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.

Cardiovascular effects of exercise in young hypertensives.

Sedentary habits are largely responsible for the alarming rise in the prevalence of hypertension among young individuals. Regular aerobic exercise has been shown to reduce not only blood pressure (BP) in resting conditions but also BP reactivity to stressors. Much less is known about the long-term effects of physical activity on target organ damage in hypertension. Some studies have documented that exercise is able to decrease rather than increase left ventricular mass and that even competitive athletics have beneficial effects on the heart. In addition, physical activity during leisure has been found to be inversely associated with the progression of subclinical atherosclerosis and to delay aging dependent arterial stiffness. Isolated systolic hypertension in physically active young people is often an innocent clinical condition caused by an elevated pulse pressure amplification and low wave arterial reflection from peripheral sites, due to increased arterial elasticity. The above findings support a strategy of exercise training as an initial approach in the management of young sedentary patients in the early stages of hypertension. Caution should be used in subjects with more severe hypertension and every hypertensive athlete should be thoroughly investigated to exclude target organ damage and coronary artery disease.

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.

High angiotensin II state without cardiac remodeling (Bartter's and Gitelman's syndromes): are angiotensin II type 2 receptors involved?

BACKGROUND/AIMS: While Angiotensin II (Ang II) is a major factor in the development of cardiomyocyte hypertrophy and a pivotal role for Ang II signals via ERK1/2 has been identified, mechanism(s) responsible are still unclear. As Bartter's and Gitelman's syndrome patients (BS/GS) have increased Ang II, and yet normo/hypotension, hyporesponsiveness to pressors and blunted Ang II signaling via type 1 receptors (AT1R), this study assesses BS/GS's left ventricular (LV) mass and structure as well as Ang II induced ERK1/2 phosphorylation compared with essential hypertensive patients (EH) and normotensive healthy subjects (C) to gain insight into Ang II mediated processes. METHODS: Indices of cardiac hypertrophy were determined by M-mode, two-dimensional echo Doppler and ERK phosphorylation by Western blot. RESULTS: None of BS/GS exhibited LV remodelling; LV mass, LV end-diastolic volume and mass/volume ratio were unchanged vs C (60+/-14 g/m2 vs 64+/-12, 64+/-12 ml/m2 vs 60+/-8 and 0.95+/-0.2 vs 1.0+/-0.2, respectively) and reduced vs EH (119+/-15, p<0.001, 78+/-9, p<0.05 and 1.52+/-0.15, p<0.01). Despite BS/GS's higher plasma renin activity and aldosterone and unchanged level of AT1R, Ang II induced ERK1/2 phosphorylation was reduced vs both C and EH: 0.64 d.u.+/-0.08 vs 0.90+/-0.06 in C, p<0.006, and vs 1.45+/-0.07 in EH, p<0.001. CONCLUSION: The data point to a direct cardioremodeling role for Ang II and support a role of Ang II type 2 receptor (AT2R) signaling as involved in the lack of cardiovascular remodeling in BS/GS. However, further studies using more direct approaches to demonstrate the effects of AT2R signaling must be pursued.

Atrial fibrillation during acute myocardial infarction: association with all-cause mortality and sudden death after 7-year of follow-up.

