Warfarin inhibits vitamin K-dependent proteins that prevent vascular calcification. We hypothesized that direct oral anticoagulants (DOACs), which do not interact with vitamin K, would slow coronary plaque progression compared to warfarin in atrial fibrillation (AF) patients. Following PRISMA guidelines and a prospectively registered protocol (PROSPERO: CRD420251026977), we systematically searched PubMed, Embase, and Cochrane databases through April 2025 for randomized controlled trials comparing DOACs with warfarin in AF patients. Primary outcomes included changes in coronary plaque volumes (PV). Mean differences were calculated using Mantel-Haenszel method, with trial sequential analysis performed for all outcomes. Three RCTs with 272 patients (136 receiving DOACs) were included. Patients receiving DOACs showed significantly slower progression of calcified PV (MD -7.07 mm3; 95% CI: -12.99 to -1.14; p=0.02; I2=0%) and fibrous PV (MD -12.52 mm3; 95% CI: -24.92 to -0.12; p=0.05; I2=0%) compared to warfarin. No significant differences were observed in total PV, non-calcified PV, fibro-fatty PV, or low attenuation PV. Trial sequential analysis indicated that 391 patients would be necessary for definitive conclusions regarding calcified PV. Risk of bias assessment indicated some concerns for all studies, with moderate certainty of evidence for most endpoints. DOACs significantly reduce progression of calcified and fibrous plaque volumes compared to warfarin in AF patients. These findings suggest DOACs may promote more stable plaque composition, potentially reducing cardiovascular event risk. However, larger studies with longer follow-up are needed to confirm these results.

Ivabradine is one of several off-label treatments for patients with postural orthostatic tachycardia syndrome (POTS). We conducted a systematic review of the literature to identify studies which evaluate ivabradine treatment in patients with POTS. The results were narratively synthesized given methodological heterogeneity among the identified studies. There were 11 studies included in the analysis with 305 participants between 2008 to 2020. The only randomized trial of 22 patients showed that ivabradine improved heart rate compared to placebo and there were symptomatic benefits in terms of physical functioning, and social functioning. All studies suggested a reduction in heart rate with ivabradine treatment; the proportion of patients with symptomatic benefit ranged from 67% to 100%. One study using the Malmo POTS score found that ivabradine improved the total score, including key components such as light-headedness with standing, feeling faint, feeling rapid heart rate, and chest pain. While two studies did not report side effects and two studies described no side effects, others reported adverse effects including bradycardia, nausea, worsening syncope, palpitations, flushing, light sensitivity, headache, light-headedness, fatigue, scalded tongue, itching and burning, and visual disturbance. In conclusion, there is low-quality evidence derived from small observational studies and one small randomized trial that ivabradine is effective in reducing heart rate and improving symptoms in patients with POTS. The exact role of ivabradine in treatment of POTS needs to be clarified in further randomized trials and more robust evidence.

Previously, we showed that vasorelaxant effects of trans-4-methoxy-β-nitrostyrene (T4MN) in rat aorta were mediated through stimulation of the soluble guanylate cyclase (sGC) pathway. The present study tested the hypothesis that bonding of the methoxy electron-donor group at the meta-position instead of the para-position into the aromatic moiety might enhance the interaction of the nitroderivative with sGC. For this purpose, vascular effects of the trans-3-methoxy-β-nitrostyrene (T3MN) were studied in rat aorta. In endothelium-intact preparations, T3MN was 100 times more potent as a vasorelaxant than its stereoisomer, T4MN. T3MN-induced vasodilatory effects remained unaffected by indomethacin, MDL-12,330A or glybenclamide but were significantly reduced by endothelium removal, L-NAME, ODQ, LY294002, TEA, 4-AP, and apamin. Under Ca2+-free conditions, T3MN was unresponsive to transient contractions evoked by caffeine, whereas it inhibited contractions induced by (i) the protein kinase C activator phorbol 12-myristate 13-acetate, (ii) the tyrosine phosphatase inhibitor sodium orthovanadate, (iii) exogenous calcium influx via receptor- or voltage-operated Ca2+ channels and (iv), in an ODQ-preventable manner, those evoked by PHE or Ca2+ influx through stores-operated Ca2+ channels activated by thapsigargin-induced Ca2+ store depletion. In conclusion, T3MN induced a potent vasorelaxant effect that seems to be mediated partly by an endothelium-dependent mechanism involving activation of the Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of the sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca2+ influx from the extracellular milieu and IP3-sensitive intracellular Ca2+ release as well as activation of potassium channels.

