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BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. [ABSTRACT FROM AUTHOR]

Concerns exist regarding the potential increased cardiovascular risk from lowering diastolic blood pressure (DBP) in hypertensive patients. We analyzed 30-year follow-up data of 10 355 hypertensive patients attending the Glasgow Blood Pressure Clinic. The association between blood pressure during the first 5 years of treatment and cause-specific hospital admissions or mortality was analyzed using multivariable adjusted Cox proportional hazard models. The primary outcome was a composite of cardiovascular admissions and deaths. DBP showed a U-shaped association (nadir, 92 mm Hg) for the primary cardiovascular outcome hazard and a reverse J-shaped association with all-cause mortality (nadir, 86 mm Hg) and noncardiovascular mortality (nadir, 92 mm Hg). The hazard ratio for the primary cardiovascular outcome after adjustment for systolic blood pressure was 1.38 (95% CI, 1.18-1.62) for DBP <80 compared with DBP of 80 to 89.9 mm Hg (referrant), and the subdistribution hazard ratio after accounting for competing risk was 1.33 (1.17-1.51) compared with DBP ≥80 mm Hg. Cause-specific nonfatal outcome analyses showed a reverse J-shaped relationship for myocardial infarction, ischemic heart disease, and heart failure admissions but a U-shaped relationship for stroke admissions. Age-stratified analyses showed DBP had no independent effect on stroke admissions among the older patient subgroup (≥60 years of age), but the younger subgroup showed a clear U-shaped relationship. Intensive blood pressure reduction may lead to unintended consequences of higher healthcare utilization because of increased cardiovascular morbidity, and this merits future prospective studies. Low on-treatment DBP is associated with increased risk of noncardiovascular mortality, the reasons for which are unclear. [ABSTRACT FROM AUTHOR]

Major depressive and bipolar disorders predispose to atherosclerosis, and there is accruing data from animal model, epidemiological, and genomic studies that commonly used antihypertensive drugs may have a role in the pathogenesis or course of mood disorders. In this study, we propose to determine whether antihypertensive drugs have an impact on mood disorders through the analysis of patients on monotherapy with different classes of antihypertensive drugs from a large hospital database of 525 046 patients with follow-up for 5 years. There were 144 066 eligible patients fulfilling the inclusion criteria: age 40 to 80 years old at time of antihypertensive prescription and medication exposure >90 days. The burden of comorbidity assessed by Charlson and Elixhauser scores showed an independent linear association with mood disorder diagnosis. The median time to hospital admission with mood disorder was 847 days for the 299 admissions (641 685 person-years of follow-up). Patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had the lowest risk for mood disorder admissions, and compared with this group, those on β-blockers (hazard ratio=2.11; [95% confidence interval, 1.12-3.98]; P=0.02) and calcium antagonists (2.28 [95% confidence interval, 1.13-4.58]; P=0.02) showed higher risk, whereas those on no antihypertensives (1.63 [95% confidence interval, 0.94-2.82]; P=0.08) and thiazide diuretics (1.56 [95% confidence interval, 0.65-3.73]; P=0.32) showed no significant difference. Overall, our exploratory findings suggest possible differential effects of antihypertensive medications on mood that merits further study: calcium antagonists and β-blockers may be associated with increased risk, whereas angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be associated with a decreased risk of mood disorders. [ABSTRACT FROM AUTHOR]

There is accruing evidence from general population studies that serum bilirubin and liver enzymes affect blood pressure (BP) and cardiovascular risk, but it is unclear whether these have an impact on hypertensive patients in terms of long-term survival or BP control. We analyzed 12 000 treated hypertensive individuals attending a tertiary care clinic followed up for 35 years for association between baseline liver function tests and cause-specific mortality after adjustment for conventional cardiovascular covariates. Generalized estimating equations were used to study the association of liver tests and follow-up BP. The total time at risk was 173 806 person years with median survival 32.3 years. Follow-up systolic BP over 5 years changed by -0.4 (alanine transaminase and bilirubin), +2.1(alkaline phosphatase), +0.9(γ- glutamyl transpeptidase) mm Hg for each standard deviation increase. Serum total bilirubin and alanine transaminase showed a significant negative association with all-cause and cardiovascular mortality, whereas alkaline phosphatase and γ-glutamyl transpeptidase showed a positive association and aspartate transaminase showed a U-shapedassociation. Serum bilirubin showed an incremental improvement of continuous net reclassification improvement by 8% to 26% for 25 year and 35 year cardiovascular mortality, whereas all liver markers together improved continuous net reclassification improvement by 19% to 47% compared with reference model. In hypertensive patients, serum liver enzymes and bilirubin within 4 standard deviations of the mean show independent effects on mortality and BP control. Our findings would support further studies to elucidate the mechanisms by which liver enzymes and bilirubin may exert an effect on BP and cardiovascular risk, but there is little support for using them in risk stratification. [ABSTRACT FROM AUTHOR]

