Background— Patients with cardiac hypertrophy are at increased cardiovascular risk. It has been hypothesized that hydroxymethylglutaryl coenzyme A reductase inhibitors may exert beneficial effects other than their cholesterol-lowering actions. The aims of the study were to assess the in vivo effects of simvastatin (SIM) on cardiac hypertrophy and on Ras signaling in rats with ascending aorta banding. Methods and Results— Wistar rats were randomized to receive either treatment with SIM or placebo, and then short-term (group I) and long-term (group II) left ventricular pressure overload was performed by placing a tantalum clip on ascending aorta. At the end of treatment period, left and right ventricular weight, body weight, and tibial length were measured and echocardiographic evaluations were performed. Ras signaling was investigated by analyzing Ras membrane localization and activation, ERK2 phosphorylation, and p27 ^kip1 and cdk4 levels. In SIM-treated rats, a significant reduction of left ventricular weight/body weight, echocardiographic left ventricular mass, and left ventricular end-diastolic diameter and end-diastolic pressure was found. In rats with pressure overload, SIM treatment significantly reduced Ras membrane targeting, Ras in vivo activation, ERK2 phosphorylation, and the ratio cdk4/p27 ^kip1 . Conclusions— HMG CoA inhibitor SIM inhibits in vivo Ras signaling and prevents left ventricular hypertrophy development in aortic-banded animals.

Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1β and IL-10, tumor necrosis factor-alpha (TNF-α), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35–40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1β, TNF-α and nitric oxide by around 35–40% and increased IL-10 production by 25–27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.

Aims Doxorubicin is widely used against cancer; however, it can produce heart failure (HF). Among other hallmarks, oxidative stress is a major contributor to HF pathophysiology. The late I_Na inhibitor ranolazine has proven effective in treating experimental HF. Since elevated [Na⁺]_i is present in failing myocytes, and has been recently linked with reactive oxygen species (ROS) production, our aim was to assess whether ranolazine prevents doxorubicin-induced cardiotoxicity, and whether blunted oxidative stress is a mechanism accounting for such protection. Methods and result In C57BL6 mice, doxorubicin treatment for 7 days produced LV dilation and decreased echo-measured fractional shortening (FS). Ranolazine (305 mg/kg/day) prevented LV dilation and dysfunction when co-administered with doxorubicin. Doxorubicin-induced cardiotoxicity was accompanied instead by elevations in atrial natriuretic peptide (ANP), BNP, connective tissue growth factor (CTGF), and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated on co-treatment with ranolazine. Alterations in extracellular matrix remodelling were confirmed by an increase in interstitial collagen, which did not rise in ranolazine-co-treated hearts. Levels of poly(ADP-ribose) polymerase (PARP) and pro-caspase-3 measured by western blotting were lowered with doxorubicin, with increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Furthermore, in HL-1 cardiomyocytes transfected with HyPer to monitor H₂O₂ emission, besides reducing the extent of cell death, ranolazine prevented the occurrence of oxidative stress caused by doxorubicin. Interestingly, similar protective results were obtained with the Na⁺/Ca²⁺ exchanger (NCX) inhibitor KB-R7943. Conclusions Ranolazine protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by a reduction in oxidative stress, suggesting that I_Na modulates cardiac redox balance, resulting in functional and morphological derangements.

The antibody trastuzumab, targeted to inhibit the signalling of ErbB2, a tyrosine kinase receptor overexpressed in 20–30% of breast cancers, improves the prognosis in women affected by this tumour, but produces cardiotoxicity, since ErbB2 is also involved in myocardial homeostasis. In this review, we discuss the pathophysiology of trastuzumab cardiomyopathy and the complex interplay between ErbB2 inhibition and anthracyclines, and we focus on the actual challenges of detecting, monitoring, and managing trastuzumab cardiotoxicity: the research of new, sensitive markers of early trastuzumab toxicity, before the ejection fraction is reduced, is an active field of research.

The side effects of anticancer drugs still play a critical role in survival and quality of life. Although the recent progresses of cancer therapies have significantly improved the prognosis of oncologic patients, side effects of antineoplastic treatments are still responsible for the increased mortality of cancer survivors. Cardiovascular toxicity is the most dangerous adverse effect induced by anticancer therapies. A survey conducted by the National Health and Nutrition Examination, showed that 1807 cancer survivors followed up for seven years: 51% died of cancer and 33% of heart disease (Vejpongsa and Yeh, 2014). Moreover, the risk of cardiotoxicity persists even with the targeted therapy, the newer type of cancer treatment, due to the presence of on-target and off-target effects related to this new class of drugs. The potential cardiovascular toxicity of anticancer agents includes: QT prolongation, arrhythmias, myocardial ischemia, stroke, hypertension (HTN), thromboembolism, left ventricular dysfunction and heart failure (HF). Compared to other cardiovascular disorders, the interest in QT prolongation and its complications is fairly recent. However, oncologists have to deal with it and to evaluate the risk-benefit ratio before starting the treatment or during the same. Electrolyte abnormalities, low levels of serum potassium and several drugs may favour the acquired QT prolongation. Treatment of marked QT prolongation includes cardiac monitoring, caution in the use or suspension of cancer drugs and correction of electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia). Syndrome of QT prolongation can be associated with potentially fatal cardiac arrhythmias and its treatment consists of intravenous administration of magnesium sulphate and the use of electrical cardioversion.

Background —The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown. Methods and Results —Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H- ras –negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed. Conclusions —In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.