Riociguat for Patients With Pulmonary Hypertension Caused by Systolic Left Ventricular Dysfunction: A Phase IIb Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Hemodynamic Study

Background— Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Methods and Results— Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (−6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min−1·m−2; 95% confidence interval, 0.2–0.5; P=0.0001) and stroke volume index (5.2 mL·m−2; 95% confidence interval, 2.0–8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (−46.6 dynes·s−1·cm−5; 95% confidence interval, –89.4 to –3.8; P=0.03) and systemic vascular resistance (−239.3 dynes·s−1·cm−5; 95% confidence interval, –363.4 to –115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups. Conclusions— Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.

Valsartan Improves Arterial Stiffness in Type 2 Diabetes Independently of Blood Pressure Lowering

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) ≥60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), −0.9 m/s (−1.4 to −0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of −15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.

Impact of current and past blood pressure on retinal arteriolar diameter in an older population

Objective To examine the effects of current and past blood pressure on retinal arteriolar diameter in a general older population. Design Cross-sectional and longitudinal studies. Setting Population-based cohort study of older residents from an area west of Sydney, Australia. Participants Two thousand three hundred and thirty-five individuals (n = 2335) (aged ⩾ 54 years) who attended the 5-year follow-up Blue Mountains Eye Study during 1997–99. Main outcome measures A computer-assisted method measured vessel diameters from digitized right eye retinal photographs. The narrowest quintile of central retinal arteriolar equivalent or arteriole-to-venule ratio (AVR) defined generalized arteriolar narrowing. Blood pressure was measured using a mercury sphygmomanometer. Results After simultaneous adjustment for age, sex, body mass index, smoking and current or past blood pressure, elevated levels of both current and past blood pressure were associated with narrower retinal arterioles [Ptrend = 0.009 and 0.007 for current and past systolic blood pressure (SBP), respectively] and lower AVR [Ptrend = 0.001 and 0.0009 for current and past diastolic blood pressure (DBP), respectively]. Generalized arteriolar narrowing was associated with both current blood pressure [adjusted odds ratio (OR) 2.4, 95% confidence interval (CI) 1.5–3.8 for the highest versus lowest quintile of current DBP] and past blood pressure (adjusted OR 1.7, 95% CI 1.1–2.6, for the highest versus lowest quintile of past DBP). Hypertension duration or control status at baseline had no additional effect on arteriolar diameter after adjusting for current blood pressure. Conclusions Our data document the independent effects of both current and past blood pressure on small vessel calibre in the retina, suggesting that retinal arteriolar narrowing may result from the cumulative effects of long-standing hypertension.

The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency.

Blood pressure and nutrition in adults. The National Health and Nutrition Examination Survey.

To provide a contemporary profile of blood pressure and nutritional and sociodemographic relationships in the adult US population, data from the first National Health and Nutrition Examination Survey ( NHANES -I), 1971-1975, were analyzed. Systolic and diastolic blood pressures increased with increasing age, but trends were different by sex and race groups. Body mass index (weight/ height2 ) was the nutritional factor most strongly and consistently related to blood pressure. Among dietary constituents, alcohol consumption and calcium and phosphorus intake were the only variables having consistent and independent relationships to blood pressure. Sodium content of food and salt use had no relationship, and sodium/potassium food content had only an inconsistent association. Regarding serum nutritional measures, serum calcium was directly related and serum phosphorus was inversely related to blood pressure. Serum urate, serum aspartate aminotransferase, and hemoglobin were also independently related to systolic and diastolic blood pressures. There were few important differences by race or sex in these correlates. These observations from a representative sample of the US population have useful implications for prevention and treatment of high blood pressure.

Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor.

Prostaglandins (PGs) are bioactive lipids that modulate a broad spectrum of biologic processes including reproduction and circulatory homeostasis. Although reproductive functions of mammals are influenced by PGs at numerous levels, including ovulation, fertilization, implantation, and decidualization, it is not clear which PGs are involved and whether a single mechanism affects all reproductive functions. Using mice deficient in 1 of 4 prostaglandin E2 (PGE2) receptors -- specifically, the EP2 receptor -- we show that Ep2(-/-) females are infertile secondary to failure of the released ovum to become fertilized in vivo. Ep2(-/-) ova could be fertilized in vitro, suggesting that in addition to previously defined roles, PGs may contribute to the microenvironment in which fertilization takes place. In addition to its effects on reproduction, PGE2 regulates regional blood flow in various vascular beds. However, its role in systemic blood pressure homeostasis is not clear. Mice deficient in the EP2 PGE2 receptor displayed resting systolic blood pressure that was significantly lower than in wild-type controls. Blood pressure increased in these animals when they were placed on a high-salt diet, suggesting that the EP2 receptor may be involved in sodium handling by the kidney. These studies demonstrate that PGE2, acting through the EP2 receptor, exerts potent regulatory effects on two major physiologic processes: blood pressure homeostasis and in vivo fertilization of the ovum.

