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The recently published Lipid-Lowering Arm of the Anglo--Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) provides interesting evidence for the use of statins in hypertensive patients with average cholesterol concentrations and other cardiovascular risk factors. The clinical benefit of atorvastatin in these patients is probably explained by both lipid-dependent and lipid-independent effects of the drug. Many of these effects are related to inhibition of the synthesis of isoprenoid, which serves as lipid attachment for a variety of proteins implicated in intracellular signalling. These proteins have an important role in cell growth, actin cytoskeleton organisation, membrane trafficking, gene expression, cell proliferation/migration and programmed cell death. In this article we summarise the different effects of statins in relation to the results observed in the ASCOT-LLA study. [ABSTRACT FROM AUTHOR]

Objectives: To examine the relationship between inflammatory biomarkers and the occurrence of cardiovascular events in patients with type 2 diabetes mellitus (DM2) and stable coronary artery disease., Methods: A total of 964 patients with stable coronary artery disease were included. Plasma levels of inflammatory markers, including tumour necrosis factor receptors 1 and 2 (TNF-R1 and TNF-R2), growth differentiation factor-15 (GDF-15), soluble suppression of tumorigenicity 2 (sST2), and high-sensitivity C-reactive protein (hsCRP) were measured. The primary endpoint was the development of acute ischaemic events (any type of acute coronary syndrome, stroke, or transient ischaemic attack)., Results: There were 232 diabetic patients and 732 non-diabetic patients. Patients with coronary artery disease and DM2 (232, 24%) had higher levels of TNF-R1, TNF-R2, GDF-15, sST2 (P<.001), and hsCRP compared to patients without DM2, indicating a higher inflammatory state. After a median follow-up of 5.39 (2.81-6.92) years, patients with DM2 more frequently developed the primary endpoint (15.9% vs 10.8%; P=.035). Plasma levels of TNF-R1 were independent predictors of the primary endpoint in patients with DM2, along with male gender, triglyceride levels, and the absence of treatment with angiotensin-converting enzyme inhibitors. None of these inflammatory markers predicted the development of this event in non-diabetic patients., Conclusions: Patients with stable coronary artery disease and DM2 exhibit elevated levels of the proinflammatory markers TNF-R1, TNF-R2, GDF-15, and sST2. Moreover, TNF-R1 is an independent predictor of acute ischaemic events only in diabetic patients., (Copyright © 2024 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Background: ATTR-CM is becoming more prevalent, and disease-modifying therapy has been investigated in recent years with promising results. Diflunisal has shown TTR-stabilizing properties assessed by biomarkers and echocardiography, but there are no trials addressing the evolution of morphological changes with CMR. Methods and Results: AMILCA-DIFLU is an exploratory pilot study prospective, single-center, non-randomized, open-label clinical trial. Patients diagnosed with ATTR-CM underwent clinical, functional, biochemical and imaging assessment before and one year after diflunisal therapy initiation. Of the twelve ATTR-CM patients included, only nine patients completed treatment and study protocol in 12 months. To increase the sample size, we included seven real-world patients with one year of diflunisal treatment. Among the group of patients who completed treatment, diflunisal therapy did not show improvement in cardiac disease status as assessed by many cardiac and inflammatory biomarkers, 6MWT and CMR parameters after one year of treatment. However, a non-significant trend towards stabilization of CMR parameters such as LVEF, ECV and T2 at one year was found. When comparing the group of patients who completed diflunisal therapy and those who did not, a significant decrease in the distance performed in the 6MWT was found in the group of patients who completed treatment at one year (-14 ± 81.8 vs. -173 ± 122.2; p = 0.032). Diflunisal was overall well tolerated, showing only a statistically significant worsening in renal function in the group of diflunisal-treatment patients with no clinical relevance or need for treatment discontinuation. Conclusions: In patients with ATTR-CM, treatment with diflunisal was overall well tolerated and tended to stabilize or slow down amyloid cardiac disease progression assessed by CMR parameters, cardiac and inflammatory biomarkers and functional capacity.

Background: Heart failure (HF) is a highly prevalent syndrome in elderly subjects. Currently, multiple drugs have shown clinical benefits in patients with HF and reduced ejection fraction (HFrEF). However, evidence is scarce in elderly patients (beyond 75 years old), even more so for the latest drugs, such as angiotensin receptor-neprilysin inhibitors (ARNIs). This study aims to evaluate the use and benefits of ARNIs in elderly patients with HFrEF. Methods : A prospective observational cohort study was designed. Patients with left ventricular systolic dysfunction (defined by left ventricular ejection fraction [LVEF] < 40%) and age ≥ 75 years from January 2016 to December 2020 were prospectively included. Patients with an indication for ARNIs at inclusion or throughout follow-up were selected. Clinical, electrocardiographic and echocardiographic variables were collected. Results : A total of 616 patients were included, 34.4% of them female, with a mean age of 83.3 years, mean LVEF of 28.5% and ischemic etiology in 53.9% of patients. Only 14.3% of patients were taking ARNIs. After a mean follow-up of 34 months, 50.2% of patients died, and 62.2% had a cardiac event (total mortality or hospital admission due to HF). Multivariate Cox regression analysis showed that the use of ARNIs was independently and significantly associated with lower rates of mortality [HR 0.36 (95% CI 0.21-0.61)], with similar results in relation to all-cause mortality in a propensity-score-matched analysis [HR 0.33 (95% CI 0.19-0.57)]. Conclusions : We observed an important underuse of ARNIs in a cohort of elderly HFrEF patients, in which treatment with ARNIs was associated with a significant reduction in mortality. Greater implementation of clinical practice guidelines in this group of patients could improve their prognosis.

