ANP

The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial.

Scott D Solomon, John J V McMurray, G Michael Felker +9 more

Therapies targeting the natriuretic peptide system have the potential to reduce death or heart failure events in heart failure with reduced ejection fraction. Here we assess XXB750, a human monoclonal antibody activating natriuretic peptide receptor 1, in patients with heart failure. Patients with heart failure and a left ventricular ejection fraction <50% were enrolled. Those patients who were on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment were randomized to receive 60 mg XXB750, 120 mg XXB750 or placebo in a blinded fashion or sacubitril/valsartan treatment in an open-label fashion. Those patients on background sacubitril/valsartan treatment were randomized to either 60 mg XXB750, 120 mg XXB750 or placebo treatment in a blinded fashion. The primary endpoint was the change in NT-proBNP levels at 16 weeks after treatment initiation, and safety was also assessed. We randomized 136 participants (70% male, 30% female) to 60 mg XXB750 (n = 26), 120 mg XXB750 (n = 55), matching placebo (n = 29) or sacubitril/valsartan (n = 25). At 16 weeks, NT-proBNP levels rose (ratio of change from baseline 1.34, 95% confidence interval (CI) 1.07-1.66) and cyclic guanosine monophosphate (cGMP) levels declined (ratio of change from baseline 0.77, 95% CI 0.65-0.91) in the pooled XXB750 arms, whereas NT-proBNP levels declined from baseline (ratio of change from baseline 0.70, 95% CI 0.45-1.10), and cGMP levels rose (ratio of change from baseline 1.38, 95% CI 1.13-1.69) in the sacubitril/valsartan arm. Death or worsening heart failure events occurred more frequently in those receiving XXB750 (25%) compared with those receiving sacubitril/valsartan (8%), or placebo (0%). Because of the excess heart failure events in participants receiving XXB750, the data monitoring committee recommended stopping the trial prematurely. In contrast to the expected mechanism of drug action, XXB750 treatment led to increased NT-proBNP levels, lowered cGMP levels and more worsening heart failure events, suggesting that XXB750 may paradoxically behave as a functional antagonist of endogenous natriuretic peptides in patients with heart failure. Clinicaltrials.gov registration: NCT06142383 .

Prognostic value of pretest probability of heart failure with preserved ejection fraction in patients with coronary artery disease: an insight from the CLIDAS-PCI database.

Tomoaki Nishikawa, Shunsuke Tamaki, Kazuhisa Nishimura +17 more

Coronary artery disease (CAD) is a major risk factor for the development of heart failure (HF) with preserved ejection fraction (HFpEF) and is associated with increased mortality. However, an optimal strategy to screen for HFpEF among patients with CAD has not yet been established. The HFpEF-ABA score was introduced to estimate the pretest probability of HFpEF and was shown to predict adverse HF events. This retrospective multicenter cohort study included patients registered in the Clinical Deep Data Accumulation System database who underwent percutaneous coronary intervention from April 2013 to March 2019. Patients with a left ventricular (LV) ejection fraction ≥ 50% and no known history of HF were included. Age, body mass index, and a history of atrial fibrillation were used to calculate the HFpEF-ABA score, and patients were dichotomized at a 50% threshold for descriptive risk stratification. The primary endpoint was a composite of all-cause death and unplanned HF hospitalization. Among 3307 patients, those with high HFpEF-ABA scores were more likely to have hypertension, renal dysfunction, anemia, larger left atrial size, higher LV mass index, and elevated brain natriuretic peptide levels, consistent with an HFpEF phenotype. Over a median follow-up of 721 days, 275 patients experienced the primary endpoint. The HFpEF-ABA score was independently associated with the primary endpoint as both a continuous and a categorical variable (hazard ratio: 1.07 [95% confidence interval: 1.00-1.14], P = 0.043, and 1.37 [1.07-1.76], P = 0.015, respectively). The HFpEF-ABA score identifies CAD patients with an HFpEF phenotype and predicts adverse outcomes.

Comprehensive assessment of novel cardiovascular biomarkers in AF.

Amelie H Ohlrogge, Daniel Engler, Patricia Schlieker +10 more

Biomarkers have the potential to improve risk prediction beyond clinical characteristics. We examined the association of four emerging cardiovascular biomarkers (angiopoietin 2 [Angpt2], bone morphogenetic protein 10 [BMP10], fibroblast growth factor 23 [FGF23], insulin-like growth factor binding protein 7 [IGFBP7]) in comparison with N-terminal pro B-type natriuretic peptide (NTproBNP) across the disease course of atrial fibrillation (AF).

Roflumilast Enhances Liraglutide's Atrial Natriuretic Peptide-Dependent Suppression of Adrenal Aldosterone Secretion.

Ariana Hosseini, Alexis J M'Sadoques, Renee A Stoicovy +7 more

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3'-5'-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide's effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases.

Atrial natriuretic peptide counteracts aldosterone secretion by preventing acute angiotensin II-induced cAMP signalling.