Systematic Review: Blood Pressure Target in Chronic Kidney Disease and Proteinuria as an Effect Modifier

BACKGROUND The optimal blood pressure target in patients with chronic kidney disease (CKD) is unclear. PURPOSE To summarize trials comparing lower versus higher blood pressure targets in adult patients with CKD and focus on proteinuria as an effect modifier. DATA SOURCES MEDLINE and the Cochrane Central Register of Controlled Trials (July 2001 through January 2011) were searched for reports from randomized, controlled trials with no language restriction. STUDY SELECTION Authors screened abstracts to identify reports from trials comparing blood pressure targets in adults with CKD that had more than 50 participants per group; at least 1-year follow-up; and outcomes of death, kidney failure, cardiovascular events, change in kidney function, number of antihypertensive agents, and adverse events. DATA EXTRACTION Reviewers extracted data on study design, methods, sample characteristics, interventions, comparators, outcomes, number of medications, and adverse events and rated study quality and quality of analyses for proteinuria subgroups. DATA SYNTHESIS Three trials with a total of 2272 participants were included. Overall, trials did not show that a blood pressure target of less than 125/75 to 130/80 mm Hg is more beneficial than a target of less than 140/90 mm Hg. Lower-quality evidence suggests that a low target may be beneficial in subgroups with proteinuria greater than 300 to 1000 mg/d. Participants in the low target groups needed more antihypertensive medications and had a slightly higher rate of adverse events. LIMITATIONS No study included patients with diabetes. Trial duration may have been too short to detect differences in clinically important outcomes, such as death and kidney failure. Ascertainment and reporting of adverse events was not uniform. CONCLUSION Available evidence is inconclusive but does not prove that a blood pressure target of less than 130/80 mm Hg improves clinical outcomes more than a target of less than 140/90 mm Hg in adults with CKD. Whether a lower target benefits patients with proteinuria greater than 300 to 1000 mg/d requires further study.

Association Between Smoking and Blood Pressure: Evidence From the Health Survey for England

Cigarette smoking causes acute blood pressure (BP) elevation, although some studies have found similar or lower BPs in smokers compared with nonsmokers. Cross-sectional data from 3 years (1994 to 1996) of the annual Health Survey for England were used to investigate any difference in BP between smokers and nonsmokers in a nationally representative sample of adults (≥16 years old). Randomly selected adults (33 860; 47% men) with valid body mass index (BMI) and BP measurements provided data on smoking status (never, past, or current) and were stratified into younger (16 to 44 years old) and older (≥45 years old) age groups. Analyses provided between 89% and 94% power to detect a difference of 2 mm Hg systolic BP between smokers and nonsmokers in the 4 age/gender strata (&agr;=0.05). Older male smokers had higher systolic BP adjusted for age, BMI, social class, and alcohol intake than did nonsmoking men. No such differences were seen among younger men or for diastolic blood pressure in either age group. Among women, light smokers (1 to 9 cigarettes/d) tended to have lower BPs than heavier smokers and never smokers, significantly so for diastolic BP. Among men, a significant interaction between BMI and the BP-smoking association was observed. In women, BP differences between nonsmokers and light smokers were most marked in those who did not drink alcohol. These data show that any independent chronic effect of smoking on BP is small. Differences between men and women in this association are likely to be due to complex interrelations among smoking, alcohol intake, and BMI.

Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study.

BACKGROUND Small, short-term, intervention studies indicate that cocoa-containing foods improve endothelial function and reduce blood pressure. We studied whether habitual cocoa intake was cross-sectionally related to blood pressure and prospectively related with cardiovascular mortality. METHODS Data used were of 470 elderly men participating in the Zutphen Elderly Study and free of chronic diseases at baseline. Blood pressure was measured at baseline and 5 years later, and causes of death were ascertained during 15 years of follow-up. Habitual food consumption was assessed by the cross-check dietary history method in 1985, 1990, and 1995. Cocoa intake was estimated from the consumption of cocoa-containing foods. RESULTS One third of the men did not use cocoa at baseline. The median cocoa intake among users was 2.11 g/d. After adjustment, the mean systolic blood pressure in the highest tertile of cocoa intake was 3.7 mm Hg lower (95% confidence interval [CI], -7.1 to -0.3 mm Hg; P = .03 for trend) and the mean diastolic blood pressure was 2.1 mm Hg lower (95% CI, -4.0 to -0.2 mm Hg; P = .03 for trend) compared with the lowest tertile. During follow-up, 314 men died, 152 of cardiovascular diseases. Compared with the lowest tertile of cocoa intake, the adjusted relative risk for men in the highest tertile was 0.50 (95% CI, 0.32-0.78; P = .004 for trend) for cardiovascular mortality and 0.53 (95% CI, 0.39-0.72; P < .001) for all-cause mortality. CONCLUSION In a cohort of elderly men, cocoa intake is inversely associated with blood pressure and 15-year cardiovascular and all-cause mortality.

Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorder.

Blood pressure varies in relation to factors such as physical activity, body position, ambient temperature, and autonomic nervous system activity. Therefore, we have developed a portable multibiomedical (PMB) recorder that monitors five parameters: indirect blood pressure, physical activity, body position, ambient temperature, and RR interval of the electrocardiogram. In the present study, we applied the PMB recorder over a 24-hour period to study the effect of insufficient sleep on blood pressure in subjects doing extensive overtime work. The parameters listed above were measured by the PMB recorder throughout a normal workday (mean period of sleep, 8 hours) and throughout a day with insufficient sleep (mean period of sleep, 3.6 hours) in 18 male technical workers aged 23 to 48 years old. Blood pressure (mean systolic/diastolic pressure +/- SD) significantly increased the day after a sleep-insufficient night (129 +/- 8/79 +/- 6 mm Hg) compared with the day after a normal night (123 +/- 8/76 +/- 7 mm Hg, P<.05). However, ambient temperature, mean number of steps per minute, and percentage of time spent in a standing position showed no significant difference between these days. Spectral analysis of RR intervals showed that the ratio of the low-frequency component on the RR power spectrum (0.05 to 0.15 Hz) to the high-frequency component (0.15 to 0.40 Hz) was higher on the sleep-insufficient day (2.17 +/- 0.37 versus 1.81 +/- 0.37), as was the urinary excretion of norepinephrine (P<.05). Heart rate was significantly higher on the sleep-insufficient day (81 +/- ll versus 76 +/- 8 beats per minute), after the data of two subjects with abnormal levels of physical activity were excluded (P<.Ol). These data suggest that lack of sleep may increase sympathetic nervous system activity on the following day, leading to increased blood pressure. The PMB recorder was useful for precisely evaluating the relationship between blood pressure and environmental factors.

Prognostic value of 24-hour blood pressure variability

Objectives: Evaluation of the prognostic value of 24-h blood pressure averages and 24-h blood pressure variability. Design: After an initial thorough clinical and laboratory evaluation which included 24-h continuous ambulatory blood pressure monitoring, a group of hypertensive patients were re-examined after an average of 7.4 years. End-organ damage at the follow-up visit was related to different measures of blood pressure levels and variability obtained at the initial or the follow-up visit or both. Methods: Seventy-three patients with essential hypertension of variable severity, in whom ambulatory blood pressure was monitored intra-arterially for 24 h (Oxford technique) were re-examined at a follow-up visit (including echocardiographic assessment of left ventricular mass index) 4-13 years later (mean 7.4 years). The severity of end-organ damage was quantified by a score and related to clinic blood pressure at follow-up and to (1) clinic blood pressure, (2) 24-h blood pressure mean, (3) 24-h short-term and long-term blood pressure variability, and (4) end-organ damage, all assessed at the initial visit (multiple regression analysis). Results: The set of independent variables considered was significantly related to end-organ damage at follow-up (R = 0.51). The individual variables most important in determining end-organ damage at follow-up were clinic blood pressure at the follow-up visit (P < 0.01), the initial level of end-organ damage (P < 0.05) and long-term blood pressure variability (among half-hour standard deviation of 24-h mean blood pressure) at the initial evaluation (P < 0.05). The prognostic individual weight of the other haemodynamic parameters considered was less and not statistically significant. Conclusions: The results confirm that the level of blood pressure achieved by treatment and the degree of end-organ damage at the time of initial evaluation are important determinants of future end-organ damage related to hypertension. They also constitute the first longitudinal evidence that the cardiovascular complications of hypertension may depend on the degree of 24-h blood pressure variability.

