Anna Maria Grandi

JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.

Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects.

Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.

Aldosterone Antagonist Improves Diastolic Function in Essential Hypertension

Abstract—Experimental studies demonstrated that mineralocorticoid antagonists prevent or reverse myocardial fibrosis. Therefore, we tested the hypothesis that the aldosterone antagonist canrenone can improve left ventricular diastolic function in essential hypertension. Using digitized M-mode echocardiography and 24-hour blood pressure monitoring (ABPM), we realized a prospective, randomized, controlled study on 34 never-treated essential hypertensives with left ventricular diastolic dysfunction. Echocardiogram and ABPM were repeated after 6 months of effective antihypertensive treatment with ACE inhibitors and calcium antagonists (second evaluation) and then after a 6-month period with 17 patients randomly assigned to add canrenone 50 mg/d to the previous treatment (third evaluation). At the basal evaluation 32 patients had left ventricular concentric hypertrophy, and 2 patients had left ventricular concentric remodeling. All the patients had normal left ventricular systolic function. At the second evaluation blood pressure was reduced (P <0.0001), left ventricular mass index decreased (P <0.0001), and diastolic function improved (P <0.0001). After randomization, the canrenone and control groups had similar 24-hour blood pressure and left ventricular morpho-functional characteristics. At the third evaluation, despite unchanged blood pressure and similar decrease of left ventricular mass index, the canrenone group, compared with control group, showed a significantly greater increase in left ventricular diastolic indices. In essential hypertension, a low dose of aldosterone antagonist added to antihypertensive treatment significantly improved left ventricular diastolic function. This improvement, not accounted for by changes in blood pressure and left ventricular mass, can be therefore ascribed to a direct action of the drug on the myocardium.

Plasma levels of matrix metalloproteinases and their inhibitors in hypertension: a systematic review and meta-analysis.

Background Hypertension is a major cause of cardiovascular remodeling. In the cardiovascular system, the remodeling of the extracellular matrix is controlled by the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs). The aim of this meta-analysis is to elucidate the behavior of plasma MMP and TIMP levels in hypertension and their relationship to cardiovascular remodeling. Methods MEDLINE and EMBASE databases were searched up to July 2011. Studies were considered eligible if they provided values of plasma MMPs and TIMPs in hypertensive patients. Given the high variability of the plasma biomarker values among studies, the standardized mean difference (SMD) was calculated. Results Ten studies provided plasma MMP-9; the SMD between 778 hypertensive patients and 669 controls was 1.95 units (P < 0.05). Thirteen studies provided plasma TIMP-1; the SMD between 851 hypertensive patients and 646 normotensive individuals was 1.92 units (P < 0.01). Three studies investigated whether plasma TIMP-1 predicted left ventricular (LV) remodeling; the SMD between 92 hypertensive patients with and 88 hypertensive patients without LV hypertrophy was 5.81 units (P < 0.05). As for diastolic heart failure (HF), five studies provided data for plasma MMP-2; the SMD between 321 hypertensive patients with and 334 hypertensive patients without HF was 2.36 units (P < 0.01). The heterogeneity among studies was high. Conclusions These results suggest that MMP-2, MMP-9 and TIMP-1 may have a role as biomarkers of cardiovascular remodeling in hypertension. If these results are confirmed in prospective clinical studies, they could provide new tools to stratify cardiovascular risk in hypertensive patients.

Twenty-Four–Hour Noninvasive Blood Pressure Monitoring and Pain Perception

Although a hypertension-related hypalgesia has been described, the relation between pain perception and the 24-hour blood pressure trend is still unknown. The ambulatory blood pressure monitoring parameters and dental pain sensitivity were correlated in 67 male subjects. The pulpar test (graded increase of test current of 0 to 0.03 mA) was performed on three healthy teeth, and mean dental pain threshold (occurrence of pulp sensation) and pain tolerance (time when the subjects asked for the test to be stopped) were evaluated. Three groups of subjects with normal (n = 34), intermediate (n = 13), and high (n = 20) blood pressure values were identified according to ambulatory monitoring results. Pain threshold differed among the three groups (P < .02), being higher in the group with highest blood pressure. The groups of hypertensive subjects showed higher pain tolerance than the normotensive group (P < .02). Pain threshold was correlated with 24-hour, diurnal, and nocturnal blood pressure values. Pain tolerance was also related to 24-hour blood pressure and to diurnal and nocturnal diastolic and mean arterial pressure values. Systolic and diastolic blood pressure loads were significantly associated with pain threshold, and diastolic load was also associated with tolerance. The blood pressure variability (SD) did not relate to pain perception. The 24-hour arterial pressure was more closely associated with pain perception than the blood pressure values obtained before the pulpar test. A close correlation between pain perception and 24-hour ambulatory blood pressure was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of enalapril on left ventricular mass and performance in essential hypertension

