Giovanni Gaudio

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.

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.

Relationship between a genetic predisposition to hypertension, blood pressure levels and pain sensitivity

INTRODUCTION The aim of this study was to determine whether the degree of blood pressure elevation and/or a genetic predisposition to hypertension have a major role in determining a reduced pain perception in hypertensives. The reasons underlying the relationship between blood pressure elevation and pain perception mechanisms are not completely understood. METHODS One hundred and four untreated hypertensive patients (65 subjects with and 39 without a positive parental history of hypertension) together with a control group of 42 subjects (20 normotensive offspring of normotensive parents, and 22 normotensive offspring of hypertensive parents) were submitted to standard blood pressure evaluation, 24-h blood pressure monitoring and dental pain perception evaluation. RESULTS Both pain threshold and tolerance were found to be higher in hypertensive than normotensive subjects (P < 0.0001 and P < 0.015, respectively). Positive significant correlations were found between both 24-h systolic and diastolic pressure and the pain perception variables. When a 2 x 2 ANOVA test was performed, factoring for the effects of both blood pressure status and family history of hypertension on pain sensitivity, a significant effect was revealed only for blood pressure status. Moreover, after controlling for blood pressure by a covariate analysis, no significant difference was found between the subjects with or without hypertensive parents as regards pain perception variables. CONCLUSIONS Pain sensitivity is correlated to blood pressure levels whereas the parental history of hypertension per se does not affect the pain perception pattern. Thus, the degree of blood pressure elevation, more than a genetic predisposition to hypertension may influence the mechanisms leading to hypalgesia in hypertension.

Simvastatin treatment modifies polymorphonuclear leukocyte function in high-risk individuals: a longitudinal study.

Background Although extensive experimental evidence supports a primary role of polymorphonuclear leukocytes (PMNs) in atherosclerosis, few data exist concerning the functional properties of these cells and their pharmacological modulation in high-risk individuals. Objective The production of the proinflammatory chemokine interleukin-8 (IL-8), migration and chemotaxis, and reactive oxygen species (ROS) generation were investigated in a longitudinal study in PMNs obtained from high-risk individuals during statin treatment. As a secondary endpoint we compared PMN function of high-risk patients with that of controls. Methods and results PMNs were isolated from 21 high-risk individuals before treatment and 3 and 30 days after the beginning of simvastatin treatment, and from healthy controls. During treatment a significant reduction was observed both in resting (P = 0.009) and N-formyl-Met-Leu-Phe (fMLP)-stimulated (P = 0.008) IL-8 production, and in the chemotactic index (P = 0.038), whereas ROS generation did not significantly change. In comparison with cells from controls, PMNs obtained from patients before starting simvastatin treatment showed higher resting and fMLP-stimulated IL-8 release (P = 0.007 and P = 0.002, respectively) and ROS generation (resting, P = 0.009; and fMLP-stimulated, P = 0.046), whereas migration and the chemotactic index did not significantly differ. Conclusions An activation of neutrophils is present in high-risk individuals, shown by the enhanced production of IL-8, and increased ROS generation. The 4-week statin treatment is able to reduce the cell capability to produce IL-8, and to decrease chemotaxis, thus affecting the proinflammatory properties of PMNs.

Ambulatory blood pressure and left ventricular changes during antihypertensive treatment : perindopril versus isradipine

Using digitized M-mode echocardiograms and 24-h ambulatory blood pressure (BP) monitoring, we compared the effects on left ventricle (LV) and BP of 6-month treatment with a calcium antagonist or an angiotensin-converting enzyme (ACE) inhibitor in 36 hypertensive patients with LV hypertrophy (group 1, 18 subjects treated with sustained-release isradipine; group 2, 18 subjects treated with perindopril). At the basal evaluation, the two groups had comparable BP and LV parameters. After treatment, both groups showed a similar and significant reduction in 24-h, day- and night-systolic and diastolic BP (SBP, DBP). The reduction in LV mass index was greater (p < 0.01) in group 2. In group 1, percentage of decrease of LV mass correlated significantly with percentage of decrease in 24-h and daytime BP; this was not true of group 2. Together with the reduction in LV hypertrophy, there was a significant increase of peak lengthening rate of LV diameter that was greater (p < 0.01) in group 1. Both drugs can reduce LV hypertrophy and improve diastolic function. The reduction of hypertrophy induced by perindopril appears to be partly independent of BP decrease and therefore partly related to a direct action of perindopril on the myocardium.

Relationship between dental pain perception and 24 hour ambulatory blood pressure: a study on 181 subjects.

OBJECTIVE To investigate dental pain perception in a large group of essential hypertensive subjects. METHODS A total of 130 hypertensive patients together with 51 normotensive subjects were submitted to tooth-electrical stimulation to determine the dental pain threshold (occurrence of pulp sensation) and tolerance (time when the subject asked for the test to be stopped). Blood pressure was measured at rest, before pain perception evaluation, and during a 24 h period by ambulatory monitoring. RESULTS The normotensive and hypertensive subjects differed with regard to pain threshold (P = 0.002) and tolerance (P = 0.01). Pain perception variables were significantly correlated with both resting blood pressure and 24 h, diurnal and nocturnal arterial pressures, the correlation between pain threshold and 24 h systolic blood pressure being the most significant (r = 0.31, P < 0.0001). By contrast, parameters indicating 24 h blood pressure variability (percentage of nocturnal blood pressure reduction and 24 h blood pressure variation coefficients) were not associated with pain perception. Moreover, among the hypertensives only, a significant relationship was observed between pain sensitivity and both baseline and 24 h pressures. No association was found when pain perception and blood pressure were correlated in the normotensive group. CONCLUSIONS The correlation between both baseline and 24 h blood pressure and pain perception has been confirmed in a large group study of normotensive and hypertensive subjects. Moreover, even among the hypertensive range of blood pressure, the higher the blood pressure is, the lower the sensitivity to pain is. These findings strengthen the hypothesis of a role of the degree of blood pressure elevation in modulating pain sensitivity.