Sanika Mohagaonkar, Egor B Skryabin, Bettina M Buchholz +4 more

Aldosterone plays a key role in blood pressure and volume regulation. Enhanced aldosterone secretion contributes to cardiovascular and renal diseases. Therefore, inhibitors of aldosterone receptors and synthase are essential drugs for the treatment of hypertension and heart failure. Both adrenocorticotropic hormone (ACTH) and angiotensin II (AngII) acutely increase aldosterone release via cAMP and Ca2+-signalling, respectively. Atrial natriuretic peptide (ANP) prevents excessive aldosterone secretion from adrenal zona glomerulosa (ZG) cells. ANP reduces ACTH-stimulated aldosterone by enhancing cAMP degradation through cGMP-stimulated phosphodiesterase (PDE2A). It is not known whether PDE2A also participates in counteracting AngII-induced aldosterone secretion.

Angiopoietin-2 and Growth Differentiation Factor-15 as Predictors of Device-Detected Atrial Fibrillation Burden.

Valentin Bilgeri, Philipp Spitaler, Jasmina Gavranovic-Novakovic +13 more

Background: Pacemakers enable continuous long-term surveillance of atrial fibrillation detected by implanted devices. Circulating biomarkers reflecting endothelial dysfunction, inflammation, and myocardial stress may help identify patients at risk for atrial fibrillation (AF) progression and higher arrhythmic burden. Methods: This analysis included patients from the prospective ACaSA study (NCT05127720) with a dual chamber pacemaker (Microport® BOREA DR or TEO DR) and monitored weekly via remote monitoring technology (SMARTVIEW®). Individuals with permanent AF or single-chamber systems were excluded. Baseline plasma concentrations of angiopoietin-2 (ANGPT2), growth differentiation factor-15 (GDF-15), fibroblast growth factor-23 (FGF-23), bone morphogenetic protein-10 (BMP10), and tumor necrosis factor-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) were quantified using enzyme-linked immunosorbent assays. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was measured using electrochemiluminescence immunoassay. Biomarkers were log2-transformed, with values below assay detection limits imputed at half the lower limit of detection. Two endpoints were assessed following a 30-day blanking period: (1) progression to persistent AF, defined as ≥7 consecutive days with >99% daily AF burden, analyzed using Cox regression; and (2) AF burden, calculated as total AF time normalized to monitored days and categorized as <25%, 25-75%, or >75%, analyzed using multinomial logistic regression. Multivariable models were adjusted for age, sex, heart failure, diabetes, and prior myocardial infarction; Cox models were limited to age, sex, and heart failure due to fewer events. Results: A total of 223 patients were included (median age 75 years; 37.2% women). During follow-up, 28 patients (13.3%) progressed to persistent AF. Higher baseline ANGPT2 was the strongest predictor of progression (HR per doubling 1.83, 95% CI 1.27-2.66, p = 0.001), followed by GDF-15 (HR 1.52, 95% CI 1.03-2.24, p = 0.036). In the burden analysis, ANGPT2 demonstrated a pronounced graded relationship with arrhythmic load, with markedly increased odds of high (>75%) AF burden (OR 8.31, 95% CI 2.63-26.26, p < 0.001). GDF-15 independently predicted both medium (OR 2.05, p = 0.025) and high burden (OR 2.32, p = 0.037). NT-proBNP displayed a borderline association with high burden (OR 2.02, p = 0.061). No significant associations were observed for FGF-23, BMP10, or TRAIL-R2. Conclusions: In continuously monitored pacemaker patients, ANGPT2 and GDF-15 emerged as key biomarkers associated with AF disease severity. ANGPT2 was strongly linked to both progression to persistent AF and high AF burden, whereas GDF-15 consistently predicted higher AF burden and also contributed to risk of progression. These findings highlight endothelial and inflammatory pathways as potential markers of atrial disease progression.

Reduced Left Atrial Reservoir Strain is Associated with Histopathologically Confirmed ANP-Amyloid Deposition.

Shun Nishino, Yujiro Asada, Chiharu Nishino +6 more

Isolated atrial amyloidosis is characterized by atrial natriuretic peptide (ANP)-amyloid deposition confined to the atria and has been primarily linked to atrial fibrillation. However, its relationship with atrial mechanical function remains unclear. We investigated the association between left atrial reservoir strain (LASr) and histopathologically confirmed ANP-amyloid deposition. We also explored the potential clinical implications.

Obesity and Heart Failure: Introducing the Theme.

Francesco Monitillo, Paolo Basile, Giuseppe Lisco

Obesity is a chronic, highly prevalent disease affecting nearly one-third of the global population and represents a major independent risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Excess adiposity-especially visceral and epicardial adipose tissue (EAT)-acts as an active endocrine and immune organ, promoting chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and adverse myocardial remodeling. Expanded EAT exerts both paracrine inflammatory effects and mechanical constraint on the myocardium, contributing to diastolic dysfunction, microvascular impairment, atrial arrhythmogenesis, and elevated filling pressures despite preserved systolic function. Evidence demonstrates a dose-response relationship between increasing body mass index and incident HF. Clinically, obesity-related HFpEF is characterized by concentric left ventricular hypertrophy, impaired relaxation, increased plasma volume, reduced exercise tolerance, and relatively low natriuretic peptide levels, complicating diagnosis. HF management includes traditional treatment with diuretics, renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. These agents widely remain foundational as they primarily target hemodynamic and neurohormonal pathways in HF. In contrast, sodium-glucose cotransporter 2 inhibitors consistently reduce HF hospitalizations across the ejection fraction spectrum, while glucagon-like peptide-1 receptor agonists and dual incretin therapies (e.g., tirzepatide) promote substantial weight loss, improve symptoms, and demonstrate promising anti-remodeling effects in obesity-related HFpEF. Recognizing obesity-driven HF as a distinct cardiometabolic entity supports an integrated therapeutic strategy combining structured weight reduction with guideline-directed HF polypharmacotherapy to address both hemodynamic burden and upstream adiposity-related mechanisms.

Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril/Valsartan in Chronic Heart Failure.

Deepak K Gupta, Lynne W Stevenson, Erica M Garner +6 more

Symptomatic hypotension can limit sacubitril/valsartan therapy. Neprilysin inhibition may augment vasodilators, such as bradykinin. We hypothesized that bradykinin contributes to blood pressure (BP) lowering with sacubitril/valsartan in stable ambulatory patients with heart failure and reduced ejection fraction <50%.

Right Ventricular-Pulmonary Artery Coupling in Patients With Atrial Fibrillation and Changes After Catheter Ablation.

Kazutoshi Hirose, Koki Nakanishi, Masao Daimon +17 more

Atrial fibrillation (AF) is a predominant risk factor for heart failure, even in patients with preserved left ventricular ejection fraction. Emerging evidence suggests the significance of right ventricular-pulmonary artery (RV-PA) uncoupling in heart failure occurrence. We aimed to elucidate the prevalence and associated factors of RV-PA uncoupling and the efficacy of catheter ablation (CA) for RV-PA adaptation in patients with AF without history of heart failure.

A chimeric natriuretic peptide (Ev-NP) inhibits isoproterenol (ISO)-induced hypertrophic growth in in vivo and in vitro models by enhancing cGMP and its downstream signaling targets: In silico docking and binding efficacy analysis with NPR-A and NPR-B receptors.

Jayashree Bheeman, Ananthan Krishnan Dhanabalan, Gopinath Nagaraj +4 more

A chimeric natriuretic peptide (Ev-NP) was engineered and created with an intention of having a dual NPR-A/NPR-B activation, resistance to degradation, and with a strong renal, and anti-hypertrophic actions in the heart. In the present study, we aim to investigate the anti-hypertrophic properties of a novel chimeric natriuretic peptide, Ev-NP (37 amino acids), against isoproterenol (ISO)-induced hypertrophy in H9c2 cells in vitro and in a rat model in vivo. The effects on anti-hypertrophy and cGMP stimulation were evaluated in H9c2 cells exposed to ISO, both with and without Ev-NP, at concentrations ranging from 10 to 50 nM over 24 h. A significant dose-dependent increase in cGMP was observed in Ev-NP-treated H9c2 cells compared to controls. Furthermore, Ev-NP treatment significantly (P < 0.001) decreased ISO-induced hypertrophic growth in H9c2 cells by elevating cGMP levels. In H9c2 cells overexpressing Npr1 and co-treated with Ev-NP, a stronger anti-hypertrophic effect was observed, as demonstrated by a significant reduction (P < 0.001) in hypertrophic marker gene expression (α-sk, BNP, and β-MHC) compared to cells treated only with ISO. Furthermore, cytokine array analysis showed that Ev-NP treatment normalized ISO-induced up-regulation of pro-inflammatory and growth factor proteins in H9C2 cells. The in vivo anti-hypertrophic study also showed that Ev-NP significantly reduced (90%) the hypertrophic growth caused by ISO in Wistar rats. Importantly, treatment with Ev-NP restored the ISO-induced reductions in cGMP and NPR-A levels in the rat hearts. In silico analysis revealed that Ev-NP exhibited a stronger affinity for the NPR-A receptor, with a binding energy of -490.17 kcal/mol, compared to NPR-B binding energy of -390.77 kcal/mol. The native ANP exhibited a binding energy of -314.68 kcal/mol with NPR-A. These findings suggest that Ev-NP has promising anti-hypertrophic properties, and its therapeutic potential can be harnessed to treat and manage cardiac hypertrophy and heart failure in humans.

[Consensus statement of the Austrian Society for Rheumatology and Rehabilitation on the management of increased cardiovascular risk in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis].

Boris Lindner, Mathias Ausserwinkler, Christina Siess +14 more

Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular diseases (CVD), which significantly contribute to an increased morbidity and mortality. Although international recommendations exist, disease-specific and pragmatic guidance for the routine clinical practice are lacking due to heterogeneous evidence and incompletely understood pathophysiological mechanisms of cardiovascular events.

Mahuang decoction targets fluid retention in heart failure with preserved ejection fraction.

Xiaoyu Liang, Ziyi Chen, Xiaopeng Hao +7 more

In heart failure with preserved ejection fraction (HFpEF), fluid volume overload constitutes a critical factor driving disease progression. Mahuang decoction (MHD), a traditional Chinese medicine with diaphoretic and diuretic properties, has shown potential in improving HFpEF, yet its mechanisms remain unclear.

Aldosterone Accelerates Systolic Decline in Volume-Overload Heart Failure.

