Biomedical subjects
Publications and source records attributed to Massimo Volpe.
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The role of angiotensin type 2 receptor (AT(2)R) on vascular responses to angiotensin II in humans remains unclear. In this study we explored whether AT(2)R is expressed and functionally active on peripheral resistance arteries of hypertensive diabetic patients treated for 1 year with either the angiotensin receptor blocker valsartan or the beta-blocker atenolol. Twenty-six hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving angiotensin receptor blockers or beta-blockers) were randomly assigned to double-blind treatment for 1 year with valsartan or atenolol once daily added to their previous therapy in a clinical trial that we reported recently and compared with 10 normal subjects. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. Vasomotor response curves to angiotensin II (1 nmol/L to 1 micromol/L) were performed on norepinephrine precontracted vessels in the presence of valsartan (10 micromol/L) with or without the AT(2)R inhibitor PD123319 (1 micromol/L). AT(2)R expression was evaluated by confocal microscopy. After 1 year of treatment, systolic and diastolic blood pressure was controlled and comparable in the valsartan and atenolol groups. Angiotensin II evoked a significant vasodilatory response only on resistance arteries from patients treated with valsartan, effect blocked by PD123319. AT(2)R expression was 4-fold higher in small arteries of valsartan-treated patients. In conclusion, AT(2)Rs are upregulated and contribute to angiotensin II-induced vasodilation in resistance arteries of hypertensive diabetic patients treated with angiotensin type 1 receptor blockers and may mediate, in part, vascular actions of these drugs in high cardiovascular risk patients.
BACKGROUND: Cardiac resynchronization therapy (CRT) has been introduced to treat drug refractory chronic heart failure (CHF). Apelin, the endogenous ligand of the APJ receptor, is under evaluation for its potential role in human CHF pathophysiology. This study aims to assess whether biventricular pacing affects plasma apelin levels in patients with severe CHF. METHODS AND RESULTS: Fourteen patients (9 men, 5 women, mean age 68+/-13 years) undergoing biventricular pace-maker/ICD implantation were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma apelin and NT-proBNP levels. The evaluation was repeated 48 h and 9+/-2 months after device implantation to assess the acute and chronic effects of CRT on apelin and NT-proBNP levels. Eight healthy age- and sex-matched subjects served as controls. In CHF patients, baseline apelin levels were reduced and NT-proBNP increased compared to control subjects (apelin: 0.47+/-0.2 vs. 0.97+/-0.3 ng/mL, p<0.001; NT-proBNP: 2007+/-114 vs. 229+/-72 pmol/L, p<0.001). Short-term evaluation did not reveal any effect of CRT on apelin or NT-proBNP levels. By contrast, at 9+/-2 months follow-up, CRT responders showed left ventricular reverse remodelling and an increase in ejection fraction, together with a significant increase in plasma apelin levels (0.99+/-0.1 vs. 0.47+/-0.2 ng/mL, p<0.001) and decrease in NT-proBNP (938+/-591 vs. 2007+/-114 pmol/L, p<0.05). CONCLUSIONS: Long-term CRT increases plasma levels of the endogenous inotrope apelin in patients with CHF.
OBJECTIVES: The goal of our study was to investigate the relationships between atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and type A natriuretic peptide receptor (NPRA) gene polymorphisms and left ventricular structure in human essential hypertension. BACKGROUND: Experimental evidence supports a key role for natriuretic peptides in the modulation of cardiac mass. This relationship has not yet been described in human disease. METHODS: A total of 203 hypertensive patients were studied by mono-bidimensional echocardiography. Three markers of the ANP gene (-C664G, G1837A, and T2238C polymorphisms) and a microsatellite marker of both NPRA and BNP genes were characterized. RESULTS: Patients carrying the ANP gene promoter allelic variant had increased left ventricular mass index (117.4 +/- 1.7 g vs. 95.7 +/- 1.7 g, p = 0.005), left ventricular posterior wall thickness (1.14 +/- 0.07 cm vs. 0.96 +/- 0.01 cm, p < 0.0001), left ventricular septal thickness (1.12 +/- 0.10 cm vs. 1.04 +/- 0.01 cm, p = 0.01), and relative wall thickening (47.5 +/- 4.1% vs. 39.4 +/- 5.3%, p = 0.001) as compared with the wild-type genotype. These associations were independent from anthropometric factors and major clinical features and were confirmed in a large subgroup of never-treated hypertensive patients (n = 148). Carrier status of the ANP gene promoter allelic variant was associated with significantly lower plasma proANP levels: 1,395 +/- 104 fmol/ml versus 3,110 +/- 141 fmol/ml in hypertensive patients carrying the wild-type genotype (p < 0.05). A significant association for NPRA gene variants with left ventricular mass index and left ventricular septal thickness was found. The analysis of BNP did not reveal any effect on cardiac phenotypes. CONCLUSIONS: Our findings show that the ANP/NPRA system significantly contributes to ventricular remodeling in human essential hypertension.
