Giuseppina Novo

Influence of climatic variables on acute myocardial infarction hospital admissions

BACKGROUND Seasonal peaks in acute myocardial infarction (AMI) incidence have been widely reported. Weather has been postulated to be one of the elements at the basis of this association. The aim of our study was to determine the influence of seasonal variations and weather on AMI hospital admissions. METHODS We correlated the daily number of AMI cases admitted to a western Sicily hospital over twelve years and weather conditions on a day-to-day basis. Information on temperature, humidity, wind force and direction, precipitation, sunny hours and atmospheric pressure was obtained from the local Birgi Air Force base. A total of 3918 consecutive patients were admitted with AMI over the period 1987-1998 (2822 men, 1096 women; M/F: 2,58). RESULTS AND CONCLUSIONS A seasonal variation was found with a significant winter peak. The results of multivariate Poisson analysis show in both sexes a significant association as regards the incidence relative ratio between the daily number of AMI hospital admission and minimal daily temperature and maximal daily humidity. The incidence relative ratios (95% confidence intervals) were, in males, 0.95 (0.92-0.98) (p<0.001) as regards minimal temperature and 0.97 (0.94-0.99) (p=0.017) as regards maximal humidity. The corresponding values in females were respectively 0.91 (0.86-0.95) (p<0.001) and 0.94 (0.90-0.98) (p=0.009). Environmental temperature, and also humidity, may play an important role in the pathogenesis of AMI. These data may help in understanding the mechanisms whereby AMI events are triggered and in organizing better the assistance to ischemic patients throughout the year.

Impact of moderate ischemic mitral regurgitation after isolated coronary artery bypass grafting.

BACKGROUND The aim of the study was to evaluate the clinical and echocardiographic outcomes, at rest and under exercise testing, of patients with moderate ischemic mitral regurgitation (IMR) undergoing isolated coronary artery bypass graft surgery (CABG). METHODS Between February 2003 and March 2008, 180 patients with moderate IMR who had isolated CABG were enrolled. Patients were matched 1:2 (n = 360) with patients who underwent isolated CABG without IMR (by propensity score). The study endpoints were freedom from all death, cardiac related-death, late events, and cardiac-related events. Late outcomes and left ventricular remodeling were evaluated according to preoperative percent of ejection fraction. Symptoms and MR grade under exercise test were investigated. Mean follow-up was 30 ± 16 months. RESULTS The 5-year freedom from all deaths and from cardiac-related deaths among patients without IMR versus with IMR was, respectively, 90.5% ± 1.8% versus 73.7% ± 2.1% (p < 0.001) and 94.2% ± 1.6% versus 79.5% ± 1.5% (p < 0.001). Ischemic mitral regurgitation affects significantly late survival only in patients with ejection fraction 40% or less. The 5-year freedom from cardiac-related events among patients without and with IMR was, respectively, 88.2% ± 2.1% and 62.1% ± 1.2% (p < 0.0001). Patients with IMR experienced more cardiac-related events in comparison with patients without IMR. Ischemic mitral regurgitation promotes left ventricular remodeling in all patients. During exercise testing, the grade of MR moved from mild to moderate in 10 patients (28.5%) and to severe in 5 (14.3%). Among the 42 patients with moderate MR at rest, 32 patients (76%) moved from moderate to severe MR during exercise. CONCLUSIONS Ischemic mitral regurgitation significantly increases the incidence of cardiac-related deaths among patients with ejection fraction 40% or less and the incidence of cardiac-related events, and promotes left ventricular remodeling. Most patients who had at-rest residual mild to moderate MR presented with a worse MR grade under exercise with the appearance of dyspnea.

Soluble CD40L and Cardiovascular Risk in Asymptomatic Low-Grade Carotid Stenosis

Background and Purpose— We investigated whether soluble CD40L (sCD40L) may predict the risk of cardiovascular (CV) events in patients with asymptomatic carotid plaques. Methods— Forty-two patients with asymptomatic low-grade carotid stenosis (ALCS) and 21 controls without any carotid stenosis were enrolled. All subjects had at least a major cardiovascular risk factor (CRF). Plasma levels of C-reactive protein (CRP), IL-6, and sCD40L were measured. Subjects were reviewed every 12 months (median follow-up, 8 years). Results— ALCS patients had higher (P<0.0001) CRP, IL-6, and sCD40L than controls. Fourteen patients experienced a CV event. Cox regression analysis showed that only high sCD40L levels (P=0.003) independently predicted cardiovascular risk. Conclusions— High levels of sCD40L may predict the risk of CV events in ALCS.

Hsp60 and heme oxygenase-1 (Hsp32) in acute myocardial infarction.

