Abstract-Growing evidence associates blood pressure (BP) variability with cardiovascular events in hypertensive patients. Here we tested the existence of a relationship between awake BP variability and target-organ damage in subjects referred for suspected hypertension. Systolic and diastolic BP variability were assessed as the standard deviation of the mean out of 24-hour, awake and asleep BP recordings in 180 untreated subjects, referred for suspected hypertension. Measurements were done at 15-minute intervals during daytime and 30-minute intervals during nighttime. Left ventricular mass index (by echo), intima-media thickness (by carotid ultrasonography), and microalbuminuria were assessed as indices of cardiac, vascular and renal damage, respectively. Intima-media thickness and left ventricular mass index progressively increased across tertiles of awake systolic BP variability (P for trendϭ0.001 and 0.003, respectively). Conversely, microalbuminuria was similar in the 3 tertiles (PϭNS). Multivariable analysis identified age (Pϭ0.0001), awake systolic BP (Pϭ0.001), awake systolic BP variability (Pϭ0.015) and diastolic BP load (Pϭ0.01) as independent predictors of intima-media thickness; age (Pϭ0.0001), male sex (Pϭ0.012), awake systolic (Pϭ0.0001) and diastolic BP (Pϭ0.035), and awake systolic BP variability (Pϭ0.028) as independent predictors of left ventricular mass index; awake systolic BP variability (Pϭ0.01) and diastolic BP load (Pϭ0.01) as independent predictors of microalbuminuria. Therefore, awake systolic BP variability by non-invasive ambulatory BP monitoring correlates with sub-clinical target-organ damage, independent of mean BP levels. Such relationship, found in subjects referred for recently suspected hypertension, likely appears early in the natural history of hypertension. Key Words: hypertension Ⅲ blood pressure variability Ⅲ target-organ damage Ⅲ intima-media thickness Ⅲ left ventricular mass index H ypertension involves an increased risk of cardiovascular events, 1 which may be predicted by the occurrence of target-organ damage, such as subclinical renal dysfunction (microalbuminuria), 2 left ventricular hypertrophy, 3 or increased intima-media thickness, this last as a surrogate marker for atherosclerosis. 4 The availability of 24-hour ambulatory blood pressure monitoring (ABPM), in addition to providing information on mean BP levels, also allows an estimate of BP variability, the clinical significance of which is currently debated. [5][6][7] It has been shown that BP variability, assessed with invasive 24-hour ABPM, which provides beatto-beat estimates of BP and therefore a large number of estimates over 24 hours, carries prognostic information, with a higher number of cardiovascular events occurring in patients with wider BP excursions. 8 Information of this kind is beginning to accumulate also with noninvasive 24-hour ABPM, which is now much of current clinical use. Here the day/night variability, as assessed by the occurrence of the dipper/nondipper pattern, has been associated with ...

The renin-angiotensin system (RAS) plays a central role in cardiovascular homeostasis. Angiotensin is the key peptide of the RAS, and exerts its influence on the heart and blood vessels both through its haemodynamic effects (via its influence on after-load and pre-load and determining coronary vasoconstriction) and through its direct cellular effects (via its actions on cell proliferation). Numerous studies in the past 10 years have demonstrated that the pharmacological inhibition of angiotensin converting enzyme (ACE), one of the two critical enzymes of the RAS, improves the outcome in patients with several cardiovascular disorders (hypertension, heart failure, ischaemic heart disease). These studies suggest a role of the RAS as a major determinant of cardiovascular risk. Recent data suggest that genetics may in turn contribute to modulating the effects of angiotensin on coronary vascular biology and ischaemia. This paper reviews the physiologic characteristics of the RAS and recent research developments related to angiotensin cell biology and pathobiology in heart disease. In particular, this review will cover the genetic aspects of RAS and their implications in cardiovascular disease.

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Several risk factors for coronary artery disease (CAD) induce atherosclerosis through endothelial activation and dysfunction, and ample evidence now suggests that the balance between production and removal of reactive oxygen species (ROS) -a condition termed oxidative stress -is implicated in such processes. A main source of ROS in vascular cells is the reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase system. This is a membrane-associated enzyme, composed of five subunits, catalyzing the one-electron reduction of oxygen, using NADH or NADPH as the electron donor. One of the system subunits, termed p22-phox, has a polymorphic site on exon 4, associated with variable enzyme activity. This polymorphism is generated by a point mutation (C 242 T) producing a substitution of histidine with tyrosine at position 72, which affects one of the heme binding sites essential for the NAD(P)H enzyme activity. The consequent decrease of superoxide production thus characterizes a phenotype candidate for conferring to the carrier a reduced susceptibility to CAD. At present, however, the body of evidence from current literature is not yet sufficient to confirm or exclude the hypothesis that the C 242 T polymorphism protects from CAD. The functional effects of this polymorphism and the potential and its pathophysiological consequences also need further investigation.

NAD(P)H oxidase is a prominent source of reactive oxygen species in the vasculature. Vascular NAD(P)H oxidase is comprised of several subunits, one of which, p22phox, is encoded by a gene exhibiting several allelic variants. Here the C(242)T nucleotide transition has been found to alter superoxide anion production and associated with an altered risk of coronary artery disease (CAD). We assessed the role of this variant in two case-control studies, and performed a meta-analysis of previously reported investigations relating it to vascular risk. Population I was comprised of 492 subjects with type 2 diabetes, with or without macrovascular disease, matched for age, sex, and duration of diabetes. Population II was comprised of 158 subjects with or without either CAD or cerebro-vascular disease, and matched for age, sex, smoking status, weight category and the presence of hypertension, dyslipidemia, and diabetes. Our findings were meta-analyzed together with additional studies retrieved from the literature. The C(242)T polymorphism distribution did not differ between cases and controls in populations I and II both at univariate and multivariate analyses, and this was confirmed in a meta-analysis with 11 previously published populations. The meta-analysis, however, suggested a protective role of the T allele on CAD as an end point in Asian populations. In conclusion, these data suggest a significant heterogeneity for a modulating role of the T allele in the C(242)T polymorphism of p22-phox for the occurrence of CAD across ethnicities, with the absence of a significant effect in Caucasians.

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