Effetti cardiotossivi precoci e tardivi del trattamento con Epirubicina. Valutazione con marker biochimici ed ecocardiografia Tissue Doppler.

Our study was carried out in a group of epirubicin(Epi)-treated patients with cancer at different sites with the aim of detecting early preclinical changes, that are predictive of the risk of heart failure. All subjects underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with Strain (ε) and Strain Rate (SR). Moreover, echocardiographic changes identified during the Epi treatment were compared with inflammatory and oxidative stress laboratory markers. Thirty-one patients (age 59±14 yrs) with histologically confirmed tumors at different sites, scheduled to be treated with an Epi-based chemotherapy regimen were enrolled. We prospectively evaluated the acute (one week after) and late effects (3, 6, 12 and 18 months of follow-up) of Epi administration. A significant impairment of the systolic LV function was observed at epirubicin dose 200 mg/m2: this was shown by a reduction of the SR peak in comparison to baseline. This reduction persisted statistically significant throughout the treatment and follow-up, up to 18 months when the Sm reduction became significant. Levels of IL-6, sIL-6R and ROS increased significantly at 200 mg/m2 and IL-6 persisted high at 300 and 400 mg/m2 Epi dose returning within baseline values during follow-up. A significant inverse correlation between ΔSR and both the increase of IL-6 and ROS was observed. The multiple regression analysis showed that both IL-6 and ROS variables were independent and strongly predictive of ΔS

Early impairment of contractility reserve in patients with insulin resistance in comparison with healthy subjects

Background: Insulin resistance (IR) is currently considered a crucial cardiovascular (CV) risk factor, which seems to play a dominant role in the evolution toward cardiac and vascular impairment. Early IR-induced cardiac dysfunction can be assessed by Doppler-derived myocardial systolic strain rate (SR) index, measured at baseline and after dobutamine stress echocardiography (DSE).Methods: Thirty IR patients (HOMA-IR = 7 ± 5.2, age 52.6 ± 2.1 years), and 20 healthy, age and sex matched controls were studied. IR had been diagnosed in all patients in the 3 months preceding the study. Dobutamine echocardiography was performed in all subjects to exclude ischemic heart disease, and left ventricular contractile reserve (LVCR) was then assessed. LVCR was evaluated as an increase in the peak of an average longitudinal SR, measured in the basal and mid segments of 2 and 4 chamber ventricular walls.Results: No significant differences between the 2 groups were revealed by baseline echocardiography. In contrast, after DSE a significant decrease of Delta SR was found in the IR group in comparison to the controls (0.54 ± 0.31 s-1vs 1.14 ± 0.45 s-1; p < 0.0001).Conclusions: Our results show that IR, even if isolated and arising within a short time period, not only represents the initial phase of future diabetes, but may adversely affect heart function, as evidenced by the depressed LVCR. Our data strengthen the need for attention to be paid to IR state and for an early therapeutic approach

Metabolomic Profiles on Antiblastic Cardiotoxicity: New Perspectives for Early Diagnosis and Cardioprotection

Antiblastic drugs-induced cardiomyopathy remains a relevant cause of morbidity and mortality, during and after chemotherapy, despite the progression in protective therapy against cardiovascular diseases and myocardial function. In the last few decades, many groups of researchers have focused their attention on studying the metabolic profile, first in animals, and, subsequently, in humans, looking for profiles which could be able to predict drug-induced cardiotoxicity and cardiovascular damage. In clinical practice, patients identified as being at risk of developing cardiotoxicity undergo a close follow-up and more tailored therapies. Injury to the heart can be a consequence of both new targeted therapies, such as tyrosine kinase inhibitors, and conventional chemotherapeutic agents, such as anthracyclines. This review aims to describe all of the studies carried on this topic of growing interest

Contractile reserve in systemic sclerosis patients as a major predictor of global cardiac impairment and exercise tolerance

Several studies have evidenced high prevalence of myocardial systolic and diastolic dysfunction among patients with systemic sclerosis (SSc). Exercise echocardiography has shown a diagnostic and prognostic role in identifying early left ventricular (LV) dysfunction in several myocardial pathological settings. The aim of our study was to evaluate early signs of LV impairment under exercise and their correlation to patient's exercise tolerance. Forty-five patients (age 60.4 ± 10.3 years) with SSc and 20 age and sex comparable controls were enrolled in the study. All patients underwent clinical evaluation, 2D echocardiography associated with Tissue Doppler and speckle tracking to evaluate LV deformation indexes, and an exercise echocardiography to evaluate left ventricle contractile reserve (LVCR) and exercise pulmonary pressures. Finally, a 6-minute walking test (6MWT) to evaluate exercise tolerance was also performed. Compared to controls, SSc patients showed an impaired diastolic function (E/E' 10.9 ± 3.7 vs 8.36 ± 2.01; p < 0.01) associated with larger left atrial dimensions (LAVI 28.4 ± 8.7 vs 19.3 ± 4.6 mL/m2; p < 0.01). During exercise echocardiography, a reduced global longitudinal strain at peak exercise (S-GLS) was highlighted compared to controls (15.7 ± 3.6 vs 18.2 ± 2.2; p = 0.001). A S-GLS cutoff <18 %, identified by ROC analysis, identified SSc patients with a reduced diastolic function, exercise tolerance at the 6MWT and higher pulmonary pressures. Our data show that in SSc patients a reduced LVCR characterizes the patients with a more extensive cardiovascular impairment in terms of LV diastolic function, pulmonary pressures and exercise tolerance. These data underline the importance of exercise echocardiography for the preclinical screening of the LV impairment in this population

