Sandra Schirinzi

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.

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.

Age of Onset of Myocardial Infarction: Is Promoter Polymorphism of the RAGE Gene Implicated?

Receptor for advanced glycation endproducts (RAGE) is a cell-surface molecule member of the immunoglobulin superfamily and engages differing ligands relevant to distinct processes. A growing body of evidence has suggested that RAGE may promote vascular inflammation through several mechanisms. The objective of this study was to identify the possible relationship between the -374 T/A polymorphism of the RAGE gene, myocardial infarction (MI), and its age of onset. A total of 691 MI patients and 234 matched controls were investigated. In this study, the frequency of the A allele and AA genotype of the -374 T/A promoter polymorphism is significantly lower in patients with MI respect to the control group (p < 0.01). Our results showed a significant role of the AA genotype on age of onset of MI. In particular, the mean age of the first MI was higher in patients with the AA genotype as compared to those that were AT or TT genotype carriers (p = 0.002). The relationship between -374 T/A RAGE polymorphism and age for the appearance of MI was independently related to common risk factors of disease (p < 0.01). Kaplan-Meier curves confirmed that subjects with the AA genotype have a later development of MI (p = 0.0022). This study is the first to investigate the role of RAGE polymorphisms on the susceptibility to develop the acute coronary events in the Italian population and identified this polymorphism as an age-related factor for MI development. The homozygous AA genotype may exert a protective role against the early development of MI.

The -374T/A variant of the rage gene promoter is associated with clinical restenosis after coronary stent placement.

Upregulation of the receptor for advanced glycation end products (RAGE) may play a crucial role in neointimal formation upon vessel injury. The −374T/A variant of the RAGE gene promoter, which has been associated with an altered expression of the cell-surface receptor, could exert a protective effect toward the development of vascular disease. The aim of this study is to determine the impact of this common genetic variant in the occurrence of clinical in-stent restenosis after coronary stent implantation. The −374T/A polymorphism of the RAGE gene promoter was evaluated by PCR-RFLPs in 267 patients with coronary artery disease who underwent coronary stent implantation and a subsequent coronary angiography 6–9 months later for suspected restenosis. In-stent restenosis was assessed by means of quantitative angiography. Carriers of the-374AA genotype showed a significantly reduced risk of developing restenosis after percutaneous transluminal intervention than non-carriers. To determine whether the protective effect of the homozygous AA genotype toward clinical restenosis was independent of potential confounders, we performed multivariable logistic regression analysis. After allowance for clinical and biochemical risk factors and stent length, the AA genotype remained significantly associated with a reduced prevalence of in-stent restenosis. No relation was evident between the RAGE genotype and established cardiovascular risk factors. In conclusion, the −374AA genotype of the RAGE gene promoter could be associated with a reduced risk of in-stent restenosis after coronary stent implantation.

APJ polymorphisms in coronary artery disease patients with and without hypertension

Apelin is an endogenous peptide that increases cardiac inotropism through its APJ receptor. Certain findings indicate that the apelinergic system may have a pathophysiological role in cardiovascular disease and there is evidence showing the role of the apelinergic system in blood pressure regulation in vitro and in animal models. The role of the apelin-APJ system in cardiovascular physiology and its interaction with other neuroendocrine pathways has not been fully elucidated. However, the small number of reported studies indicates that apelin signaling may be involved in the regulation of blood pressure, cardiac contractile function, fluid balance, angiogenesis and inhibition of apoptosis. We evaluated the possible relationship between the G212A and A445C APJ polymorphisms and coronary artery disease (CAD) in Italian patients and in healthy controls by RFLP-PCR. We analyzed the allelic and genotypic frequencies of APJ polymorphisms in 664 patients (378 with hypertension) and 143 controls. There were no differences between allelic and genotypic frequencies in patients in respect to the controls for both polymorphisms analyzed. In the CAD population, there was an increased frequency of the G212 allele in patients with hypertension in respect to patients without hypertension. No differences were present in the two subgroups for the A445C polymorphism. Although the functional role of the G212A polymorphism has not yet been identified, it is possible to hypothesize that the presence of the A allele may cause a gain in function of the apelin/APJ system associated with a lower risk of hypertension.

