Mark A. Supiano

Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial

IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206062.

Progressive handgrip exercise: evidence of nitric oxide-dependent vasodilation and blood flow regulation in humans

In the peripheral circulation, nitric oxide (NO) is released in response to shear stress across vascular endothelial cells. We sought to assess the degree to which NO contributes to exercise-induced vasodilation in the brachial artery (BA) and to determine the potential of this approach to noninvasively evaluate NO bioavailability. In eight young (25 ± 1 yr) healthy volunteers, we used ultrasound Doppler to examine BA vasodilation in response to handgrip exercise (4, 8, 12, 16, 20, and 24 kg) with and without endothelial NO synthase blockade [intra-arterial N(G)-monomethyl-L-arginine (L-NMMA), 0.48 mg · dl(-1) · min(-1)]. Higher exercise intensities evoked significant BA vasodilation (4-12%) that was positively correlated with the hyperemic stimulus (r = 0.98 ± 0.003, slope = 0.005 ± 0.001). During NO blockade, BA vasodilation at the highest exercise intensity was reduced by ∼70% despite similar exercise-induced increases in shear rate (control, +224 ± 30 s(-1); L-NMMA, +259 ± 46 s(-1)). The relationship and slope of BA vasodilation with increasing shear rate was likewise reduced (r = 0.48 ± 0.1, slope = 0.0007 ± 0.0005). We conclude that endothelial NO synthase inhibition with L-NMMA abolishes the relationship between shear stress and BA vasodilation during handgrip exercise, providing clear evidence of NO-dependent vasodilation in this experimental model. These results support this paradigm as a novel and valid approach for a noninvasive assessment of NO-dependent vasodilation in humans.

Characterizing Frailty Status in the Systolic Blood Pressure Intervention Trial

BACKGROUND The Systolic Blood Pressure Intervention Trial (SPRINT) is testing whether a lower systolic blood pressure (BP) target of 120 mm Hg leads to a reduction in cardiovascular morbidity and mortality among hypertensive, nondiabetic adults. Because there may be detrimental effects of intensive BP control, particularly in older, frail adults, we sought to characterize frailty within SPRINT to address ongoing questions about the ability of large-scale trials to enroll representative samples of noninstitutionalized, community-dwelling, older adults. METHODS We constructed a 36-item frailty index (FI) in 9,306 SPRINT participants, classifying participants as fit (FI ≤ 0.10), less fit (0.10 < FI ≤ 0.21), or frail (FI > 0.21). Recurrent event models were used to evaluate the association of the FI with the incidence of self-reported falls, injurious falls, and all-cause hospitalizations. RESULTS The distribution of the FI was comparable with what has been observed in population studies, with 2,570 (27.6%) participants classified as frail. The median FI was 0.18 (interquartile range = 0.14 to 0.24) in participants aged 80 years and older (N = 1,159), similar to the median FI of 0.17 reported for participants in the Hypertension in the Very Elderly Trial. In multivariable analyses, a 1% increase in the FI was associated with increased risk for self-reported falls (hazard ratio [HR] = 1.030), injurious falls (HR = 1.035), and all-cause hospitalizations (HR = 1.038) (all p values < .0001). CONCLUSIONS Large clinical trials assessing treatments to reduce cardiovascular disease risk, such as SPRINT, can enroll heterogeneous populations of older adults, including the frail elderly, comparable with general population cohorts.

Differential Effects of Raloxifene and Estrogen on Insulin Sensitivity in Postmenopausal Women

OBJECTIVES: To test the hypothesis that both raloxifene and estrogen would improve insulin sensitivity in postmenopausal women and that the magnitude of the effect would be similar for both drugs.

Impact of Aldosterone Receptor Blockade Compared With Thiazide Therapy on Sympathetic Nervous System Function in Geriatric Hypertension

Aldosterone receptor blockade and thiazide therapy effectively lower blood pressure in geriatric hypertension. Their impact on sympathetic nervous system function has not been evaluated. In a double-blind, randomized study, 36 patients with stage 1 hypertension underwent 6 months of therapy with either aldosterone receptor blockade (spironolactone, n=19; 68±1 years) or hydrochlorothiazide (n=17; 68±2 years). Arterial blood pressure, [3H]-norepinephrine (NE) kinetics (extravascular NE release rate), and &agr;-adrenergic responsiveness (forearm vasoconstriction to graded intrabrachial artery NE infusions) were evaluated at baseline, after a 4-week antihypertensive medication withdrawal, and after spironolactone or hydrochlorothiazide treatment. Arterial blood pressure decreased significantly with both spironolactone (160±3 to 134±2 mm Hg; 77±2 to 68±2 mm Hg) and hydrochlorothiazide (161±4 to 145±4 mm Hg; 78±2 to 73±2 mm Hg) treatment. Sympathetic nervous system activity was significantly reduced after spironolactone (plasma NE: 378±40 to 335±20 pg/mL, P=0.04; [3H]-NE release rate: 2.74±0.3 to 1.97±0.2 &mgr;g/min per meter squared, P=0.04) but not hydrochlorothiazide (plasma NE: 368±25 to 349±23 pg/mL, P=0.47; [3H]-NE release rate: 2.63±0.4 to 2.11±0.2 mg/min per meter squared, P=0.21). &agr;-Adrenergic responsiveness was unchanged with either drug treatment. These findings demonstrate a beneficial effect of aldosterone receptor blockade on reducing sympathetic nervous system activity and blood pressure in hypertensive older patients.

