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Biomedical subjects

Massimo Volpe

Publications and source records attributed to Massimo Volpe.

At least 37 records · Page 2Linked to original sources
PubMed2005

Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: results of the ForLife study.

OBJECTIVES: Stroke has a high prevalence in Italy, and is the third cause of death worldwide. Hypertension is the most important risk factor contributing to the risk of stroke. The aims of this study were to assess the risk of stroke in a large cohort of hypertensive patients, and to determine the percentage with controlled blood pressure, to establish the contribution of this factor to the risk of stroke. METHODS: The study involved general practitioners to make it representative of clinical practice. They were asked to recruit 10 consecutive hypertensive patients, treated and untreated. Data collection included a full medical history and a physical examination. The 10-year absolute risk of stroke was calculated by an algorithm derived, with some modification, from the Framingham study. RESULTS: Most untreated hypertensive patients were grade 1 or 2. In treated hypertensive patients, controlled blood pressure values occurred in 18.4%, the percentage being less in patients with left ventricular hypertrophy and diabetes. In diabetic hypertensive patients the more stringent blood pressure control recommended by the guidelines was achieved in only 3.0% of cases. The average 10-year stroke risk was 17%, a greater risk being more common in elderly patients, diabetic individuals and in those with left ventricular hypertrophy. CONCLUSION: Current antihypertensive treatment achieved blood pressure control in a limited fraction of hypertensive patients seen by general practitioners. The risk of stroke in hypertensive patients is by no means negligible, which emphasizes the need for more attention to be paid to the prevention of this disease.

Aged↗
PubMed2005

Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds.

BACKGROUND: A recent editorial published by Verma and Strauss, entitled 'Angiotensin receptor blockers and myocardial infarction', examined, through a partial analysis of individual trials, the use of angiotensin receptor blockers (ARBs) in a variety of clinical settings. This editorial was reported widely in the lay press and media, and generated disappointment and concern among physicians in many countries, probably because of its provocative subtitle in the British Medical Journal: 'These drugs may increase myocardial infarction and patients may need to be told'. OBJECTIVE AND METHODS: In order to explore the influence of ARBs on myocardial infarction, we performed a more comprehensive and updated meta-analysis, taking into account all major international, randomized trials using ARBs compared with another active drug or conventional therapy (placebo), and reporting information on rates of myocardial infarction. RESULTS: We found no significant differences in fatal and non-fatal myocardial infarction between treatment with ARBs, placebo or active treatment, and the same result was obtained when considering only trials in which ARBs were compared with angiotensin-converting enzyme inhibitors (ACEIs), or when pooling all trials together. The pooled analysis of these trials shows that the relative risk of myocardial infarction lies substantially on the indifference line. CONCLUSION: Our analysis demonstrates that, at this time, there is no evidence of increased risk of myocardial infarction in patients treated with ARBs.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Polymorphisms in prothrombotic genes and their impact on ischemic stroke in a Sardinian population.

Genetic factors are involved in the individual predisposition to develop ischemic stroke (IS). In the present study we tested the role of the Factor VII G10976A and -C122T polymorphisms on the susceptibility to develop IS in a genetically homogenous and clinically well ascertained case-control study including 294 cases (median age 75 years; 176 males/118 females) and 286 controls (median age 73 years; 163 males/123 females) in Sardinia, Italy. In addition, we carried out an exploratory analysis with respect to other frequently studied polymorphisms of haemostatic factor genes:Factor II G20210A, Factor V G1691A,,Fibrinogen alpha-chain Thr312Ala, Fibrinogen beta-chain -C148T, Factor XIII G185T, GPIIb/IIIa T1565C. Among all the genes tested, FVII -C122T showed a significant, independent contribution to IS predisposition both in crude and adjusted analyses (crude OR 1.52, 95% CI 1.09-2.10, P=0.013; adjusted OR 1.48, 95% CI 1.04-2.09, P=0.028, respectively). Haplotype analyses revealed a conserved population structure with high linkage disequilibrium between both FVII mutations tested. Blood levels of FVII had an inverse relationship with the polymorphism involved. Apart from genetic influence, there was a significant role for hypertension (OR=1.7, 95% CI 1.19-2.43, P=0.003), hypercholesterolemia (OR=2.21, 95% CI 1.38-3.54, P=0.001) and atrial fibrillation (OR=1.66, 95% CI 1.06-2.58, P=0.026) on IS occurrence. In summary, we describe evidence for a possible direct association of FVII gene molecular variants with the occurrence of IS in a genetically homogenous human sample.