AIMS: Atrial fibrillation/flutter (AF/FL) is a common complication of acute myocardial infarction (AMI). Indeed, the determinants of AF/FL in AMI-patients and the association of AF/FL with mortality are not well-known. The purpose of the present study was to investigate the relationship between presence of AF/FL and mortality in patients with AMI and to report on predictors of AF/FL. METHODS: We studied 505 patients enrolled in three intensive care units with definite AMI and followed up for 7 years. No patient was lost to follow-up. Patients with AF/FL during the 1st week of hospitalisation were compared with those with steady sinus rhythm. End-points were all-cause mortality and modes of death. RESULTS: At multivariable logistic regression analysis, elderly, body mass index, congestive heart failure (CHF), history of hypertension and plasma cholesterol (in a negative fashion) were independently associated with the presence of AF/FL. At survival analysis, after full adjustment, AF/FL was not associated with in-hospital mortality. After 7 years of follow-up, AF/FL was found to be associated with all-cause mortality [adjusted odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.2-2.3], together with age, diabetes mellitus, creatine kinase-MB isoenzyme (CK-MB) peak, CHF, estimated glomerular filtration rate and thrombolysis. At adjusted logistic polynomial regression analysis, AF/FL was found to be associated with an excess of mortality for reasons of sudden death (SD) (adjusted OR = 2.7; 95% CI = 1.2-6.4). No interaction was observed between AF/FL and medications on in-hospital mortality. For 7-year mortality, angiotensin-converting enzyme (ACE)-inhibitors and digitalis showed an independent negative (protective) interaction chiefly on SD (adjusted OR = 0.06; 95% CI = 0.01-0.74, and RR = 0.10; 95% CI = 0.02-0.58, respectively). CONCLUSIONS: Patients with AMI and AF/FL portend a poor prognosis in the long-term chiefly because of an excess of SD. Treatment with ACE-inhibitors and digitalis may have long-term beneficial effects on SD.

Mechanism of local anesthetic effect. Involvement of F0 in the inhibition of mitochondrial ATP synthase by phenothiazines.

The mechanism whereby tertiary amine local anesthetics affect the activity of membrane proteins was investigated by studying the interaction of phenothiazines with mitochondrial ATP synthase. These drugs caused inhibition of the activity of the membrane-bound enzyme at concentrations that do not perturb the phospholipid bilayer. The inhibitory effect appeared consequent to interaction with multiple sites located on both the F1 and the F0 components of the enzyme complex, since: (a) Dixon plots were parabolic; (b) the membrane-bound enzyme was more sensitive to the drug effect than the isolated F1 component; (c) conditions that decreased oligomycin sensitivity also decreased the sensitivity to phenothiazines; (d) irreversible binding of photochemically activated phenothiazines to the ATP synthase complex, followed by detachment of the F1 moiety and reconstitution with purified F1 resulted in an inhibited enzyme complex. These data are interpreted as indicating that tertiary amine local anesthetics affect the activity of membrane proteins by interacting with hydrophobic sites located on both their integral and peripheral domains.

Mechanism of Na+/K(+)-ATPase activation by trypsin and kallikrein.

The mechanism of the Na+/K(+)-ATPase activation by trypsin (from bovine pancreas) and kallikrein (from human plasma) was investigated on enzyme preparations from different sources (beef heart and dog kidney) and at different degrees of purification (beef heart). Kallikrein was effective on both beef and dog enzymes, whereas trypsin stimulated only the beef-heart Na+/K(+)-ATPase. The extent of activation by the proteinases was inversely related to the degree of purification (maximal enzyme activation about 60 and 20% on the partially purified and the more purified enzymes, respectively). Enzyme activation was observed up to 0.5-0.6 microgram/ml of proteinase. At higher concentrations the activation decreased and was converted into inhibition at proteinase concentrations above 1.0 micrograms/ml. Na+/K(+)-ATPase stimulation was due to an increase in the Vmax of the enzyme reaction. Km for ATP remained unaffected. The activating effect was favoured by sodium and counteracted by potassium. Accordingly, Na(+)-ATPase activity was stimulated to a greater extent (up to 350%), whereas K(+)-dependent p-nitrophenylphosphatase activity proved to be insensitive to the actions of the proteinases. The Na+/K(+)-ATPase stimulation by both proteinases was antagonized by either ouabain or canrenone, two drugs that bind on the extracellular side of the Na+/K(+)-ATPase molecule. On the contrary, the enzyme inactivation observed at high proteinase concentrations was not counteracted by these two drugs. The stimulation of either Na+/K(+)- or Na(+)-ATPase activity was shown to be an irreversible effect without any significant protein degradation detectable by SDS gel electrophoresis. The results obtained suggest that proteinases exert their stimulatory effects by interacting preferentially with the E2 conformation of Na+/K(+)-ATPase at site(s) located on the extracellular moiety of the enzyme.