Xin Cao, Luyi Xie, Yoshinobu Nagasawa +2 more

High-output heart failure (HF) occurs with sustained volume overload. Hence, clarifying how compensated high-output states transition to maladaptive HF is essential for developing interventions that preserve cardiac function. Therefore, this study investigated the mechanism by which volume overload induced by aortocaval shunt (AVS) and aldosterone (Ald) affects the progression of myocardial function and structural remodeling. AVS was surgically induced in rats, and osmotic mini-pumps delivering Ald (1.0 μg·h-1) for 4 weeks were intraperitoneally implanted. Cardiac function and structure were serially assessed using echocardiography before surgery and at 4, 12, and 24 weeks under isoflurane. At 23 weeks, atrial natriuretic peptide was analyzed, and at 24 weeks, comprehensive electrophysiological, hemodynamic, morphometric, and histological examinations were performed to characterize cardiopathy. Early diastolic mitral annular velocity (E') remained relatively unchanged after 24 weeks, whereas early diastolic filling wave (E) velocity, atrial contraction wave velocity, and E/E' ratio increased. However, AVS did not markedly reduce systolic function; it was associated with progressive elevation of cardiac output, left ventricular hypertrophy, and dilation. Histological and morphometric analyses confirmed concentric hypertrophy, eccentric remodeling, and focal fibrosis. Ald induced similar diastolic changes and structural remodeling but caused an earlier decline in systolic function at 8 weeks. These findings demonstrate a 2-phase trajectory of high-output stress: an early compensated stage with elevated filling pressure, followed by a decompensated stage with progressive systolic decline. Moreover, Ald accelerates this systolic decline. Therefore, targeting Ald receptors in the early compensation phase may protect against systolic impairment caused by volume overload.

Sacubitril/Valsartan as a Cardiac Radioprotector.

Mihaela Ghita-Pettigrew, Brianna N Kerr, Kathryn H Brown +12 more

The role of the natriuretic peptides in radiation heart injury (RHI) has not been thoroughly examined. Pharmacologic modulation of the natriuretic peptide system with sacubitril/valsartan (sac/val) has led to improvements in heart failure therapy, and preliminary data suggest that RHI is associated with decreased atrial natriuretic peptide (ANP). In this study, we assessed sac/val as a radioprotector in a partial-heart irradiation mouse model and explored preliminary trends in patients receiving thoracic irradiation.

Change in dapagliflozin trial eligibility status and prognosis among patients with acute heart failure with preserved ejection fraction.

Lo-Chieh Ling, Wei-Ming Huang, Hao-Chih Chang +6 more

Disease-modifying therapy for heart failure with preserved ejection fraction (HFpEF) remains limited. The Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial demonstrated the benefits of disease‑modifying therapy and outlined the eligibility criteria for this treatment. The present study investigated how often treatment eligibility changes after hospitalization for acute decompensation and whether eligibility at discharge influences 1-year outcomes.

Cholinergic neurons in the dorsal nucleus of the vagus nerve are involved in the mechanism of action of electroacupuncture at HT7 in a mouse model of chronic heart failure.

Shi-Yue Wang, Hao-Sheng Wu, Sheng-Bing Wu +1 more

To investigate the role and mechanism of the dorsal motor nucleus of the vagus nerve (DMV) in the effects of electroacupuncture (EA) at HT7 in a mouse model of chronic heart failure (CHF).

Low factor XI activity in heart failure: A Potential marker of disease severity?

Mahmoud Mansour, Makxim Kagarlyk, Eias Massalha +6 more

Advanced heart failure (HF) is characterized by progressive cardiac remodeling and recurrent episodes of decompensation, highlighting the need for biomarkers reflecting disease severity. Coagulation factor XI (FXI), beyond its established role in hemostasis, may influence inflammatory and remodeling pathways in the heart, but its relevance in advanced HF remains unclear.

Bioinspired cardiac-targeted metal-organic framework nanozyme for modulating inflammatory responses in heart failure with preserved ejection fraction.

Yuesheng Gui, Xiaowan Fan, Kairui Xiao +10 more

Heart failure with preserved ejection fraction (HFpEF) is a common heart failure type with poor prognosis. Its mechanisms are unclear, and specific diagnostic criteria and effective treatments are lacking. Recent studies have emphasized the impact of inflammation and oxidative stress on the occurrence and development of HFpEF. Anti-inflammatory interventions targeting oxidative stress show promise, but traditional antioxidants are insufficient.

Mesenchymal stem cell-conditioned media alleviates diabetic cardiomyopathy by modulating glycemic control, oxidative stress-induced injury and inflammation regulation.