Does Brachial Artery Flow–Mediated Vasodilation Provide a Bioassay for NO?

This study sought to better define the role of nitric oxide (NO) in brachial artery flow-mediated vasodilation (FMD) in young, healthy humans. Brachial artery blood velocity and diameter were determined (ultrasound Doppler) in eight volunteers (26 ± 1 yrs) before and after 5-min forearm circulatory occlusion with and without intra-arterial infusion of the endothelial nitric oxide synthase (eNOS) inhibitor L-NMMA (0.48 mg/dl/min). Control (CON) and L-NMMA trials were performed with the occlusion cuff placed in the traditional distal position, as well as proximal to the measurement site. FMD was significantly reduced, but not abolished, by L-NMMA in the distal cuff trial (8.9 ± 1.3 to 6.0 ± 0.7%, CON vs. L-NMMA, P = 0.02), with no effect of L-NMMA on FMD with proximal cuff placement (10.6 ± 1.2 to 12.4 ± 1.7%, CON vs. L-NMMA, P = 0.39). When the reduction in shear stimulus following L-NMMA was taken into account, no drug difference was observed for either distal (0.26 ± 0.02 to 0.23 ± 0.03, CON vs. L-NMMA, P = 0.40) or proximal (0.23 ± 0.08 to 0.23 ± 0.03, CON vs. L-NMMA, P = 0.89) FMD trials. These findings challenge the assertion that NO is obligatory for brachial artery FMD, and call into question the sensitivity of this procedure for non-invasive determination of NO bioavailability in young, healthy humans.This study sought to better define the role of NO in brachial artery flow–mediated vasodilation (FMD) in young, healthy humans. Brachial artery blood velocity and diameter were determined (ultrasound Doppler) in 8 volunteers (26±1 year) before and after 5-minute forearm circulatory occlusion with and without intra-arterial infusion of the endothelial NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 0.48 mg/dL per minute). Control (CON) and L-NMMA trials were performed with the occlusion cuff placed in the traditional distal position, as well as proximal to the measurement site. FMD was significantly reduced, but not abolished, by L-NMMA in the distal cuff trial (8.9±1.3%–6.0±0.7%, CON versus L-NMMA; P=0.02), with no effect of L-NMMA on FMD with proximal cuff placement (10.6±1.2%–12.4±1.7%, CON versus L-NMMA; P=0.39). When the reduction in shear stimulus after L-NMMA was taken into account, no drug difference was observed for either distal (0.26±0.02–0.23±0.03, CON versus L-NMMA; P=0.40) or proximal (0.23±0.08–0.23±0.03, CON versus L-NMMA; P=0.89) FMD trials. These findings challenge the assertion that NO is obligatory for brachial artery FMD and call into question the sensitivity of this procedure for noninvasive determination of NO bioavailability in young, healthy humans.

Alterations in Platelet Function During Aging: Clinical Correlations with Thromboinflammatory Disease in Older Adults

Platelets have a dynamic functional repertoire that mediates hemostatic and inflammatory responses. Many of these functions are altered in older adults, promoting a prothrombotic, proinflammatory milieu and contributing to risk of adverse clinical events. Drawing primarily from human studies, this review summarizes important aspects of aging‐related changes in platelets. The relationship between altered platelet functions and thrombotic and inflammatory disorders in older adults is highlighted. Established and developing antiplatelet therapies for the treatment of thrombotic and inflammatory disorders are also discussed in light of these data.

Role of angiotensin converting enzyme genotype in sodium sensitivity in older hypertensives.

BACKGROUND Individuals differ in their blood pressure (BP) response to changes in dietary sodium (Na+) intake. It is possible that differences in BP responses to dietary Na+ are influenced by genes. METHODS A total of 35 older (62.9 +/- 1.2 years) hypertensive subjects had their mean arterial blood pressure (MABP) determined after 8 days of low (20 mmol/day) and high (200 mmol/day) Na+ intake. The insertion/ deletion polymorphism of the angiotensin converting enzyme (ACE) gene was genotyped with standard polymerase chain reaction methods. RESULTS Of the 35 subjects, 24 were classified as sodium-sensitive (> or = 5 mm Hg increase in MABP in response to the increase in dietary Na+) and 11 were classified as sodium-resistant (<5 mm Hg increase in MABP). Those homozygous for the insertion allele of the ACE gene (insertion/insertion [II]; n = 8) had lower (P = .04) MABP responses to the increase in dietary Na+ (0 +/- 3 mm Hg) compared to heterozygotes (insertion/deletion [ID]; n = 20) (9 +/- 2 mm Hg; P = .0001) and those homozygous for the deletion allele (deletion/deletion [DD]; n = 7) (9 +/- 3 mm Hg; P = .05). The prevalence of sodium sensitivity was higher (P = .0083) in DD (71%) and ID (83%) compared to II (25%) genotype groups. CONCLUSIONS Based on these data in older hypertensive individuals, we conclude that the ACE gene ID and DD genotypes are associated with an increase in BP during a high Na+ diet, which is consistent with the phenotypic characteristic of sodium sensitivity.

