Nitric oxide metabolites (nitrite and nitrate) in several clinical condition.

We determined the concentration of nitric oxide metabolites (NO2-+NO3-), expressed as NOx, in several clinical conditions. Regarding this, we have examined 25 subjects with arterial hypertension, 41 subjects with chronic kidney disease in conservative treatment, 106 subjects with metabolic syndrome subdivided according to the presence (n = 43) or not (n = 63) of diabetes mellitus, 48 subjects with obstructive sleep apnea syndrome (OSAS), 14 women with systemic sclerosis complicated with Raynaud's phenomenon, 42 dialyzed subjects and 105 young subjects with acute myocardial infarction (AMI). In subjects with arterial hypertension, chronic kidney disease, metabolic syndrome, systemic sclerosis, as well as, in dialyzed and AMI subjects, we found at baseline a NOx increase. In dyalized subjects after a standard dialysis session, we observed a decrease in NOx. The increase in NOx in juvenile AMI was significantly influenced by cigarette smoking and less by cardiovascular risk factors and the extent of coronary lesions; at 3 and 12 months later than the initial event, we observed a decrease of NOx that remains significantly higher than the control group. In subjects with OSAS no difference in NOx was noted in comparison with normal controls, although their subdivision according to the apnea/hypopnea index operates a clear distinction regarding NOx concentration.

Myocardial infarction in young adults: risk factors, clinical characteristics and prognosis according to our experience.

OBJECTIVES: Myocardial infarction is a relatively unusual phenomenon in young subjects. The aim if this work is to characterize the risk profile and factors influencing outcomes of these patients since it makes possible to manage prevention interventions. PATIENTS AND METHODS: We examined cardiovascular risk factors, clinical presentation, angiographic picture and outcome of a group of young patients hospitalized for a myocardial infarction. We enrolled 121 young patients consecutively admitted to our hospital for a myocardial infarction and examined them not only at the initial stage, but also after 3 months and one year; finally a long-term telephonic follow up was performed, when possible. RESULTS: We found some peculiarity making these patients quite different from the older ones who develop a myocardial infarction: cigarettes smoking, family history of ischemic heart disease and hyperlipidemia were the most frequent cardiovascular risk factors, while diabetes and hypertension were less represented; moreover coronary angiography showed more frequently a less extensive coronary atherosclerosis. Patients who developed a cardiovascular event at follow-up presented a significantly higher prevalence of hypertension and obesity and a significantly lower frequency of healthy coronary arteries and of previous revascularization. CONCLUSIONS: Myocardial infarction in young adults presents several peculiarities, represented not only by the risk profile, but also by the angiographic picture and the prognosis. Considering the long life expectancy of the involved population, the essential role of preventive interventions should be strongly underlined.

Role of genetic polymorphisms in myocardial infarction at young age.

Acute myocardial infarction (AMI) in young adult presents a typical pattern of risk factors, clinical, angiographic and prognostic characteristics. In the last years we demonstrated that hemorheological profile is altered in these patients in a persistent way and independently of the number of risk factors and of the extent of coronary lesions. Thus, the hyperviscosity syndrome following AMI could be considered an intrinsic characteristic of these patients. Consequently it is possible to hypothesise the presence of a genetic background at the origin of this predisposition. If this background is able to influence the risk of ischemic heart disease, this should be particularly evident in young subjects. Since inflammatory mechanisms play a central role in mediating all phases of atherosclerosis, genes encoding for inflammatory or anti-inflammatory molecules are candidates for the risk of developing atherosclerosis. As atherosclerosis is the first cause of mortality in Western countries and if pro-inflammatory genotypes contribute to risk of coronary heart disease, alleles associated to disease susceptibility should not be included in the genetic background favouring longevity: People genetically predisposed to a weak inflammatory activity have fewer chances to develop cardiovascular disease and, therefore, have better chance for a long-life. According to this hypothesis, we studied in our population of young patients with AMI, the distribution of some polymorphisms influencing a inflammation and found an higher prevalence of pro-inflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, SNP G1059C of PCR gene) and a lower prevalence of anti-inflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP -1082 G/A of IL10 gene, CCR5Δ32). Results of these studies show that early myocardial infarction could be associated with a genetic predisposition to an intense inflammatory response, associated also to an hyperviscosity syndrome.

Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). However, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO) are the key enzymes in the conversion of arachidonic acid to prostaglandins (PG) and leukotrienes (LT) and are implicated in a wide variety of inflammatory disorders, including atherosclerosis. In fact, PGE2 activates Matrix Metallo-proteinases whereas LTB4 is a chemoactractant for monocytes and activates gene expression in inflammatory cells. We have tested the hypothesis that anti-inflammatory variants of these genes confer genetic resistance to MI and conversely favour longevity. So, we analyzed MI patients, age-related controls and centenarians. The pro-inflammatory alleles of COX-2 and 5-LO were overrepresented in MI and under-represented in centenarians whereas age-related controls displayed intermediate values. MI is a multifactorial disease, hence MI might be the result of a cumulative effect which contributes with different timing to achieve a threshold where the chance to develop the diseases is very high. In particular, differences in inflammatory status can contribute to the chance of developing a risk phenotype. However, these studies might contribute to the determination of a risk profile which may allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug.

Genetic risk factors in myocardial infarction at young age.

The role of genetic susceptibility to coronary artery disease (CAD) seems to be quite important in young patients. In the last years the attention has been focused on polymorphisms influencing some biological functions (coagulation and fibrinolysis, platelets, vascular function, lipid metabolism, inflammation). The study of prothrombotic polymorphisms has kindled a deep interest. The role of atherosclerosis and thrombosis is different in the different ages. In all the studies we examined, the polymorphism G20210A in the prothrombin gene was associated with an increased risk of acute myocardial infarction (AMI) in young people, especially when other risk factors were present. Contradictory results have been found in the studies on Factor V Leiden: according to many authors the activated protein C resistance (APCR) is associated with an increased risk of AMI only in smokers, above all if women. On the other hand, some polymorphisms of the Factor VII gene seem to be protective. Young AMI could be also caused by a reduction of the fibrinolytic activity, as it was found when the allele 4G in the promoter of plasminogen activator inhibitor (PAI) gene is present. The attention has also been focused on the effects of variations in genes that influence platelet functions. According to a metanalysis of studies published up to 1999, there is no association between the polymorphism PlA1/A2 of the GP IIIa gene and young AMI, whereas there is doubt about the role of the polymorphism in the GP IIb e GP Ib genes. Moreover, it seems to be present an association with the polymorphisms in the thrombopoietin gene (C4830A and A5713G). Also the role of some genes coding for proteins influencing the vascular functions has been valued. Few studies were performed on genetics of the renin-angiotensin-aldosterone system and the results are insufficient and contradictory, such as those about the association between the polymorphism G894T in the eNOS gene or the polymorphism C677T in the MTHFR gene and young AMI. Genes coding for proteins involved in the lipid metabolism have been closely examined. Many polymorphisms were discovered in the Apo B gene: the variant C-516T was found to be associated with increased LDL levels, whereas the results about the association between this and other polymorphisms in the same gene (I/D of LAL sequence, PvuII, MspI, Asp4311Ser) and young AMI are discordant. On the other hand, the variant e4 of the ApoE gene was associated with an increased risk of AMI at young age in many works. In the last years, a particular interest has kindled the study of the relationship between inflammation, atherosclerosis and CAD. Even if the studies performed are few, it was found an association between young AMI and polymorphism C-260T in the CD14 gene, between coronarics atherosclerosis and polymorphism A516C in the E Selectin gene or polymorphisms Leu125Val and Ser563Asn in the PECAM1 gene.

Polymorphonuclear leukocyte membrane fluidity and cytosolic Ca(2+) content in young adults with acute myocardial infarction. Evaluation at the initial stage and after 12 months.

Our aim was to examine two aspects of polymorphonuclear leukocyte (PMN) rheology (membrane fluidity and cytosolic Ca2+ content), at baseline and after in vitro activation, in a group of young adults with acute myocardial infarction (AMI) at the initial stage and after 12 months. We enrolled 21 AMI subjects aged < or = 45 years (mean age 41.1 +/- 3.5 years) and evaluated PMN membrane fluidity, labelling intact PMN cells with the fluorescent probe 1,4-(trimethylamino)-phenyl-4-phenylhexatriene and the PMN cytosolic Ca2+ content marking PMN cells with the fluorescent probe Fura 2-AM, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (fMLP). During the initial stage PMN membrane fluidity and cytosolic Ca2+ content did not distinguish AMI patients from control subjects; after 12 months, when compared with the initial stage, PMN cytosolic Ca2+ content was significantly increased. In vitro PMN activation with PMA and fMLP caused no variation of the two PMN parameters in control subjects, while in AMI patients membrane fluidity decreased and cytosolic Ca2+ content increased; the same behaviour pattern was observed after 12 months. The constant functional alteration of PMN cells in young AMI patients highlights the role of activated leukocytes as a component of the inflammatory reaction that follows ischemia.