Several studies have established that the increase in arterial stiffness (AS) is a cardiovascular risk factor but to date no studies have evaluated in hypertensive patients its prognostic value in comparison with another powerful risk factor, left ventricular mass (LVM) as measured by echocardiography. We prospectively evaluated the prognostic value of AS and LVM in patients with essential hypertension. The population studied comprised 793 patients (56% men) aged 54±14 years. For 519 patients, baseline measurements were made before any antihypertensive treatment, for 274 patients, the measurement were obtained during the follow-up period under antihypertensive treatment. AS was assessed from ambulatory monitoring of blood pressure and timing of Korottkoff sounds. Left ventricular mass was measured in 523 patients. After a mean follow-up of 97 months, 122 cardiovascular events were recorded in the whole population and 74 in the group with LVM determination. AS as continuous or discontinuous variable was independently related to cardiovascular events. The existence or not of antihypertensive treatment at the time of its measurement did not affect its prognostic value. When LVM was forced in the model, AS remained significantly related to cardiovascular events. Thus, AS has an independent prognostic value in the hypertensive, whether measured before or after the administration of antihypertensive treatment. This prognostic value persists after taking LVM into account.

Uric acid may have a role in the development of hypertension and renal dysfunction. We explored the relationship among longitudinal blood pressure, renal function, and cardiovascular outcomes in a large cohort of patients with treated hypertension. We used data from the Glasgow Blood Pressure Clinic database. Patients with a baseline measure of serum uric acid and longitudinal measures of blood pressure and renal function were included. Mortality data were obtained from the General Register Office for Scotland. Generalized estimating equations were used to explore the relationship among quartiles of serum uric acid, blood pressure, and estimated glomerular filtration rate. Cox proportional hazard models were developed to assess mortality relationships. In total, 6984 patients were included. Serum uric acid level did not influence the longitudinal changes in systolic or diastolic blood pressure but was related to change in glomerular filtration rate. In comparison with patients in the first quartile of serum uric acid, the relative decrease in glomerular filtration rate in the fourth was 10.7 (95% confidence interval, 7.9-13.6 mL/min per 1.73 m(2)) in men and 12.2 (95% confidence interval, 9.2-15.2 mL/min per 1.73 m(2)) in women. All-cause and cardiovascular mortality differed across quartiles of serum uric acid in women only (P<0.001; hazard ratios for all-cause mortality 1.38 [95% confidence interval, 1.14-1.67] for the fourth quartile of serum uric acid compared with the first). Serum uric acid level was not associated with longitudinal blood pressure control in adults with treated hypertension but was related to decline in renal function and mortality in women.

The relationship between circadian blood pressure (BP) variations and the extent of subclinical cardiac organ damage is still debated. In a general population, we investigated the association of night-to-day BP fall, as well as nocturnal BP level (mean and lowest values), with left ventricular (LV) hypertrophy and the value of both BP parameters in predicting new-onset LV hypertrophy. Office BP, 24-hour ambulatory BP values, and laboratory investigations were assessed on entry in 1682 subjects (50.2% men; mean age, 50.2±13.7 years) of the Pressioni Arteriose Monitorate E Loro Associazioni. Echocardiographic LV mass was measured at the initial evaluation and 10 years later. Multiple regression analyses, including daytime systolic BP (SBP), age, sex, and body mass index, showed that the lowest SBP level and the extent of nocturnal SBP decline were independently related to baseline LV mass. After adjustment for several confounders, both mean nocturnal SBP (relative risk for each 10-mm Hg increase in SBP, 1.15; 95% confidence interval, 1.01-1.23; P<0.0001) and the lowest SBP level (relative risk for each 10-mm Hg increase in SBP, 1.10; 95% confidence interval, 1.02-1.19; P=0.01) were independent predictors of new-onset LV hypertrophy. This was not the case for the magnitude of nighttime SBP fall (hazard ratio for each 10% decrease in SBP, 0.91; 95% confidence interval, 0.80-1.04; P=0.18). In a general population, nighttime BP level rather than the nocturnal BP decline may be regarded as a reliable parameter for predicting the development of LV hypertrophy in subjects with normal LV mass. This finding may have important implications for optimizing cardiovascular prevention in the general population.

To clarify the genetic mechanisms of stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), a quantitative trait locus (QTL) analysis was performed. Using 295 F2 rats of a cross between SHRSP/Izm and SHR/Izm, 2 major QTLs for stroke latency under salt loading were identified on chromosomes (chr) 1 and 18. Evaluation of 6 reciprocal single and double congenic rats for these QTLs showed that substitution of the SHRSP for the SHR fragment at the chr 1 and 18 QTLs increased the relative risk for stroke by 8.4 and 5.0, respectively. The combined effect of the 2 QTLs was 10× greater than that of the background genome (by Cox hazard model). Blood pressure monitoring by radio telemetry indicated that the combination of the 2 QTLs had a clear effect on the salt-dependent blood pressure increase, suggesting an important role for the salt-sensitive blood pressure increase in the susceptibility of SHRSP to stroke. A haplotype analysis of 11 substrains of SHRSP and SHR using 340 simple sequence repeat markers in the chr 1 QTL suggested that the 7-Mbp fragment between D1Rat260 and D1Rat178 was most likely to harbor the responsible gene(s), which was confirmed by a study of additional subcongenic strains. This study indicated a major role for 2 QTLs on chr 1 and 18 in stroke susceptibility in SHRSP under salt loading. The salt-sensitive blood pressure increase was implied to play a key role in the stroke susceptibility.

We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00133692.

Studies in patients with an impaired efferent baroreflex led us to discover that ingesting water induces a robust increase in blood pressure and vascular resistance. This response was also present in healthy subjects with intact baroreflexes, described as osmopressor response. This study was to discover the physiology of the osmopressor response by determining functional activation of the aquaporin-1 water channel receptor on red blood cell membranes in young healthy subjects. In a randomized, controlled, crossover fashion, 22 young healthy subjects (age, 19-27 years) ingested either 500 or 50 mL of water. Heart rate, blood pressure, cardiac index, and total peripheral vascular resistance were measured using a Finometer hemodynamic monitor. Blood sampling was performed at 5 minutes before and at 25 and 50 minutes after either the water ingestion or control session. Immunoblotting for aquaporin-1 tyrosine phosphorylation was performed before and after subjects ingested either 500 or 50 mL of water. At 25 minutes after the ingestion of 500 mL of water, total peripheral resistance increased significantly, and plasma osmolality decreased. Functional expression of aquaporin-1 tyrosine phosphorylation on red blood cell membranes increased significantly at 25 and 50 minutes after subjects ingested 500 mL of water compared with that before water ingestion. This study concludes that water ingestion produces upregulation of aquaporin-1 tyrosine phosphorylation on red blood cell, which presents as a novel biological marker that occurs simultaneously with the osmopressor response.