Heterogeneity in the response to angiotensin receptor-neprilysin inhibitors on ventricular arrhythmogenicity and sympathetic tone activation

Abstract Background Sympathetic nervous system (SNS) hyperactivation is a hallmark of heart failure (HF) with reduced (r) ejection fraction (EF), associating with susceptibility to ventricular arrhythmias (VA). While in patients with HFrEF the dual angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan has an overall favorable impact on patients’ morbidity and mortality, its effect on ventricular arrhythmogenicity is still a matter of debate. In this regard, the effects of angiotensin receptor-neprilysin inhibitors (ARNI) therapy on sympathetic activity is largely unknown, possibly influencing the burden of ventricular arrhythmias (VA). Purpose To evaluate the interaction between ARNI therapy, cardiac sympathetic activity, as assessed with 123I-metaiodobenzylguanidine (MIBG) scintigraphy, and VA in patients with HFrEF. Methods Twenty-one patients with HFrEF (mean age 71±10 years; 16 males) and an implanted cardioverter/defibrillator and significant VA burden (10% daily ventricular ectopic beats and/or episodes of ventricular tachycardia in a 24-hours period at baseline Holter monitoring assessment or ICD interrogation) underwent MIBG scintigraphy at baseline and 6-months after ARNI therapy. Each patient was on otherwise on guideline-directed optimized medical therapy. The MIBG heart-to-mediastinum ratio was computed as a measure of myocardial sympathetic tone and considered normal if 1.6. Results Twelve/21 (57%) patients had a non-ischemic cardiomyopathy (NICM). The average daily VEB burden was 11±4% with 1 and 8 patients showing episode(s) of sustained and non-sustained VT monomorphic, respectively. At MIBG scintigraphy, the average H/M ratio was 1.4±0.2, with only 2 (10%) patients showing a normal H/M ratio (1.6). ARNI were titrated to the average dose of 74 mg daily. At follow-up, improved left ventricular (LV) EF was found in 90% of patients (before therapy: 32±4%; after therapy 39±5%; P0.001); conversely, only in 12/21 patients 75% of whom with non-ischemic cardiomyopathy (NICM); P0.05 a significant improvement of the VA burden was observed. Patients with an improved VA burden showed a lower LVEF at baseline (29±4 vs 33±3; p=0.023), a higher delta LVEF (9±5% vs 4±4%; P=0.05), and a higher heart-to-mediastinum ratio of MIBG (1.6±0.2 vs 1.4±0.2; P=0.038) after ARNI than those with persistently severe VA burden (Figure 1). At multivariable analysis, the delta heart-to-mediastinum ratio was the strongest predictor of an "improved" VA burden at follow-up (OR 7.8, 95% CI 1.2-49.5 per 0.1 increase; P=0.02). Conclusions ARNI therapy was associated with lowered cardiac sympathetic tone, potentially influencing VA burden during prolonged therapy