Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial.

Although the role of homocysteine (HCys) in secondary cardiovascular prevention has been scaled down, hyper-homocysteinemia remains a risk factor for cerebrovascular events. The aim of this study was to investigate the efficacy of nutraceuticals in lowering HCys serum levels versus a conventional vitamin supplementation in hypertensive subjects at low cardiovascular risk. One-hundred and four patients (mean age 62.8±14.5 years, 63.5% males), 52 for each treatment group, were enrolled. The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 µmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 µg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 µg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis400®) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 µmol/L for Normocis400® subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 µmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis400® (p less than 0.035). The ideal HCys level (i.e. less than 10 µmol/L) was reached in 55.8% of cases in theNormocis400® group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis400® appears to be safe, well tolerated and effective in reducing HCys levels.

Effects of the Antihypertensive Fixed-Dose Combinations on an Early Marker of Hypertensive Cardiac Damage in Subjects at Low Cardiovascular Risk.

BACKGROUND: In hypertensive subjects (HTs), isolated left ventricular diastolic dysfunction (LVDD) is an early marker of cardiac damage and is associated with poor prognosis. However, few intervention trials investigated the effects of antihypertensive therapy on isolated LVDD regression. This study investigates the blood pressure (BP)-lowering efficacy and the effect on LVDD of antihypertensive drugs administered as fixed-dose combinations in untreated HTs with isolated LVDD. METHODS: A total of 168 HTs (23% of them having impaired fasting glucose (IFG)) aged 48±4.2 years were randomized to receive open-label once-daily oral treatment of beta-blocker + diuretic, angiotensin-converting enzyme inhibitor (ACEI) + diuretic, angiotensin II receptor blocker (ARB) + diuretic, ARB + calcium channel blocker (CCB), or ACEI + CCB. Clinic and 24-hour ambulatory BP values were measured before randomization and at the follow-up. Regression of LVDD was defined as normalization of both the E/A (ratio of early-to-late ventricular filling wave velocity) and E/E' (mitral velocity to early diastolic velocity of the mitral annulus) ratios. Comparisons were made between categorical variables using the χ(2) test and between continuous variables by gender using analysis of variance for repeated measures. RESULTS: BP reduction did not differ between groups. LVDD regression was significantly more prevalent in the ARB + CCB or ACEI + CCB groups than with other combinations; in HTs with IFG, it was most prevalent (46%) with ACEI + CCB. CONCLUSIONS: Independently of BP reduction, the fixed-dose combinations ARB + CCB and ACEI + CCB led to regression of isolated LVDD. In those with an IFG, ACEI + CCB was most effective.

Ambulatory blood pressure monitoring for risk stratification in obese and non-obese subjects from 10 populations.

Overweight clusters with high blood pressure (BP), but the independent contribution of both risk factors remains insufficiently documented. In a prospective population study involving 8467 participants (mean age 54.6 years; 47.0% women) randomly recruited from 10 populations, we studied the contribution of body mass index (BMI) to risk over and beyond BP, taking advantage of the superiority of ambulatory over conventional BP. Over 10.6 years (median), 1271 participants (15.0%) died and 1092 (12.9%), 637 (7.5%) and 443 (5.2%) experienced a fatal or nonfatal cardiovascular, cardiac or cerebrovascular event. Adjusted for sex and age, low BMI (<20.7 kg m(-2)) predicted death (hazard ratio (HR) vs average risk, 1.52; P<0.0001) and high BMI (> or = 30.9 kg m(-2)) predicted the cardiovascular end point (HR, 1.27; P=0.006). With adjustments including 24-h systolic BP, these HRs were 1.50 (P<0.001) and 0.98 (P=0.91), respectively. Across quartiles of the BMI distribution, 24-h and nighttime systolic BP predicted every end point (1.13 < or = standardized HR < or = 1.67; 0.046 < or = P<0.0001). The interaction between systolic BP and BMI was nonsignificant (P > or = .22). Excluding smokers removed the contribution of BMI categories to the prediction of mortality. In conclusion, BMI only adds to BP in risk stratification for mortality but not for cardiovascular outcomes. Smoking probably explains the association between increased mortality and low BMI.

Hypnosis as sole anaesthesia for skin tumour removal in a patient with multiple chemical sensitivity.

