Ines Monte

Head-to-head comparison of real-time three-dimensional transthoracic echocardiography with transthoracic and transesophageal two-dimensional contrast echocardiography for the detection of patent foramen ovale.

AIMS To assess the incremental value of real-time three-dimensional echocardiography (RT-3DTE) over contrast transthoracic echocardiography (TTE), compared with contrast transesophageal echocardiography (TEE) in the identification of patent foramen ovale (PFO). METHODS AND RESULTS Eighty-one consecutive patients with history of migraine headache (MH) or unexplained cerebrovascular events (CE) were examined using RT-3DTE, contrast TTE, and contrast TEE in sequence. Feasibility of RT-3DE in patients with MH and CE was 98 and 91%, respectively. Mean time for 3D colour data set acquisition was 9 +/- 5 min. PFO was diagnosed using contrast TEE in 36 patients (overall prevalence = 44%). Diagnostic accuracy of RT-3DE was significantly higher than that of contrast TTE: sensitivity 83 vs. 44%, P < 0.001; specificity 100 vs. 100%, P7 = NS; positive predictive value 100 vs. 100%, P = NS; negative predictive value 88 vs. 69%, P < 0.01; accuracy 93 vs. 75%, P < 0.003. Five of the six patients in whom RT-3DTE did not identify PFOs showed a defect diameter smaller than 2 mm. CONCLUSION RT-3DTE is a feasible, accurate, and reproducible technique to detect PFO without the need of saline contrast injection. Its accuracy is superior to contrast 2D TTE and close to that of contrast TEE.

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.

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

Cardiotoxicity induced by chemotherapeutic agents and radiotherapy is a growing problem. In recent years, an increasing number of new drugs with targeted action have been designed. These molecules, such as monoclonal antibodies and tyrosine kinase inhibitors, can cause different type of toxicities compared to traditional chemotherapy. However, they can also cause cardiac complications such as heart failure, arterial hypertension, QT interval prolongation and arrhythmias. Currently, a field of intense research is the vascular toxicity induced by new biologic drugs, particularly those which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) and other tyrosine kinases. In this review, we aim at focusing on the problem of vascular toxicity induced by new targeted therapies, chemotherapy and radiotherapy, and describe the main mechanisms and emphasizing the importance of early diagnosis of vascular damage, in order to prevent clinical complications.

The Incremental Prognostic Value of Echocardiography in Asymptomatic Stage A Heart Failure

OBJECTIVE This multicenter study consisted of echocardiographic examination of subjects with stage A heart failure (HF) with cardiovascular risk factors and normal electrocardiogram and clinical examination results to (a) define whether stage A subjects with risk factors are really free of functional or structural cardiac abnormalities and (b) assess the impact of the presence of risk factors and incremental value of echocardiographic parameters in the prediction of progression of HF or in the development of cardiovascular events. METHODS A total of 1097 asymptomatic subjects underwent echocardiographic examination as a screening evaluation in the presence of cardiovascular risk factors. Left ventricular (LV) dysfunction, both systolic (ejection fraction) and diastolic (transmitral flow velocity pattern), was evaluated according to standard criteria. The subjects were divided according to different criteria: the presence of one or more risk factors, presence or absence of LV systolic dysfunction, and presence or absence of LV diastolic dysfunction. A follow-up period of 26 ± 11 months was performed, observing primary (cardiac death, myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute pulmonary edema, stroke, and transient ischemic attack) and secondary (cardiologist-made diagnosis of HF and HF hospitalization) end points. RESULTS The multivariate analysis for independent predictors of primary end points showed that age (P = .001), gender (P = .02), dyslipidemia (P = .01), obesity (P = .001), and systolic dysfunction (P = .048) represented the significant predictors. The multivariate logistic regression analysis for independent predictors of secondary end points showed that gender (P = .02), LV systolic dysfunction (P = .01), and LV diastolic dysfunction (P < .01) represented the significant predictors. The multivariate analysis for independent predictors of combined end points showed that only age (P < .003), gender (male: P < .001), obesity (P < .04), and systolic dysfunction (P < .001) represented the significant predictors. Echocardiography showed a high incremental value in the detection of systolic LV dysfunction and the prediction of cardiovascular events during follow-up in subjects with at least two risk factors. CONCLUSION This study demonstrated that preclinical functional or structural myocardial abnormalities could be detected by echocardiography in asymptomatic subjects with two or more cardiovascular risk factors and without electrocardiogram abnormalities (stage A of HF classification). The presence or absence of LV systolic dysfunction or LV diastolic dysfunction, as demonstrated by echocardiography, has an incremental value to cardiovascular risk factors in predicting both the evolution toward more severe HF stage C and the occurrence of cardiovascular events.