Mechanism of local anesthetic effect on mitochondrial ATP synthase as deduced from photolabelling and inhibition studies with phenothiazine derivatives.

The mode of interaction between mitochondrial ATP synthase and two phenothiazine derivatives, chlorpromazine (CPZ) and trifluoperazine (TFP), was studied as a model for the interaction of local anesthetic drugs with membrane proteins. Photolabelling experiments demonstrated that CPZ and TFP interact with various subunits of either the peripheral F1 moiety of the membrane-embedded F0 sector. Both drugs, however, labelled the membrane sector much more heavily. Qualitative differences in labelling were observed between CPZ and TFP, indicating non-identical sites of interaction. These diversities appeared related to the different hydrophobicities of the two drugs since: (a) TFP, which has a higher lipid/water partition coefficient, labelled the more hydrophobic subunits more markedly than CPZ; (b) reduced glutathione, a hydrophilic free radical scavenger that does not penetrate the membrane continuum, had a negligible effect on the labelling by TFP, whereas it reduced the labelling of various subunits by CPZ; (c) the labelling by [3H]TFP was poorly antagonized by cold CPZ, whereas it was almost totally prevented by fluphenazine, a phenothiazine similar to TFP in hydrophobic character. Consistently, double-inhibition experiments showed that TFP and fluphenazine are mutually exclusive inhibitors of mitochondrial ATP synthase, whereas TFP and CPZ are mutually nonexclusive. The nature of the phospholipid bilayer influenced neither the labelling nor the inhibition patterns. The complex of these data indicate that tertiary amine local anesthetics affect the activity of membrane proteins by interacting with a multiplicity of relatively aspecific hydrophobic sites located preferentially, but not exclusively, on the membrane-embedded domains. It is suggested that at least two phenothiazine derivatives of different hydrophobicities be used in photolabelling experiments, before any generalization is made, since the molecular targets of these drugs vary according to their hydrophobic character.

F1-ATPase from different submitochondrial particles.

1. F1-ATPase has been extracted by the diphosphatidylglycerol procedure from mitochondrial ATPase complexes that differ in ATPase activity, cold stability, ATPase inhibitor and magnesium content. 2. The ATPase activity of the isolated enzymes was dependent upon the activity of the original particles. In this respect, F1-ATPase extracted from submitochondrial particles prepared in ammonia (pH 9.2) and filtered through Sephadex G-50 was comparable to the enzyme purified by conventional procedures (Horstman, L.L. and Racker, E. (1970) J. Biol. Chem. 245, 1336--1344), whereas F1-ATPase extracted from submitochondrial particles prepared in the presence of magnesium and ATP at neutral pH was similar to factor A (Andreoli, T.E., Lam, K.W. and Sanadi, D.R. (1965) J. Biol. Chem. 240, 2644--2653). 3. No systematic relationship has been found in these F1-ATPase preparations between their ATPase inhibitor content and ATPase activity. Rather, a relationship has been observed between this activity and the efficiency of the ATPase inhibitor-F1-ATPase association within the membrane. 4. It is concluded that the ATPase activity of isolated F1-ATPase reflects the properties of original ATPase complex provided a rapid and not denaturing procedure of isolation is employed.

Activation of (Na+ + K+)-dependent ATPase by lipid vesicles of negative phospholipids.

1. Kidney (Na+ + K+)-stimulated ATPase was depleted of phospholipids by extraction with lubrol and inserted in lipid structures of known composition. Both ouabain-sensitive ATPase and phosphatase reactions could be partially restored by lipid replacement. 2. Lipid vesicles of natural and synthetic negative phospholipids proved to be effective. The low activity of uncharged liposomes was increased when negative charges were included into the bilayer structure. 3. Reactivation by negative phospholipids was accompanied by spontaneous re-assembly of a stable lipid-protein complex. By contrast, the interaction of lipid deficient ATPase complex with uncharged lamellae was possible only after sonication of lipid-protein suspension. Reactivation did not ensue. 4. The ouabain-sensitive ATPase reactivated by synthetic dioleoylphosphatidylglycerol yielded curvilinear Arrhenius plots. The same pattern was seen with the original undepleted microsomal preparation. A discontinuity close to the temperature of fluid-order transition was found with dimyristoyl phosphatidylglycerol. 5. It is concluded that reassembly of lipid-deficient (Na+ + K+)-stimulated ATPase requires the addition of diacylphospholipids with fluid acyl-chains and negatively charged polar heads able to assemble in an expanded lamellar configuration.

