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Purpose: The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo. Methods: The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment. Results: In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin. Conclusion: This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic impact of myocardial contraction fraction (MCF), in patients with severe aortic stenosis (AS) remains unexplored. We investigated the association between MCF and 1-year all-cause mortality in patients with severe AS who underwent a transcatheter aortic valve replacement (TAVR). Hypothesis: MCF, a volumetric measurement of myocardial shortening analogous to strain, may help to improve risk stratification in patients with severe AS referred for TAVR especially in those with preserved left ventricular ejection fraction (LVEF). Methods: Patients with severe AS referred for TAVR were divided into 2 groups according to the estimated MCF (MCF≤30% versus MCF>30%). MCF was assessed as the ratio of stroke volume (SV) to myocardial volume. ROC curves were performed for assessing the best cut-off point of MCF for predicting the primary outcome. The primary endpoint was 1-year all-cause mortality. A Cox regression analysis was performed for independent risk factors of mortality. Baseline patient and echo characteristics were included using a backward stepwise selection method, and variables significant at α= 0.10 were included for adjusted multivariate analysis. Results: Of 126 patients, (mean age 82± 5 years, 45% male), 44% showed MCF≤30%. When comparing against patients with preoperative MCF>30%, these patients showed higher body mass index (28,2±5,7 kg/m2 versus 25,9±4,5 kg/m2, p=0,02), higher surgical Euroscore II (6,2±4,5 versus 4,7±3,2 p=0,032), lower LVEF (54,2±11,9% versus 58,5±10,8%, p=0,042) and more severe AS (AVA index 0,40±0,09 cm2/m2 versus 0,45±0,10 cm2/m2, p=0,03). The median follow-up was of 14 (0-96) months, and 16% of patients died. Patients with MCF≤30% showed significantly increased all-cause mortality (Figure , log-rank p<0.002). In a multivariate model correcting for left atrial volume index (LAVI), MCF≤30% was independently associated with increased risk for all-cause 1-year mortality (HR 3.3, 95% CI [1.1-9.2], p<0.021). Conclusions: In a large population of patients with symptomatic severe AS, MCF≤30% is independently associated with increased mortality. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Seropian, Cassaglia, Miksztowicz and González.)

Aims: The aim of this study was to evaluate whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict outcome in heart failure (HF) patients undergoing heart transplantation (HTX)., Methods and Results: Data from 111 HF patients undergoing HTX 2010-2015 were retrospectively reviewed. NLR and PLR were calculated before HTX, immediately after HTX, and at 6 and 24 hours. Primary endpoint was in-hospital mortality, and secondary endpoints were 1 year mortality and renal replacement therapy (RRT). Prognostic factors were assessed by multivariate analysis, and the predictive values of NLR and PLR for mortality were compared. The discriminatory performance for predicting in-hospital mortality was better for NLR [area under the receiver operating characteristic curve (AUC) = 0.644, 95% confidence interval 0.492-0.797] than for PLR (AUC = 0.599, 95% confidence interval 0.423-0.776). Best cut-off value was 2.41 for NLR (sensitivity 86%, specificity 67%) and 92.5 for PLR (sensitivity 86%, specificity 68%). When divided according to best cut-off value, in-hospital mortality was significantly higher in the high NLR group (17.5% vs. 3.2%, P < 0.05), but not in the high PLR group (16.5% vs. 6.3%, P = ns). One year mortality was not significantly higher for either group (37.5% vs. 6.5% for NLR; 36.7% vs. 9.4% for PLR, P = ns for both), while RRT was significantly higher in both the NLR and PLR high groups (33.8% vs. 0%; 32.9% vs. 3.1%, respectively, P < 0.001). Multivariate analysis indicated that only high NLR (hazard ratio = 3.403, P < 0.05) and pre-transplant diabetes (hazard ratio = 3.364, P < 0.05) were independent prognostic factors for 1 year mortality., Conclusions: High NLR was a predictor for in-hospital mortality, and an independent prognostic factor for 1 year mortality. Both high NLR and high PLR were predictors for RRT., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1β in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30-50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1β induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1β failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1β induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1β. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.

Vitamin D (VitD) deficiency is associated with increased morbidity and mortality. We evaluated the association of VitD deficiency (<50 mmol/l) and cardiovascular risk factors in a healthy population, from July-November 2012, in a private center at Buenos Aires province. 333 people were included, aged 41.6±12.4 years (58.6% men), 49.2% practiced no physical activity, 56.8% were overweight (70.3% man vs 37.7% women, p<0.001), 12.5% with systolic blood pressure (SBP) >140 mmHg and 6% diastolic blood pressure (DBP) >90 mmHg. VitD deficiency was observed in 29.1% (31.3% man vs 26.1% women, p=0.3), more frequent with obesity (OR 1.85, IC95:1.05-3.25, p=0.02), HDL-cholesterol (HDL-C)<50 mg/dl (OR 1.71, IC95:1.06-2.76, p=0.02) and triglycerides>150 mg/dl (OR 1.77, IC95:1.02-3.06, p=0.03). A trend towards VitD deficiency and SBP>140 mmHg (OR 1.88, IC95:0.93-3.77, p=0.07) or DBP>90 mmHg (OR 1.39, IC95:0.5-3.65, p=0.5) was observed. Lineal correlation between VitD and HDL-C (p<0.001) or triglycerides (p<0.001) was observed. Multiple logistic regression showed that VitD deficiency association with low HDL-C was independent of age, female sex, obesity and physical activity. Association of VitD deficiency with hypetriglyceridemia was independent of age, female sex and obesity. This study shows an association between VitD deficiency and cardiovascular risk factors like obesity, low HDL <50 mg/dl and hypertriglyceridemia. A trend toward higher SBP was also observed. Experimental studies are granted in order to establish a cause-effect relationship.

Hemodynamic parameters and natriuretic peptide levels were evaluated in cardiac hypertrophy produced by sequentially applied renovascular (RV) and deoxycorticosterone acetate-salt (DS) models of hypertension. We studied hypertensive rats by RV or DS treatment at 2 and 4 wk, as well as by the combination of 2 wk of each treatment in an inverse sequence: RV 2 wk/DS 2 wk (RV2/DS2) and DS 2 wk/RV 2 wk (DS2/RV2). The in vivo cardiac function, interstitial fibrosis, and synthesis and secretion of types A (ANP) and B (BNP) natriuretic peptides were monitored in hypertensive models compared with their corresponding sham (Sh2, Sh4). There were no differences in relaxation parameters among RV or DS groups and combined treatments. Left ventricular +dP/dt(max) increased only in RV4 (P < 0.01 vs. Sh4), and this increase was abolished in RV2/DS2. Interstitial collagen concentration increased after 4 wk in both RV4 and RV2/DS2 groups. Although there were no changes in collagen concentration in either DS2 or DS4 groups, clipping after 2 wk of DS (DS2/RV2) remarkably stimulated interstitial fibrosis (P < 0.01 vs. DS2). Plasma BNP increased in RV treatment at 4 wk (P < 0.001 vs. Sh4), but not in DS. Interestingly, RV applied after the 2 wk of DS treatment induced a marked increase in BNP levels (P < 0.001 vs. Sh4). In this regard, plasma BNP appears to be a reliable indicator of pressure overload. Our results suggest that the second stimulus of mechanical overload in combined models of hypertension determines the evolution of hypertrophy and synthesis and secretion of ANP and BNP.

To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.