Abeer M Abd El-Hameed, Fatimah A R AbdulAlim, Hebatullah A Abdulgawad

A major consequence of diabetes mellitus (DM) is a diabetic cardiomyopathy (DC). It is a clinical confusion that is identified when individuals with DM develop ventricular dysfunction without having coronary artery disease, heart disease or high blood pressure. It is marked by early diastolic dysfunction and late systolic heart failure. Although mesenchymal stem cell-conditioned media (MSC-CM) have demonstrated promise as therapies for a variety of illnesses, their therapeutic use is hampered by a lack of clinical studies and thorough knowledge of the underlying process. By focusing on oxidative stress, inflammation, and heart failure brought on by hyperglycaemia, this study investigates the positive effect and the possible mechanism by which MSCs-CM alleviate DC in a streptozotocin-induced diabetic rat model by two different delivery routes. 50 male albino rats were randomly assigned to 5 groups, each with 10 subjects, following the induction of diabetes. Amaryl was given to one group as part of their regular diabetes treatment. Every day, 0.5 mL of stem cell-conditioned media was given intravenously (IV) through the tail vein to a different group known as the DC group. Furthermore, 0.5 mL of stem cell-conditioned media was locally administered to a different DC group, going straight into the pancreas. For comparison, a typical control group was also included. All treatments continued for 28 days. Results showed significant alterations in serum glucose, insulin, HbA1c, lipid profile, and cardiac function parameters (atrial natriuretic peptide, troponin I, aspartate aminotransferase, creatine kinase MB) in DC group compare with controls. Treatment by Amaryl® and MSCs-CM demonstrated significant improvements in these parameters, indicating potential therapeutic benefits in diabetic cardiomyopathy. Furthermore, DC exhibited elevate levels of inflammatory markers (CRP, TNFα, IL-6 and Selectin), oxidative stress indicators (malondialdehyde, catalase, superoxide dismutase, and reduced glutathione), and cardiac injury biomarkers (erythropoietin, nuclear respiratory factor 2, vascular endothelial growth factor, and iNOS), which were attenuated by Amaryl® and MSCs-CM treatment (Fig. 3). These findings suggest the antioxidative, anti-inflammatory, and cardioprotective effects of MSCs-CM in diabetic cardiomyopathy highlighting their potential as a viable novel strategy for diabetic cardiovascular complications.

Early treatment with nootkatone prevents pressure overload-induced ventricular remodeling and heart failure.

Zhongyuan Liu, Zixin Zhou, Wenjing Yuan +4 more

Heart failure (HF) represents the clinical end stage of most cardiovascular diseases and remains a major cause of mortality, morbidity, and poor quality of life worldwide. In the present study, we use a mouse model induced by abdominal aortic constriction (AAC) that mimics HF and evaluate the potential therapeutic effects of nootkatone (NKT) on this model. Ejection fraction (EF) and fractional shortening (FS) progressively deteriorated in the AAC mice. The AAC mice were treated with NKT for 8 weeks starting on the eighth day post-AAC. Early NKT treatment prevented cardiac dysfunction in the AAC mice at 8 and 12 weeks after administration, along with thinner left ventricular posterior wall, lower left ventricular mass and ratio of heart weight/tibial length, and fewer cardiomyocyte areas. Furthermore, we found that NKT significantly reduced the expression levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), collagen types Ⅰ and Ⅲ, TGF-β1, Smad3, and the phosphorylation of Smad3. Furthermore, NKT decreased the activation of cardiac fibroblasts and myocardial fibrosis in the AAC mice. Our data suggest that NKT can delay or reverse the progression of HF after AAC and reduce myocardial hypertrophy and fibrosis possibly via inhibition of the TGF-β1/Smad3 signaling pathway.

Idebenone protects against doxorubicin-induced cardiac injury by inhibiting ferroptosis in cardiomyocytes.

Jie Mao, Zhiyi Zhou, Yuting Xu +3 more

Heart failure (HF) remains a global health challenge with limited efficacious therapies, necessitating novel strategies targeting its underlying pathological mechanisms. Emerging evidence implicates dysregulated iron metabolism and ferroptosis-an iron-dependent form of regulated cell death-as critical drivers of cardiomyocyte attrition in heart failure pathogenesis. This study investigates the therapeutic potential of idebenone (IDE), a clinically approved mitochondrial-targeted antioxidant and short-chain analog of coenzyme Q10, in modulating ferroptosis-mediated cardiac dysfunction. We confirmed that idebenone significantly attenuated pathological markers of cardiac stress, reducing expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in cardiomyocytes. Furthermore, idebenone treatment suppressed lipid peroxidation and mitochondrial iron overload. In the HF animal model, idebenone administration improved left ventricular ejection fraction, restored redox homeostasis and reduced cardiac iron deposition. These findings establish idebenone as a promising strategy to mitigate ferroptosis-driven myocardial injury, providing a translational framework for developing idebenone-based therapies for heart failure management.

Emerging risk factors for stroke and bleeding in patients with atrial fibrillation and heart failure-a narrative review.

Jan Zabierowski, Bartosz Hudzik, Jolanta Nowak +1 more

Atrial fibrillation (AF) and heart failure (HF) frequently coexist, which leads to adverse clinical outcomes and a significant increase in the risk of both ischemic stroke and major bleeding. Although still valuable due to their widespread adoption, traditional risk scores (e.g. CHA2DS2-VASc, HAS-BLED) may not adequately capture group-specific differences in the context of substantial therapeutic and demographic changes that have occurred in recent years. This review summarizes emerging risk factors for stroke and bleeding, focusing on clinical and structural markers, and highlighting the novel biomarker-based approach. Factors such as chronic kidney disease, poor nutritional status, metabolic-associated fatty liver disease, frailty, and polypharmacy appear to substantially modify the risk. Biomarkers, including natriuretic peptides, high-sensitivity cardiac troponins, and growth differentiation factor-15, along with various markers of inflammation and hypercoagulability, provide valuable prognostic information. Incorporating echocardiographic measures, such as left atrial size, morphology, and appendage flow, together with electrocardiographic factors, including AF type and episode duration, may further refine stroke and bleeding prediction. New risk models, such as those based on novel biomarker strategies and machine learning, offer promising results in predicting stroke and bleeding when compared to traditional and well-validated risk scores. A better understanding and integration of these emerging risk factors can enhance existing risk stratification tools, guiding clinicians toward a more individualized decision-making process, while improving strategies for preventing stroke and major bleeding in this specific and vulnerable population.