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PubMed2005

[Activation of the renin-angiotensin-aldosterone system in heart failure].

Several studies have demonstrated that a prolonged over-activation of neurohormonal mechanisms contributes to drive structural and functional abnormalities of the cardiovascular system and leads to poor prognosis in patients with congestive heart failure (CHF). In particular, activation of the renin-angiotensin-aldosterone system (RAAS) leads to increased levels of angiotensin II and plasma aldosterone, and promote development of arterial vasoconstriction and remodeling, sodium retention, oxidative process, and cardiac fibrosis. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers may modulate this excessive over-activity and improve survival in those patients. However, high circulating and tissue levels of angiotensin II and aldosterone may persist and contribute to further progression of CHF. Many aspects of the pathophysiological role of the RAAS in CHF are still debated, and a more thorough comprehension of this fundamental system is needed. This article reviews the current knowledge on the biochemical and functional organization of the RAAS, its pathophysiological role in CHF, and the potential therapeutic implications.

Heart Failure↗
PubMed2005

Functional assessment of coronary atherosclerosis in the catheterization laboratory: the key role of fractional flow reserve.

Patients with suspected coronary artery disease often undergo coronary angiography without prior non-invasive functional stress testing, mainly because of logistic reasons, shortcomings of the non-invasive tests, and a more widespread confidence in invasive techniques. The availability in the catheterization laboratory of the pressure-derived fractional flow reserve (FFR) has provided the interventional cardiologist with the ideal tool for appropriate decision-making based on the functional significance of the coronary stenosis detected at the angiogram. In fact, FFR allows a more refined and individualized understanding of the true severity of coronary artery disease, and, therefore, a more appropriate selection of the epicardial lesions to be treated, especially in patients with dubious lesions and complex disease. A clinical decision-making based on coronary pressure measurement results in a more effective strategy than placing stents on a "trial and error" basis. This is particularly true in case of drug-eluting stents where an approach based on an indiscriminate multi-stenting will annihilate the benefits of these new stents and be unacceptably expensive. In addition, many angiographically mild stenoses happen to be hemodynamically significant and, therefore, deserve revascularization, especially in the drug-eluting stent era.

Catheterization↗
PubMed2005

Integrated cardiovascular risk management for the future: lessons learned from the ASCOT trial.

Cardiovascular disease is the leading cause of morbidity and mortality in Western countries, and hypertension-related cardiovascular events affect about 37 million people per year worldwide. In this perspective, treatment of hypertension is a reference illustrating strategies of cardiovascular prevention. Hypertensive patients are at increased risk of undergoing a cardiovascular event throughout their lives, and treatment of high blood pressure is one of the most effective strategies to reduce global cardiovascular risk. However, due to its multifactorial pathophysiology and frequent association with other important risk factors and clinical conditions such as dyslipidemia, diabetes, left ventricular dysfunction, and renal impairment, treatment of hypertension requires an integrated approach, including life-style measures, antihypertensive drugs and other therapies (statins, ASA, etc.). Nonetheless, worldwide, general practitioners continue to focus on managing a single risk factor, e.g. blood pressure, rather than on overall cardiovascular risk profiles. Another debated issue is whether it matters how blood pressure is lowered in hypertensive patients at high risk. In other words, are the latest antihypertensive drugs more effective than older blood pressure strategies in terms of reduction of cardiovascular events? The recent results of the ASCOT Study address these controversial issues and throw new light on the management of cardiovascular risk in hypertension.

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PubMed2004

Deletion of p66shc gene protects against age-related endothelial dysfunction.

BACKGROUND: Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66shc protein controls cellular responses to oxidative stress. Mice lacking p66shc (p66shc-/-) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model. METHODS AND RESULTS: Aortic rings from young and old p66shc-/- or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O2-) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66shc-/- mice. Accordingly, an age-related decline of NO release was found in WT but not in p66shc-/- mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66shc-/- mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O2- production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66shc-/- mice. CONCLUSIONS: We report that inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Selective inhibition of protein kinase Cbeta2 prevents acute effects of high glucose on vascular cell adhesion molecule-1 expression in human endothelial cells.

