Search Results (3)

Pressure-overload-induced heart failure is characterized by pathological ventricular remodeling, including hypertrophy and fibrosis, which compromise cardiac function and worsen outcomes. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has shown therapeutic promise in heart failure with reduced ejection fraction (HFrEF). This study evaluated its antihypertrophic, antifibrotic, and metabolic effects in a murine pressure-overload model. Male C57BL/6 mice (~25 g) underwent transverse aortic constriction (TAC) and received oral Vericiguat (10 mg/kg/day) for 14 days. Cardiac hypertrophy was assessed by gross morphology and heart weight; fibrosis was quantified using Masson’s trichrome and Picrosirius red staining. Collagen deposition and wall stress indices were measured by image analysis. Proteomic profiling of fibroblast- and myocyte-enriched tissues identified differentially expressed proteins (DEPs) across metabolic, structural, mitochondrial, and signaling pathways. Vericiguat significantly reduced heart weight and attenuated TAC-induced hypertrophy. Histological staining revealed marked reductions in myocardial fibrosis and collagen accumulation in the Vericiguat-treated TAC group compared to untreated TAC controls. Quantitative analysis demonstrated improved wall stress indices. Proteomic data showed consistent modulation of DEPs, with restoration of mitochondrial and energy-regulating proteins suppressed by TAC, indicating enhanced bioenergetic support. Collectively, Vericiguat mitigates pressure-overload-induced remodeling through coordinated antihypertrophic, antifibrotic, and metabolic reprogramming mechanisms. These findings support its potential as a therapeutic strategy for heart failure and warrant further clinical investigation. Full article

Metabolic syndrome prevalence is between 24 and 27% and poses a significant risk for the development of atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes (T2D), or other comorbidities. Currently, no drugs are approved for metabolic syndrome treatment itself, so the risk factors are treated with therapies approved for cardiac and metabolic conditions. These are approved drugs for dyslipidemia treatment such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cornerstone antihypertensive drugs, or novel class glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) for T2D and overweight or obesity treatment. We have also evaluated new pharmacological interventions in clinical development that have reached Phase 2 and/or Phase 3 randomized clinical trials (RCTs) for the management of the risk factors of metabolic syndrome. In the pipeline are glucose-dependent insulinotropic polypeptide (GIP), GLP-1, glucagon receptor (GCGR), amylin agonists, and a combination of the latter for T2D and overweight or obesity treatment. Non-entero-pancreatic hormone-based therapies such as ketohexokinase (KHK) inhibitor, growth differentiation factor 15 (GDF15) agonists, monoclonal antibodies (mAbs) as activin type II receptors (ActRII) inhibitors, and a combination of anti-α-myostatin (GFD8) and anti-Activin-A (Act-A) mAbs have also reached Phase 2 or 3 RCTs in the same indications. Rilparencel (Renal Autologous Cell Therapy) is being evaluated in patients with T2D and chronic kidney disease (CKD) in a Phase 3 trial. For dyslipidemia treatment, novel PCSK9 inhibitors (oral and subcutaneous) and cholesteryl ester transfer protein (CETP) inhibitors are in the final stages of clinical development. There is also a surge of a new generation of an antisense oligonucleotide (ASO) and small interfering RNA (siRNA)-targeting lipoprotein(a) [Lp(a)] synthesis pathway that could possibly contribute to a further step forward in the treatment of dyslipidemia. For resistant and uncontrolled hypertension, aldosterone synthase inhibitors and siRNAs targeting angiotensinogen (AGT) messenger RNA (mRNA) are promising new therapeutic options. It would be interesting if a few drugs in clinical development for metabolic syndrome such as 6-bromotryptophan (6-BT), vericiguat, and INV-202 as a peripherally-acting CB1 receptor (CB1r) blocker would succeed in finally gaining the first drug approval for metabolic syndrome itself. Full article

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. The standard treatment of HF includes angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors, mineralocorticoid-receptor antagonists, beta-blockers, and sodium-glucose-co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with decreased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of reduced EF (HFrEF) therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater number of medications for the management of these patients. This review covers vericiguat’s metabolism, molecular mechanisms, and drug–drug interactions. Full article