Hypertension is a key risk factor for cardiovascular disease, and new treatments are needed. Uric acid reduction lowers blood pressure (BP) in adolescents, suggesting a direct pathophysiological role in the development of hypertension. Whether the same relationship is present in older adults is unknown. We explored change in BP after allopurinol initiation using data from the UK Clinical Practice Research Datalink. Data were extracted for patients with hypertension aged >65 years who were prescribed allopurinol with pretreatment and during treatment BP readings. Data from comparable controls were extracted. The change in BP in patients with stable BP medication was the primary outcome and was compared between groups. Regression analysis was used to adjust for potential confounding factors, and a propensity-matched sample was generated. Three hundred sixty-five patients who received allopurinol and 6678 controls were included. BP fell in the allopurinol group compared with controls (between-group difference in systolic and diastolic BP: 2.1 mmHg; 95% confidence interval, -0.6 to 4.8; and 1.7 mmHg; 95% confidence interval, 0.4-3.1, respectively). Allopurinol use was independently associated with a fall in both systolic and diastolic BP on regression analysis (P<0.001). Results were consistent in the propensity-matched sample. There was a trend toward greater fall in BP in the high-dose allopurinol group, but change in BP was not related to baseline uric acid level. Allopurinol use is associated with a small fall in BP in adults. Further studies of the effect of high-dose allopurinol in adults with hypertension are needed. [ABSTRACT FROM AUTHOR]

Chloride (C1-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary C1- intake increases blood pressure, yet paradoxically, higher serum C1- appears associated with lower mortality and cardiovascular risk. This implies that serum C1- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum C1- was an independent predictor of mortality. To distinguish the effect of C1- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+/HCO3- and C1- levels. Generalized estimating equation was used to determine the effect of baseline C1- on follow-up blood pressure. The total time at risk was 197 101 person-years. The lowest quintile of serum C1- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum C1- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+, and HCO3- levels. The group with Na+>135 and CI->100 had the best survival, and compared with this group, the Na+>135 and CI-<100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum C1- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between C1- and risk. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor. The implication of this variability in hypertension clinical practice is unclear. BPV as average real variability (ARV) was calculated in 14,522 treated patients with hypertension in 4 time frames: year 1 (Y1), years 2 to 5 (Y2-5), years 5 to 10 (Y5-10), and years >10 (Y10+) from first clinic visit. Cox proportional hazards models for cause-specific mortality were used in each time frame separately for long-term BPV, across time frames based on ultra long-term BPV, and within each time frame stratified by mean BP. ARV in systolic blood pressure (SBP), termed ARV(SBP), was higher in Y1 (21.3±11.9 mm Hg) in contrast to Y2-5 (17.7±9.9 mm Hg), Y5-10 (17.4±9.6 mm Hg), and Y10+ (16.8±8.5 mm Hg). In all time frames, ARV(SBP) was higher in women (P<0.01) and in older age (P<0.001), chronic kidney disease (P<0.01), and prevalent cardiovascular disease (P<0.01). Higher long-term and ultra long-term BPV values were associated with increased mortality (all-cause, cardiovascular, and noncardiovascular mortality; P for trend, <0.001). This relationship was also evident in subgroups with mean SBP<140 mm Hg in all time frames. Monitoring BPV in clinical practice may facilitate risk reduction strategies by identifying treated hypertensive individuals at high risk, especially those with BP within the normal range. [ABSTRACT FROM AUTHOR]