Cardiorespiratory fitness (CRF) in heart failure (HF) declines with age. Interleukin-1 is a proinflammatory cytokine involved in aging and HF. We aimed to determine the changes in CRF before and after treatment with anakinra, recombinant interleukin-1 receptor antagonist, in patients with HF stratified according to age younger and older than 60 years in phase II clinical trials. We analyzed data from 73 patients [37 (51%) female], 49 (67%) patients <60 years and 24 patients (33%) ≥60 years. All patients received anakinra 100 mg subcutaneously daily for a median of 4 (interquartile range from 2 to 12) weeks. We measured peak oxygen consumption (VO 2peak ) and high-sensitivity C-reactive protein (hsCRP). When compared with older patients, younger patients had higher baseline peak VO 2 [15.2 (12.4-17.7) vs. 12.4 (10.3-14.3) mL·kg -1 ·minute -1 , P = 0.001], yet no significant differences in hsCRP [6.6 (3.6-16.6) vs. 5.2 (2.7-11.2) mg/L, P = 0.18]. In both groups, anakinra decreased hsCRP [<60 years: -3.6 (-8.1 to -1.9) mg/L; P < 0.001; ≥60 years: -2.7 (-9.0 to -1.4) mg/L; P < 0.001] and increased peak VO 2peak [<60 years: +0.5 (-0.9 to 2.5) mL·kg -1 ·minute -1 ; P = 0.036; ≥60 years: +1.1 (0.2-2.3) mL·kg -1 ·minute -1 ; P < 0.001]. No significant differences in changes across time were observed between the age groups. Older patients with HF have a greater baseline impairment in CRF than younger patients despite similar levels of systemic inflammation, and they seem to have a similar improvement in CRF after treatment with anakinra. The lack of an active control group (placebo) is a significant limitation and additional studies are needed to validate and expand these findings assessing clinical outcomes.

Chronic stress-induced cardiac hypertrophy remains a critical precursor to heart failure, with current therapies limited by incomplete mechanistic targeting. Cyclin-dependent kinases (CDKs), pivotal regulators of cell cycle and stress signaling, are emerging therapeutic targets in cardiovascular pathologies. Using bioinformatics analysis of human hypertrophic cardiomyopathy data sets (GSE5500, GSE136308) and a murine transverse aortic constriction (TAC) model, we investigated the therapeutic effects of the CDK inhibitor R547 (10 mg/kg, intraperitoneal every 3 days) on pressure overload-induced cardiac remodeling. Cardiac function was assessed by echocardiography, while molecular mechanisms were probed through proteomics and pathway analyses. CDKs were significantly upregulated in heart tissues of human heart failure and TAC mice. R547 treatment attenuated cardiac hypertrophy (↓37.7% cardiomyocyte cross-sectional area; P < 0.001) and fibrosis (↓70.8% collagen volume fraction; P < 0.05) versus TAC controls. Echocardiographic improvements included preserved left ventricular ejection fraction (66 ± 2.1% vs. 81 ± 4.9% in TAC; P < 0.05) and reduced ventricular wall thickening. Mechanistically, R547 concurrently inhibited PI3K/AKT/mTOR hypertrophic signaling and TGF-β/Smad3 fibrotic pathways, with corresponding downregulation of ANP, BNP, β-MHC, and collagen I. This study identifies CDK-driven signaling as a nodal regulator of pressure overload cardiomyopathy. The dual inhibition of PI3K/AKT and TGF-β/Smad3 pathways by R547 demonstrates superior efficacy in mitigating both structural and functional deterioration, positioning it as a promising multifactorial therapy for cardiac hypertrophy.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and multifaceted clinical syndrome, often underdiagnosed because of its heterogeneous presentation and overlapping comorbidities. Recent randomized trials have demonstrated the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing heart failure hospitalizations and cardiovascular mortality. In this review, we analyze the main challenges of HFpEF diagnosis and discuss current diagnostic algorithms. Based on recent evidence and recommendations, we propose a possible way to simplify and accelerate the diagnostic process of HFpEF, to support an early initiation of disease-modifying therapies. An interactive web-based version of the proposed algorithm is available at www.hfpefdiagnosis.com for research or exploratory purposes.

Nuclear factor erythrocyte 2-associated factor 2 (Nrf2) is an important transcriptional regulator that plays a protective role in myocardial remodeling. Omaveloxolone (Omav) acts as an activator of Nrf2 and plays a protective role by decreasing oxidative stress and inflammation. The purpose of this study was to explore the role of Omav in myocardial remodeling and investigate the potential mechanism involved. Transverse aortic constriction was performed to construct a mouse cardiac remodeling model, and sham surgery was used as a control. The results showed that Omav treatment significantly improved TAC-induced myocardial remodeling and cardiac dysfunction. In addition, Omav treatment mitigated M1 macrophage polarization, promoted M2 macrophage polarization, and reduced the cardiac inflammatory response and oxidative stress. Cell experiments revealed that Omav can reduce the expression of p-STAT3 induced by PE, thereby inhibiting the polarization of M1 macrophages and promoting the polarization of M2 macrophages. However, the Nrf2 inhibitor ML385 significantly inhibited OMAV-mediated reduction of p-STAT3, macrophage polarization, and activation of the NRf2-KEAP1 pathway. Omav activates the Nrf2-Keap1 pathway, affects STAT3 phosphorylation, ultimately alleviates M1 macrophage polarization, promotes M2 macrophage polarization, and improves myocardial remodeling. Omav may be a potential therapeutic agent for pathologic myocardial remodeling.

