Deodato Assanelli

Inherited Thrombophilic Disorders in Young Adults With Ischemic Stroke and Patent Foramen Ovale

Background and Purpose— The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study. Methods— We investigated 125 consecutive subjects (age, 34.7±7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)G1691A mutation, the prothrombin (PT)G20210A variant, and the TT 677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. Results— A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO−). The PTG20210A variant was more frequent in the PFO+ group compared with control subjects and the PFO− group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO−, 11% versus 1.1%; 95% CI, 1.09 to 109;P =0.047). A similar distribution was observed for subjects carrying either the PTG20210A variant or the FVG1691A mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO−, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1;P =0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66;P =0.015), and in 0 subjects in the PFO− group. A trend toward a difference in the frequency of the FVG1691A mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%;P =0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups. Conclusions— In young adults, the PTG20210A variant and, to a lesser extent, the FVG1691A mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.

Polymorphisms of the Interleukin-1β Gene Affect the Risk of Myocardial Infarction and Ischemic Stroke at Young Age and the Response of Mononuclear Cells to Stimulation In Vitro

Objectives— To investigate the role of interleukin-1&bgr; (IL-1&bgr;) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age. Methods and Results— A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the −511C/T IL-1&bgr; polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (P=0.0020 in MI; P=0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1&bgr; and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1&bgr; during cell stimulation resulted in a marked reduction of tissue factor activity expression. Conclusions— −511C/T IL-1&bgr; gene polymorphism affects the risk of MI and ischemic stroke at young age and the response of mononuclear cells to inflammatory stimulation.

ESC Study Group of Sports Cardiology: recommendations for participation in leisure-time physical activity and competitive sports for patients with ischaemic heart disease.

Background Evidence for the proper management of ischemic heart disease (IHD) in the general population is well established, but recommendations for physical activity and competitive sports in these patients are scarce. The aim of the present paper was to provide such recommendations to complement existing ESC and international guidelines on rehabilitation and primary/secondary prevention. Design and methods Due to the lack of studies in this field, the current recommendations are the result of consensus among experts. Sports are classified into low/moderate/high dynamic and low/moderate/high static, respectively. Results Patients with a definitive IHD and higher probability of cardiac events are not eligible for competitive sports (CS) but for individually designed leisure time physical activity (LPA); patients with definitive IHD and lower probability of cardiac events as well as those with no IHD but with a positive exercise test and high risk profile (SCORE>5%) are eligible for low/moderate static and low dynamic (IA-IIA) sports and individually designed LPA. Patients without IHD and a high risk profile + a negative exercise-test and those with a low risk profile (SCORE<5%) are allowed all LPA and competitive sports with a few exceptions. Conclusions Individually designed LPA is possible and encouraged in patients with and without established IHD. Competitive sports may be restricted for patients with IHD, depending on the probability of cardiac events and the demands of the sport according to the current classification.

Cumulative Effect of Predisposing Genotypes and Their Interaction With Modifiable Factors on the Risk of Ischemic Stroke in Young Adults

Background and Purpose— Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals. Methods— The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the &egr;4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls. Results— Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with ≥2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive. Conclusions— These data suggest a gene–dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Morphometric changes induced by amino acid supplementation in skeletal and cardiac muscles of old mice.

Aging is associated with progressive structural disorganization of muscular and cardiac fibers, decreasing functional capacity, and increased rates of disease and death. Aging is also characterized by disturbances in protein synthesis with impaired cellular organelle functions, particularly in the mitochondria. The availability of amino acids is a key factor for the overall metabolism of mammals and exogenous supplements of amino acid mixtures (AAm) could be a valid therapeutic strategy to improve quality of life, avoiding malnutrition and muscle wasting in the elderly. We investigated the morphoquantitative effects of long-term AAm supplementation on the mitochondria and sarcomeres (by electron microscope) and on collagen matrix deposition (by histologic techniques) in both skeletal and cardiac muscles of young and aged mice. Our data showed that old animals have fewer mitochondria and massive fibrosis in both muscles. Long-term AAm supplementation increased the number and volume of mitochondria and sarcomeres and decreased fibrosis in both skeletal muscle and hearts in old rats. These findings indicate that AAm restored muscular morphologic parameters and probably improved the mechanical performance of these organs.

