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Sacubitril/Valsartan Linked to Improved Cardiac Autonomic Nervous System in HFrEF


This international study, from investigators in Germany and Austria, looked at the effect sacubitril/valsartan can have among patients who have heart failure with reduced ejection fraction (HFrEF) and the impact on their cardiac autonomic nervous system.

Data from an international investigation show the benefits that sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), can have among patients living with heart failure with reduced ejection fraction (HFrEF) by improving imbalance in the cardiac autonomic nervous system (CANS). This imbalance has been linked to mortality in HFrEF, noted the study authors.

Findings were presented at the recent American Heart Association Scientific Sessions 2022 held in Chicago, and they show that the ARNI—already known to reduce mortality risk and HF-related hospitalization among this patient group—improves the CANS on several fronts. The principal comparison measure the investigators used was heart rate variability (HRV), which was measured before sacubitril/valsartan was started and 3 months after through echocardiography (ECG) and standardized 12-lead Holter ECG.

“A reduction in standard deviation of normal-to-normal intervals (SDNN) to values < 50 ms is associated with an annual mortality of > 50%,” the authors wrote. “Whether ARNI affects CANS has not been studied.”

Among the 48 patients in this analysis (mean [SD] age, 65 [13] years; 88% male patients; 72% had ischemic cardiomyopathy)—from the original 63 recruited between June 2021 and March 2022, these 48 were still on sacubitril/valsartan at follow-up—the sacubitril/valsartan dose increased close to 73% between first measure and follow-up: 106 (24) vs 183 (88) mg (P < .001). In addition, the SDNN improved close to 42%, from 30 (2) to 42 (3) ms at follow-up (P < .001).

Improvements were also seen on 3 other measures related to CANS:

  • There was a 55% increase in the mean square of differences between consecutive R-R intervals (RMSSD) (P < .001)
  • Heart rate decreased by 12% (P = .005)
  • Heart rate deceleration capacity rose 370% (P < .001)

No change was seen in periodic repolarization dynamics between first measure and follow-up: 7.6 (5.9) vs 6.0 (4.3) deg2 (P = .09).

The study authors’ analysis also showed that left ventricular ejection fraction (LVEF) improved and plasma N-terminal-pro hormone brain natriuretic peptide (NT-proBNP) fell in accordance with HRV changes:

  • LVEF rose from 28% (6%) to 38% (10%) (P < .001)
  • Plasma NT-proBNP decreased to 1838 (621) pg/mL from 5083 (790) pg/mL (P = .002)

The overall New York Heart Association class of disease also improved from class III to class II.

“Significant increase of parasympathetic CANS tone was observed after initiation of ARNI therapy as evidenced by decreased heart rate, increased deceleration capacity, SDNN, and RMSSD,” the authors concluded. “Part of the beneficial effects of ARNI might be related to the accentuation of parasympathetic CANS modulating mortality risk and risk for HFrEF hospitalizations.”


AA Boehmer, Schubert T, Dobre BC, et al. Influence of ARNI on cardiac autonomic nervous system. Presented at: AHA Scientific Sessions; November 5-7, 2022; Chicago, Illinois. Abstract SU2217.

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