Best of heart failure

41 contemporary clinical practice (featuring drugs) who can be titrated to target beta- be in the range of 20 to 40% [ 31 ]. Hyperpolarization-activated c nucleotide-gated channel inh Hyperpolarization-activated cyclic nuc channels play important roles both in t neuronal excitability. HCN channels o tion voltage, permeate to potassium and an inward current, which is modulated adenosine monophosphate (cAMP). In thologies, dysfunctional HCN channels to be a direct cause of rhythm disorder of-function in atrial fibrillation, ventric failure might help enhance ectopic elect mote arrhythmogenesis [ 32 ]. Novel compounds with enhanced selec channel isoforms are being studied as p new drug development. Ivabradine is t inhibitor being clinically approved in 20 chronic stable angina pectoris and HF. Iv HR-reducing drug that works only in si inhibiting the so-called funny current (I through the blockade of the I f channel (Fi The current across the I f channel is a um current, and the I f channel is activate and regulated by direct binding of cAM rectly modulates the HCN channel by in of channel opening during diastole; in t depolarization slope becomes steeper an Fig. 1 The mechanism of action of ivabradine. Ivabradine within SA node selectively blocks the HCN channel, inhibits the If current, slows diastolic depolarization, and lowers heart rate. HCN channel hyperpolarization-activated cyclic nucleotide-gated; If current inward flow of positively charged ions that initiates the spontaneous diastolic depolarization phase, modulating heart rate; SA node sinoatrial node Heart Fail Rev (2018) 23:517 – 525 recommended to be in reach the target 97/10 should not be given c to risk for angioedema, stopped for 36 h bef patients with eGFR < impairment, the starti daily and ARNI is not hepatic impairment [ 3 With the results of t ommendations have b HF Guidelines. First, ACE inhibitors or an strategy of RAS inhibit or ARB or ARNI. T strategy of inhibition of evidence: A), or A (level of evidence: B – beta-blockers and aldo is recommended for p morbidity and mortalit In the 2017 Focuse with chronic symptom tolerate an ACE inhibit recommended to furth 36 •• ]. In those patie switched to ARNI fro to note that ARNI sho with ACE inhibitors or inhibitor due to angio should not be administ edema [ 1 •• ]. In the stu inhibition, blacks and angioedema [ 35 ]. It is be educated about rec ma and to alert health scription of ACE inhi In a phase II trial i served ejection fractio greater extent than di tolerated [ 39 ]. The eff compe sated HF, in a IV symptoms, or in p time and is being teste Ivabradine Ivabradine is a specifi channel. If ion channel in spontaneously activ node, the AV node, an is a mixed Na/K curre at voltages in the dia 39 Page 4 of 9 drug [ 44 – 49 ]. In the BEAUTIFUL trial, more than 10,000 pa- tients with CAD and LV systolic dysfunction were randomly assigned to receive ivabradine or placebo in addition to first choice cardiovascular medication, including beta-blockers. Ivabradine reduced the incidence of admission to hospital for myocardial infarction and coronary revascularization in a sub- group of patients with HR of 70 bpm or greater [ 20 ]. In the CARVIVA HF trial, the effect of HR reduction with carvedilol, ivabradine, and their combination on exercise capacity was assessed in HF patients [ 50 ]. The distance walked on the 6- min walking test and the exercise time on mixed venous oxygen saturation test significantly improved in the ivabradine and the combination (ivabradine plus carvedilol) groups (both p < 0.01 vs baseline), as did peak oxygen uptake and ventilatory anaer- obic threshold ( p < 0.01 for ivabradine and p < 0.03 for combi- nation vs carvedilol, respectively). Patients receiving ivabradine or the combination had better quality of life ( p < 0.01 vs base- line for ivabradine and p < 0.02 for combination) versus no change with carvedilol [ 50 ]. The pivotal clinical trial for ivabradine was the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) study, which included 6558 patients. Patients were eligible for participation in this randomized, double-blind, pla- cebo-controlled, parallel-group study if they had symptomatic HF and a left ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 bpm or higher, had been admitted to hospital for HF within the previous year, and were on stable background treatment including a beta-blocker if tol- erated [ 51 ]. Subjects were randomized