Synergistic effect of apolipoprotein E polymorphisms and cigarette smoking on risk of ischemic stroke in young adults.

Background and Purpose— The effect of apolipoprotein E (APOE) polymorphisms on stroke risk may be influenced by the coexistence of modifiable predisposing conditions. We explored the interactions of APOE genotypes and conventional risk factors in a case-control study of young adults with cerebral infarct. Methods— We analyzed 124 consecutive patients (age, 34.7±7.3 years) and 147 age- and sex-matched controls. APOE genotypes were determined by restriction fragment-length polymorphism analysis. Results— The prevalence of the &egr;4 allele and &egr;34 genotype was slightly higher in cases than in controls (0.125 versus 0.071 and 0.242 versus 0.136, respectively). Carriers of the &egr;34 genotype and &egr;4 allele were associated with an increased risk of stroke on multivariate analysis compared with the &egr;33 genotype and non-&egr;4 carriers, respectively (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.10 to 4.76; and OR, 2.27; 95% CI, 1.13 to 4.56). ORs for stroke were 2.99 (95% CI, 1.64 to 5.45), 2.69 (95% CI, 1.25 to 5.77), and 5.39 (95% CI, 1.59 to 18.30) for smokers with the &egr;33 genotype, nonsmokers with the &egr;34 genotype, and smokers with the &egr;34 genotype, respectively, compared with nonsmokers with the &egr;33 genotype. Similar results were obtained when &egr;4 carriers and non-&egr;4 carriers were compared in the same interaction model. No significant interaction between APOE and hypertension was found. Conclusions— In young adults, the APOE &egr;4 allele and cigarette smoking act synergistically, increasing an individual’s propensity to have a cerebral ischemic event. This finding may help in determining an individual’s predisposition to stroke and more targeted preventive interventions.

Ambient intelligence and pervasive systems for the monitoring of citizens at cardiac risk: New solutions from the EPI-MEDICS project

In western countries, heart disease is the main cause of premature death. Most of cardiac deaths occur out of hospital. Symptoms are often interpreted incorrectly. Victims do not survive long enough to benefit from in-hospital treatments. To reduce the time before treatment, the only useful diagnostic tool to assess the presence of a cardiac event is the electrocardiogram (ECG). Event and transtelephonic ECG recorders are used to improve decision-making but require setting up new infrastructures. The Pervasive solution proposed by the European EPI-MEDICS project is an intelligent Personal ECG Monitor for the early detection of cardiac events. It includes decision-making techniques, generates different alarm levels and forwards alarm messages to the relevant care providers by means of new generation wireless communication. It is cost saving, involving care provider only if necessary without specific infrastructure. Healthcare becomes personalized, wearable, ubiquitous.

Exclusion of candidate genes in a family with arterial tortuosity syndrome

Arterial tortuosity syndrome (ATS) is a rare hereditary disorder with variable clinical presentation including tortuosity and elongation of the major arteries, often associated with pulmonary artery stenosis, pulmonary hypertension, and skin and joint laxity, suggestive of a connective tissue disorder. ATS is transmitted in an autosomal recessive mode, but the causal gene is unknown. We report an Italian pedigree with three inbred families in which five patients show signs of ATS. In particular, four adult patients present arterial tortuosity and elongation of the main arteries. Two of these patients, with the most severe degree of arterial tortuosity, also show severe peripheral stenosis of the main pulmonary artery. The fifth young patient shows a severe pulmonary valve stenosis in the absence of arterial tortuosity. All patients show signs of Ehlers–Danlos syndrome (EDS): soft skin with abundant subcutaneous tissue and joint laxity, hernias, and disorganization of the extracellular matrix (ECM) of fibronectin (FN) and of actin microfilaments in cultured skin fibroblasts. Linkage analysis of the genes involved in EDS and other connective tissue disorders, excluded COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, ADAMTS2, ELN, FN1, TNXA, and TNXB as candidate genes in the family under study, thus indicating that ATS is a distinct clinical and molecular entity.