Microalbuminuria and sRAGE in High-Risk Hypertensive Patients Treated with Nifedipine/Telmisartan Combination Treatment: A Substudy of TALENT

Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR) are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products). In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE) plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.

Relationship between sRAGE and eotaxin-3 with CRP in hypertensive patients at high cardiovascular risk.

BACKGROUND Cardiovascular disease (CVD) is the leading cause of death in Western countries and is highly prevalent in patients with kidney disease. Traditional risk factors for CVD often accompany kidney dysfunction, and chronic kidney disease per se is considered an additional risk factor. Risk stratification for CVD remains suboptimal even after the introduction of global risk assessment by various scores. This has prompted the search for novel markers of cardiovascular risk, and several biomarkers have been suggested as candidates, together with C-reactive protein (CRP). The objective of the present study was to investigate the relationship between novel biomarkers of vascular inflammation (soluble form of the receptor for advanced glycation end products [sRAGE] and eotaxin-3) with CRP in a population of hypertensive patients at high cardiovascular risk. METHODS Plasma sRAGE, high-sensitivity CRP (hs-CRP) and eotaxin-3 were measured in 399 hypertensive patients (265 men, mean age 58 ± 8 years)with diabetes mellitus, metabolic syndrome or organ damage. RESULTS Plasma concentrations of sRAGE, eotaxin-3 and hs-CRP were not different between diabetic and nondiabetic subjects. Univariate analysis showed that plasma levels of sRAGE and eotaxin-3 were not associated with hs-CRP in either subgroup. CONCLUSION Our study confirms the robust and widely studied role of CRP as an important marker of vascular inflammation. We also postulate the possible involvement of sRAGE and eotaxin, 2 novel biomarkers, in CVDs. On the basis of our results, we can put forward the hypotheses that hs-CRP, s-RAGE and eotaxin are reliable but unrelated cardiovascular risk markers.

Correlazione tra livelli plasmatici di galactina e aterosclerosi coronarica: nuovo marcatore di instabilità clinica?

L’infiammazione gioca un ruolo chiave nella aterosclerosi. La galactina-3 e un mediatore dell’attivazione dei macrofagi derivato dall’endotelio, attivamente coinvolto nella regolazione di molti aspetti del comportamento delle cellule infiammatorie. Lo scopo di questo studio e quello di quantificare i livelli plasmatici di galactina-3 nei pazienti con malattia coronarica (CAD) e le sue diverse manifestazioni cliniche al momento dell’osservazione, per verificare se la galactina-3 potrebbe essere un biomarker utile nella valutazione della malattia aterosclerotica. Sono stati arruolati 125 pazienti affetti da CAD angiograficamente documentata (70 stabili, 55 instabile). I livelli plasmatici di galactina-3 sono stati quantificati utilizzando un kit ELISA. Pazienti instabili (n=55) avevano livelli plasmatici di galactina-3 superiori rispetto ai soggetti stabili [27.75 ng/mL (19.27-39.09) vs 6.48 ng/ml (4.88-8.83), p<0.001]. Sembra inoltre essere presente una correlazione tra i livelli plasmatici di galactina-3 e il numero di vasi compromessi: i pazienti con CAD trivasale avevano livelli piu elevati di galactina-3 rispetto ai pazienti con malattia mono- o bivasale [17.39 ng/ml (10.75-29.82) vs 9.18 ng/ml (5.56-23.22), p=0.058]. Il riscontro di livelli plasmatici di galactina-3 significativamente piu elevati nei pazienti con angina instabile rispetto a quelli con angina stabile conferma il coinvolgimento di galactina-3 nel promuovere l’attivazione dei macrofagi e l’attrazione dei monociti. Nonostante la distribuzione della CAD nei pazienti con malattia coronarica acuta e cronica malattia siano simili, si puo ipotizzare che la galactina-3 possa essere un utile biomarker di placca aterosclerotica e in particolare della sua destabilizzazione.

