Antonio L’Abbate

ABO blood group alleles: a risk factor for coronary artery disease. An angiographic study

OBJECTIVES To analyze the impact of ABO groups on coronary heart disease risk factors, coronary involvement and prognosis. METHODS An observational single center study was conducted to examine 4901 consecutive patients with heart disease receiving coronary angiography and ABO group determination at National Research Council Institute of Clinical Physiology between January 1993 and December 2003, with maximum 10 years follow-up. All-cause death and cardiac death, were the considered end points. RESULTS When compared to the official distribution of ABO groups in the Italian population (O 40%, A 36%, B 17%, AB 7%), a substantially different distribution was observed in the study population (O 43.3%, A 41.4%, B 11.2%, AB 4.1%). In addition, a significant association was found between group non-O and family history of ischemic heart disease, hypercholesterolemia and presence of coronary atherosclerosis. Higher prevalence of A and B alleles was found in patients with myocardial infarction (P<0.05). Group non-O was a powerful predictor of cardiac mortality in patients aged <65 years, particularly in women (HR 1.53, 95% CI 1.06-2.21 and HR 5.29, 95% CI 1.57-17.82, respectively). CONCLUSIONS Group non-O is associated with increased mortality in patients with ischemic heart disease. Group non-O increases the risk for cardiac death in non-elderly patients, particularly in younger females, and groups A and B prevail in myocardial infarction. ABO group determination might aid in genetic screening for ischemic heart disease and become relevant in the management of risk factor control.

Persistence of Mortality Risk in Patients With Acute Cardiac Diseases and Mild Thyroid Dysfunction

Introduction:There are no studies on the long-term prognostic role of abnormal thyrotropin value in patients with acute cardiac diseases. Aim of the study was to assess the incidence and persistence of risk of cardiac and overall deaths in patients with acute cardiac diseases. Methods:A total of 1026 patients (mean age: 67.7 years) were divided into 4 groups: (1) euthyroid (EU, n=579); (2) subclinical-like hypothyroidism (SLHYPO, n=68); (3) subclinical-like hyperthyroidism (SLHYPER, n=23) and (4) low-triiodothyronine syndrome (LowT3, n=356). Follow-up started from the day of thyroid hormone evaluation (mean follow-up: 30 months). The events considered were cardiac and overall deaths. Results:Survival rate for cardiac death was lower in SLHYPO and in LT3 than in EU (log rank test; &khgr;2=33.6; P < 0.001). Survival rate for overall death was lower in SLHYPO, SLHYPER and LowT3 than in EU (48.3; P < 0.001). After adjustment for several risk factors, the hazard ratio for cardiac death was higher in SLHYPO (3.65; P=0.004) in LowT3 (1.88; P=0.032) and in SLHYPER (4.73; P=0.047). Hazard ratio for overall death was higher in SLHYPO (2.30; P=0.009), in LowT3 (1.63; P=0.017) and in SLHYPER than in EU (3.71; P=0.004). Hazards for SLHYPO, SLHYPER and LowT3 with respect to EU were proportional over the follow-up period. Conclusion:In patients with acute cardiac disease, a mildly altered thyroid status was associated with increased risk of mortality that remains constant during all the follow-up.

T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy

BackgroundInsulin resistance (IR) and endothelial dysfunction are frequently associated in cardiac disease. The T−786→C variant in the promoter region of the endothelial nitric oxide synthase (eNOS) gene has been associated with IR in both non-diabetic and diabetic subjects. Aim of the study was to assess the reciprocal relationships between T−786→C eNOS polymorphism and IR in ischemic and non-ischemic cardiomyopathy.MethodA group of 132 patients (108 males, median age 65 years) with global left ventricular (LV) dysfunction secondary to ischemic or non-ischemic heart disease was enrolled. Genotyping of T−786→C eNOS gene promoter, fasting glucose, insulin, and insulin resistance (defined as HOMA-IR index > 2.5) were determined in all patients.ResultsGenotyping analysis yielded 37 patients homozygous for the T allele (TT), 70 heterozygotes (TC) and 25 homozygous for C (CC). Patients with CC genotype had significantly higher systemic arterial pressure, blood glucose, plasma insulin and HOMA index levels than TT. At multivariate logistic analysis, the history of hypertension and the genotype were the only predictors of IR. In particular, CC genotype increased the risk of IR (CI% 1.4-15.0, p < 0.01) 4.5-fold. The only parameter independently associated with the extent of LV dysfunction and the presence of heart failure (HF) was the HOMA index (2.4 CI% 1.1-5.6, p < 0.04).ConclusionsT−786→C eNOS polymorphism was the major independent determinant of IR in a population of patients with ischemic and non-ischemic cardiomyopathy. The results suggest that a condition of primitive eNOS lower expression can predispose to an impairment of glucose homeostasis, which in turn is able to affect the severity of heart disease.