Very few studies have looked at longitudinal intraindividual blood pressure responses to weather conditions. There are no data to suggest that specific response to changes in weather will have an impact on survival. We analyzed >169000 clinic visits of 16010 Glasgow Blood Pressure Clinic patients with hypertension. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) data. Percentage change in blood pressure was calculated between pairs of consecutive clinic visits, where the weather alternated between 2 extreme quartiles (Q1-Q4 or Q4-Q1) or remained in the same quartile (Qn-Qn) of each weather parameter. Subjects were also categorized into 2 groups depending on whether their blood pressure response in Q1-Q4 or Q4-Q1 were concordant or discordant to Qn-Qn- Generalized estimating equations and Cox proportional hazards model were used to model the effect on longitudinal blood pressure and mortality, respectively. Qn-Qn showed a mean 2% drop in blood pressure consistently, whereas Q4-Q1 showed a mean 2.1% and 1.6% rise in systolic and diastolic blood pressure, respectively. However, Q1-Q4 did not show significant changes in blood pressure. Temperature-sensitive subjects had significantly higher mortality (1.35 [95% confidence interval, 1.06-1.71]; P=0.01) and higher follow-up systolic blood pressure (1.85 [95% confidence interval, 0.24-3.46]; P=0.02) compared with temperature-nonsensitive subjects. Blood pressure response to temperature may be one of the underlying mechanisms that determine long-term blood pressure variability. Knowing a patient's blood pressure response to weather can help reduce unnecessary antihypertensive treatment modification, which may in turn increase blood pressure variability and, thus, risk. [ABSTRACT FROM AUTHOR]

This article describes a study which examined the association between hematocrit and long-term mortality in hypertensive patients to determine the sex-specific differences in risk posed by hematocrit after the initiation of antihypertensive treatment. Researchers utilized data from the Glasgow Blood Pressure Clinic in Scotland. They discovered an increased risk of death attributed to higher hematocrit in both men and women irrespective of their achievement of target blood pressure.

Background: Very few studies have looked at longitudinal BP changes in relation to weather variation. There is no data to suggest that specific BP response to changes in weather have an impact on survival.METHODS: We analysed >169000 clinic visits of 16000 Glasgow BP Clinic hypertensive patients. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) from meteorological data. Analyses were restricted to pairs of consecutive clinic visits where the weather alternated between two extreme quartiles (Q1->Q4 or Q4->Q1) or remained in the same quartile (Qn->Qn) of each weather parameter. The BP phenotype analysed was the percent change in SBP and DBP between two consecutive clinic measurements at least 30 days apart and within each year. The %ΔBP between groups were tested using paired-T tests. Subjects were categorised into two groups depending on Q1->Q4 or Q4->Q1 BP response compared to Qn->Qn (concordant or discordant). Generalised estimating equations and Cox proportional hazards model were used to model the effect on longitudinal BP and mortality respectively.Results: For temperature, visits Qn->Qn showed a mean 2% drop in BP consistently while Q4->Q1 showed a mean 4% rise in SBP and Q1->Q4 elicited variable changes in BP around 0. Compared to subjects with a concordant BP response to temperature, those who showed a discordant response had significantly higher mortality (1.35 [95% CI :1.06-.71];p=0.01) and higher follow-up SBP (1.85 [0.24-3.46]; p=0.02).Conclusions: Variation in weather has a complex relationship to longitudinal BP and response to weather fluctuations is a predictor of long-term risk and BP control. [ABSTRACT FROM AUTHOR]

Objectives: Extremes of serum Na+, K+ and HCO3 have been associated with poorer outcomes. The role of serum Cl- has been largely considered to be linked to serum Na+ and HCO3 levels.Design and Methods: We studied the association of serum and other serum electrolytes in relation to mortality outcomes in 13,415 hypertensive patients attending the Glasgow Blood Pressure Clinic (GBPC) with serum Cl- assessed at the registration visit. Cox proportional hazards (Cox-PH) models were used for survival analysis. To determine whether Cl- effects are independent of low serum sodium, we performed the analysis in subjects with Na+ >135 and stratified by Na+ and Cl- levels.Results: The total time at risk was 197,101 person years during which 3,373 all-cause deaths occurred. Compared to quintile 1 (Cl-<=100), each higher quintile of Cl- was associated with lower mortality (H.R.[95%C.I.]0.82[0.74-0.90];0.79[0.71-0.87];0.79[0.70-0.89];0.80[0.68-0.93]) after adjustment for all conventional risk factors, other serum electrolytes and diuretic use (Figure-1). In the subset with Na+>135, each unit increase in Cl- was associated with a 3% reduction in mortality(H.R =0.97 CI:0.96-0.98). Finally subjects with Na+>135&Cl->100(reference) had the best survival and those with Na+<135 and Cl-<100 the poorest survival. The group with normal Na+>135 and Cl-<100 had significantly higher mortality than the reference group (1.21[1.11-1.31]).Conclusion: Serum Cl- independently predicts mortality outcomes in the hypertensive population irrespective of serum Na+, K+ and HCO3 levels. [ABSTRACT FROM AUTHOR]