Rossana Falcone

Galectin-3 plasma levels and coronary artery disease: a new possible biomarker of acute coronary syndrome.

Inflammation plays a key role in atherosclerosis. Galectin-3 is a macrophage- and endothelium-derived mediator actively involved in the regulation of many aspects of inflammatory cell behaviour. The aim of this study is to quantify plasma Galectin-3 in patients with coronary artery disease (CAD) and different clinical manifestation at the moment of observation in order to verify whether Galectin-3 could be a useful biomarker of atherosclerotic state. We enrolled 125 patients affected by CAD, angiographically documented (70 stable, 55 unstable). They underwent accurate examinations and anamnestic data was collected. The most important traditional risk factors, such as age, hypertension, and body mass index, were reported. Plasma Galectin-3 was quantified using an ELISA kit. Unstable patients (n = 55) had a higher plasma Galectin-3 levels in respect to the stable subjects (27.75 ng/mL (19.27–39.09) vs 6.48 ng/ml (4.88–8.83), p<0.001. A trend in correlation between plasma Galectin-3 levels and number of vessels compromised seems to be present: CAD patients with three-vessel disease had higher levels of Galectin-3 than patients with one-or two-vessel disease (17.39 ng/ml (10.75–29.82) vs 9.18 ng/ml (5.56–23.22), p= 0.058. The significantly higher plasma Galectin-3 levels in patients with unstable angina in respect to the stable angina confirm the involvement of Galectin-3 in promoting macrophage activation and monocyte attraction. Despite the distribution of CAD in patients with acute and chronic coronary disease being similar, we may hypothesize that Galectin-3 could be a useful biomarker of atherosclerotic plaque and in particular of its destabilization.

Soluble RAGE Plasma Levels in Patients with Coronary Artery Disease and Peripheral Artery Disease

The objective of the present study was define in a relatively large patient population with coronary artery disease (CAD) whether the concomitant presence of peripheral artery disease (PAD), which is known to convey additional cardiovascular risk, was associated with different circulating levels of sRAGE with respect to CAD alone and control subjects. Clinical and laboratory parameters including the ankle brachial index (ABI) and sRAGE (enzyme-linked immunosorbent assay kit) were investigated in 544 patients with angiographically documented CAD and 328 control subjects. 213/554 CAD patients (39%) showed an ABI <0.9 associated with typical symptoms (group CAD + PAD), whereas 331 patients were free from PAD. The concentration of plasma sRAGE was significantly lower (P < 0.0001) in CAD population, with and without PAD, than in control subjects. Among CAD patients, those with PAD showed lower levels of sRAGE. The distribution of the three groups (CAD, CAD + PAD, and controls) according to sRAGE tertiles showed that lower levels were more frequent in patients with CAD and CAD + PAD, whereas higher levels were more frequently found in controls. CAD patients presenting with PAD have lower sRAGE levels than CAD patients without peripheral atherosclerosis showing that stable atherosclerotic lesions in different vascular districts are inversely related to soluble decoy receptor sRAGE.

Apelin plasma levels predict arrhythmia recurrence in patients with persistent atrial fibrillation.

Low levels of the regulatory peptide apelin have been reported in patients with lone atrial fibrillation (AF). We evaluate the potential utility of assessing apelin plasma levels as a predictor of AF recurrence in individuals presenting for electrical cardioversion. Plasma levels of apelin, brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein were measured in 93 patients, with persistent AF before successful external electrical cardioversion. Significantly lower apelin plasma levels were found in patients with AF recurrence as respect to population with persistence of sinus rhythm during a six months follow-up. The hazard increased with duration of AF, left atrial dimension, BNP concentrations. Subjects with apelin levels below the median had a hazard ratio of 3.1 of arrhythmia recurrence with respect to those with high apelin levels (p< 0.05). A significant difference in BNP levels was found between patients with and without AF recurrence during the follow-up. After adjusting for potential confounders, both BNP and apelin retained their statistical significance as independent predictors of arrhythmia recurrence. Patients with both low apelin and elevated BNP had a worse prognosis compared with those with either low apelin or elevated BNP alone. Low plasma apelin levels before external electrical cardioversion are an independent prognostic factor for arrhythmia recurrence in patients with AF treated with antiarrhythmic drugs. Apelin may be of particular value for the identification of high-risk patients in addition to BNP.

Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Atherosclerosis: Possible Correlation with Clinical Presentation

Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand receptor ubiquitous present on epithelial, neuronal, vascular and inflammatory cells, usually expressed at low levels in homeostasis and to increased degrees at sites of stress or injury. The aim of the present study was to evaluate sRAGE plasma levels in patients with Acute Coronary Syndrome (ACS) and to assess its diagnostic efficacy in identification of patients with acute events. Plasma levels of sRAGE were determined in 860 patients with Coronary Artery Disease (CAD): 530 patients presented stable angina and 330 were observed during acute ischemic event (147 with unstable angina and 183 with myocardial infarction). sRAGE plasma levels were significantly lower in patients with ACS than in patients with stable angina: [median 584 pg/mL (IQR: 266–851 pg/mL) in MI patients, median 769 pg/mL (IQR: 394–987 pg/mL) in patients with unstable angina, median 834 pg/mL (IQR 630–1005 pg/mL) in patients with stable angina; P < 0.001]. sRAGE levels did not differ among ACS patients stratified by the extent of coronary artery disease. In conclusion, this study confirm the role of sRAGE in activation and progression of inflammatory process and suggests the possibility that sRAGE can be considered an indicator of destabilization of vulnerable plaque.

Possible role of -374T/A polymorphism of RAGE gene in longevity

Demographic and social changes in the last decades have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of –374T/A polymorphism in subjects aged >90 years and in middle-aged individuals. We observed association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders.

RAGE gene polymorphism in heart failure patients with and without angiographic evidence of significant coronary atherosclerosis.

Heart failure (HF) is a multifactorial disorder in which clinical, environmental and genetic components take part. For this reason it is possible that common gene variants could affect development, progression and response to pharmacological therapy. In recent years the role of AGEs in the pathogenesis of cardiovascular diseases has become recognized but little is known about the role of the AGE-RAGE system in heart failure. The aim of the present study was to identify possible relationship between -374 T/A RAGE gene polymorphism with heart failure. The population in this study consists of 386 subjects with HF, selected according to the presence of depressed Left Ventricular Ejection Fraction (LVEF) <45%, and 639 patients with CAD documented at coronary angiography. Within the population with HF there are 228 patients with disease secondary to not ischemic cause and 158 with post-ischemic condition. The sample of AA genotype was significantly lower in patients with post-ischemic HF in respect to HF secondary to non-ischemic causes (p<0.001). A significant difference between the two groups was also observed regarding the allele frequency. In addition, differences in the allelic and the genotypic frequencies of homozygous genotypes were found between the HF patients free from evidence of coronary significant lesions and patients with at least one hemodynamically significant coronary lesion, both HF and CAD. In patients with at least one vessel compromised the presence of A allele and the homozygous AA genotype were significantly lower than in patients with lesion-free coronary. In conclusion, our research reveals that the -374 T/A polymorphism is related to the genesis of atherosclerotic coronary artery disease but not to its evolution. The protective role of AA genotype in respect to atheromatous disease is therefore confirmed also in the HF population with non-ischemic origin.

Cardiovascular risk factors and Sympatho-Vagal balance: Importance of time-domain heart rate variability

Objective: Cardiovascular Disease (CVD) is the leading cause of death and disability worldwide. sDyregulation of the autonomic nervous system associated with various pathological conditions often occurs in presence of cardiovascular risk factors. Heart Rate Variability (HRV) may be used to assess autonomic imbalances. The aim of our study is to evaluate the correlation between HRV and the main cardiovascular risk factors in subject who underwent digital ambulatory 24 hours Holter ECG monitoring for clinical investigations. Methods: We evaluated time domain parameters of HRV by Holter ECG monitoring in a large population categorized based on the presence or absence of the major cardiovascular risk factors. Results: We found significant differences in time domain parameters of HRV in patients with and without common risk factor for CVD such as diabetes, family history for Coronary Artery Disease and dyslipidemia. We also analyzed our study population based on age and we found a positive correlation with the standard deviation of all NN intervals (SDNN), square root of the mean of the sum of the square of the differences between adjacent NN intervals (RMSSD), mean R-R intervals and by the number of adjacent NN intervals differing by more than 50 ms divided by the total number of all NN intervals (pNN50) and an inverse correlation for the others parameters. Conclusion: Non-modifiable risk factors (age, gender, family history) along with dyslipidemia and diabetes, are related to a change in HRV, while modifiable risk factors (smoking, hypertension, overweight, hyperhomocysteinemia) showed no correlation. This would seem to indicate that the genetic components more than lifestyle habits and behavior act on the nervous control of the heart. Our study shows the possibility to find interesting clinical-prognostic data, analyzing simple parameters obtained from instrumental methods of investigation performed for other clinical reasons.

