reaction Reporting Systems; Aminobutyrates; Arrhythmias, Cardiac; Biphenyl Compounds; Cardiovascular Agents; Cardiovascular Diseases; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; United States; United States Food and Drug Administration