Plasma Biomarkers Associated With Heart Failure Hospitalization Among Patients With Atrial Fibrillation and Subtypes of Heart Failure.

Tymon Pol, Johan Lindbäck, Jonas Oldgren +4 more

Atrial fibrillation is associated with heart failure (HF) through a complex cause-and-effect relationship. We performed multiplex screening of plasma proteins in patients with atrial fibrillation to identify biomarkers and pathways associated with hospitalization for HF. Additionally, we aimed to identify potential pathophysiological differences between HF with reduced ejection fraction and HF with preserved ejection fraction at baseline in patients with atrial fibrillation.

Linking clinical and imaging diagnostic assessments of the feline hypertrophic cardiomyopathy phenotype.

Felipe Gaia de Sousa, Ruthnea Aparecida Lazaro Muzzi, Roberto Baracat de Araújo +3 more

Hypertrophic cardiomyopathy (HCM) phenotype represents the most commonly diagnosed cardiac disorder in felines, characterized by heterogeneous clinical presentations and a well-established genetic basis. This study aims to integrate clinical, laboratory, and imaging diagnostic assessments of the feline HCM phenotype, providing a comprehensive perspective on how complementary diagnostic approaches enhance disease understanding and precision. The HCM phenotype is defined by concentric hypertrophy of the left ventricular free wall and/or interventricular septum, often accompanied by secondary left atrial remodeling due to chronic pressure and volume overload. Clinical signs typically emerge with disease progression, frequently culminating in congestive heart failure (CHF) and respiratory signs; however, some cats may remain asymptomatic. Accurate diagnosis of the HCM phenotype requires an integrative approach combining thorough clinical evaluation and advanced imaging modalities to avoid misdiagnosis, which may negatively impact prognosis and quality of life. Detailed clinical history and physical examination are essential for diagnostic orientation, particularly in symptomatic patients. Routine laboratory tests support systemic assessment, although no pathognomonic biomarker has been identified to date. Cardiac biomarkers such as atrial natriuretic peptide (ANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac troponin I (cTnI) provide complementary diagnostic information, albeit with lower sensitivity than imaging techniques. While electrocardiography may reveal conduction disturbances suggestive of HCM, transthoracic echocardiography remains the diagnostic gold standard. In addition to confirming the diagnosis, echocardiographic evaluation allows for disease staging, longitudinal monitoring, and evidence-based therapeutic decision-making. Our study reinforces the need for an integrated diagnostic framework that combines clinical examination, laboratory testing, and imaging evaluation. By promoting a multidimensional diagnostic perspective, this study contributes to refining the understanding of the feline HCM phenotype and supports the development of more precise diagnostic and therapeutic strategies, ultimately improving clinical outcomes in affected cats.

A Cluster of Potential Molecular Contributors in Myocardial-Tissue-Derived In Situ Proteomic Profiling Mediate Myocardial Hypertrophy Linked to Right Heart Dysfunction.

Shengjie Liao, Xing Zhou, Yichen Xiong +4 more

Myocardial hypertrophy is an adaptive response in the initial stage of heart failure (HF), which exacerbates HF by causing cardiac decompensation and impaired contractility. In proteomic analysis, 216 differentially expressed proteins were obtained in the RHD patients relative to normal controls, including 141 upregulated and 75 downregulated proteins. Among these candidate proteins, protein phosphatase 3 catalytic subunit alpha (PPP3CA), indolethylamine N-methyltransferase (INMT), a disintegrin and metalloproteinase 9 (ADAM9), and myosin light chain-2 (MYL2) exhibited significantly higher expression in the myocardial tissues from patients compared with controls. Moreover, bioinformatic analysis demonstrated that dysregulation of PPP3CA, INMT, ADAM9, and MYL2 may alter the expression of proteins involved in cell adhesion, gap junction coupling, and tight junction stability, weakening cell-cell contacts and disrupting intercellular homeostasis, ultimately facilitating myocardial hypertrophy. In the Angiotensin (Ang) II-induced myocardial hypertrophy model in AC16 cardiomyocytes, the protein expression of PPP3CA, ADAM9, and INMT was elevated. Furthermore, PPP3CA, ADAM9, and INMT were involved in Ang II-induced myocardial hypertrophy by upregulating the expression of smooth muscle α-actin, atrial natriuretic factor, and connective tissue growth factor. Our study identifies molecular alterations associated with the development of myocardial hypertrophy, which may provide insights into potential therapeutic strategies for RHD and subsequent heart failure.

Exploring the Prospective Insights Into the Prognostics of N-terminal Pro-B-Type Natriuretic Peptide in Predicting Heart Failure Readmissions in a Tertiary Healthcare Setting.

Ghulam Muhammad Shoaib, Uday Shree Akkala Shetty, Muhammad Zaman Baloch +1 more

Heart failure (HF) is a significant cause of morbidity and hospital readmission despite improvements in treatment. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive biomarker of ventricular wall stress and could be able to give prognostic insight into the post-discharge outcome. The aim of the study was to evaluate the prognostics of NT-proBNP in predicting heart failure readmissions in a tertiary healthcare setting.

Effect of carperitide on clinical outcomes among patients with acute heart failure: a meta-analysis of randomized and propensity‑matched studies.