A female patient with multiple chemical sensitivity and previous anaphylactoid reactions to local anaesthetics was admitted for removal of a thigh skin tumour under hypnosis as sole anaesthesia. The hypnotic protocol included hypnotic focused analgesia and a pre-operative pain threshold test. After inducing hypnosis, a wide excision was performed, preserving the deep fascia, and the tumour was removed; the patient's heart rate and blood pressure did not increase during the procedure. When the patient was de-hypnotised, she reported no pain and was discharged immediately. Our case confirms the efficacy of hypnosis and demonstrates that it may be valuable as a sole anaesthetic method in selected cases. Hypnosis can prevent pain perception and surgical stress as a whole, comparing well with anaesthetic drugs.

Gestational diastolic hypertension with gene mutation-related pheochromocytoma positive at 18F-DOPA PET/CT: Diagnostic and therapeutic implications / Hipertensión diastólica gestacional con feocromocitoma relacionado a mutación genética y PET/TC con 18F-DOPA positiva: implicaciones diagnósticas y terapéuticas

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Obesity is a strong determinant of hypertensive target organ damage in young-to-middle-age patients.

OBJECTIVE: To examine the impact of overweight and obesity on development of target organ damage in the early stage of hypertension. SUBJECTS: Participants were 727 young-to-middle-age subjects screened for stage 1 hypertension and followed for 8 years. MEASUREMENTS: Ambulatory blood pressure (BP), albumin excretion rate and echocardiographic data were obtained at entry, every 5 years and/or before starting antihypertensive treatment. RESULTS: During the follow-up, hypertension needing treatment was developed by 54.7% of the subjects with normal weight, 66.6% of those with overweight and 73.0% of those with obesity (P<0.001). Kaplan-Meier curves showed that patients with obesity or overweight progressed to sustained hypertension earlier than those with normal weight (P<0.001). At study end, rate of organ damage was 10.7% in the normal weight, 16.4% in the overweight and 30.1% in the obese subjects (P<0.001). In a multivariable logistic regression analysis, overweight (P=0.008) and obesity (P<0.001) were significant predictors of final organ damage. Inclusion of changes in 24-h BP and body mass index, and of baseline organ damage did not virtually modify these associations (P=0.002 and <0.001, respectively). Obesity was a significant predictor of both left ventricular hypertrophy (P<0.001) and microalbuminuria (P=0.015) with an odds ratio (95% confidence interval) of 8.5 (2.7-26.8) and 3.5 (1.3-9.6), respectively. CONCLUSION: These data indicate that in hypertensive subjects obesity has deleterious effects on the cardiovascular system already at an early age. Preventive strategies addressed to achieve weight reduction should be implemented at a very early stage in young people with excess adiposity and high BP.

Phosducin rs12402521 polymorphism predicts development of hypertension in young subjects with overweight or obesity.

BACKGROUND AND AIMS: The G-protein regulator phosducin has been shown to be associated with stress-dependent blood pressure, but whether obesity is a modulator of the relationship between phosducin and risk of hypertension is unknown. We studied the effect of two phosducin polymorphisms on risk of hypertension in 273 overweight or obese (Ov-Ob) young-to-middle-age participants from the HARVEST and 287 normal weight (NW) participants. METHODS AND RESULTS: Genotyping of phosducin SNPs rs12402521 and rs6672836 was performed by real time PCR. For rs12402521, 64.6% of the participants were homozygous for the G allele, 27.9% heterozygous, and 7.5% homozygous for the A allele. During 7.7 years of follow-up, 339 subjects developed hypertension. In a Cox multivariable model, carriers of the A allele had a 1.28 (95% CI,1.00-1.63, p = 0.046) increased risk of hypertension. However, increased incidence of hypertension associated with A allele (AA + AG, 79% and GG, 59%, p = 0.001) was observed only among Ov-Ob individuals with a hazard ratio of 1.60 (95% CI, 1.13-2.21, p = 0.007) whereas in NW subjects the incidence of hypertension did not differ by genotype (56% in both groups). In the whole cohort, there was a significant interaction of phosducin genotype with body mass index on the risk of hypertension (p = 0.012). For SNP rs6672836 no association was found with incident hypertension. No haplotype effect was detected on the risk of hypertension. CONCLUSION: These data suggest that phosducin rs12402521 polymorphism is an important genetic predictor of obesity-related hypertension. In Ov-Ob carriers of the A allele aggressive nonpharmacological measures should be implemented.

In high risk hypertensive subjects with incidental and unilateral renal artery stenosis percutaneous revascularization with stent improves blood pressure control but not glomerular filtration rate.

