Martino Deidda

Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment

BACKGROUND Oxidative stress and RAAS play an important role in the occurrence of anthracyclines-induced cardiotoxicity. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits activation of superoxide sources and induces anti-inflammatory effects. METHODS The possible role of telmisartan in preventing myocardial damage induced by epirubicin (EPI) was investigated. Forty-nine patients free from cardiovascular diseases affected by a variety of solid cancers were examined. Eligible patients were randomized to receive telmisartan (40 mg/d; TEL, n = 25) or placebo (PLA, n = 24) starting 1 week before chemotherapy. Patients were studied by means of echocardiography, tissue Doppler, and strain and strain rate (SR) imaging. We also measured plasma levels of inflammatory and oxidative stress markers. All parameters were assessed at baseline and 7 days after every new EPI dose of 100 mg/m(2). RESULTS An impairment of the SR peak was observed at the EPI dose of 200 mg/m(2), with no significant differences between TEL and PLA (1.41 +/- 0.31 vs 1.59 +/- 0.36/s). At growing cumulative doses of EPI, SR normalized only in TEL, showing a significant difference in comparison to PLA at EPI doses of 300 mg/m(2) (1.69 +/- 0.42 vs 1.34 +/- 0.18/s, P < .001) and 400 mg/m(2) (1.74 +/- 0.27 vs 1.38 +/- 0.24/s, P < .001). Moreover, a significant increase in reactive oxygen species and interleukin-6 was found in PLA; but these remained unchanged in TEL. CONCLUSIONS We confirmed that EPI-induced cardiotoxicity is primarily related to the inactivation of the cardiac antioxidant defenses. In addition, we showed that telmisartan can reduce EPI-induced radical species, antagonize the inflammation, and reverse the early myocardial impairment.

Gender determinants of cardiovascular risk factors and diseases.

This article addresses the various aspects concerning gender dissimilarities in the cardiovascular system. It examines sex differences in the genetic susceptibility to cardiovascular disease (CVD) development or outcome: with the presence of either XX or XY chromosomes, every cell is sexually differentiated and there exist postpuberal differences between male and female cardiovascular systems. The main action mechanisms of sex steroid hormones are discussed, mainly as to testosterone (Te) in men and 17beta-estradiol (E2) and progesterone (Pro) in women. In women, susceptibility to CVD is known to increase in the postmenopausal period, when the ovarian hormone function expires. Some concepts of the sex-based differences in anatomy and physiology are also explained. Although they have the same structural elements, women and men use them in a different way to guarantee cardiovascular system homeostasis. Some examples of differences between men and women in pathological cardiovascular function are given. A further important issue regards the prevalence and role of cardiovascular risk factors in the two genders. Compared to boys of the same age, adolescent girls and premenopausal women have a more favorable risk profile: lower blood pressure (BP), less atherogenic lipid profile, and lower prevalence of cardiovascular risk factors. Women develop CVD later than men and diabetic women have a considerably higher mortality rate compared to men of the same age. Finally, there exist several clinically significant differences between men and women as to prevalence, presentation, management and outcome of CVD. Clinical peculiarities related to gender in presentation of some CVDs, such as coronary heart disease (CHD), stroke and heart failure, are described. We are absolutely convinced that only an accurate knowledge of the sex-specific pathophysiology may allow determination of the appropriate diagnostic instruments and to implement tailored treatments of CVD in men and women.

Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection

AbstractAlthough treatment for heart failure induced by cancer therapy has improved in recent years, the prevalence of cardiomyopathy due to antineoplastic therapy remains significant worldwide. In addition to traditional mediators of myocardial damage, such as reactive oxygen species, new pathways and target cells should be considered responsible for the impairment of cardiac function during anticancer treatment. Accordingly, there is a need to develop novel therapeutic strategies to protect the heart from pharmacologic injury, and improve clinical outcomes in cancer patients. The development of novel protective therapies requires testing putative therapeutic strategies in appropriate animal models of chemotherapy-induced cardiomyopathy. This Position Paper of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to: (1) define the distinctive etiopatogenetic features of cardiac toxicity induced by cancer therapy in humans, which include new aspects of mitochondrial function and oxidative stress, neuregulin-1 modulation through the ErbB receptor family, angiogenesis inhibition, and cardiac stem cell depletion and/or dysfunction; (2) review the new, more promising therapeutic strategies for cardioprotection, aimed to increase the survival of patients with severe antineoplastic-induced cardiotoxicity; (3) recommend the distinctive pathological features of cardiotoxicity induced by cancer therapy in humans that should be present in animal models used to identify or to test new cardioprotective therapies.