The effect of enalapril on left ventricular (LV) morphology and function was studied in 12 hypertensive patients. The subjects were evaluated after 2 weeks of placebo and after 4 months of treatment with enalapril (20 or 40 mg once daily), using M-mode digitized echocardiograms. The drug reduced arterial blood pressure in all patients. Systemic vascular resistance decreased significantly without changes in cardiac output and heart rate. No patient had significant side effects. After treatment LV mass decreased significantly (233 +/- 46 to 204 +/- 37 g, p less than 0.01); the reduction was due to a decrease in septal and posterior wall thickness, without changes in LV diameter. LV systolic function remained unchanged, whereas peak lengthening rate of LV dimension, an index of LV diastolic function, increased significantly (4.05 +/- 1.8 to 5.11 +/- 1.8 s-1, p less than 0.01). After treatment the basal inverse correlation between peak shortening rate and wall stress did not change, the inverse correlation between peak lengthening rate and wall stress became closer and the basal inverse correlation between peak lengthening rate and LV mass disappeared. In conclusion, antihypertensive treatment with enalapril led to a significant regression of LV hypertrophy associated with improvement in LV diastolic performance and no deterioration of LV systolic function.

Hypertension-related hypoalgesia, autonomic function and spontaneous baroreflex sensitivity

OBJECTIVE The mechanisms involved in the relationship between pain perception and hypertension are poorly understood. This study has sought to investigate whether the spontaneous baroreflex sensitivity and the autonomic nervous system balance are related to hypertension-associated hypoalgesia. METHODS In the morning, 73 untreated male subjects (45 hypertensives, 28 normotensives) were submitted to a simultaneous recording of electrocardiographic and blood pressure signals in resting condition. The tracings were analysed off-line to evaluate the spectral components of the low frequency (LF) and high frequency (HF) powers (autoregressive algorithm; LF/HF ratio used in subsequent analysis as an index of sympathovagal balance), and the alphaLF (alphaLF), an index of baroreflex sensitivity. After the rest period, the subjects underwent dental pain perception evaluation (pulpar tester: test current increasing from 0 to 0.03 mA, expressed in relative Units) to determine the dental pain threshold and tolerance. Afterwards, a 24-h ambulatory blood pressure monitoring was performed. RESULTS A significant relationship was observed between alphaLF and pain threshold (r = -0.34; p = 0.003). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, alphaLF was a predictive independent factor associated with pain threshold (model p = 0.019; r = -0.31; p = 0.025). Moreover, the 24-h systolic pressure was independently associated with pain threshold (model p = 0.019; r = 0.30, p = 0.031). The relationship between alphaLF and relative tolerance was not statistically significant. When the association between the LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant relationship was observed. Since no significant interaction was found, the effect of alphaLF and LF/HF ratio on pain perception was assumed to be similar in normotensive and hypertensive subjects. CONCLUSIONS The relationship found between unstimulated baroreflex sensitivity and pain threshold suggests a modulation of pain perception by baroreflex pathways in hypertension-associated hypoalgesia. In a baseline condition, the autonomic nervous system balance does not seem to influence pain sensitivity.

Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up

AIMS Our study investigated reactive oxygen species (ROS) generation and angiotensin II type 1 receptor (AT(1)-R) expression in primed polymorphonuclear leukocytes (PMNs) of dyslipidaemic subjects over prolonged statin treatment. METHODS AND RESULTS Sixteen untreated dyslipidaemic subjects with moderately increased cardiovascular risk (National Cholesterol Education Program, Adult Treatment Panel III) were studied before and during long-term (1 year) simvastatin treatment. Neutrophils from dyslipidaemic subjects generated more ROS in comparison with cells from healthy control subjects. After 1 year of simvastatin treatment, ROS production (delta N-formyl-Met-Leu-Phe-induced generation and area under the curve) was significantly reduced. At baseline, AT1-R mRNA expression was also higher in dyslipidaemic subjects than in healthy controls and it was reduced after clinical treatment with simvastatin. In a subgroup of patients, a reduced angiotensin II-induced ROS generation was also observed upon clinical simvastatin treatment. Moreover, a direct effect of statin on the upregulated AT(1)-R expression was demonstrated in vitro in neutrophils of untreated dyslipidaemic subjects. CONCLUSION A consistent reversion of pro-inflammatory oxidative functional response and reduction of AT(1)-R expression in primed PMNs was observed in patients during long-term statin treatment. The AT1-R reduction over treatment may contribute to the normalization of dysregulated neutrophil activation which occurs in the pre-clinical phase of atherosclerosis.