BACKGROUND: Enhanced expression of adhesion molecules by the endothelium may account for vascular damage in diabetics and nondiabetic patients who develop stress hyperglycemia during acute myocardial infarction. We analyzed the phosphorylation of protein kinase Cbeta2 (PKCbeta2) at serine/threonine residues, which may contribute to the endothelial dysfunction during acute hyperglycemia. Furthermore, this study was designed to investigate whether selective blockade of this regulatory mechanism may prevent the development of endothelial hyperadhesiveness. METHODS AND RESULTS: Incubation of the human aortic endothelial cells with high glucose (22.2 mmol/L) resulted in significant increase of vascular cell adhesion molecule (VCAM)-1 protein expression (172+/-15% versus control; P<0.01). Phorbol 12-myristate 13-acetate, a potent activator of PKC, mimicked the effect of high glucose on VCAM-1 expression. High glucose led to a rapid increase (181+/-22% versus control; P<0.01) of membrane-bound PKCbeta, reflecting activation of this enzyme. The nonselective inhibitor of PKCbeta1 and PKCbeta2 isoforms LY379196, as well as CGP53353, a highly selective inhibitor of PKCbeta2, prevented in a dose-dependent manner upregulation of VCAM-1. Incubation with high glucose was associated with increased PKCbeta2 phosphorylation at the Ser-660 residue, and both LY379196 and CGP53353 prevented this event. Exposure of the cells to high glucose also reduced the protein level of the inhibitory subunit of nuclear factor-kappaB, IkappaBalpha, leading to its enhanced binding activity. Selective inhibition of PKCbeta abolished IkappaBalpha degradation. CONCLUSIONS: Our findings demonstrate for the first time that phosphorylation of Ser-660 represents a selective regulatory mechanism for glucose-induced upregulation of VCAM-1. Therefore, PKCbeta2-selective inhibitors may be promising drugs for treatment of endothelial dysfunction during acute hyperglycemia and possibly in diabetes.

Cells, Cultured↗
PubMed2004

Atrial natriuretic peptide gene polymorphisms and risk of ischemic stroke in humans.

BACKGROUND AND PURPOSE: A precise definition of genetic factors responsible for common forms of stroke is still lacking. The purpose of the present study was to investigate the contributory role of the genes encoding atrial natriuretic peptide (ANP) and type A natriuretic peptide receptor (NPRA) in humans' susceptibility to develop ischemic stroke. METHODS: Allele and genotype frequencies of ANP and NPRA were characterized in an Italian case-control study with patients affected by vascular disease or risk factors. Subjects were recruited from the island of Sardinia (206 cases, 236 controls). RESULTS: A significant association between the ANP/TC2238 polymorphic site and stroke occurrence was found when a recessive model of inheritance was assumed. The risk conferred by this mutant genotype, when estimated by multivariate logistic regression analysis, was 3.8 (95% confidence interval, 1.4 to 10.9). A significantly increased risk of stroke recurrence was observed among cases carrying the ANP/CC2238 genotype compared with cases carrying the ANP/TT2238 genotype (P=0.04). No direct association of NPRA with stroke occurrence was detected. However, a significant epistatic interaction between the ANP/CC2238 genotype and an allelic variant of NPRA led to a 5.5-fold increased risk of stroke (95% confidence interval, 1.5 to 19.4). CONCLUSIONS: Our findings support a direct contributory role of ANP to stroke in humans. A significant interaction between ANP and NPRA on stroke occurrence was found.

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PubMed2004

In the search for stroke genes: a long and winding road.

In spite of a significant improvement in control of numerous predisposing risk factors, stroke remains a major health problem and a common cause of death and disability in our societies. Genetic predisposition to stroke development exists and has been documented in both animal models and in humans. However, a precise definition of genetic factors responsible for common forms of stroke is still lacking, mainly due to its complex nature, the confounding presence of other predisposing risk factors, and the genetic heterogeneity of human populations. In contrast, important breakthroughs have been reached for monogenic forms of stroke, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). An animal model of stroke, the stroke-prone spontaneously hypertensive rat, has provided valuable information on genetic factors involved in stroke predisposition. Among them, the gene-encoding atrial natriuretic peptide has been identified as a stroke gene in both the stroke-prone spontaneously hypertensive rat and, subsequently, in two different human populations. In particular, structural alterations of the gene are consistently present in diseased individuals, suggesting an important role of mutation-dependent mechanisms in stroke predisposition. Finally, the recent use of intermediate disease phenotypes provides a reductionist approach that may contribute to important accumulating information on genes contributing to cerebrovascular accidents.