Polimorfismo -374 T/A nel promotore del gene RAGE e longevità: confronto tra popolazioni con differente età

Il recettore per prodotti finali della glicazione avanzata (RAGE) e una molecola di superficie cellulare, membro della superfamiglia delle immunoglobuline, che interagisce con differenti ligandi. Un crescente numero di evidenze suggerisce che RAGE possa promuovere l’infiammazione vascolare attraverso meccanismi diversi. L’obiettivo di questo studio e identificare la possibile relazione tra il polimorfismo -374 T/A del gene RAGE, l’infarto miocardico (IM) e la sua eta di insorgenza. Sono stati reclutati un totale di 691 pazienti con infarto miocardico e 234 controlli sani. In questo studio, la frequenza dell’allele A e del genotipo AA del polimorfismo -374 T/A del promotore e significativamente piu bassa nei pazienti con infarto miocardico rispetto al gruppo di controllo (p<0.01). I nostri risultati hanno mostrato un ruolo significativo del genotipo AA nel determinare l’eta di insorgenza di infarto miocardico. In particolare, l’eta media del primo infarto miocardico era piu alta nei pazienti con genotipo AA rispetto a quelli portatori del genotipo AT o TT (p=0.002). Il rapporto tra il polimorfismo -374 T/A del promotore del gene RAGE e l’eta della comparsa di infarto miocardico e risultato indipendentemente correlato ai comuni fattori di rischio di malattia (p<0.01). Le curve di Kaplan-Meier hanno confermato che i soggetti con genotipo AA sviluppano infarto miocardico piu tardivamente (p=0.0022). Questo studio e il primo a valutare il ruolo dei polimorfismi di RAGE sulla suscettibilita a sviluppare gli eventi coronarici acuti nella popolazione italiana e ad identificare questo polimorfismo come un fattore legato all’eta dello sviluppo di infarto miocardico. Il genotipo omozigote AA potrebbe dunque esercitare un ruolo protettivo nello sviluppo precoce di infarto miocardico.

Studio dei polimorfismi nel gene del recettore dell’apelina in pazienti con e senza ipertensione arteriosa

Apelina e un peptide endogeno che aumenta l’inotropismo cardiaco attraverso l’interazione con il suo recettore APJ. Alcuni risultati indicano che il sistema apelinergico possa avere un ruolo fisiopatologico nell’ambito delle malattie cardiovascolari e ci sono prove che mostrano il ruolo del sistema apelinergico nella regolazione della pressione sanguigna in vitro e in modelli animali. Il ruolo di apelina-APJ nella fisiologia del sistema cardiovascolare e la sua interazione con altri processi neuroendocrini non e stato completamente chiarito. Tuttavia, gli studi riportati indicano che la trasmissione del segnale mediata da apelina possa essere coinvolta nella regolazione della pressione arteriosa, funzione contrattile cardiaca, bilancio idrico, l’angiogenesi e l’inibizione dell’apoptosi. Abbiamo valutato la possibile relazione tra i polimorfismi G212A e A445C di APJ e la presenza di malattia coronarica (CAD) in pazienti italiani e nei controlli sani mediante RFLP-PCR. Abbiamo analizzato le frequenze alleliche e genotipiche dei polimorfismi APJ in 664 pazienti (378 con ipertensione) e 143 controlli. Non c’erano differenze tra le frequenze alleliche e genotipiche nei pazienti rispetto ai controlli per entrambi i polimorfismi analizzati. Nella popolazione CAD abbiamo osservato un aumento della frequenza dell’allele G212 nei pazienti con ipertensione rispetto ai pazienti senza ipertensione. Nessuna differenza e stata invece evidenziata nei due sottogruppi per il polimorfismo A445C. Anche se il ruolo funzionale del polimorfismo G212A non e stato ancora identificato, e possibile ipotizzare che la presenza dell’allele A sia in grado di causare un aumento nella funzione del sistema apelina/APJ associato ad un minor rischio di ipertensione arteriosa (IA).