Cardiometabolic complications represent a leading cause of morbidity and mortality among cancer survivors, who increasingly face a dual burden of residual oncologic risk and rising cardiovascular (CV) vulnerability. The shared pathophysiologic mechanisms linking cancer, dyslipidemia, insulin resistance, and chronic inflammation foster an environment conducive to accelerated atherosclerosis, heart failure, and metabolic dysregulation. Hyperglycemia and hyperlipidemia, frequently coexisting in long-term cancer survivors, especially those exposed to cardiotoxic chemotherapies, hormonal therapies, or corticosteroids, are key drivers of adverse CV outcomes. Despite this recognized risk, comprehensive preventive strategies in cardio-oncology remain limited and often rely on conventional therapies insufficient to fully address the complexity of cardiometabolic disease in this population. Notably, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have emerged as powerful tools in CV risk reduction. SGLT2i have demonstrated robust benefits in heart failure, renal protection, and glycemic control, while PCSK9i provide profound and sustained reductions in low-density lipoprotein cholesterol, with emerging pleiotropic anti-inflammatory and antiatherosclerotic effects. We propose that a combinatorial strategy integrating SGLT2i and PCSK9i may offer synergistic protection against the intertwined cardiometabolic risks seen in cancer survivors. This approach targets multiple mechanistic pathways, glucose and lipid metabolism, vascular inflammation, endothelial dysfunction, and organ remodeling, potentially redefining the standard of care in high-risk cardio-oncology populations. Further clinical investigation is warranted to validate this hypothesis and establish optimal therapeutic protocols.

Although a solid pathophysiologic rationale supports intravenous vasodilators (IVV) for acute heart failure (AHF), trial evidence is conflicting and international guidelines offer only weak recommendations. We conducted an international survey to capture contemporary, real-world practice and clinician opinion regarding IVV use in AHF. A 29-item, web-based questionnaire was distributed to cardiologists involved in AHF management. Items explored indications, contraindications, preferred agents, monitoring strategies, and interaction with guideline-directed medical therapy. We analyzed responses from 170 physicians in 32 countries (67% male; mostly aged 30-50 years). Sixty-two percent treat <10 patients per month with IVV; nitroglycerin is the drug of choice for 48%, followed by sodium nitroprusside in 29%. Nearly half (48%) would start IVV also out of the intensive-care setting and 58% consider repeated noninvasive blood pressure monitoring sufficient. Key indications are acute decompensated heart failure (88%) and pulmonary edema (87%), yet 42% would also use IVV for advanced low-output HF, 25% for cardiogenic shock, and 24% for isolated right ventricular failure. Hypotension is cited as the principal contraindication (51%), although the reported thresholds for blood pressure vary widely. Respondents favor IVV in reduced or mildly reduced ejection fraction (55%) more often than in preserved ejection fraction (17%). Opinions diverge sharply on whether to pause or continue oral neurohormonal therapies during infusion. This survey shows that IVV are used in a limited number of patients with AHF and practice is highly heterogeneous across centers. These findings underscore the need for prospective trials to clarify which subsets derive hemodynamic or prognostic benefit.

Colchicine has been studied as an anti-inflammatory treatment for cardiovascular prevention, but findings from randomized trials have been inconsistent. This meta-analysis evaluated the efficacy and safety of colchicine in reducing major adverse cardiovascular events (MACE) and its individual components, using ChatGPT as an assistant throughout the process. Randomized trials of colchicine for cardiovascular prevention were systematically identified, and data extraction, risk of bias assessment, and meta-analyses were performed with ChatGPT under human supervision. The primary outcome was MACE, while secondary outcomes included myocardial infarction (MI), stroke, revascularization, cardiovascular mortality, and all-cause mortality. Eleven trials involving 30,888 patients were included. Colchicine significantly reduced MACE (risk ratio 0.75, 95% CI 0.63-0.88), though no significant effects were observed for MI, stroke, cardiovascular mortality, or all-cause mortality. In addition to its clinical findings, this study illustrates the potential of ChatGPT to assist in systematic reviews and meta-analyses by automating screening, data extraction, bias assessment, and statistical code generation. This integration reduced researcher time by over 70% while maintaining accuracy through human validation. Overall, colchicine appears to lower the risk of MACE but the results of the CLEAR trial have lowered certainty, while the findings highlight the feasibility and efficiency gains of using large language models in evidence synthesis workflows.