Changes in pain perception during treatment with angiotensin converting enzyme-inhibitors and angiotensin II type 1 receptor blockade.

Objectives Besides the well-known role of the angiotensin system in blood pressure control, an interaction of angiotensin and pain perception has been suggested. This study sought to investigate whether an angiotensin converting enzyme inhibitor, which facilitates bradykinins, algesic peptides, and/or an AT1 receptor antagonist may modify hypertension-related hypoalgesia in humans. The study was approved by the ethical committee of our Department. Methods A total of 22 hypertensive patients were submitted to dental pulp stimulation to obtain the dental pain threshold and tolerance, and to 24 h blood pressure monitoring together with a control group of 55 normotensives. Then the hypertensives were randomized to enalapril or losartan treatment and were re-evaluated (dental pain perception and ambulatory monitoring) after 8 weeks of the first treatment and after an additional 8 weeks of the second treatment. Results Untreated hypertensives showed a reduced perception to painful stimuli when compared with normotensives. A significant reduction of both pain threshold and tolerance was observed during the anti-hypertensive treatments (Friedman test:P = 0.007 and P = 0.006, respectively). Pain sensitivity was similar during the two treatments and it did not differ from pain sensitivity values of normotensive controls. ANCOVAs were computed to evaluate the relationship between anti-hypertensive agents and pain sensitivity, after controlling for blood pressure. A 24 h mean pressure served as covariate, removing any effect of blood pressure; a significant difference was observed entering both pain threshold and tolerance as dependent variables (F = 5.28, P = 0.0076;F = 8.16, P = 0.0007, respectively). Conclusions Both the angiotensin converting enzyme inhibitor enalapril and the AT1 receptor blocking agent losartan acted similarly on pain threshold and tolerance, pain sensitivity being increased during the two anti-hypertensive treatments. The blood pressure reduction during drug assumption could not account for the pain sensitivity changes observed. The latter may be due to a specific pharmacodynamic mechanism mediated through angiotensin II AT1 receptors.

Insulin and Diastolic Dysfunction in Lean and Obese Hypertensives: Genetic Influence

We investigated the influence of genetic predisposition to hypertension by studying the relation between insulin sensitivity and left ventricular (LV) mass and function in untreated lean and obese hypertensives. We selected 50 lean hypertensives with normotensive parents (negative family history of hypertension [F-]), 64 lean hypertensives with 1 or both parents hypertensive (positive family history of hypertension [F+]), 40 obese F- hypertensives, and 43 obese F+ hypertensives. The 4 groups were comparable regarding age, gender, 24-hour blood pressure profile, and known duration of hypertension. We measured glucose, insulin, and C-peptide during fasting and during an oral glucose tolerance test; LV morphology and function were assessed by digitized M-mode echocardiography. Glucose (fasting and test) levels were normal in all and similar among the 4 groups. Insulin and C-peptide (fasting and stimulated) levels were higher in obese hypertensives than in lean hypertensives; at similar body mass index, insulin and C-peptide levels were higher in F+ than in F- groups. Compared with lean hypertensives, obese hypertensives had greater LV mass index; LV systolic function was normal in all and similar among the groups. The indices of LV diastolic function were significantly lower in F+ than in F- groups. LV mass index did not correlate with metabolic parameters; the indices of LV diastolic function were inversely correlated with insulin area during test in only the 2 F+ groups. In conclusion, genetic predisposition to hypertension is associated with a reduced insulin sensitivity and affects the response of the myocardium to increased insulin levels, inducing a greater impairment of diastolic function. Insulin sensitivity and genetic predisposition to hypertension seem to have no influence on LV mass.

Global link between heart rate and blood pressure oscillations at rest and during mental arousal in normotensive and hypertensive subjects.

UNLABELLED Complex phenomena modulate the interplay between heart rate and blood pressure variability, in particular after adjustments induced by stimuli or in pathophysiological conditions. This study sought to investigate in 25 hypertensive and 16 normotensive male subjects whether relationships operating at rest may be preserved after a central nervous system arousal induced by a mental stress test. As a secondary endpoint, we evaluated the potential changes of the components of heart rate and blood pressure variability during stress. RESULTS A significant correlation was observed between components of RR and systolic blood pressure (SBP) variability (p<0.0001), after controlling for the subjects status (normotensive vs. hypertensive) and for stress-steps (baseline condition, during stress test and recovery). Moreover, the multiple regression model accounted for the potential effects of the baseline alpha(LF) value and for the baseline heart rate and systolic blood pressure. The relationship operating between the LF/HF(RR) ratio and LF/HF(SBP) ratio was not different either at the different steps of stress test (interaction: p=0.87) or in the two groups of normotensive and hypertensive subjects (interaction: p=0.76). The variables of RR and SBP variabilities were modified during stress and recovery. In particular, the LF/HF(RR) ratio and LF/HF(SBP) ratio increased during stress and decreased during recovery. CONCLUSIONS The association between heart rate and blood pressure oscillations was preserved during central nervous system arousal by mental stress both in normotensives and hypertensives. A central integration may account for this constant relationship, the correlation being independent from baseline heart rate, blood pressure and baroreflex sensitivity.