Soluble Receptor for Advanced Glycation End-products Levels in Chronic Heart Failure and Its Correlation to Left Ventricular Ejection Function

The Receptor for Advanced Glycation End-products (RAGE), a multi-ligand member of the immunoglobulin superfamily, is a ubiquitous receptor present on epithelial, neuronal, vascular and inflammatory cells. AGEs have been implicated in vascular and myocardial dysfunction and in development of atherosclerosis but little are known about the role of the AGE-RAGE system in heart failure. The main objective of the study was to assess sRAGE plasma levels in patients with Chronic Heart Failure (CHF) focusing on patients with severe reduction of left ventricle function. We measured sRAGE plasma levels in 389 patients with CHF and 319 stable patients with Coronary Artery Disease (CAD). Patients with CHF had significantly lower values of soluble RAGE in respect to stable CAD population. The linear regression analysis showed that LVEF (Left Ventricularv Ejection Fraction) significantly correlated with sRAGE plasma concentrations; sRAGE plasma levels were significantly lower in patients with severe left ventricular systolic dysfunction compared with those with ejection Fraction ≥ 30%. Our data support a positive correlation between soluble RAGE plasma levels and left ventricular ejection fraction in the CHF population; we demonstrated that in subjects with CHF and severe left ventricular systolic dysfunction, soluble RAGE plasma concentrations were significantly lower in comparison with patients with moderate left ventricular dysfunction. This study suggests the possibility that soluble RAGE can be considered a new element to be used in prognostic stratification in patients affected by CHF.

Primary Headache and Silent Myocardial Ischemia in Patients with Coronary Artery Disease

Objective: The mechanisms by which migraine is linked to ischemic vascular disease remain uncertain and are likely to be complex. The aim of this study was to investigate the correlation between silent myocardial ischemia (SMI) and a history of documented primary headache in a large population of patients with exercise-induced myocardial ischemia. Methods: The study involved 1,427 consecutive patients (918 symptomatic and 509 asymptomatic patients) with exercise-induced myocardial ischemia and documented coronary artery disease (CAD). Results: Patients with anginal symptoms during exercise-induced myocardial ischemia had a significantly higher prevalence of primary headache than those without (41 vs. 30%, p < 0.001). Patients with angina pectoris in daily life also had greater prevalence of primary headache than those without anginal symptoms (37 vs. 20%; p < 0.0001). Symptomatic patients during percutaneous transluminal coronary angiography or myocardial infarction had a greater prevalence of primary headache than asymptomatic patients (p < 0.001 and p = 0.005, respectively). Conclusions: Our data suggest that a history of headache in CAD population is correlated to a high probability of anginal symptoms and a decreased probability of SMI. The anamnestic absence of headache requires a close monitoring for patients with risk factors for CAD, because this population seems to have a lower susceptibility to pain and the risk of developing SMI might be increased.

Ruolo del polimorfismo del gene RAGE in pazienti affetti da Scompenso Cardiaco con e senza evidenza angiografica di aterosclerosi coronarica emodinamicamente significativa

Nello scompenso cardiaco (SC), malattia multifattoriale in cui giocano un ruolo diversi fattori, varianti genetiche possono influenzarne lo sviluppo, la progressione e la risposta alla terapia farmacologica. Poco si sa circa il ruolo del sistema AGE-RAGE nello SC. Al fine di identificare i possibili rapporti tra il polimorfismo -374 T/A del gene RAGE e lo SC abbiamo quindi arruolato 386 pazienti con SC sia post-ischemico sia secondario a causa non ischemica e 639 con Coronary Artery Disease (CAD). Dalla nostra analisi e emerso che le frequenze del genotipo AA e dell’allele A erano significativamente piu basse nei pazienti con SC post-ischemico rispetto a quelli con SC secondario a cause non-ischemiche e fra i pazienti con almeno una lesione coronarica emodinamicamente significativa, sia tra quelli con SC che tra quelli con CAD, rispetto a quelli a coronarie indenni. In conclusione, la nostra ricerca suggerisce che il polimorfismo -374 T/A sia legato alla genesi della malattia aterosclerotica coronarica, ma non alla sua evoluzione e conferma, anche fra la popolazione con SC di origine non-ischemica, il ruolo protettivo del genotipo AA nello sviluppo della malattia ateromasica.