We previously identified a quantitative trait locus (QTL) for stroke proneness between the kallikrein (Klk) and Mt1pa markers on rat chromosome 1. To gain functional insights, we constructed congenic strains by introgressing either the whole or selected chromosomal segments from the stroke-prone (SHRsp) onto the stroke-resistant (SHRsr) spontaneously hypertensive rat genome and vice versa. The phenotype was the latency to develop stroke under a Japanese high-salt, low-potassium diet for 3 mo [known as Japanese diet (JD)]. Blood pressure (BP) was measured by tail cuff throughout the experiment. Urinary protein excretion was monitored in all lines under JD. The SHRsp-derived lines carrying the SHRsr allele, and particularly the D1Rat134-Mt1pa chromosomal segment, had a significant delay of stroke occurrence and improved survival compared with SHRsp (P < 0.001). On the other hand, a significant occurrence of stroke events (20%) was detected in the reciprocal lines by the end of the 3-mo treatment with JD (P = 0.003). The stroke phenotype was also associated with increased proteinuria. Our results underscore the functional importance of the Chr 1 stroke QTL. Furthermore, they underscore the utility of stroke/congenic lines in dissecting the genetics of stroke.
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BACKGROUND: A genetic origin of cerebrovascular accidents has long been suspected on the basis of epidemiologic evidence and familial aggregation. Nevertheless, the final phenotype is largely influenced by concomitant risk factors. We aimed to investigate whether impairment of endothelium-dependent vasodilation can be used as an informative intermediate vascular phenotype in hypertensive patients with familial history of stroke. METHODS: Fourteen hypertensive individuals, seven with familial history of stroke (FH+), seven without familial history of stroke (FH-), and six normotensive volunteers (C) were included in the study. High-resolution ultrasound and Doppler were used to measure radial artery diameter and blood flow at rest, during reactive hyperemia, and after intra-arterial infusion of N(G)-monomethyl-l-arginine (L-NMMA) to inhibit NO synthase. RESULTS: Basal blood flow and diameter were comparable in all groups. Flow-mediated dilation was impaired in FH+ (3.2% +/- 2%), compared with FH- (9.6% +/- 1%; P = . 01) and C (15.9% +/- 3%; P = . 001). The L-NMMA decreased basal flow in FH- (16.0 +/- 2 v 13.8 +/- 1 mL/min; P = . 04), and C (23.3 +/- 2 v 16.5 +/- 2 mL/min, P = .003) but did not exert any significant effect in FH+ subjects (16.4 +/- 3 v 15.8 +/- 2 mL/min, P = .77). CONCLUSIONS: These findings demonstrate that NO bioavailability is reduced in hypertensive subjects with familial history of stroke. Such a phenotype may represent an early marker of susceptibility to cerebrovascular events in this population.
PURPOSE OF REVIEW: Stroke represents the most devastating cardiovascular disease in the Western world, accounting for approximately 700,000 cases each year, including 500,000 first attacks and 200,000 recurrent episodes. High blood pressure is the most relevant modifiable risk factor for developing stroke. RECENT FINDINGS: In hypertensive patients, especially those with additional cardiovascular risk factors or clinical settings such as diabetes, target organ damage or associated clinical conditions, even small decreases in blood pressure levels are associated with large reductions in the incidence of cerebrovascular events. The benefits of blood pressure reductions, however, are not strictly proportional to stroke incidence, and it has been recently postulated that the different classes of antihypertensive drugs may have specific properties for organ protection and cerebrovascular accident prevention. SUMMARY: In particular, the hypothesis of a higher cerebrovascular protection provided by newer antihypertensive agents with respect to the conventional antihypertensive therapy is an attractive perspective that deserves further investigation.