Further purification and characterization of the succinyl-CoA:3-hydroxy-3-methylglutarate coenzyme A transferase from rat-liver mitochondria.

Succinyl-CoA:3-hydroxy-3-methylglutarate coenzyme A transferase, previously identified in rat-liver mitochondria (Deana et al. (1981), Biochim. Biophys. Acta 662, 119-124), was purified to near homogeneity and further characterized. After the last purification steps consisting of Ultrogel AcA-44 filtration and agarose-hexane-coenzyme A chromatography, the enzyme was apparently tetrameric with a mass of 48-52 kDa determined by gel filtration on Sephadex G-75, ultracentrifugation through a sucrose gradient and SDS-gel electrophoresis. By means of a HPLC technique developed for measuring the CoA esters we could determine the enzyme activity in both forward and reverse directions and show that the kinetic constants, i.e., Km of reactants and Vmax, are not too different for the two reactions. Double-reciprocal plots of the enzyme velocities versus the concentration of one substrate at different fixed concentrations of the other substrate gave families of straight lines converging below the substrate-abscissa for both forward and backward reactions, indicating a kinetic mechanism of rapid equilibrium random Bi-Bi type. The competitive inhibition of the product succinate with respect to both reactants, 3-hydroxy-3-methylglutarate and succinyl-CoA, as well as the Haldane relationships are consistent with this conclusion. An inhibitory effect on CoA transferase activity by acetate, acetoacetate, acetyl-CoA, acetoacetyl-CoA, coenzyme A, carnitine, ZnCl2 and high concentrations of the monovalent anions ClO4-, F-, I- and Cl- was also found.

Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: The goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. METHODS AND RESULTS: Patients who were >/=60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (>/=160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P<0.001) and, during follow-up, a lower incidence of stroke (P<0.05) and of cardiovascular complications (P=0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P<0.001). The influence of active treatment on ECG voltages (P<0.05) and on the incidence of stroke (P<0.05) and cardiovascular events (P=0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. CONCLUSIONS: Patients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.

High heart rate: a risk factor for cardiovascular death in elderly men.

OBJECTIVE: To examine the association between heart rate and 12-year incidence rates of total and cardiovascular death in a cohort of elderly subjects stratified by sex. SUBJECTS AND METHODS: The study was carried out in 763 white men and 1175 women aged 65 years or older who were participating in the Cardiovascular Study in the Elderly. Subjects were divided into quintiles of heart rate; the top quintile comprised those with a heart rate of greater than 80/min and the bottom quintile, those with a heart rate of less than 64/min. RESULTS: In the men, the number of deaths from cardiovascular causes was significantly increased in those in the top quintile of heart rate (crude relative risk, 1.55) but decreased in those in the bottom quintile (crude relative risk, 0.65). Similar relationships were found in the women, but the associations did not reach statistical significance (all-cause, P = .11; cardiovascular, P = .15). After adjustment for baseline age, body mass index, hypertension, diabetes mellitus, angina or previous myocardial infarction (coronary heart disease), regular medication, lipid levels, smoking, alcohol intake, forced expiratory volume in 1 second, and other confounders, the relative risk for cardiovascular death in the men was 1.38 (95% confidence interval, 0.94-2.03) for the subjects in the top quintile of heart rate and 0.82 (95% confidence interval, 0.52-1.28) for those in the bottom quintile. In the Cox analysis, predictors of time to cardiovascular death were heart rate (P < .001), age (P < .001), coronary heart disease (P < .001), clinical heart failure (P = .001), diabetes mellitus (P = .001), hypertension (P = .02), and triglyceride levels (P = .04), whereas total (P = .20) and high-density lipoprotein-cholesterol (P = .21) levels and smoking (P = .74) were found to be nonsignificant by the model. The heart rate-cardiovascular death association held true when subjects who died in 2 years after enrollment were excluded (P = .008). CONCLUSIONS: An elevated heart rate may be a strong predictor of cardiovascular death in elderly men. Conversely, a low heart rate is related to a better outcome in these subjects.