Brain Responses to Emotional Stimuli During Breath Holding and Hypoxia: An Approach Based on the Independent Component Analysis

Voluntary breath holding represents a physiological model of hypoxia. It consists of two phases of oxygen saturation dynamics: an initial slow decrease (normoxic phase) followed by a rapid drop (hypoxic phase) during which transitory neurological symptoms as well as slight impairment of integrated cerebral functions, such as emotional processing, can occur. This study investigated how breath holding affects emotional processing. To this aim we characterized the modulation of event-related potentials (ERPs) evoked by emotional-laden pictures as a function of breath holding time course. We recorded ERPs during free breathing and breath holding performed in air by elite apnea divers. We modeled brain responses during free breathing with four independent components distributed over different brain areas derived by an approach based on the independent component analysis (ICASSO). We described ERP changes during breath holding by estimating amplitude scaling and time shifting of the same components (component adaptation analysis). Component 1 included the main EEG features of emotional processing, had a posterior localization and did not change during breath holding; component 2, localized over temporo-frontal regions, was present only in unpleasant stimuli responses and decreased during breath holding, with no differences between breath holding phases; component 3, localized on the fronto-central midline regions, showed phase-independent breath holding decreases; component 4, quite widespread but with frontal prevalence, decreased in parallel with the hypoxic trend. The spatial localization of these components was compatible with a set of processing modules that affects the automatic and intentional controls of attention. The reduction of unpleasant-related ERP components suggests that the evaluation of aversive and/or possibly dangerous situations might be altered during breath holding.

Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

BackgroundUp-regulation of HO-1 by genetic manipulation or pharmacological pre-treatment has been reported to provide benefits in several animal models of myocardial infarction (MI). However, its efficacy following MI initiation (as in clinical reality) remains to be tested. Therefore, this study investigated whether HO-1 over-expression, by cobalt protoporphyrin (CoPP) administered after LAD ligation, is still able to improve functional and structural changes in left ventricle (LV) in a rat model of 4-week MI.MethodsA total of 144 adult male Wistar rats were subjected to either left anterior coronary artery ligation or sham-operation. The effect of CoPP treatment (5 mg/kg i.p. at the end of the surgical session and, then, once a week for 4 weeks) was evaluated on the basis of survival, electro- and echocardiography, plasma levels of B-type natriuretic peptide (BNP), endothelin-1 and prostaglandin E2, coronary microvascular reactivity, MI size, LV wall thickness and vascularity. Besides, the expression of HO-1 and connexin-43 in different LV territories was assessed by western blot analysis and immunohistochemistry, respectively.ResultsCoPP induced an increased expression of HO-1 protein with >16 h delay. CoPP treatment significantly reduced mortality, MI size, BNP concentration, ECG alterations, LV dysfunction, microvascular constriction, capillary rarefaction and restored connexin-43 expression as compared to untreated MI. These functional and structural changes were paralleled by increased HO-1 expression in all LV territories. HO activity inhibition by tin-mesoporphyrin abolished the differences between CoPP-treated and untreated MI animals.ConclusionsThis is the first report demonstrating the putative role of pharmacological induction of HO-1 following coronary occlusion to benefit infarcted and remote territories, leading to better cardiac function in a 4-week MI outcome.

Genetic score based on high-risk genetic polymorphisms and early onset of ischemic heart disease in an Italian cohort of ischemic patients

Several single-nucleotide polymorphisms (SNPs) have been recognized as associated with ischemic heart disease (IHD) although the optimal set of risk genotypes has not be identified. This study aimed to examine whether identified high-risk SNPs are associated with early onset of IHD. In the GENOCOR study, 44 high-risk SNPs were genotyped in 114 patients with early onset of IHD (46.2 ± 5.1 years) and 384 patients with late onset of IHD (60.7 ± 5.9 years). The associations between individual SNPs and early onset IHD were assessed. A multilocus genetic risk score (GRS) for each associated risk genetic markers was constructed by summing the number of risk alleles. The SNPs significantly associated with IHD were: -482C>T of Apolipoprotein C III gene (ApoC3, p=0.02); 1171 5A>6A of Matrix metalloproteinase 3 stromelisine I gene (p=0.01); G98T of Selectin E gene (p=0.05); C/G of 9p21.3 locus (p=0.01). Likelihood ratio test showed a strong interaction for increasing risk of early IHD between the presence of ApoC3 and 9p21.3 locus with hypertriglyceridemia (p=0.0008, 0.0011) as well as between 9p21.3 locus and smoking (p=0.0010) after correction for multiple testing. The OR for premature IHD for GRS unit was 1.3 (95% CI 1.1-1.6, p=0.001). Patients in the top tertile of GRS were estimated to have a 3.2-fold (95% CI 1.5-6.8; p=0.001) increased risk of early IHD compared with those in the bottom tertile. The results show that currently identified high-risk SNPs confer an additive biomarker for cardiovascular events. GRS may provide important incremental information on the genetic component of IHD.