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.

A recommended practical approach to the management of target therapy and angiogenesis inhibitors cardiotoxicity: An opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology

The US National Cancer Institute estimates that cardiotoxicity (CTX) from target therapy refers mostly to four groups of drugs: epidermal growth factor receptor 2 inhibitors, angiogenic inhibitors, directed Abelson murine leukemia viral oncogene homolog inhibitors, and proteasome inhibitors. The main cardiotoxic side-effects related to antiepidermal growth factor receptor 2 therapy are left ventricular systolic dysfunction and heart failure. Angiogenesis inhibitors are associated with hypertension, left ventricular dysfunction/heart failure, myocardial ischemia, QT prolongation, and thrombosis. Moreover, other agents may be related to CTX induced by treatment. In this study, we review the guidelines for a practical approach for the management of CTX in patients under anticancer target therapy.

From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A translational overview

Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.

A recommended practical approach to the management of anthracycline-based chemotherapy cardiotoxicity: an opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology

Anthracyclines are the mainstay of treatment of a variety of haematological malignancies and solid tumours. Unfortunately, the clinical use of these drugs is limited by cumulative, dose-related cardiotoxicity which may ultimately lead to a severe and irreversible form of cardiomyopathy. Thus, there is an increasing need for close cooperation among cardiologists, oncologists and haemato-oncologists. As anthracyclines save lives, the logical goal of this cooperation, besides preventing or mitigating cardiotoxicity, is to promote an acceptable balance between the potential cardiac side effects and the vital benefit of anticancer treatment. This manuscript, which is specifically addressed to the cardiologist who has not accumulated much experience in the field of cancer therapy, focuses on several topics, that is old and new mechanisms of cardiac toxicity, late cardiac toxicity, the importance of overall risk assessment, the key role of a cardiology consult before starting cancer therapy, and the pros and cons of primary and secondary prevention programmes.

High Variability of Fabry Disease Manifestations in an Extended Italian Family

Fabry disease (FD) is an inherited metabolic disorder caused by partial or full inactivation of the lysosomal hydrolase α-galactosidase A (α-GAL). The impairment of α-GAL results in the accumulation of undegraded glycosphingolipids in lysosomes and subsequent cell and microvascular dysfunctions. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the exonic mutation M51I in the GLA gene, a disease-causing mutation associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two male patients is not related to differences in α-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from FD. One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease.

Feasibility, Reproducibility, and Agreement between Different Speckle Tracking Echocardiographic Techniques for the Assessment of Longitudinal Deformation

Background. Left ventricular (LV) longitudinal deformation can be assessed with new echocardiographic techniques like triplane echocardiography (3PE) and four-dimensional echocardiography (4DE). We aimed to assess the feasibility, reproducibility, and agreement between these different speckle-tracking techniques for the assessment of longitudinal deformation. Methods. 101 consecutive subjects underwent echocardiographic examination. 2D cine loops from the apical views, a triplane view, and an LV 4D full volume were acquired in all subjects. LV longitudinal strain was obtained for each imaging modality. Results. 2DE analysis of LV strain was feasible in 90/101 subjects, 3PE strain in 89/101, and 4DE strain in 90/101. The mean value of 2DE and 3PE longitudinal strains was significantly higher with respect to 4DE. The relationship between 2DE and 3PE derived strains (r = 0.782) was significantly higher (z = 3.72, P < 0.001) than that between 2DE and 4DE (r = 0.429) and that between 3PE and 4DE (r = 0.510; z = 3.09, P = 0.001). The mean bias between 2DE and 4DE strains was −6.61 ± 7.31% while −6.42 ± 6.81% between 3PE and 4DE strains; the bias between 2DE and 3PE strain was of 0.21 ± 4.16%. Intraobserver and interobserver variabilities were acceptable among the techniques. Conclusions. Echocardiographic techniques for the assessment of longitudinal deformation are not interchangeable, and further studies are needed to assess specific reference values.