Metabolomic approach to profile functional and metabolic changes in heart failure

Heart failure (HF) is characterized by a series of adaptive changes in energy metabolism. The use of metabolomics enables the parallel assessment of a wide range of metabolites. In this study, we appraised whether metabolic changes correlate with HF severity, assessed as an impairment of functional contractility, and attempted to interpret the role of metabolic changes in determining systolic dysfunction

The Echocardiographic Parameters of Systolic Function Are Associated with Specific Metabolomic Fingerprints in Obstructive and Non-Obstructive Hypertrophic Cardiomyopathy

The purpose of this study was to assess whether metabolomics, associated with echocardiography, was able to highlight pathophysiological differences between obstructive (OHCM) or non-obstructive (NOHCM) hypertrophic cardiomyopathy. Thirty-one HCM patients underwent standard and advanced echocardiography; a plasma sample was collected for metabolomic analysis. Results. Patients with OHCM compared with subjects with NOHCM had higher values of 2DLVEF (66.5 ± 3.3% vs. 60.6 ± 1.8%, p &lt; 0.01), S wave (7.6 ± 1.1 vs. 6.3 ± 0.7 cm/s, p &lt; 0.01) and 3D global longitudinal strain (17.2 ± 4.2%, vs. 13.4 ± 1.3%, p &lt; 0.05). A 2-group PLS-Discriminant Analysis was performed to verify whether the two HCM groups differed also based on the metabolic fingerprint. A clear clustering was shown (ANOVA p = 0.014). The most discriminating metabolites resulted as follows: in the NOHCM Group, there were higher levels of threitol, aminomalonic acid, and sucrose, while the OHCM Group presented higher levels of amino acids, in particular those branched chains, of intermediates of glycolysis (lactate) and the Krebs cycle (fumarate, succinate, citrate), of fatty acids (arachidonic acid, palmitoleic acid), of ketone bodies (2-OH-butyrate). Our data point out a different systolic function related to a specific metabolic activity in the two HCM phenotypic forms, with specific metabolites associated with better contractility in OHCM

Effects of metformin and exercise training, alone or in combination, on cardiac function in individuals with insulin resistance

Introduction: In patients affected by insulin resistance (IR), metformin (MET) therapy has been shown to exert its positive effects by improving glucose tolerance and preventing the evolution to diabetes. Recently, it was shown that the addition of metformin to physical training did not improve sensitivity to insulin or peak oxygen consumption (peak VO2). The purpose of this study was to establish the effect of metformin and exercise, separately or in combination, on systolic left ventricular (LV) function in individuals with IR. Methods: Seventy-five patients with IR were enrolled and subsequently assigned to MET, combination MET and exercise, or exercise alone. The LV systolic and diastolic functions were evaluated with standard echocardiography tissue Doppler imaging (TDI) and speckle tracking echocardiography at baseline and after 12 weeks of treatment. Results: MET, administered alone or in association with exercise, improved longitudinal LV function, as evidenced by an increase in systolic (S) wave on TDI, alongside increases in longitudinal global strain and strain rate in comparison to the group undergoing physical training alone. The traditional echocardiographic parameters showed no statistically significant differences among the three groups before or after the different cycles of therapy. Conclusions: Treatment with MET, either with or without exercise, but not exercise alone, produced a significant increase in global longitudinal LV systolic function at rest. These findings validate the observation that the use of MET alone or in association with exercise has a crucial role to counteract the negative effects of IR on cardiovascular function

12 Sex-related differential susceptibility to ponatinib-induced cardiotoxicity and its relationship to modulation of notch signalling in a muine model

Abstract Aims Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukaemia, has proven cardiovascular toxicity. Although sex is a risk factor for PON-induced cardiotoxicity in humans, little is known about its mechanisms, in general, and sex-related mechanisms in particular. To determine the mechanisms of sex-related PON-induced cardiotoxicity and identify potential rescue strategies in a murine model. Methods Twenty-four-month-old male and female C57B5 mice were treated with 3 mg/kg/day of PON or vehicle via oral gavage for 28 days, with/without siRNA-Notch1 or siRNA-scrambled via tail vein every 3 days. Results PON + scrambled siRNA-treated male mice had a higher number of TUNEL-positive cells, a higher percentage of senescence-associated β-galactosidase positive senescent cardiac areas, as well as a lower reactivity degree for the survival marker Bmi1 than female counterparts. Proteomics analysis of cardiac tissue showed upstream activation of nitric oxide synthase (NOS) type 2, downstream activation of cell death and production of reactive oxygen species in PON + scrambled siRNA- compared to vehicle or PON + Notch1 siRNA-treated male mice. Upstream analysis showed beta-estradiol activation, while downstream analysis showed activation of cell survival and inhibition of cell death in PON + scrambled siRNA compared to vehicle-treated female mice. PON + scrambled siRNA-treated mice also showed a down-regulation of cardiac actin, which was more marked in male; as well as vessel density, which was more marked in female mice. Female hearts showed a greater extent of cardiac fibrosis than male counterparts at baseline, with no significant changes after PON treatment. In contrast, PON + scrambled siRNA-treated mice had less fibrosis than vehicle or PON + Notch1-siRNA-treated mice. Left ventricular systolic dysfunction shown in PON + scrambled siRNA-treated male mice and—to a lesser extent—by female mice was similarly reversed in both PON + Notch1-siRNA-treated male and female mice (Table 1). Conclusions We found a sex-related differential susceptibility and Notch1 modulation in PON-induced cardiotoxicity. This can improve our understanding of sex-related differences and help identify biomarkers in PON cardiotoxicity