Sudden cardiac death prevention in the era of novel heart failure medications

Abstract

Sudden cardiac death (SCD) occurs unexpectedly and is usually a result of ventricular arrhythmia in patients with structural heart disease. The implantable cardioverter-defibrillator (ICD), with or without biventricular pacing, has been proven to be protective for heart failure patients with reduced ejection fraction of <35 % (HFrEF). This device therapy prevents SCD, with additional optimal medications, namely angiotensin-converting enzyme-inhibitors, angiotensin-II receptor-blockers, beta-blockers and mineralocorticoid receptor-antagonists. HFrEF patients present the majority of SCD incidents, as they are characterized by cardiac fibrosis, the main arrhythmogenic element. The introduction of angiotensin-receptor-neprilysin inhibitors, sodium-glucose co-transporter-2 inhibitors and guanylate-cyclase stimulators was associated with reduction of SCD. Additionally, clinical trials have evaluated the improved outcome of these new medications on left ventricular ejection fraction, arrhythmias and HFrEF. These beneficial effects could possibly lead to important changes in decision-making on ICD implantation for primary prevention in patients with HFrEF and reduce the need for device therapy. In this review, we highlight the pathophysiological mechanisms of the new drug agents, and evaluate the possible effect they could have on the role of device therapy as a primary prevention of SCD.

Keywords: Heart failure with reduced ejection fraction; ICD; Sudden cardiac death; Therapy.

Fig. 1

Left ventricular ejection fraction (LVEF) change after initiation of treatment with ARNIs. ARNI = angiotensin-receptor-neprilysin inhibitor; LVEF = left ventricular ejection fraction.

Fig. 2a

Physiological mechanisms of the new medications ARNIs, SGLT2is and vericiguat. (1) ARNIs have additive concurrent effects inhibiting both ARBs with valsartan and neprilysin with sacubitril. Valsartan inhibits the RASS pathway improving renal function and cardiac outcome by clearance of sodium, water and glucose from the interstitial space rather than from the circulation. Valsartan improves vasoconstriction. Sacubitril increases the circulating levels of natriuretic peptides and the concurrent reduction of NT-ProBNP, both which reverse the negative effects driven by the activation of RAA and SNS. Sacubitril reduces natriuresis and LVEDP, an independent predictor of arrhythmia, and improves LV remodeling. (2) SGLT2is also inhibit RAAS for a better clearance of fluid from the interstitial space. Potential indirect systemic effects include: increased energy production from glucose and FA oxidation, increased NO, decreased SNS function, decreased inflammation. Potential direct myocardial effects include: decreased fibrosis and decreased heart rate. (3) cGMP deficiency results in low NO, inflammation, myocardial and vascular dysfunction. Vericiguat targets the sGC-cGMP pathway by enhancing sGC sensitivity to endogenous NO. The increasing levels of cGMP improve systemic and pulmonary vasodilation, decrease LV afterload and hypertrophy, eventually reversing fibrosis. ARBs = angiotensin II receptor blockers, ARNIs = angiotensin-receptor-neprilysin inhibitors, cGMP = cyclic guanosine monophosphate, FA = fatty acid, HCN = Hyperpolarization-activated cyclic nucleotide–gated, LV = left ventricular, LVEDP = left ventricular end-diastolic pressure, NO = nitric oxide, NT-proBNPs = The N-terminal prohormone of brain natriuretic peptides, RAAS = renin-angiotensin-aldosterone system, SCD = sudden cardiac death, sCG = soluble guanylate cyclase, SGLT2is = sodium-glucose co-transporter 2 inhibitors, SNS = sympathetic nervous system.

Fig. 2b

Physiological mechanisms omecamtiv mecarbil and ivabradine. (1–3) The new medications, vericiguat, ARNIs and SGLT2is improve heart failure, VT/VF and consequently reduce SCD. (4) Omecamtiv mecarbil improves cardiomyocyte contraction and reverses the heart malfunctions caused by tissue heterogeneity and cardiac fibrosis. (5) Ivabradine blocks HCN channels located on cardiomyocytes and slows diastole depolarization, slowing the heart rate. This improves pathologies of oxygen demand, LV filling, diastole and coronary perfusion, which morbidly lead to heart failure VT/VF and finally to SCD. ARBs = angiotensin II receptor blockers, ARNIs = angiotensin-receptor-neprilysin inhibitors, cGMP = cyclic guanosine monophosphate, FA = fatty acid, HCN = Hyperpolarization-activated cyclic nucleotide–gated, LV = left ventricular, LVEDP = left ventricular end-diastolic pressure, NO = nitric oxide, NT-proBNP = N-terminal pro-hormone B-type Natriuretic Peptide, RAAS = renin-angiotensin-aldosterone system, SCD = sudden cardiac death, sCG = soluble guanylate cyclase, SGLT2is = sodium-glucose co-transporter 2 inhibitors, SNS = sympathetic nervous system, VT = ventricular tachycardia, VF = ventricular fibrillation.