to ivabradine (titrated to a maximum of 7.5 mg twice daily) or placebo and followed for a median of 22.9 months. For the primary endpoint of cardio- vascular death or hospital admission for worsening HF, the relative risk reduction was 18% (hazard ratio, 0.82; 95% CI, 0.75 – 0.90). The effects were driven mainly by hospital admis- sions for worsening HF (672 [21%] placebo vs 514 [16%] ivabradine; hazard ratio 0.74, 0.66 – 0.83; p < 0.0001) and deaths due to HF (151 [5%] vs 113 [3%]; hazard ratio 0.74, 0.58 – 0.94, p = 0.014) [ 51 ]. Some of this effect might be ex- plained by reduced myocyte ischemia and increased available energy for myocyte maintenance and repair. In the SHIFT study, LV end-systolic volume index was reduced by 5.5 mL/ m 2 , representing an approximate 10% reverse remodeling in addition to angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blockers (ARB), or beta-blocker therapy [ 52 ]. Reduction of HR has also been associated with reduced LVend-diastolic pressure, improved LV relaxation, endothelial cell proliferation, prevention of HF-related LV capillary rare- faction, and increased endothelial nitric oxide synthase expres- sion (leading to improved nitric oxide-dependent coronary va- sodilatation) [ 53 ]. In the prospective, open-label multicenter INTENSIFY study, the effectiveness and tolerability of ivabradine as well as its impact on quality of life (QOL) in systolic HF patients were evaluated over a 4-month period. A total of 1956 patients with chronic HF ere included. After 4 months of treatment with ivabradine, HR was reduced to 67 ± 9 bpm. Furthermore, the proportion of patients presen ing with signs of decompensation decreased to 5.4%, and the pro- portion of patients with brain natriuretic peptide levels > 400 pg/mL dropped to 26.7%, accompanied by a shift in New York Heart Association (NYHA) classification towards lower grading (24.0 and 60.5% in NYHA I and II, respectively). These benefits were accompanied by improved QOL and good general tolerability [ 52 ]. The main cli ical trials investigating ivabradine in patients with HFrEF are presented in Table 1 . The potential mechanisms of ivabradine benefits The benefits of HR reduction with ivabradine were directly re- lated to the magnitude of HR reduction achieved by the drug and to the absolute value to which HR was maximally reduced [ 5 ]. A subsequent echocardiographic study from SHIFT trial provid- ed further insight regarding the mechanism of benefit, showing that ivabradine use was associated with reverse LV re odeling [ 52 ]. Subjects with the largest reduction in LV volumes deriv d the greatest benefit in terms of clinical endpoints [ 52 ]. Reil et al. [ 54 ] present data from another SHIFT echocar- diographic substudy that HR reduction with ivabradine ay also directly benefit the vasculature. In t is study, the arterial elastance (Ea), total arterial compliance (TAC), and en - systolic elastance (Ees) were calc lated at baseline and after 8 months of treatment. After follow-up, HR was sign ficantly reduced in the ivabradine group ( p < 0.0001) and was accom- panied by marked reduction in Ea ( p < 0.0001) and improved TAC (measured as the ratio of stroke volume to pulse pres- sure) ( p < 0.004) compared with placebo. Although contrac- tility remained unchanged, ventricular – art rial coupling was markedly improved ( p < 0.002), resulting in a high r stroke volume (SV) ( p < 0.0001) in the ivabradine-treated patien s. Because Ees was unaltered, improved ventricular – ar erial coupling is responsible for increased SV [ 54 ]. This indic tes that long-term treatment with ivabradine may improve pulsa- tile components of LV afterload and potentially offer additive or even synergistic effects with conventional vas dilato s that primarily target arteriolar resistance and/or venous tone [ 54 ]. The presence of concomitant erectile dysfunction (ED) with HF is connected with endothelial dysfunction [ 55 ]. It was demonstrated that ivabradine treatment can improve en- dothelial function and ED in experimental models. Mert et al. assessed the effect of ivabradine treatment on ED in patients with HF via International Index of Erectile Function (II EF-5) questionnaire. In 24 patients, between 18 and 70 years of age, male with chronic HF known for at least 1 year, New York Heart Association functional class I – II, LVEF less than 40%, in sinus rhythm with a resting HR of at least 70 bpm, IEFF-5 520 Heart Fail Rev (2018) 23:517 – 525