Aims: Heart failure (HF) with reduced left ventricle ejection fraction (LVEF) is an entity with poor prognosis characterized by decompensations. Bioelectrical impedance analysis (BIA) is used to assess volume overload (VO) and may be useful to identify apparently stable HF outpatients at risk of decompensation. The aim of this study is to analyse whether VO assessed by BIA is associated with worsening heart failure (WHF) in stable outpatients with HF and reduced LVEF (HFrEF)., Methods and Results: This is a prospective single-centre observational study. Consecutive stable HF outpatients with LVEF below 40% underwent BIA, transthoracic echocardiography, blood sampling, and physical examination and were followed up for 3 months. VO was defined as the difference between the measured weight and the dry weight assessed by BIA. Demographic, clinical, anthropometric, echocardiographic, and analytical parameters were recorded. The primary endpoint was WHF, defined by visits to the emergency department for HF or hospitalization for HF. A total of 100 patients were included. The median VO was 0.5 L (interquartile range 0-1.6 L). Eleven patients met the primary endpoint. Univariate binary logistic regression analysis showed that left ventricle filling pressures assessed by E/e', N-terminal pro B-type natriuretic peptide, inferior vena cava dilatation (≥21 mm), signs of congestion, and VO were associated with the primary endpoint. Binary logistic regression multivariate analysis showed that VO was the only independent predictor for the primary endpoint (adjusted OR 2.7; 95% CI 1.30-5.63, P = 0.008). Multivariate Cox regression analysis also showed an adjusted hazard ratio (HR) for VO of 2.03; 95% CI 1.37-3.02, P < 0.001. Receiver-operating characteristic curve analysis showed an area under the curve for VO of 0.88 (95% CI 0.79-0.97, P < 0.001) with an optimal cut-off of 1.2 L., Conclusions: VO assessed by BIA is independently associated with WHF in stable outpatients with HFrEF at 3 months., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Transthyretin cardiac amyloidosis (ATTR amyloidosis) is a frequent etiology of heart failure. Inflammation and mineral metabolism are associated with myocardial dysfunction and clinical performance. Cardiac global longitudinal strain (GLS) allows function assessment and is associated with prognosis. Our aim was to describe possible correlations between GLS, biomarker levels and clinical performance in ATTR amyloidosis., Methods: Thirteen patients with ATTR amyloidosis were included. Clinical characteristics; echocardiographic features, including strain assessment and 6 min walk test (6MWT); and baseline inflammatory, mineral metabolism and cardiovascular biomarker levels were assessed., Results: Of the 13 patients, 46.2% were women, and the mean age was 79 years. TAPSE correlated with NT-ProBNP (r -0.65, p < 0.05) and galectin-3 (r 0.76, p < 0.05); E/E' ratio correlated with hsCRP (r 0.58, p < 0.05). Left ventricular GLS was associated with NT-ProBNP (r 0.61, p < 0.05) (patients have a better prognosis if the strain value is more negative) and left atrial GLS with NT-ProBNP (r -0.73, p < 0.05) and MCP1 (r 0.55, p < 0.05). Right ventricular GLS was correlated with hsTnI (r 0.62, p < 0.05) and IL6 (r 0.881, p < 0.05). Klotho levels were correlated with 6MWT (r 0.57, p < 0.05)., Conclusions: While inflammatory biomarkers were correlated with cardiac function, klotho levels were associated with clinical performance in the population with TTR-CA., Competing Interests: The authors declare no conflicts of interest.

Background : Mineral metabolism (MM), mainly fibroblast growth factor-23 (FGF-23) and klotho, has been linked to cardiovascular (CV) diseases. Cardiac rehabilitation (CR) has been demonstrated to reduce CV events, although its potential relationship with changes in MM is unknown. Methods : We performed a prospective, observational, case-control study, with acute coronary syndrome (ACS) patients who underwent CR and control patients (matched by age, gender, left ventricular ejection fraction, diabetes, and coronary artery bypass grafting), who did not. The inclusion dates were from August 2013 to November 2017 in CR group and from July 2006 to June 2014 in control group. Clinical, biochemical, and MM biomarkers were collected at discharge and six months later. Our objective was to evaluate differences in the modification pattern of MM in both groups. Results : We included 58 CR patients and 116 controls. The control group showed a higher prevalence of hypertension (50.9% vs. 34.5%), ST-elevated myocardial infarction (59.5% vs. 29.3%), and treatment with angiotensin-converting enzyme inhibitors (100% vs. 69%). P2Y12 inhibitors and beta-blockers were more frequently prescribed in the CR group (83.6% vs. 96.6% and 82.8% vs. 94.8%, respectively). After six months, klotho levels increased in CR patients whereas they were reduced in controls (+63 vs. -49 pg/mL; p < 0.001). FGF-23 was unchanged in the CR group and reduced in controls (+0.2 vs. -17.3 RU/dL; p < 0.003). After multivariate analysis, only the change in klotho levels was significantly different between groups (+124 pg/mL favoring CR group; IC 95% [+44 to +205]; p = 0.003). Conclusions : In our study, CR after ACS increases plasma klotho levels without significant changes in other components of MM. Further studies are needed to clarify whether this effect has a causal role in the clinical benefit of CR.