AIM: In high-risk hypertensive subjects (HTs) with incidental unilateral renal artery stenosis (RAS), the effectiveness of percutaneous revascularization with stent (PR-STENT) on blood pressure (BP) and glomerular filtration rate (GFR) is not established. METHODS: Eighteen HTs aged 65.7 ± 9.2 years with angiographically diagnosed unilateral RAS (≥ 60%) were randomized to receive PR-STENT (N=9) or to NO-STENT (N=9). BP (mercury sphygmomanometer) and GFR (99mTc-DTPA clearances during renal scintigraphy) were evaluated yearly for three years. Echo-Doppler of renal arteries was performed to verify the anatomic patency and flow velocities of the reperfused artery. Analysis of variance compared BP and GFR values changes from baseline to the follow-up; differences for continuous variables were evaluated between groups with the Tukey's post hoc test after adjustment for age, change of BP between baseline and at the follow-up, GFR and body mass index (BMI). RESULTS: Baseline systolic BP and GFR values were not different between groups. The significantly greater GFR increase observed in PR-STENT than in NO-STENT at univariate analysis at the end of follow-up (62.5 ± 19.2 vs. 42.24 ± 17.6, P<0.02) disappeared after adjustment for confounding factors. However, systolic BP remained significantly lower in PR-STENT than in NO-STENT (140.1 ± 4.6 vs. 170.0 ± 8.3, P<0.0001) also after adjustment for age, GFR and BMI. CONCLUSION: PR-STENT reduces systolic BP without improving GFR. Due to the strong association between high BP and renal damage, this study raises the question on whether PR-STENT should be performed in all HTs with unilateral and incidental RAS.

Glycaemic fall after a glucose load. A population-based study.

BACKGROUND AND AIMS: A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level. METHODS AND RESULTS: In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and ß-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BG < fasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and ß-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p<0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1). CONCLUSION: It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and ß-cell function are better, some risk factors are less prevalent, and coronary mortality is lower.

Isolated atrial fibrillation (IAF) after local anaesthesia with epinephrine in an anxious dental patient.

Cardiac arrhythmias are not uncommon in dental practice, depending on many factors, including patient features, dental treatment and drugs administered. We describe a case of isolated atrial fibrillation (IAF) developed, in a young patient, soon after a supraperiosteal injection. The patient was admitted to hospital and recovered spontaneously. Since stress is a possible cause of IAF, this may has been triggered by endogenous and/or exogenous epinephrine. We highlight the need for careful preoperative evaluation, including anxiety assessment and treatment in all dental patients.

Endocrine arterial hypertension: therapeutic approach in clinical practice.

This review describes the therapeutic approach of endocrine arterial hypertension in clinical practice. In mineralocorticoid-related hypertension, adrenalectomy is the treatment of choice for aldosterone-producing adenomas and monolateral primary aldosteronism, whereas pharmacologic blood pressure (BP) control is indicated for the other forms of primary aldosteronism such as bilateral adrenal hyperplasia. Spironolactone is the drug of choice, but intolerable side effects limit its use; amiloride or eplerenone are a valid alternative. If BP remains uncontrolled, angiotensin converting enzyme inhibitors (ACE-I), angiotensin II receptor antagonists (AII-RA) and calcium channel blockers (CCB) may be added. Hypertension accompanying Cushing's syndrome can be approached with surgery, but antihypertensive treatment both pre- and postoperative is required as well. Eplerenone, AII-RA and ACE-I are indicated, while peroxisome proliferator activated receptor upsilon agonists may help for the insulin resistance syndrome. Drugs that suppress steroidogenesis should be used with care because of their serious side effects. Subjects with catecholamine-dependent hypertension due to a neuroendocrine neoplasm need to undergo preoperative alpha-adrenergic blockade with phenoxybenzamine or doxazozine. When adequate alpha-adrenergic blockade is achieved, beta-adrenergic blockade with low dose propranolol may be added. If target BP is not achieved, CCB and/or metyrosine are indicated. Laparoscopic adrenalectomy is the procedure of choice for solitary intra-adrenal neoplasms <8 cm. Acute hypertensive crises that may occur before or during surgery should be treated intravenously with sodium nitroprusside, phentolamine, nicardipine or labetalol. For malignant neoplasms, chemo- and radiopharmaceutical therapy may be considered.