Insulin sensitivity is associated with blood pressure response to sodium in older hypertensives.

The purpose of this study was to determine whether sodium-resistant hypertensives are more insulin resistant and whether dietary sodium restriction improves insulin sensitivity in older hypertensives. Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test to determine the insulin sensitivity index (SI) after 1 wk each of low- (20 mmol ⋅ l-1 ⋅ day-1) and high- (200 mmol ⋅ l-1 ⋅ day-1) sodium diets in 21 older (63 ± 2 yr) hypertensives. Subjects were grouped on the difference in mean arterial blood pressure (MABP) between diets [sodium sensitive (SS): ≥5-mmHg increase in MABP on the high-sodium diet ( n = 14); sodium resistant (SR): <5-mmHg increase in MABP on the high-sodium diet ( n = 7)]. There was no dietary sodium effect on fasting plasma insulin or SI. An analysis of variance indicated a significant ( P = 0.0002) group effect, with SS individuals having lower fasting plasma insulins on the low- (13 ± 2 vs. 27 ± 3 μU/ml) and high- (12 ± 2 vs. 22 ± 3 μU/ml) sodium diets compared with SR individuals. Similarly, there was a significant ( P= 0.0002) group effect in regard to SI, with SS individuals having significantly higher SI on the low- (3.26 ± 0.60 vs. 0.91 ± 0.31 μU × 10-4 ⋅ min-1 ⋅ ml-1) and high- (3.45 ± 0.51 vs. 1.01 ± 0.30 μU × 10-4 ⋅ min-1 ⋅ ml-1) sodium diets compared with SR individuals. We conclude that SR individuals exhibit a greater degree of insulin resistance than SS individuals and that dietary sodium restriction fails to improve insulin sensitivity regardless of sodium sensitivity status.The purpose of this study was to determine whether sodium-resistant hypertensives are more insulin resistant and whether dietary sodium restriction improves insulin sensitivity in older hypertensives. Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test to determine the insulin sensitivity index (SI) after 1 wk each of low- (20 mmol.l-1.day-1) and high- (200 mmol.l-1.day-1) sodium diets in 21 older (63 +/- 2 yr) hypertensives. Subjects were grouped on the difference in mean arterial blood pressure (MABP) between diets [sodium sensitive (SS): > or = 5-mmHg increase in MABP on the high-sodium diet (n = 14); sodium resistant (SR): < 5-mmHg increase in MABP on the high-sodium diet (n = 7)]. There was no dietary sodium effect on fasting plasma insulin or SI. An analysis of variance indicated a significant (P = 0.0002) group effect, with SS individuals having lower fasting plasma insulins on the low- (13 +/- 2 vs. 27 +/- 3 microU/ml) and high- (12 +/- 2 vs. 22 +/- 3 microU/ml) sodium diets compared with SR individuals. Similarly, there was a significant (P = 0.0002) group effect in regard to SI, with SS individuals having significantly higher SI on the low- (3.26 +/- 0.60 vs. 0.91 +/- 0.31 microU x 10(-4).min-1.ml-1) and high- (3.45 +/- 0.51 vs. 1.01 +/- 0.30 microU x 10(-4).min-1.ml-1) sodium diets compared with SR individuals. We conclude that SR individuals exhibit a greater degree of insulin resistance than SS individuals and that dietary sodium restriction fails to improve insulin sensitivity regardless of sodium sensitivity status.

Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes

BACKGROUND The previously published results of the Systolic Blood Pressure Intervention Trial showed that among participants with hypertension and an increased cardiovascular risk, but without diabetes, the rates of cardiovascular events were lower among those who were assigned to a target systolic blood pressure of less than 120 mm Hg (intensive treatment) than among those who were assigned to a target of less than 140 mm Hg (standard treatment). Whether such intensive treatment affected patient‐reported outcomes was uncertain; those results from the trial are reported here. METHODS We randomly assigned 9361 participants with hypertension to a systolic blood‐pressure target of less than 120 mm Hg or a target of less than 140 mm Hg. Patient‐reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12‐Item Health Survey, the Patient Health Questionnaire 9‐item depression scale (PHQ‐9), patient‐reported satisfaction with their blood‐pressure care and blood‐pressure medications, and adherence to blood‐pressure medications. We compared the scores in the intensive‐treatment group with those in the standard‐treatment group among all participants and among participants stratified according to physical and cognitive function. RESULTS Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ‐9 scores were relatively stable over a median of 3 years of follow‐up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood‐pressure care was high in both treatment groups, and we found no significant difference in adherence to blood‐pressure medications. CONCLUSIONS Patient‐reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.)