Animals↗
PubMed2004

Beyond hypertension toward guidelines for cardiovascular risk reduction.

BACKGROUND: Most current clinical guidelines focus primarily on the management of individual cardiovascular risk factors, such as high blood pressure (BP), hypercholesterolemia, or diabetes. A more appropriate clinical approach to reducing cardiovascular disease risk would be based on a comprehensive evaluation of risk profile, and accurate stratification of global (absolute) risk in individual patients. We propose that global risk should be used as the main determinant of whom to treat, how to treat, and how much to treat. METHODS: In this article we use a series of case studies to demonstrate the implications of replacing the traditional "single risk factor-based" approach to managing hypertension by one based on global risk assessment. In some situations patients with mildly elevated BP levels would not be recommended for antihypertensive drug treatment whereas others with lower BP would be treated, depending upon the entire risk profile. CONCLUSION: We propose to replace the single risk factor-based approach with the assessment of global cardiovascular risk, both in the clinical management of individual patients and in guidelines.

Aged↗
PubMed2004

Role of genetic factors in the etiopathogenesis of cerebrovascular accidents: from an animal model to the human disease.

1. The present work summarizes current knowledge on the genetic susceptibility to stroke, a complex cardiovascular phenotypic trait due to both gene/environment and gene/ gene interactions. 2. Evidence for the existence of genes directly contributing to stroke occurrence was first obtained in the animal model of the stroke-prone (sp) spontaneously hypertensive rat (SHR) through a linkage analysis approach in F2 segregating hybrid populations. In fact, several Quantitative Trait Loci (QTLs) were detected in different chromosomes of the rat. Candidate genes were identified (ANP, BNP, Adrenomedullin) and subsequently analyzed to obtain information on the fine disease mechanisms possibly dependent from specific sequence mutations. 3. The most important achievement was represented by the fact that the gene encoding ANP appeared to play a role in the disease of both rats and humans, thus providing a suggestive parallelism between the animal model and the human cerebrovascular disease. A more extensive analysis is required to identify the potential pathogenic role of genetic factors involved in human stroke.

Animals↗
PubMed2004

Gene polymorphisms of the renin-angiotensin-aldosterone system and the risk of ischemic stroke: a role of the A1166C/AT1 gene variant.

OBJECTIVE: The role of the renin-angiotensin-aldosterone system (RAAS) genes on predisposition to develop stroke, a multifactorial and polygenic cardiovascular trait, is still under investigation. In the present study we characterized the contributory role of RAAS genes in the susceptibility to develop ischemic stroke in humans. METHODS: Allele and genotype frequencies of RAAS genes were characterized in a population of 215 cases (including only atherothrombotic and lacunar forms) and 236 controls selected in Sardinia, a large Mediterranean island with a well-known segregated population. Statistical analysis was performed in the whole population and, based on a significant interaction between angiotensin II receptor (AT1) genotype and hypertension, was also repeated in the hypertensive subgroup. RESULTS: A significant association of the C1166/AT1 gene allelic variant with stroke was found when assuming a dominant model of transmission [unadjusted odds ratio (OR)=1.5, 95% confidence interval (CI) 1.1-2.2, P=0.024]. The strength of the association became more evident in the subgroup of hypertensive individuals (135 cases and 110 controls). In fact, in this cohort the independent OR for the AT1 gene was 2.1, 95% CI 1.2-3.7, P=0.006 in the dominant model and 2.0, 95% CI 1.3-3.2, P=0.002 in the additive model. No other RAAS gene was identified as a contributor to stroke. CONCLUSIONS: Our findings support a predisposing role of an AT1 gene variant in the development of ischemic stroke. In particular, the AT1 gene variant exerted a major impact on ischemic stroke occurrence in the presence of hypertension.

Aged↗
PubMed2004

Treatment priorities and current prescribing patterns in hypertension: results of GRASP, an international physician survey.

The GRASP (Global Research on Attitudes about hypertension and Stroke Prevention) survey, conducted in 11 countries and involving 825 physicians, was designed to investigate physician perceptions and priorities in the treatment of hypertension and influences on choice of antihypertensive therapy. The prevention of stroke was identified as a major priority in this survey, but there appeared to be some degree of mismatch between the evidence from large controlled trials and current patterns of prescribing for stroke prevention. The results of GRASP confirm the desirability of research to identify methods and strategies that will facilitate the integration of clinical trial results into general practice treatment of hypertension.

Antihypertensive Agents↗