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

Serum uric acid shows a J-shaped trend with coronary mortality in non-insulin-dependent diabetic elderly people. The CArdiovascular STudy in the ELderly (CASTEL).

The relationship between serum uric acid (SUA) and risk of coronary heart disease (CHD) mortality remains controversial, particularly in diabetic subjects. The aim of the present study is to evaluate whether SUA independently predicts CHD mortality in non-insulin-dependent elderly people from the general population and to investigate the interactions between SUA and other risk factors. Five hundred and eighty-one subjects aged >/=65 years with non-insulin-dependent diabetes mellitus were prospectively studied in the frame of the CArdiovascular STudy in the ELderly (CASTEL). Historical and clinical data, blood tests and 12-year fatal events were recorded. SUA as a continuous item was divided into tertiles and, for each tertile, adjusted relative risk (RR) with 95% confidence intervals (CI) was derived from multivariate Cox analysis. CHD mortality was predicted by SUA in a J-shaped manner. Mortality rate was 7.9% (RR 1.28, CI 1.05-1.72), 6.0% (reference tertile) and 12.1% (RR 1.76, CI 1.18-2.27) in the increasing tertiles of SUA, respectively, without any difference between genders. In diabetic elderly subjects, SUA independently predicts the risk of CHD mortality in a J-shaped manner.

Pulse hypertension: a new component of the metabolic syndrome in elderly women?

The classification of arterial hypertension (HT) to define metabolic syndrome (MS) is unclear in that different cutoffs of blood pressure (BP) have been proposed. We evaluated the categorization of HT most qualified to define MS in relationship with coronary heart disease (CHD) mortality at a population level. A total of 3257 subjects aged > or =65 years were followed up for 12 years. MS was defined according to the criteria of the National Education Cholesterol Program using three different categories of HT: MS-1 (systolic blood pressure (SBP) > or =130 and diastolic blood pressure (DBP) > or =85 mm Hg), MS-2 (SBP > or =130 or DBP > or =85 mm Hg) and MS-3 (pulse pressure (PP) > or =75 mm Hg in men and > or =80 mm Hg in women). Gender-specific adjusted hazard ratio (HR) with 95% confidence intervals (CI) for CHD mortality was derived from Cox analysis in the three MS groups, both including and excluding antihypertensive treatment. In women with MS untreated for HT, the risk of CHD mortality was always significantly higher than in those without MS, independent of categorization; the HR of MS was 1.73 (CI 1.12-2.67) using MS-1, 1.75 (CI 1.10-2.83) using MS-2 and 2.39 (CI 3.71-1.31) using MS-3. In women with MS treated for HT, the HR of CHD mortality was significantly increased only in the MS-3 group (1.92, CI 1.1-2.88). MS did not predict CHD in men. In conclusion, MS can predict CHD mortality in elderly women with untreated HT but not in those with treated HT; in the latter, PP is the most predictive BP value.

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis.

BACKGROUND: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. METHODS: To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. RESULTS: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4). CONCLUSIONS: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.

Triglycerides + high-density-lipoprotein-cholesterol dyslipidaemia, a coronary risk factor in elderly women: the CArdiovascular STudy in the ELderly.

BACKGROUND: The relationship between serum triglycerides (TG) level and the risk of coronary heart disease (CHD) mortality remains controversial. AIMS: To evaluate whether TG level is a risk factor for CHD in elderly people from general population, and to look for interactions between TG and other risk factors. METHODS: 3257 subjects aged >or= 65 years followed up for 12 years from the CArdiovascular STudy in the ELderly. Blood tests and anthropometric measurements were performed. Continuous items were divided into quintiles and, for each quintile, adjusted hazard ratio (HR) with 95% confidence interval (CI) for CHD mortality was derived by genders from Cox analysis. RESULTS: In women, the HR of being in the fifth rather than in the first quintile of TG was 2.45 (CI 1.48-3.51). In turn, high-density-lipoprotein cholesterol (HDL-C) inversely predicted CHD mortality; the HR of being in the first rather than in the fifth quintiles of HDL-C was 1.52 (CI 1.24-2.36). The risk of CHD mortality further increased up to 3.81 (CI 1.62-5.43) when high TG and low HDL-C were combined. No predictive role for either TG or HDL-C was detected in men. CONCLUSIONS: TG and HDL-C were independent predictors of CHD mortality in elderly women. The combination high TG + low HDL-C quadrupled the risk of CHD mortality in this gender only.