Effects of treadmill exercise and training frequency on anabolic signaling pathways in the skeletal muscle of aged rats

Physical exercise is the most effective intervention against sarcopenia of aging; however, the cellular and molecular mechanisms mediating training-induced adaptations are not yet completely understood. Furthermore, it is unclear whether exercise training initiated late in life affects myocyte anabolic signaling in a dose-dependent manner. Hence, we sought to investigate the effects of treadmill exercise and training frequency on anabolic pathways, including insulin signaling, in the skeletal muscle of old rats. Aged (14-16-month-old) male Wistar rats were trained on a treadmill for 3 (EX3) or 5 days/week (EX5) during 8 weeks and compared with age-matched sedentary controls (SED). Four-month-old rats were used as young controls (YC). Protein expression levels of insulin receptor (IR), insulin receptor substrate 1 (IRS-1), activated (phosphorylated) mammalian target of rapamycin (p-mTOR) and glucose transporter GLUT4 were determined in quadriceps muscle extracts via immunoblotting. Mitochondrial cytochrome c oxidase (COX) activity was assessed by histochemical staining, while electron microscopy was employed to quantify the sarcomere volume (V(src)). Body weight (BW) increased, whereas muscle weight (MW) and V(src) decreased with age. EX5, but not EX3 increased MW and V(src), without affecting BW. The expression of IR and GLUT4 was higher in SED rats relative to the YC group. Conversely, protein levels of IRS-1 and p-mTOR as well as COX activity were reduced in advanced age. Compared with SED rats, EX3 animals displayed reduced IR expression and increased IRS-1 levels and COX activity. The expression of GLUT 4 and p-mTOR was unaffected by EX3. EX5 up-regulated IRS-1 and p-mTOR expression and COX activity, while decreasing GLUT4 levels, with no effect on IR expression. In summary, substantial impairments in muscle anabolic pathways, including insulin signaling, were detected in aged sedentary rats. These changes were ameliorated by exercise training, concomitant with improvements in muscle trophism. Benefits were more evident in rats trained for 5 days/week, suggesting that physical exercise initiated late in life affects anabolic signaling in a dose-dependent manner.

Homocysteine levels are associated with the severity of peripheral arterial disease in Type 2 diabetic patients

Summary.  Background: Homocysteine levels are positively associated with the risk of cardiovascular disease. They might be determined by both MTHFR677C→T polymorphisms and folate or B‐vitamin status. Objectives: To investigate the possible association between plasma homocysteine levels and its genetic or environmental determinants and either the presence or the severity of peripheral arterial disease (PAD), in Type 2 diabetic patients. Methods: From a cohort of 944 patients with Type 2 diabetes, 135 patients with PAD were selected, and frequency‐matched for age and sex with 219 Type 2 diabetic control patients without macrovascular complications. According to the increasing severity of the disease, patients were divided into PAD1 (only diffuse calcifications of the arteries without any stenosis or occlusion), PAD2 (one or two stenosis or occlusions) and PAD3 (three or more). Results: Homocysteine levels were similar in control and case patients (10.3 µmol L−1 vs. 10.7 µmol L−1, P = 0.53); however, a significant increase was found in PAD3 patients: odds ratio = 2.77 (95% confidence interval 1.14, 6.72) for patients with homocysteine levels above the median vs. those under the median in multivariate analysis. Although all significantly associated with homocysteine levels, neither MTHFR genotype nor folic acid or vitamin B12 levels were associated with severity of PAD. A significant interaction (P < 0.05) was found between folic acid and MTHFR polymorphism in determining the levels of homocysteine. Conclusions: In Type 2 diabetes, homocysteine was associated with the angiographic severity of PAD, but neither the genotypes nor vitamin levels contributed to this association.