BACKGROUND: Hypertension is the most common treatable risk factor for stroke. Efforts have been made to raise the awareness of both hypertension and stroke. There is a lack of clear understanding of the current state of knowledge, attitudes, and perceptions about hypertension and stroke among patients, the public, and physicians. OBJECTIVES: To understand the level of knowledge, attitudes, and perceptions regarding hypertension and stroke among patients, the public, and physicians and to highlight the practices of physicians in managing hypertension given current hypertension guideline recommendations. METHODS: Current Contents, Embase, and Medline databases were searched to identify manuscripts published between January 1994 and December 2004 reporting surveys concerning the knowledge and perceptions of patients, the public, and physicians regarding hypertension and stroke. Studies were summarized and collated into a spreadsheet. RESULTS: Of a total of 85 manuscripts identified, only 43 contained information meeting the study objectives. Based on the reported results, it was observed that patients and public alike are generally aware that hypertension is one of the risk factors of stroke, and that stroke could be a consequence of hypertension, but do not consider hypertension to be a serious health concern. Physicians appreciate the importance of managing hypertension to avoid future complications such as stroke. However, they do not conform to the recommendations made in various hypertension guidelines. They have higher thresholds than guideline recommendations for defining and categorizing hypertension, for starting antihypertensive therapy, and for target blood pressure goals. They do not aggressively manage hypertension in older people, considering that the elderly are at greater risk for developing stroke. CONCLUSIONS: Patients and public are aware of the link between hypertension and stroke but do not appreciate the consequences of uncontrolled hypertension. Physicians worldwide need to engage in patient communication regarding hypertension, stroke, and the dangers of uncontrolled hypertension, and need to implement guideline recommendations for hypertension diagnosis and management.
In recent years, medical practice has been influenced substantially by several factors, including the overwhelming development of evidence-based medicine, which is a consequence of the impressive, growing number of large clinical trials, the so-called "mega-trials." These clinical studies are designed mostly to investigate the effects of drugs or treatments on hard end points that cannot be tested by individual physicians in their daily clinical practice. The growing role of this epidemiologic approach to medicine, which is based mostly on the assessment of the average response or behavior of large populations rather than of individuals, is systematically replacing the former knowledge and reference points of the physician, as a substitute rather than as an aid. Taking into account the case of hypertension and particularly the renin-angiotensin system-blocking agents, this article reviews the issues and limitations of transferring evidence from mega-trials to clinical practice and suggests new strategies to make trials more effective and transferable to the case of individual patients.
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OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.
The clinical history of patients with heart failure (HF) is complicated by arterial thromboembolism. Platelet activation is reported in this population, but the underlying mechanism has not been clarified. Forty-two patients with HF scored according to New York Heart Association (NYHA) classification had higher levels of collagen-induced platelet aggregation, platelet tumor necrosis factor-alpha (TNF-alpha) receptor expression, and serum thromboxane B2 and higher circulating levels of TNF-alpha than 20 healthy subjects. Coincubation of platelets from HF patients with an inhibitor of TNF-alpha receptors significantly reduced collagen-induced platelet aggregation. In vitro study demonstrated that TNF-alpha amplified the platelet response to collagen; this effect was inhibited by TNF-alpha receptor antagonist and inhibitors of arachidonic acid metabolism. This study showed that TNF-alpha behaves as a trigger of platelet activation through stimulation of the arachidonic acid pathway.
Effective treatment of high blood pressure levels represents a crucial point in reducing global cardiovascular risk, and several studies have clearly demonstrated a significant reduction in cardiovascular and renal morbidity and mortality with a more intensive blood pressure-lowering treatment. Other factors beyond blood pressure control may be important in reducing the risk related to hypertension. Pharmacologic agents blocking the renin-angiotensin system, in particular the angiotensin II-receptor blocker (ARB), a novel class of antihypertensive agents, represent an important addition to the therapeutic options for hypertension management, and recent large, international, randomized, trials have demonstrated that ARBs have clinical benefits across the spectrum of disease severity. In this article, we provide some evidence derived from these trials, supporting a role for ARBs in primary and secondary prevention of cardiovascular and renal disease, beyond blood pressure control.
Endothelial dysfunction, the complex, multifaceted, pathologic product of various vasculotoxic agents or injuries, is an intermediate attractant phenotype of cardiovascular diseases that usually has a long and unpredictable natural history. Furthermore, endothelial dysfunction may not only represent a vascular disease marker, but actually may play an important pathogenetic role that leads to the progression of the disease and the unfavorable outcomes. Among these vascular diseases, cerebrovascular accidents, particularly stroke, clearly represent a paradigmatic example of the potential role of dysfunctional endothelium. Elevated blood pressure has long been recognized as one of the most important risk factors for stroke; other factors, however, seem to play an important role. Indeed, epidemiologic evidence suggests that, in spite of an improved control of blood pressure, the secular trends of stroke in well-controlled populations are increasing. In this brief review, we analyze current evidence suggesting that endothelial dysfunction can play a role in the pathogenesis of ischemic stroke.
