Effect of Vericiguat on cardiAc Remodeling in Patients With Heart faiLure and Reduced Ejection fractioN (HFrEF): A Prospective sTudy usIng NOvel Echocardiographic Imaging Techniques (VALENTINO)

Effect of Vericiguat on cardiAc Remodeling in Patients With Heart faiLure and Reduced Ejection fractioN (HFrEF): A Prospective sTudy usIng NOvel Echocardiographic Imaging Techniques (VALENTINO)

The biological process that underlies the pathogenesis of heart failure (HF) is termed cardiac remodeling. Pathological cardiac remodeling includes structural and functional change of the heart. Structural cardiac remodeling in HF include dilatation and/or hypertrophy of cardiac chambers, in particular the left ventricle (LV), but can also involve the right ventricle (RV) and both atria; moreover, cardiac valves, in particular the mitral valve, have been shown to undergo adaptive enlargement in HF to counteract leaflet tethering that leads to functional regurgitation 1. Functional changes of the heart in HF includes reduction of LV systolic and diastolic function, ischemia, abnormalities in myocardial deformation, and alteration in intracardiac vortex flow formation and energetics. At the tissue level, cardiac remodeling is marked by interstitial reparative and replacement fibrosis and inflammation.

Cyclic guanosine monophosphate (cGMP) is an intracellular second messenger molecule that is important in the pathogenesis of HF. The main kinase effector of cGMP, protein kinase G, counteracts many biological derangements contributing to HF in experimental models. The production of cGMP in the heart, kidney, lung, liver, and brain is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC), and regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). In the cardiovascular system, cGMP pathway is involved in the pathogenesis of myocardial fibrosis, inflammation, myofilament insensitivity, vascular dysfunction, and cardiomyocyte hypertrophy 2.

Vericiguat is a direct sGC stimulator with a dual mode of action: it sensitizes sGC to the body's own NO and increases sGC activity in the absence of NO, causing vasorelaxation, antiproliferation, and antifibrotic effects. A recent randomized trial, Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA), found that vericiguat reduced a composite endpoint of hospitalization for HF and cardiovascular death in high-risk patients with HF with LV ejection fraction (LVEF) less than 45 percent 3. The mechanisms underlying the clinical benefit of vericiguat are uncertain but may include effects on fibrosis and inflammation.

Evaluation of LV size by 2D imaging has traditionally be challenging owing to technical limitations, such as foreshortening leading to underestimation of LV volumes using the Simpson's method. Latest advance in 3D echocardiography technology and automated cardiac functional analysis software has revolutionized evaluation and monitoring of LV and LA function in patients with HF. 3D echocardiography allows accurate measurement of LV, LA, and RV volumes and ejection fraction without needing any geometric assumption, with results reproducible and comparable to cardiac magnetic resonance, the imaging gold standard for chamber quantification. Furthermore, speckle tracking echocardiography allows evaluation of cardiac muscle deformation, which are more sensitive and load-independent markers of cardiac function. Echocardiography has the advantage of being wide available, with no harmful effect, and can be repeated in follow-up of patients.

Our group is experienced in the evaluation of the cardiac structure and function in patients with HF using 3D, speckle tracking, and other advanced echocardiographic techniques 4-11. The investigators therefore propose to conduct a pilot study to examine the effect of vericiguat on cardiac remodeling in patients with HF and reduced EF (HFrEF) with particular attention paid to the remodeling of LV and LA, using novel imaging techniques including 3-dimensional (3DE), with automated 3D analysis, and speckle tracking echocardiography.

Inclusion Criteria:

• Age ≥ 18y
• Chronic HF; New York Heart Association (NYHA) class II-III, LVEF ≤40% (recent 12 months), and on guideline-directed heart failure therapy
• Recent (6 months) heart failure hospitalization or intravenous diuretic use (without hospitalization) within 3 months
• Elevated NT-proBNP 1000-6000 pg/ml (1600-6000 pg/ml if atrial fibrillation) within 30 days
• Clinically stable (systolic blood pressure ≥100 mm Hg and no intravenous diuretics for 48 hours)
• Meet one of the following criteria:
• a. Male
• b. Female who is not of reproductive potential, defined as a female who either: (1) postmenopausal (defined as at least 12 months with no menses in women ≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; OR (3) has a congenital or acquired condition that prevents childbearing
• c. Female who is of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: (1) practice abstinence from heterosexual activity, OR (2) use (or have her partner use) acceptable contraception during heterosexual activity. Acceptable methods of contraception are:
• i. Single method (one of the following is acceptable):
• • Intrauterine device, vasectomy of a female subject's male partner, or contraceptive rod implanted into the skin
• ii. Combination method (use of two of the following)
• • Diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male condom or female condom, or hormonal contraceptive

Exclusion Criteria:

• Prior or screening echocardiographic images of suboptimal image quality
• Any addition, discontinuation, or dose modification of heart failure medications (i.e. ARB, ACEi, SGLT2i, ARNI, beta-blocker, MRA) within 4 weeks before vericiguat treatment initiation
• Use of long-acting nitrates, phosphodiesterase type 5 inhibitor, riociguat
• Awaiting heart transplantation, continuous intravenous diuretics, or current/anticipated ventricular assist device
• Chronic kidney disease (estimated glomerular filtration rate <15 ml/min/1.73 m2) or dialysis
• Severe pulmonary disease requiring continuous oxygen
• Severe hepatic insufficiency
• Has primary valvular heart disease requiring surgery or intervention, or is within 3 months after valvular surgery or intervention
• Has hypertrophic obstructive cardiomyopathy
• Has acute myocarditis, amyloidosis, sarcoidosis, Takotsubo cardiomyopathy
• Has post-heart transplant cardiomyopathy
• Has tachycardia-induced cardiomyopathy and/or uncontrolled tachyarrhythmia
• Has acute coronary syndrome (unstable angina, non-ST elevation myocardial infarction [NSTEMI], or ST elevation myocardial infarction [STEMI]) or coronary revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) within 6 months, or indication for coronary revascularization at the time of screening
• Has symptomatic carotid stenosis, transient ischemic attack (TIA) or stroke within 60 days
• Has complex congenital heart disease
• Has active endocarditis or constrictive pericarditis
• Breastfeeding or plans to breastfeed during the course of the trial