Treatment with enalapril modifies the pain perception pattern in hypertensive patients.

The cardiovascular system shares numerous anatomic and functional pathways with the antinociceptive network. The aim of this study was to investigate whether angiotensin-converting enzyme (ACE) inhibitor treatment could affect hypertension-related hypalgesia. Twenty-five untreated hypertensive patients, together with a control group of 14 normotensive subjects, underwent dental pain perception evaluation by means of a pulpar test (graded increase of test current applied to healthy teeth). After the evaluation of the dental pain threshold (occurrence of pulp sensation) and tolerance (time when the subjects asked for the test to be stopped), all the subjects underwent a 24-hour ambulatory blood pressure monitoring. The hypertensive group then was treated with 20 mg/d enalapril, whereas the normotensive subjects remained without any treatment. After a time interval of 6+/-2 months, the dental pain sensitivity was retested in all the subjects, and ambulatory blood pressure was recorded during treatment in the hypertensive patients. At the first assessment, hypertensive patients showed a higher pain threshold than normotensive subjects (P<.001). On retesting of pain sensitivity in hypertensive patients, a significant decrease of both pain threshold and tolerance, leading to their normalization, was observed during treatment (P<.001 and P<.005, respectively), in the presence of reduced 24-hour and office blood pressure values. A slight, though significant, correlation was observed between variations in pain tolerance and baseline blood pressure changes occurring during treatment. During follow-up, the normotensive subjects did not show any significant pain perception or office blood pressure changes. Hypertension-related hypalgesia was confirmed. Mechanisms acting both through lowering of blood pressure and specific pharmacodynamic properties may account for the normalization of pain sensitivity observed in hypertensive patients during treatment with ACE inhibitors.

Endogenous beta-endorphins in hypertension: Correlation with 24-hour ambulatory blood pressure

OBJECTIVES The aims of this study were to determine whether hypertensive patients showed increased endogenous opioid tone and to find a possible correlation between beta-endorphin levels and 24-h ambulatory blood pressure. We also investigated whether circulating beta-endorphin levels were associated with pain perception at rest. BACKGROUND Experimental studies suggest an involvement of the endogenous opioid system in cardiovascular control mechanisms. METHODS We determined baseline beta-endorphin plasma levels by radioimmunoassay in 81 consecutive subjects (48 hypertensive, 33 normotensive) after a 30-min rest and before 24-h ambulatory blood pressure monitoring. In 72 of 81 subjects with a dental formula suitable for the pulpar test (graded increase of test current -0 to 0.03 mA applied to three healthy teeth), pain perception was also investigated. RESULTS Hypertensive patients showed higher beta-endorphin plasma levels than normotensive subjects (p < 0.002). Circulating endogenous opioid levels correlated with 24-h diastolic blood pressure (p < 0.01), whereas the relation with systolic pressure did not reach statistical significance. When 24-h blood pressure recordings were divided into daytime and nighttime values, and blood pressure loads (percent of measurements > or = 140 mm Hg for systolic blood pressure and > or = 90 mm Hg for diastolic pressure) were calculated, a significant correlation was found between beta-endorphin levels and diastolic pressures and load. Similarly, presampling diastolic blood pressure was significantly correlated with beta-endorphin levels. Of the 72 subjects tested, hypertensive patients showed a lower pain sensitivity than normotensive subjects. A positive correlation was found between pain threshold and circulating beta-endorphin levels (p < 0.05). CONCLUSIONS Sustained arterial pressure is probably involved in the tonic activation of cardiovascular mechanisms linked to endogenous opioid tone. Circulating plasma endorphins may account, at least in part, for the pain perception pattern relating to blood pressure levels at rest.