A Randomized Controlled Trial of Team-Based Care: Impact of Physician-Pharmacist Collaboration on Uncontrolled Hypertension

ABSTRACTOBJECTIVEEvaluate the effectiveness of collaborative management of hypertension by primary care-pharmacist teams in community-based clinics.STUDY DESIGNA 12-month prospective, single-blind, randomized, controlled trial in the Providence Primary Care Research Network of patients with hypertension and uncontrolled blood pressure.METHODSAs compared to usual primary care, intervention consisted of pharmacy practitioners participating in the active management of hypertension in the primary care office according to established collaborative treatment protocols. At baseline, there was no significant difference in blood pressure between groups. Primary outcome measures were the differences in mean systolic and diastolic blood pressures between arms at study end. Secondary measures included blood pressure goal attainment (<140/90 mmHg), hypertension-related knowledge, medication adherence, home blood pressure monitoring, resource utilization, quality of life, and satisfaction.RESULTSA total of 463 subjects were enrolled (n = 233 control, n = 230 intervention). Subjects receiving the intervention achieved significantly lower systolic (p = 0.007) and diastolic (p = 0.002) blood pressures compared to control (137/75 mmHg vs. 143/78 mmHg). In addition, 62% of intervention subjects achieved target blood pressure compared to 44% of control subjects (p = 0.003). The intervention group received more total office visits (7.2 vs. 4.9, p < 0.0001), however had fewer physician visits (3.2 vs. 4.7, p < 0.0001) compared to control. Intervention subjects were prescribed more antihypertensive medications (2.7 vs. 2.4, p = 0.02), but did not take more antihypertensive pills per day (2.4 vs. 2.5, p = 0.87). There were minimal differences between groups in hypertension-related knowledge, medication adherence, quality of life, or satisfaction.CONCLUSIONSPatients randomized to collaborative primary care-pharmacist hypertension management achieved significantly better blood pressure control compared to usual care with no difference in quality of life or satisfaction.

Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group.

The relations between 24 hour urinary electrolyte excretion and blood pressure were studied in 10,079 men and women aged 20-59 sampled from 52 centres around the world based on a highly standardised protocol with central training of observers, a central laboratory, and extensive quality control. Relations between electrolyte excretion and blood pressure were studied in individual subjects within each centre and the results of these regression analyses pooled for all 52 centres. Relations between population median electrolyte values and population blood pressure values were also analysed across the 52 centres. Sodium excretion ranged from 0.2 mmol/24 h (Yanomamo Indians, Brazil) to 242 mmol/24 h (north China). In individual subjects (within centres) it was significantly related to blood pressure. Four centres found very low sodium excretion, low blood pressure, and little or no upward slope of blood pressure with age. Across the other 48 centres sodium was significantly related to the slope of blood pressure with age but not to median blood pressure or prevalence of high blood pressure. Potassium excretion was negatively correlated with blood pressure in individual subjects after adjustment for confounding variables. Across centres there was no consistent association. The relation of sodium to potassium ratio to blood pressure followed a pattern similar to that of sodium. Body mass index and heavy alcohol intake had strong, significant independent relations with blood pressure in individual subjects.

Seasonal variations in home and ambulatory blood pressure in the PAMELA population

Objective Clinic blood pressure values are known to change according to seasonal influences. We therefore examined home and 24 h ambulatory blood pressure values to determine whether these measurements are also affected by the seasons. Design and methods In 2051 subjects of the Pressione Arteriose Monitorate E Loro Associazioni (PAMELA) study, we measured clinic (sphygmomanometric measurements), home (semi-automatic device) and ambulatory (Spacelabs 90207) systolic blood pressure, diastolic blood pressure and heart rate. Because the overall sample was evenly distributed over each month (except August), we were able to make a cross-sectional determination of whether the values differed between seasons. The corresponding heart rates were also evaluated. Results As expected, summer was associated with the lowest clinic blood pressure and winter with the highest, and this was the case also for home and 24 h average blood pressure, although seasonal differences in the latter were less pronounced. Seasonal clinic, home and ambulatory blood pressure patterns were similar for normotensive subjects (n = 1152), untreated hypertensives (n = 540) and treated hypertensives (n = 359). Heart rate values did not differ by season. Conclusions Seasonal influences on blood pressure are not limited to conventional measurements but characterize daily values as well. These effects are visible in both normal and elevated blood pressure values, regardless of the effect of antihypertensive drugs. This has implications both for the clinician and for studies aimed at evaluating the effects of antihypertensive treatment.

Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study.