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State, Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS−/− and eNOS+/− mice were studied. WT and eNOS+/− mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS−/−. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS−/−) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS−/− and eNOS+/− mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS−/−. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern.

La onda R prominente en V1 pero no en V2 es un signo específico de infarto transmural lateral grande

INTRODUCTION AND OBJECTIVES In the absence of right ventricular hypertrophy or bundle-branch block, a prominent R wave in V(1) or V(2) is considered to reflect a lateral myocardial infarction. We investigated the differences in infarct location, size and transmural extent between patients with prominent R wave in V(1) and those with prominent R wave in V(2). METHODS We studied 50 patients with a previous first infarction involving left ventricular inferior and/or lateral wall at contrast-enhanced magnetic resonance. RESULTS A prominent R wave in V(1) was present in 8 patients (16%), in V(2) in 23 (46%). At magnetic resonance, the infarction involved the inferior wall in 11 patients (22%), the lateral wall in 6 (12%), and both walls in 33 patients (66%). The sensitivity of a prominent R wave in V(1) in detecting a lateral infarction was low (17.9%), while the specificity was high (90.9%). The sensitivity and specificity of a prominent R wave in V(2) were 46.2% and 54.5%, respectively. In patients with a prominent R wave in V(1), infarct size and lateral and transmural extent were greater than in patients without this pattern (P<.005, <.001, and <.05, respectively); conversely, infarct size and transmural extent in the inferior wall and in its basal-posterior segment were not significantly different. In patients with a prominent R wave in V(2), infarct size, lateral and transmural extent were not different from patients without this pattern. CONCLUSIONS Only a prominent R wave in V(1) is a specific sign of large and transmural lateral infarction.

Thyroid hormone, amiodarone therapy, and prognosis in left ventricular systolic dysfunction

Background: Amiodarone protects patients with left ventricular systolic dysfunction (LVSD) against serious arrhythmias, but it also has numerous side effects on non-cardiac organs, such as the thyroid. Indeed, amiodarone may inhibit the peripheral conversion of T4 into T3. Pathologically reduced serum levels of T3 — the so-called “low T3 syndrome” (LOWT3) — increase mortality in patients with LVSD and not on amiodarone. Aim: The aim of the study was to examine the relationship between thyroid hormone status, amiodarone therapy, and outcome in a population with LVSD. Material/subjects and methods: A total of 2344 patients with LVSD and free of overt hyper- and hypothyroidism were enrolled. The population was divided into 4 groups: group 1 (LOWT3 and amiodarone therapy, no.=126), group 2 (isolated amiodarone therapy, no.=74), group 3 (isolated LOWT3, no.=682), group 4 (controls, no.=1462). Results: Kaplan-Meier curves showed, after a mean follow-up of 31 months, increased total and cardiac mortality in groups 1 (30% and 20%, respectively), 2 (23%, 11%), and 3 (22%, 12%) compared to group 4 (total mortality log-rank 82.8, pa<0.0001; cardiac mortality log-rank 63.1, p<0.0001). At Cox analysis, adjusted for several clinical variables, survival was reduced in groups 1 and 3 compared to group 4. Group 2 had a similar mortality to group 4, although the number of patients was too limited to accurately assess the effect of amiodarone on long-term prognosis. Conclusions: LOWT3 exerts an adverse impact on prognosis in LVSD, which is not influenced by concomitant amiodarone therapy.

Role of echo-contrast in quantitative analysis

In the early years of M-mode and two-dimensional echocardiography, contrast agents were used to derive a qualitative information. Thus, contrast agents were injected into the cardiac cavities to identify specific structures [1], or were injected intravenously to detect abnormal flow direction. The main clinical applications of this use of contrast agents were the detection of intracardiac shunts [2, 3] and of tricuspid regurgitation [4, 5]. Nowadays, this information is provided by Doppler echocardiography, and the clinical applications of intravenous contrast agents are limited to the identification of intracardiac shunts of small entity (as in the case of patent foramen ovale [6]), to the detection of extra cardiac shunts (as in pulmonary fistulae [7]) or to the enhancement of the Doppler signal [8]. Indeed, in the majority of current studies, contrast agents are used to derive quantitative information regarding blood flow.