Tsuyoshi Shiga, Atsushi Suzuki, Sachie Inoue +1 more

Carperitide, which is an α-human A-type natriuretic peptide, is used intravenously for the treatment of acute heart failure (AHF) primarily in Japan. However, its clinical effectiveness has not been established. The aim of this meta-analysis was to assess the effect of carperitide on the clinical outcomes of patients with AHF.

Elevated plasma cancer antigen-125 level is associated with increased risk of new-onset atrial fibrillation after acute myocardial infarction.

Yuan Fu, Kun Zuo, Mulei Chen +2 more

New-onset atrial fibrillation (NOAF) is the most commonly encountered arrhythmia during the course of acute myocardial infarction (AMI) and is independently associated with a worse prognosis.

Human fetal circulating factors from pregnancies complicated by obesity upregulate genes associated with pathological hypertrophy in neonatal rat cardiomyocytes.

Owen R Vaughan, Andrew Goodspeed, Carmen C Sucharov +2 more

Obesity in pregnant women increases offspring cardiovascular risk and causes fetal cardiac dysfunction. The underpinning mechanisms remain unclear. We hypothesized that circulating factors in serum from fetuses of women with obesity induce pathological cardiomyocyte hypertrophy. Pregnant women with obesity or healthy weight were recruited at term and provided umbilical cord serum and placentas, which were used for isolation of primary trophoblast cells. Primary cardiomyocytes were isolated from neonatal rats. Compared with cord serum from healthy weight women, cord serum from women with obesity upregulated cardiomyocyte mRNA expression of atrial natriuretic factor (Anf) and brain natriuretic peptide (Bnp) and increased the ratio of β-to α-myosin heavy chain expression (Myh7:Myh6), when it was supplemented into the culture medium. This effect was prevented by treating the cord serum with heat-freeze cycling and DNase or RNase digestion. Separately, conditioned medium from trophoblast cells from women with obesity increased cardiomyocyte Anf expression without altering Bnp or Myh7:Myh6. MicroRNAs miR-142 and miR-17, which are associated with cardiac function, were increased in abundance in extracellular vesicles isolated from cord serum from women with obesity. However, miR-142-3p, miR-142-5p, and miR-17-5p did not increase Anf, Bnp, or Myh7:Myh6 expression when they were transfected into cardiomyocytes. Neither cord serum nor the upregulated microRNAs from women with obesity altered cardiomyocyte size. The results show that human fetal circulating and placenta-derived factors induce gene expression hallmarks of pathological hypertrophy in cardiomyocytes and may mediate cardiac dysfunction in children of women with obesity.NEW & NOTEWORTHY Obesity in pregnant women increases risk for heart problems in their children. This study treated heart cells growing in a dish with blood plasma from the umbilical cords of newborn babies. Plasma from babies of women with obesity activated genes linked to heart failure. This means we could design treatments targeting plasma molecules, like microRNAs, or the way the placenta releases them. This could improve children's heart health if the mother has obesity.

Natriuretic Peptides as Multisystem Regulators: From Clinical Biomarkers to Therapeutic Targets in Cardio-immunology.

Jathniel Panneflek, Mahmoud Barbarawi, Yasitha Kakarlapudi +3 more

Natriuretic peptides (NPs) ANP, BNP, and CNP extend beyond biomarkers of wall stress to regulators of cardiovascular, renal, metabolic, and immune pathways via cGMP-PKG signaling. We synthesize mechanistic and translational evidence, highlight NP "resistance," and appraise therapeutic strategies that augment NP signaling.

CNP inhibits T3 - induced hypertrophic growth in H9c2 cells: Impact of HDAC inhibitor.

Gopinath Nagaraj, Elangovan Vellaichamy

C-type natriuretic peptide (CNP) is a multifaceted paracrine factor that regulates vital physiological functions of the cardiovascular system. The present study was designed to investigate the anti-hypertrophic activity of CNP in the presence and absence of HDAC inhibitor Suberoylanilide hydroxamic acid (SAHA) in T3-induced H9c2 cells. The H9c2 cells were treated with T3 (10 nM) for 48 hours to induce hypertrophic growth. T3 alone-treated cells exhibited an increase in cell size (p < 0.001) as compared with control H9c2 cells. CNP treatment effectively reverted the increased cell size by 61 %, and also altered the expression of hypertrophic marker genes. Interestingly, a significantly enhanced anti-hypertrophic activity was noticed in CNP co-treatment with SAHA, and also a more significant decrease in the expression of hypertrophic marker genes (α-sk, and α-MHC) was also observed. Moreover, CNP treatment with SAHA effectively reversed the T3-induced changes in the expression of Npr1 and Npr2 genes in H9c2 cells. In addition, CNP co-treated with SAHA reversed the T3-induced abnormal calcium influx by normalizing of CaMKII and SERCA2a. The findings of the present study clearly show that CNP co-treatment with SAHA significantly enhances the CNP-mediated anti-hypertrophic activity, probably by restoring Npr1 and Npr2 gene expression and calcium influx. Taken together, we conclude that CNP in combination with SAHA represents a novel therapeutic approach for the treatment and management of cardiac hypertrophy and heart failure.

Prevalence, associated factors, and prognostic value of P wave abnormality in patients with coronary artery disease.