BACKGROUND: Vasoconstrictive, proliferative and oxidative effects of angiotensin II (Ang II) are mediated by Ang II type 1 (AT1) receptors. The effects of Ang II via the Ang II type 2 (AT2) receptor subtype (AT2R) are less well defined. Growing evidence shows the existence of cross-talk between the Ang II receptor subtypes, which is revealed by AT1R blockade. Hence, under certain conditions, AT2R may act as an antagonistic system with respect to the AT1R. METHODS: The present study was designed to investigate the effects of long-term treatment with the AT1R antagonist losartan on the AT2R-mediated response to Ang II in thoracic aortas isolated from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Untreated animals from both groups were used as controls. The mRNA expression of AT1R and AT2R was measured by reverse transcription-polymerase chain reaction. RESULTS: During contraction in response to norepinephrine, Ang II induced concentration-dependent relaxation only in aortas isolated from SHR chronically treated with losartan (8 weeks; 30 mg/kg/day in drinking water). These relaxations were inhibited by the selective AT2R blocker PD123319, N(G)-nitro-L-arginine methyl ester (L-NAME), and B2receptor antagonist HOE-140. Accordingly, nitric oxide (NO) production was increased by Ang II only in the aortas of treated SHR. After AT1R blockade, AT2R mRNA was significantly increased. These findings demonstrate that, in hypertensive rats, chronic AT1R blockade is associated with an inverted vasomotor response to Ang II via AT2R-mediated NO production. CONCLUSIONS: The losartan-unmasked AT2R-vasorelaxation could significantly contribute to the beneficial hemodynamic effects of AT1R blockade. In view of this, our study highlights the importance of the integrated Ang II receptor network, which may help to define further the mechanisms of the well-established vascular protective effects of AT1R blockers.
In the prevention and treatment of cardiovascular disease, pharmacological treatment strategies should have several aims: (i) in individuals without overt cardiovascular disease, but with risk factors such as hypertension and/or diabetes, pharmacotherapy should prevent or delay disease development; (ii) in patients who have already progressed to cardiovascular disease, pharmacotherapy should help either to prevent or regress target organ damage (TOD); and (iii) in patients with TOD, pharmacotherapy should prevent events. Any medication intended for long-term therapy also should be well tolerated. Inhibiting the renin-angiotensin system has proven a successful therapeutic strategy in cardiovascular and renal medicine. Angiotensin-converting enzyme (ACE) inhibitors have demonstrated important advantages over conventional agents such as beta-blockers and thiazide diuretics, and have become a relevant part of treatment for heart failure post-myocardial infarction, left ventricular dysfunction and renal disease. Tolerability concerns may prevent their use in some patients, however. Angiotensin AT1 receptor blockers (ARBs) provide a different form of blockade of the renin-angiotensin system and a growing body of evidence suggests that this alternative approach may confer additional cardiovascular protection for some patient subgroups. In addition, ARBs generally are better tolerated than ACE inhibitors, enhancing patient compliance and persistence with long-term therapy. Furthermore, evidence in favour of combining an ACE inhibitor and an ARB in certain circumstances is continuously growing.
BACKGROUND: Loss of cognitive function is a common condition in the elderly population. Cognitive impairment is defined as the transitional stage of cognitive decline, between normal aging and early dementia. We tested whether arterial stiffness, evaluated as pulse wave velocity (PWV), is associated with cognitive impairment in older subjects, and whether PWV is increased at a comparable extent in older subjects with cortical or subcortical cerebral lesions when compared with age-matched controls referred for memory deficits. SUBJECTS AND METHODS: Eighty-four subjects (78 +/- 5 years, 30 men and 54 women) referred for memory deficit with no history of stroke or atrial fibrillation were studied. Carotid-femoral PWV was determined non-invasively with Complior. The Mini Mental State Examination was assessed as a measure of global cognitive function. The sum of the score on the Activities of Daily Living and Instrumental Activities of Daily Living scales was used as a measure of personal independency. Based upon brain imaging, subjects were classified as referred for memory deficits with normal brain imaging, or control, with subcortical microvascular lesions or with cortical atrophy. RESULTS: PWV, normalized for mean blood pressure, was inversely correlated with the Mini Mental State Examination (r = -0.26, P < 0.05), even after controlling for education, prevalent cardiovascular (CV) disease, CV risk factors, and medication use (beta coefficient = -0.28, P < 0.01). PWV was also inversely correlated with personal independency (r = -0.36, P < 0.01; beta coefficient = -0.38, P < 0.01, after multiple adjustment). In the presence of no significant differences in age, education, traditional CV risk factor levels, carotid plaques, or prevalence of CV disease, higher PWV values were more frequent in subjects with cortical atrophy than in patients with subcortical microvascular lesions or controls (P < 0.05). CONCLUSIONS: PWV was associated with cognitive impairment and with a greater personal dependency, independently of major modifiable CV risk factors.