This article reports further analyses of the Hypertension Optimal Treatment (HOT) Study data with the aim to describe (1) the value of baseline serum creatinine and its clearance (estimated by Cockroft and Gault formula) as predictors of cardiovascular events, (2) the effects of intensive lowering of BP on cardiovascular events and renal function in patients with reduced renal function, and (3) the effects on cardiovascular events of adding acetylsalicylic acid to antihypertensive therapy in patients with reduced renal function. The results show that (1) baseline elevation in serum creatinine and a reduction in estimated creatinine clearance are powerful predictors of cardiovascular events and death. (2) Reduced renal function at baseline did not preclude the desired control of BP. In contrast to patients with normal renal function, the incidence of major cardiovascular events did not differ in the three groups of patients with mild renal insufficiency randomized to different diastolic BP targets. No significant changes in serum creatinine were seen at the end of the 3.8-yr treatment period in the great majority of patients. However, there was a small group of patients (0.58% of the total study population) whose renal function deteriorated (increase > or =30% over baseline and final serum creatinine concentration > or =2 mg/dl) despite satisfactory reduction of diastolic BP. (3) The results of this reanalysis of the HOT Study suggest though do not prove that the association of acetylsalicylic acid with intensive antihypertensive therapy offers additional benefit in hypertensive patients with reduced renal function.

Longitudinal study of blood pressure and white matter hyperintensities

Objective: To investigate the relationship between baseline hypertension and severity of white matter hyperintensities (WMH) at 4-year follow-up in a sample of subjects aged 59 to 71 years old at entry. Methods: Subjects were participants in the Epidemiology of Vascular Ageing study, a longitudinal study on vascular aging and cognitive decline. At 4-year follow-up, 845 subjects had a cerebral MRI. MRI examinations were read by a single rater to determine the severity of WMH, ranging from absent to severe. Hypertension at each wave of the study was defined as systolic blood pressure ≥160 mm Hg, diastolic blood pressure ≥95 mm Hg, or use of antihypertensive medication. Results: Hypertension at baseline was significantly associated with an increased risk of having severe WMH at 4-year follow-up. When taking into account both blood pressure levels and antihypertensive drug intake, analysis showed that the risk of having severe WMH was significantly reduced in subjects with normal blood pressure taking antihypertensive medication compared with those with high blood pressure taking antihypertensive agents. Cross-sectional relationships between hypertension and WMH at 4-year follow-up showed that the frequency of severe WMH was significantly higher in people who were hypertensive at both baseline and 4-year follow-up than those who were hypertensive only at 4-year follow-up. Conclusions: Hypertension is a major risk factor for severe WMH. Subjects taking antihypertensive drugs and who have controlled blood pressure had a reduced risk of severe WMH. Longitudinal studies are needed to investigate whether reduction of the development of WMH, by treatment and prevention of hypertension, might reduce the subsequent risk of cognitive deterioration or stroke.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

BACKGROUND Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING Medtronic.

A longitudinal study of the relationship between intraocular and blood pressures.

The relationship between intraocular and systemic blood pressures was investigated in a prospective study of 572 middle-aged men. There was no consistent relationship between intraocular pressure at first visit and age. Subjects with an intraocular pressure greater than 20 mm Hg had a significantly higher systolic blood pressure than controls matched for age. An autoregressive model was used to examine the relationship between change in intraocular pressure and initial intraocular pressure, age, and blood pressure. When the authors compared data obtained 1 or 2 years apart, a change in intraocular pressure was positively correlated with a change in systolic blood pressure. Thus, the results of this study indicate that changes in intraocular pressure over time are associated with changes in systolic blood pressure and that intraocular pressure does not necessarily increase with age.

Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3–GUCY1B3, NPR3–C5orf23, ADM, FURIN–FES, GOSR2, GNAS–EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Targeted Disruption of Soluble Epoxide Hydrolase Reveals a Role in Blood Pressure Regulation*

Renal microsomal cytochrome P-450 monooxygenase-dependent metabolism of arachidonic acid generates a series of regioisomeric epoxyeicosatrienoic acids that can be further metabolized by soluble epoxide hydrolase to the corresponding dihydroxyeicosatrienoic acids. Evidence exists that these metabolites affect renal function and, in particular, blood pressure regulation. To examine this possibility, blood pressure and renal arachidonic acid metabolism were examined in mice with a targeted disruption of the soluble epoxide hydrolase gene. Systolic blood pressure of male soluble epoxide hydrolase-null mice was lower compared with wild-type mice in both the absence and presence of dietary salt loading. Both female soluble epoxide hydrolase-null and wild-type female mice also had significantly lower systolic blood pressure than male wild-type mice. Renal formation of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids was markedly lower for soluble epoxide hydrolase-null versus wild-type mice of both sexes. Although disruption of soluble epoxide hydrolase in female mice had minimal effects on blood pressure, deletion of this gene feminized male mice by lowering systolic blood pressure and altering arachidonic acid metabolism. These data provide the first direct evidence for a role for soluble epoxide hydrolase in blood pressure regulation and identify this enzyme as a novel and attractive target for therapeutic intervention in hypertension.