Kazutoshi Hirose, Hiroyuki Kiriyama, Shun Minatsuki +13 more

P-wave terminal force in V1 (PTFV1) on electrocardiography is an easily available and cost-effective surrogate marker reflecting myocardial electrical and structural remodeling. An abnormal PTFV1 was recently suggested to be a reliable predictor of adverse cardiovascular events, whereas its performance in the setting of coronary artery disease (CAD) remains unknown.

Prevalence of heart failure stages in elderly population: from a community-dwelling elderly people survey.

Manyun Huang, Min Wang, Xin Gong +7 more

Heart failure (HF) is a major public health concern in China, but there is a lack of epidemiological data on the prevalence of early-stage HF in the elderly.

High Rate Triggers Increased Atrial Release of BMP10, A Biomarker for Atrial Fibrillation and Stroke, and BMP10 Affects Ventricular Cardiomyocytes.

Laura C Sommerfeld, Jessica Schrapers, Karl-Felix Müller +19 more

BMP10 (bone morphogenetic protein 10) is a ligand of the TGF (transforming growth factor) β superfamily secreted mainly by atrial cardiomyocytes. Elevated BMP10 blood concentrations predict atrial fibrillation (AF), AF recurrence after ablation, and AF-related cardiovascular complications like stroke. The conditions increasing BMP10 secretion and the downstream effects of BMP10 in cardiomyocytes are poorly understood. We assessed BMP10 secretion dynamics and BMP10 effects in a human 3-dimensional model of atrial and ventricular engineered heart tissue (EHT).

Prognostic Impact of Fibroblast Growth Factor 21 in Patients With Heart Failure.

Hiroaki Sunaga, Kuniko Yoshida, Kazuki Kagami +10 more

Systemic and cardiac metabolic disorders play a key role in patients with heart failure (HF). Fibroblast growth factor 21 (FGF21) is mainly secreted from the liver and has various effects on cardiomyocytes, including protection against oxidative stress, cardiac hypertrophy, and inflammation. However, the pathophysiologic and prognostic impact of FGF21 remains unknown.

Effect of carperitide on mortality and ANP levels in acute heart failure: A systematic review and meta-analysis.

Allahdad Khan, Shree Rath, Saad Ahmed Waqas +7 more

Acute heart failure (AHF) is a common and severe condition associated with high morbidity and mortality. Carperitide, a recombinant human atrial natriuretic peptide, has been widely used in Japan for managing AHF. However, its effectiveness in improving clinical outcomes such as mortality rates remains unclear, with conflicting evidence from studies.

Neurohumoral Dysregulation in Acute Myocardial Infarction With Chronic Kidney Disease: Implications for Prognosis and Management.

Oksana Polianska, Victor Tashchuk, Olha Hulaha +3 more

Background Acute myocardial infarction (AMI) and chronic kidney disease (CKD) often coexist, and both are associated with neurohumoral imbalances that may worsen cardiovascular outcomes. Reduced kidney function can contribute to arterial stiffness and activation of the renin-angiotensin-aldosterone system (RAAS), which promotes vasoconstriction, sodium and water retention, myocardial remodeling, and fibrosis, mechanisms that exacerbate both cardiac and renal dysfunction. Endothelial injury is also common in these patients, and von Willebrand factor (vWF) serves as a recognized marker of endothelial dysfunction, contributing to thrombotic risk and microvascular impairment. Objective To explore the cross-sectional associations between renal function and the biomarkers aldosterone, angiotensin-converting enzyme (ACE), atrial natriuretic peptide (ANP), and vWF in patients with AMI and heart failure. Methods In this cross-sectional study, 106 patients hospitalized for AMI and heart failure were stratified by estimated glomerular filtration rate (GFR) into Group 1 (≤90 mL/min) and Group 2 (>90 mL/min). While CKD is conventionally defined as GFR <60 mL/min, the ≤90 mL/min cutoff was chosen to evaluate biomarker variation across a broader renal function range, including early decline. All eligible patients from the study period were included; no formal power calculation was performed. Neurohumoral markers were measured via enzyme-linked immunosorbent assay (ELISA). Heart failure was an inclusion criterion for all participants. Results Baseline characteristics were comparable between groups. Aldosterone and ACE were higher in patients with GFR ≤90 mL/min (p-values 0.01-0.05; below the prespecified α = 0.01). ANP and vWF did not differ between groups, which may reflect limited sensitivity to early renal function differences or other physiological influences. Conclusion The observed association between reduced GFR and elevated aldosterone and ACE suggests RAAS-related neurohumoral activation in AMI patients with heart failure. The lack of difference in ANP and vWF highlights potential marker-specific limitations. Targeting RAAS and other relevant pathways may offer therapeutic benefits for improving outcomes in this population; however, such approaches require confirmation in prospective interventional trials. These findings are exploratory and hypothesis-generating, underscoring the need for larger, longitudinal, and interventional studies to clarify the prognostic and therapeutic implications.

Association between circulating biomarkers and atrial fibrillation burden in patients with paroxysmal atrial fibrillation: a subanalysis of the RACE V study.

Maria Hee Jung Park Frausing, Michiel Rienstra, Mads Brix Kronborg +7 more

Biochemical markers of inflammation, coagulation and myocardial stress have been associated with both prevalent and incident atrial fibrillation (AF), but little is known about the relationship between biomarker expression and AF burden.