Heat shock proteins (Hsps) are produced in response to various stressors, including ischemia-reperfusion, and they can exit cells and reach the blood. In this pilot study, we determined serum levels of Hsp60 and heme-oxygenase-1 (HO-1; also named Hsp32) in subjects with acute myocardial infarction (AMI) to assess their clinical significance and potential prognostic value. We also performed a bioinformatics analysis of the 2 molecules in search of structural clues on the mechanism of their release from cells. We studied 40 patients consecutively admitted for AMI (male:female patient ratio=20:20, mean age: 64 ± 13 years) and 40 matched controls. A blood sample was drawn for biochemical analyses within 24 h of symptoms onset, and Hsp60 and HO-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA). All patients were followed up for 6 months to register adverse post-AMI cardiovascular events. A multivariate analysis demonstrated that elevated Hsp60 (P=0.0361), creatine phosphokinase-muscle brain (CK-MB) (P=0.0446), and troponin (P=0.0490) were predictive of post-AMI adverse events. In contrast, increased HO-1 showed a significant association with less severity of coronary artery diseases (P=0.0223). These findings suggest that Hsp60 and HO-1 play distinct roles in the pathogenesis of AMI and subsequent AMI-related pathology. The possibility that these proteins differ in their roles and mechanisms of action in AMI and post-AMI pathology was supported also by the bioinformatics estimates of probability of their localization in various subcellular compartments. The results clear the way for subsequent investigation on the pathogenetic role and clinical significance of Hsp60 and HO-1 in AMI.

The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS

Atrial fibrillation (AF) is the most common rhythm disturbance in medical practice and represents a very expensive health problem. AF can be managed with the prevention of thromboembolism and either a rate control of rhythm strategy. As both strategies have important limitations, probably a preventative strategy in patients at risk of developing arrhythmia can be a more attractive option. The renin-angiotensin system (RAS) seems to be involved in the genesis of arrhythmia by the following two mechanisms: 1. the induction of atrial fibrosis and structural remodelling by mitogen-activated protein kinase (MAPK) expression and reduction of collagenase activity; 2. the induction of electrical remodelling by shortening of the atrial effective refractory period (AERP) and of the action potential duration. For these reasons it has been hypothesized that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin-II receptor blockers (ARBs) may play a role in preventing AF recurrence. The aim of the present review was to analyse evidence supporting the usefulness of RAS inhibition in patients with AF in order to focus on which specific subset of patients it would most favour. After reviewing the literature, we conclude that, although many studies and meta-analysis have supported the advantage of RAS block in preventing AF recurrence, it is premature to recommend the use of ACE-Is and ARBs specifically for the prevention of AF. However we believe that as these drugs are safe and manageable, they should be considered the drugs of choice in patients with AF and coexisting clinical conditions such as hypertension, coronary disease, heart failure and diabetes mellitus.

Markers of inflammation are strong predictors of subclinical and clinical atherosclerosis in women with hypertension.

Cardiovascular diseases in women still rises and remains their leading cause of death in most developed countries; yet we have less sex-specific data in women than in men as a result of lower enrollment in clinical trials and low rates of sex-specific reporting. The aim of our study was to evaluate in hypertensive postmenopausal women the potential predictive role of markers of inflammation, for example, fibrinogen and C-reactive protein (CRP), on subclinical and clinical atherosclerosis, beyond that of the other established cardiovascular risk factors. We studied 127 asymptomatic hypertensive postmenopausal women with different degrees of carotid intima–media thickness, as examined by the eco-color-doppler ultrasonography, evaluating in a 5 years follow-up cerebrovascular and cardiovascular morbidity and mortality. We preliminarily found that both fibrinogen and CRP levels were associated with the extension of carotid atherosclerosis (P<0.0001 and P=0.0445, respectively). We also found that among all established traditional cardiovascular risk factors (including obesity, diabetes, smoking habit, family history of coronary artery disease, dyslipidemia) only older age (P=0.0162), elevated fibrinogen (P=0.0298), and CRP (P=0.0345) were independent predictors of subclinical atherosclerosis. At the end of follow-up patients clinical events were registered in the 24% of patients and multivariate analysis revealed the following predictors of events: elevated CRP levels [odds ratio (OR): 12.6], the presence of family history of coronary artery disease(OR: 8.8) and older age (OR: 1.1). Beyond the utility of CRP and fibrinogen levels in the prediction of subclinical and clinical atherosclerosis, the therapeutic implications of these results remain to be evaluated by further studies.

Cardiopulmonary Exercise Testing in Patients with Chronic Heart Failure: Prognostic Comparison from Peak VO2 and VE/VCO2 Slope.

