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Management of Hypertension in Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jesse Kane, Clive Goulbourne, Hal A. Skopicki
Generally, treatment of HFrEF includes several classes of antihypertensive agents, such as ARNIs, ACEis, ARBs, beta-blockers, and MRAs. Sodium-glucose co-transport protein 2 (SGLT2) inhibitors, which were initially approved as anti-diabetic agents, and the soluble guanylate cyclase stimulator vericiguat have also recently been added to the armamentarium. When optimized or in the presence of persistent hypertension, most HF physicians advocate additional medications to reach normotensive ranges.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The three new drugs—depicted in the scheme opposite—for treating worsening chronic cardiac failure with reduced ejection are Cinaciguat (BAY 58–2667), Vericiguat and Omecamtiv mecarbil (CK-1827452). Cinaciguat (e.g., Lapp et al., 2009, Erdmann et al., 2013) is associated with the second messenger cyclic guanosine 3′,5′-momo-phosphate (cGMP), that is of importance in the regulation of a variety of processes among them ion channel conductance, glycogenolysis, cellular apoptosis or myocardial contractility. Patients suffering from heart failure show a pathologically reduced cGMP concentration. cGMP is produced from guanosine-5′ triphosphate by the action of soluble guanylate cyclase (sGC); Cinaciguat activates NO-nonresponsive sGC independent of oxidative stress and enhances cGMP concentration, thereby inducing vasodilation preferentially in diseased vessels. Vericiguat (Pieske et al., 2017) is also a sGC stimulator; stimulation is independent of NO, too, however sGC is sensibilized for NO so that Vericiguat acts synergistic with NO. Omecamtiv mecarbil (Cytokinetics) is a cardiac selective myosin activator (myosin is the molecular motor that drives muscle contraction), acting positively inotrope and augmenting the left ventricular systolic function (prolonging the duration of left ventricular systole) without the undesirable secondary effects of altered calcium homeostasis (Liu et al., 2016). Omecamtiv mecarbil activates the myocardial ATPase at the site where the myosin head domain binds to actin via phosphate hydrolysis as a prerequisite for a conformation change required for mechanical contraction. Omecamtiv mecarbil binds in a way that allows an allosterical modulation of both the enzymatic and mechanical properties of the cardiac myosin motor; in the absence of actin, this drug inhibits ATP hydrolysis, suggesting that the actin-bound conformation of myosin is stabilized by Omecamtiv mecarbil (Malik et al., 2011). Morgan et al. (2010) reported the design, synthesis, and optimization of omecamtiv mecarbil, starting from a nitro-aromatic hit compound. Alternatively, heart failure may be treated by gene therapy. SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase transfers Ca2+ ions from the cytosol of the cell to the lumen of the SR at the expense of ATP hydrolysis during muscle relaxation. It has been demonstrated by experiments with human cells and animal studies that the gene for the SERCA isoform 2a, the expression rate of which is strongly reduced in case of heart failure, can be delivered virus-mediated (e.g., by lentiviral vector, adeno-associated virus type 1) into the cardiac myocardium to treat the failing myocardium (Periasamy and Kalyanasundaram, 2008; Penny and Hammond, 2017).
Vericiguat for the treatment of heart failure with reduced ejection fraction
Published in Expert Review of Cardiovascular Therapy, 2023
Ahmed K. Siddiqi, Stephen J. Greene, Marat Fudim, Robert J Mentz, Javed Butler, Muhammad Shahzeb Khan
A major ongoing randomized clinical trial of vericiguat is VICTOR (Vericiguat in adults with chronic heart failure and reduced ejection fraction) [40], a vital phase 3, randomized, placebo-controlled clinical trial of vericiguat in patients with chronic heart failure and reduced ejection fraction (EF<40%), who have not had a recent worsening heart failure event. Approximately, 6000 adults with chronic HF and reduced ejection fraction with no history of hospitalization for HF for 6 months, or use of outpatient IV diuretics within 3 months prior to randomization will be enrolled. The primary efficacy endpoint will be time to first occurrence of CV death or heart failure hospitalization. The VICTOR trial is expected to take 39 months to complete, including patients from about 34 countries and approximately 500 different sites around the globe. This study will serve the purpose of assessing the efficacy of vericiguat in patients with HF who have not had a recent event of worsening HF unlike the VICTORIA trial [31].
Individualizing the treatment of patients with heart failure with reduced ejection fraction: a journey from hospitalization to long-term outpatient care
Published in Expert Opinion on Pharmacotherapy, 2022
Carlos Escobar, Juan Luis-Bonilla, Maria G. Crespo-Leiro, Alberto Esteban-Fernández, Nuria Farré, Ana Garcia, Julio Nuñez
Thus, the 2021 ESC guidelines recommend the use of ACEi or sacubitril/valsartan (preferred), beta blockers, MRA, and SGLT2 inhibitors as baseline therapy among patients wIth HFrEF to reduce the risk of HF-related hospitalization and death. If the patient has history of worsening HF, vericiguat should be considered to reduce the risk of hospitalization and cardiovascular death. Although the recommendation was IIb for vericiguat, as the power of the effect was <20%, this could have been higher (IIa), given the robustness of the results of the VICTORIA trial [61]. Lastly, if the patient remains symptomatic, in sinus rhythm, with a heart rate >70 bpm, ivabradine should be considered to reduce the risk of HF-related hospitalization and cardiovascular death (Figure 3, Table 2) [12].
Pharmacological treatment options for heart failure with reduced ejection fraction: A 2022 update
Published in Expert Opinion on Pharmacotherapy, 2022
Kristian Hellenkamp, Kathleen Nolte, Stephan von Haehling
Vericiguat is a novel soluble guanylate cyclase (sGC) stimulator, which enhances the activity of cyclic guanosine monophosphate (cGMP). In a healthy population, nitric oxide (NO) is generated in endothelial cells upon physiological stimuli and diffuses to vascular or cardiac muscle cells, binds and stimulates the sGC receptor to generate cGMP. The sGC receptor consists of an α-subunit and a heme-binding β-subunit, which is needed for binding NO. Furthermore, the presence of a reduced Fe2+ heme moiety is necessary for activating cGC by NO and hence the production of cGMP[29]. In patients with HF in whom endothelial dysfunction is very prevalent, a relative sGC deficiency and a reduction in cGMP synthesis has been detected. This leads to microvascular dysfunction in the myocardium, cardiomyocyte stiffness and interstitial fibrosis and thereby to myocardial dysfunction. Experimental studies investigating sGC stimulation have shown vasodilatory properties, reduction in ventricular afterload, antifibrotic effects and improved myocardial remodeling[34]. Therefore, direct NO-independent sGC stimulation to compensate for the cGMP deficit in HF has been suggested to be an interesting treatment target in HF.