Clinical relevance of nighttime blood pressure and of daytime blood pressure variability.

BACKGROUND: The purpose of this study was to assess whether hypertensive target organ damage is related to average nighttime blood pressure (BP) and to BP variability. METHODS: Sixty-seven normotensive subjects and 171 borderline, 309 mild, 140 moderate, and 41 severe hypertensive patients were studied with noninvasive ambulatory BP monitoring. Each subject was assigned a target organ damage score of 0 to 5 on the basis of funduscopic changes and degree of left ventricular hypertrophy calculated from electrocardiogram and chest roentgenogram. RESULTS: When the 728 subjects were subdivided into five classes of increasing daytime BP, in each class a significantly higher degree of target organ damage was present in the subjects with higher nighttime diastolic BP. A similar, although nonsignificant, trend was observed in the subjects with higher nighttime systolic BP. In particular, higher nighttime BP levels were accompanied by a more severe degree of left ventricular hypertrophy. As for variability, subjects with higher daytime systolic BP SD, but not with higher daytime diastolic SD, displayed a more severe degree of target organ damage; this was accounted for by a higher degree of retinal abnormalities. The association between target organ damage and systolic BP SD was present both in men and women, while that with nighttime BP was present only in men. No relationship was found between degree of cardiovascular complications and peaks of pressure. CONCLUSIONS: These results suggest that a reduced day-night BP difference and an increased daytime BP variability, evaluated as the SD, are associated with a higher degree of hypertensive cardiovascular complications. Whether this BP profile is the cause or the consequence of target organ damage remains to be established.

24-hour leg and forearm haemodynamics in transected spinal cord subjects.

OBJECTIVE: A circadian rhythm of blood pressure has been demonstrated both in subjects who are physically active during the day and in those confined to bed. The study of the circadian rhythm of arterial flow and peripheral resistance, on the other hand, is limited to pioneer experiments. This paper is aimed at demonstrating that leg peripheral resistance has circadian fluctuations which are modulated by spinal neural traffic. METHODS: Eleven normal (able-bodied) human subjects and 11 patients with spinal transection due to spinal cord injury (SCI) were studied. They were confined to bed for 24 h. Blood pressure and heart rate were monitored every 15 min with an automatic device and leg flow with an automatic strain-gauge plethysmograph synchronised to the pressurometer. Peripheral resistance was calculated at the same intervals. RESULTS: In able-bodied subjects leg resistance was significantly higher during waking hours (when the sympathetic system is more activated) than during sleep, while in subjects with spinal cord injury no difference was detected between day-time and night-time. CONCLUSIONS: The circadian rhythm is controlled by adrenergic fibres transmitted via the spinal cord.

Predictors of vascular remodelling in hypertensive subjects with well-controlled blood pressure levels.