Metabolomics: a new era in cardiology?

The metabolome represents the collection of all metabolites in a biological cell, tissue, organ or organism, which are the end-products of cellular processes. Metabolomics is the systematic study of small-molecule metabolite profiles that specific cellular processes leave behind. RNA messenger gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell. Metabolic profiling, in turn, amplifies changes both in the proteome and the genome, and represents a more accurate approximation to the phenotype of an organism in health and disease. In this article, we have provided a description of metabolomics, in the presence of other, more familiar ‘omics’ disciplines, such as genomics and proteomics. In addition, we have reviewed the current rationale for metabolomics in cardiology, its basic methodology and the data actually available in human studies in this discipline. The discussed topics highlight the importance of being able to use the metabolomics information in order to understand disease mechanisms from a systems biology perspective as a noninvasive approach to diagnose, grade and treat cardiovascular diseases.

Could ADMA levels in young adults born preterm predict an early endothelial dysfunction

BACKGROUND Sporadic data present in literature report how preterm birth and low birth weight are risk factors for the development of cardiovascular diseases in later life. High levels of asymmetric dimethylarginine (ADMA), a strong inhibitor of nitric oxide synthesis, are associated with the future development of adverse cardiovascular events and cardiac death. AIMS 1) to verify the presence of a statistically significant difference between ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) and 2) to seek correlations between ADMA levels in ex-ELBW and anthropometric and clinical parameters (gender, chronological age, gestational age, birth weight, and duration of stay in Neonatal Intensive Care Unit). METHODS Thirty-two ex-ELBW subjects (11 males [M] and 21 females [F], aged 17-29years, mean age 22.2 ± 2.3 years) were compared with 25 C (7 M and 18F). ADMA levels were assessed by high-performance liquid chromatography with highly sensitive laser fluorescent detection. RESULTS ADMA levels were reduced in ex-ELBW subjects compared to C (0.606+0.095 vs 0.562+0.101 μmol/L, p<0.05), and significantly correlated inversely with gestational age (r=-0.61, p<0.00001) and birth weight (r=-0.57, p<0.0002). CONCLUSIONS Our findings reveal a significant decrease in ADMA levels of ex-ELBW subjects compared to C, underlining a probable correlation with preterm birth and low birth weight. Taken together, these results may underlie the onset of early circulatory dysfunction predictive of increased cardiovascular risk.

Gender-specific aspects in primary and secondary prevention of cardiovascular disease

Gender differences in biological substrates of disease determine different clinical manifestations of CV disease with important implications for prevention, diagnosis and therapy in the two sexes. In women, the activity of sex hormones reduces the influence of CV risk factors during the reproductive age, and delays the onset of CHD of 2 decades compared to men. However, women as men suffer from CV events, and in women mortality from all CV causes and have greater than the sum of the others 7 causes of death together. Women are more likely than men to die of a first myocardial infarction a probability of developing heart failure or a second infarction than their male counterparts. The levels of lipid components vary in different ages of life and in the two genders. TC and LDL increase in men between 35 and 50 years of age. On the contrary LDL levels do not change significantly in fertile women in which they have a lower predictive value for CHD than in men, HDL levels are higher in premenopausal women than in men of the same age and their role in predicting CHD is considerably higher in women. High triglycerides and Lp(a) are more important as a risk factor in women than in men. Because of the greater incidence of cardiovascular diseases in men until the early 80s, the information about the importance of risk factors associated with an increased risk of cardiovascular events has been gathered mainly in men and transferred to women. Most studies on lipid-lowering therapy did not have the adequate statistical power to show significant reductions in CV events in women. Regarding the indications for use of statins in daily practice, current data suggest that in secondary prevention statins are equally effective in both genders while in primary prevention the CV benefits of lipid-lowering therapy in women are less clear than in men and therefore should be used according to the degree of risk calculated from the available score systems.

Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

Cardioprotection by gene therapy: A review paper on behalf of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology

Ischemic heart disease remains the leading cause of death worldwide. Ischemic pre-, post-, and remote conditionings trigger endogenous cardioprotection that renders the heart resistant to ischemic-reperfusion injury (IRI). Mimicking endogenous cardioprotection by modulating genes involved in cardioprotective signal transduction provides an opportunity to reproduce endogenous cardioprotection with better possibilities of translation into the clinical setting. Genes and signaling pathways by which conditioning maneuvers exert their effects on the heart are partially understood. This is due to the targeted approach that allowed identifying one or a few genes associated with IRI and cardioprotection. Genes critical for signaling pathways in cardioprotection include protectomiRs (e.g., microRNA 125b*), ZAC1 transcription factor, pro-inflammatory genes such as cycloxygenase (COX)-2 and inducible nitric oxide synthase (iNOS), antioxidant enzymes such as hemoxygenase (HO)-1, extracellular and manganese superoxidase dismutases (ec-SOD and Mg-SOD), heat shock proteins (HSPs), growth factors such as insulin like growth factor (IGF)-1 and hepatocyte growth factor (HGF), antiapoptotic proteins such as Bcl-2 and Bcl-xL, pro-apoptotic proteins such as FasL, Bcl-2, Bax, caspase-3 and p53, and proangiogenic genes such as TGFbeta, sphingosine kinase 1 (SPK1), and PI3K-Akt. By identifying the gene expression profiles of IRI and ischemic conditioning, one may reveal potential gene targets responsible for cardioprotection. In this manuscript, we review the current state of the art of gene therapy in cardioprotection and propose that gene expression analysis facilitates the identification of individual genes associated with cardioprotection. We discuss signaling pathways associated with cardioprotection that can be targeted by gene therapy to achieve cardioprotection.

Association of automated carotid IMT measurement and HbA1c in Japanese patients with coronary artery disease.

AIMS The purpose of this study was to evaluate whether carotid IMT (cIMT) identified using automated software is associated with HbA1c in Japanese patients with coronary artery disease. METHODS 370 consecutive patients (males 218; median age 69 years ± 11) who underwent carotid-US and first coronary angiography were prospectively analyzed. After ultrasonographic examinations were performed, the plaque score (PS) was calculated and automated IMT analysis was obtained with a dedicated algorithm. Pearson correlation analysis was performed to calculate the association between automated IMT, PS and HbA1c. RESULTS The mean value of cIMT was 1.00 ± 0.47 mm for the right carotid and 1.04 ± 0.49 mm for the left carotid; the average bilateral value was 1.02 ± 0.43 mm. No significant difference of cIMT was detected between men and women. We found a direct correlation between cIMT values and HbA1c (p=0.0007) whereas the plaque score did not correlate with the HbA1c values (p>0.05) CONCLUSION: The results of our study confirm that automated cIMT values and levels of HbA1c in Japanese patients with coronary artery disease are correlated whereas the plaque score does not show a statistically significant correlation.

Cardiopulmonary and endothelial effects of metformin treatment in an insulin resistant population

Insulin resistance(IR) is considereda primaryetiologic factor in thedevelopment of cardiac dysfunction. A high prevalence of IR has beenfound in the non-ischemic heart failure population. It predates thedevelopment of the disease, and independently defines a worseprognosis[1].Severalstudieshaveshownthatareductioninendothelialfunction [2] may represent the link between IR and decline incardiovascular performance. Treatment with metformin has beenreported to prevent the above-mentioned cardiac abnormalities [3]and the evolution of IR diabetes [4]. However, metformin has also beenshown to slightly but significantly reduce oxygen consumption in apopulation of healthy individuals [5].The present study investigated a population of individuals affectedby IR without known cardiovascular disease. The aim was to examinethe possible effects of early metformin treatment on exercise oxygenconsumption and vasodilatory function, measured as endothelial flowreserve (EFR).Twenty consecutive individuals (7 women and 13 men; meanage 46±11 years) with a recent diagnosis of IR calculated accordingto the homeostatic model assessment (HOMA) index ([insulin (μU/mL)×glycaemia (mmol/L)]/22); (HOMA 5±3.5) were enrolled in thestudy. Exclusion criteria were an echocardiographic LVEF of ≤55%,hypertension with cardiac hypertrophy, a previous treatment withinsulin sensitizers.At enrolment, patients underwent ECG and bi-dimensional Dopplerechocardiogram with tissue Doppler imaging (TDI). EFR measurementwasassessedbymeansofaperipheralarterialtone(PAT)device [6,7].Anintegrated maximal cardiopulmonaryexercise test was performed on anelectricallybrakedcycleergometer.Arampprotocolwasapplied.Breath-by-breath VO