Background: Cardiopulmonary exercise testing with ventilatory expired gas analysis (CPET) has proven to be a valuable tool for assessing patients with chronic heart failure (CHF). The maximal oxygen uptake (peak V02) is used in risk stratification of patients with CHF. The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) has recently demonstrated prognostic significance in patients with CHF. Methods: Between January 2006 and December 2007 we performed CPET in 184 pts (146 M, 38 F, mean age 59.8 ± 12.9 years), with stable CHF (96 coronary artery disease, 88 dilated cardiomyopathy), in NYHA functional class II (n.107) - III (n.77), with left ventricular ejection fraction (LVEF) ≤ 45%,. The ability of peak VO2 and VE/VCO2 slope to predict cardiac related mortality and cardiac related hospitalization within 12 months after evaluation was examined. Results: Peak VO2 and VE/VCO2 slope were demonstrated with univariate Cox regression analysis both to be significant predictor of cardiac-related mortality and hospitalization (p < 0.0001, respectively). Non survivors had a lower peak VO2 (10.49 ± 1.70 ml/kg/min vs. 14.41 ± 3.02 ml/kg/min, p < 0.0001), and steeper Ve/VCO2 slope (41.80 ± 8.07 vs. 29.84 ± 6.47, p < 0.0001) than survivors. Multivariate survival analysis revealed that VE/VCO2 slope added additional value to VO2 peak as an independent prognostic factor (χ2: 56.48, relative risk: 1.08, 95% CI: 1.03 – 1.13, p = 0.001). The results from Kaplan-Meier analysis revealed a 1-year cardiac-related mortality of 75% in patients with VE/VCO2 slope ≥ 35.6 and 25% in those with VE/VCO2 slope < 35.6 (log rank χ2: 67.03, p < 0.0001) and 66% in patients with peak VO2 ≤ 12.2 ml/kg/min and 34% in those with peak VO2 > 12.2 ml/kg/min (log rank χ2: 50.98, p < 0.0001). One-year cardiac-related hospitalization was 77% in patients with VE/VCO2 slope ≥ 32.5 and 23% in those with VE/VCO2 slope < 32.5 (log rank χ2: 133.80, p < 0.0001) and 63% in patients with peak VO2 ≤ 12.3 ml/kg/min and 37% in those with peak VO2 > 12.3 ml/kg/min (log rank χ2: 72.86, p < 0.0001). The VE/VCO2 slope was demonstrated with receiver operating characteristic curve analysis to be equivalent to peak VO2 in predicting cardiac-related mortality (0.89 vs. 0.89). Although area under the receiver operating characteristic curve for the VE/VCO2 slope was greater than peak VO2 in predicting cardiac-related hospitalization (0.88 vs 0.82), the difference was no statistically significant (p = 0.13). Conclusion: These results add to the present body of knowledge supporting the use of CPET in CHF patients. The VE/VCO2 slope, as an index of ventilatory response to exercise, is an excellent prognostic parameter and improves the risk stratification of CHF patients. It is easier to obtain than parameters of maximal exercise capacity and is of equivalent prognostic importance than peak VO2.

Prediction of cardio- and cerebro-vascular events in patients with subclinical carotid atherosclerosis and low HDL-cholesterol

Low HDL-cholesterol concentrations are associated with increased cardiovascular risk and recent evidences suggest that HDL may aggravate the atherosclerotic process promoting inflammation: HDL are anti-inflammatory in the absence of inflammation but can become proinflammatory in the presence of atherosclerosis. Yet, no data is available on the cardiovascular outcome in subjects with low HDL-cholesterol and early stages of atherosclerosis. Therefore, we included in a prospective 5-year follow-up study 150 subjects with low HDL-cholesterol concentrations and subclinical carotid atherosclerosis, as assessed by carotid colour doppler, evaluating at baseline all the established traditional cardiovascular risk factors (e.g. male gender, older age, obesity, hypertension, diabetes, smoking, family history of coronary artery disease, hypercholesterolemia), as well as levels of two markers of inflammation (C-reactive protein and fibrinogen). At the end of the follow-up we registered vascular events in the 21% of patients and we found that lower HDL-cholesterol concentrations were associated with ischemic stroke (p=.0164), peripheral arterial disease (p=.0248) and the presence of any clinical event (p=.0105). By multivariate analysis we searched, among all baseline parameters, for independent variables associated with the events and we found a predictive role for elevated fibrinogen concentrations (OR 6.3, 95% CI 2.0-19.6, p=.0016), family history of coronary artery disease (OR 4.5, 95% CI 1.7-12.8, p=.0045) and lower HDL-cholesterol levels (OR 1.4, 95% CI 1.1-1.9, p=.0278). These findings further suggest a synergistic role of low-HDL and inflammation on the atherosclerotic disease progression from subclinical lesions to clinical events. Yet, their therapeutical implications remain to be established in future studies.

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies. Expert opinion: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.

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.