We evaluated the structural/functional characteristics of the arterial wall in a cohort of hypertensives with well-controlled blood pressure (BP) levels. We studied 40 hypertensives with well-controlled BP. We assessed by B-mode ultrasound the mean intima-media thickness (mean-IMT) and maximum-IMT (M-MAX) of carotid artery (common, bulb, internal) bilaterally. Endothelial function was evaluated by post-occlusion flow-mediated dilation (FMD) of the brachial artery. Along with traditional risk factors, we studied the impact of serum high-sensitivity C-reactive protein (hs-CRP) and osteoprotegerin (OPG). Forty normotensive subjects served as controls. In the hypertensives, the BP levels were well controlled (office BP: 129/79 mm Hg, ambulatory BP monitoring: 121/75 mm Hg). Compared with controls, higher BP levels and body mass index were present in hypertensives, whereas age and metabolic parameters were similar. In hypertensives, the IMT (mean-IMT 0.68 mm, M-MAX 0.81 mm) was significantly higher than in controls (mean-IMT 0.60 mm, M-MAX 0.71 mm). FMD was impaired in hypertensives (5.9%) compared with controls (9.2%). In multivariate analyses, it turned out that in hypertensives IMT parameters were related to age, hs-CRP and OPG. Low-density lipoprotein (LDL) cholesterol was the only factor related to FMD. IMT and FMD had no relationship with BP levels. In conclusion, in hypertensives with well-controlled BP, the pro-atherogenic remodelling (IMT) is mainly dependent on age and the inflammatory cytokines, OPG in particular. The functional impairment of the arterial wall (FMD) was related to the levels of LDL cholesterol. Under these conditions, when the impact of BP is minimized, the role of inflammatory cytokines and lipids on structural/functional remodelling becomes predominant.

Reproducibility and clinical value of the trough-to-peak ratio of the antihypertensive effect: evidence from the sample study.

The objectives of our study were to assess the reproducibility of the trough-to-peak ratio (T/P) and to see whether a high T/P is accompanied by more organ protection or vice versa. The study included 175 (mean+/-SD age, 51+/-9 years) subjects with mild-moderate essential hypertension who had echocardiographic evidence of left ventricular (LV) hypertrophy taken from the SAMPLE study (Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation), an open-label multicenter study. The study included a 3-week washout pretreatment period, a 12-month treatment period with lisinopril (n=84) or lisinopril plus hydrochlorothiazide (n=91) once daily, and a 4-week placebo follow-up period. Results of 24-hour ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index (LVMI) were obtained before and after 3 and 12 months of treatment. T/Ps were computed in each patient by dividing the systolic and diastolic blood pressure changes at trough (changes in the last 2 hours of the monitoring period) by those at peak (average of the 2 adjacent hours with the maximal blood pressure reduction between the 2nd and 8th hour from drug intake) after 3 and 12 months of treatment. Average 24-hour blood pressure was similarly reduced at 3 and 12 months. Trough blood pressure changes at 3 and 12 months were closely correlated, as were the corresponding peak blood pressure changes. However, the 3- and 12-month T/Ps correlated to a lesser degree (r<0.42). Furthermore, the reduction of LVMI induced by treatment was similarly correlated with the treatment-induced reduction in 24-hour average, trough, and peak blood pressures but not with the T/Ps. This was also evident when the contribution to LV hypertrophy regression by 24-hour blood pressure changes and T/Ps was assessed in a multivariate regression analysis. In patients with a T/P >/=0.5 or <0.5, the regression of LVMI was similar. In conclusion, peak and trough blood pressure changes are reproducible and predict the regression of LVMI induced by treatment as well as average 24-hour blood pressure. T/Ps are less reproducible, and their value does not predict regression of organ damage by antihypertensive treatment.

Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations.

Faster resting heart rate has been shown to be associated with a higher risk of developing hypertension and a greater incidence of cardiovascular morbidity and mortality. The aim of this study was to investigate the distribution of heart rate and its relationship with blood pressure and other cardiovascular risk factors in three populations. One European general population (Belgian study), one North American general population (Tecumseh study), and one European hypertensive population (HARVEST trial) were studied. Within each population, mixture analysis was used to investigate whether a mixture of two normal distributions explained the variance in heart rate better than a single distribution. In the men of all populations, mixture analysis identified a larger subpopulation of subjects with normal heart rate and a smaller one with fast heart rate. The subgroups with tachycardia had higher blood pressure and lipid levels than those with normal heart rate. In the populations in which they were measured, fasting insulin and postload glucose were also higher in the men with faster heart rate. A subgroup with tachycardia could also be singled out among the women from Tecumseh, but no relation between heart rate and blood pressure could be found. These findings show that in Western societies, high heart rate pertains to a distinct subgroup of subjects, who are more frequently men and exhibit the characteristic features of the insulin resistance syndrome. Sympathetic overactivity is likely to be the mechanism underlying this clinical condition.