Renal Sympathetic Denervation: Early Impact on Ambulatory Resistant Hypertension

Although guidelines recommend ambulatory blood pressure (BP) monitoring (ABPM), few data are available regarding the effects of renal denervation (RDN) on 24‐hour ABPM values. A total of 44 patients with mean systolic BP ≥135 mm Hg on ABPM despite adequate therapy were included. Basal systolic BP (SBP) and diastolic BP (DBP) were 154±11 mm Hg and 86±12 mm Hg, respectively. At 1 month, SBP and DBP were reduced to 146±18 mm Hg (P=.01) and 82±14 mm Hg and showed no further decrease up to 6 months. Only 55% of the patients responded to RDN (≥−5 mm Hg SBP), with a mean responder rate drop of 21/11 mm Hg. Neither the number of ablation points nor the amount of impedance drop was predictive of response. Only approximately half of patients with resistant hypertension responded to RDN. However, in these responders, a remarkable reduction of 24‐hour BP occurred as early as 1 month after RDN.

Hypertension is a major cardiovascular (CV) risk factor affecting one quarter of the adult population in Western societies.¹ Up to 12% of patients have resistant hypertension, defined as uncontrolled systolic blood pressure (SBP) despite therapy with ≥3 different antihypertensive agents, including a diuretic.², ³ Until now, surgical sympathectomy has been reported to significantly reduce blood pressure (BP) in resistant hypertension; however, perioperative morbidity was high.⁴, ⁵ By showing that percutaneous endovascular renal denervation (RDN) could represent a safe and effective alternative, the Symplicity HTN‐1 and HTN‐2 trials for resistant hypertension recently renewed interest in sympathectomy.⁶, ⁷ The proof‐of‐concept study with the Simplicity catheter has led to a series of trials—recently also conducted with improved catheter systems—to investigate the effects of this invasive approach.⁸, ⁹, ¹⁰, ¹¹ All studies consistently determined reductions in systolic and diastolic office BP values.⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³ In addition, beneficial impact on sleep apnea, glucose intolerance, heart function, renal function, and rhythm disorders have been reported.¹⁴, ¹⁵, ¹⁶, ¹⁷ Until now, few data have become available with regard to the effects of RDN on resistant hypertension as verified in ambulatory BP monitoring (ABPM)⁸, ¹³, ¹⁸, ¹⁹, ²⁰the procedure recommended by guidelines and the literature for accurate evaluation of hypertension and for exclusion of pseudoresistance.²¹, ²² It has been clearly demonstrated that ABPM avoids overestimation and underestimation of BP and is also associated with risk prediction for CV events.²³, ²⁴, ²⁵ In the present study, we analyzed the effect of RDN on 24‐hour ABPM values up to a follow‐up of 6 months for better appraisal of BP changes.     

Masked Hypertension Defined by Home Blood Pressure Monitoring Is Associated With Impaired Flow‐Mediated Vasodilatation in Patients With Cardiovascular Risk Factors

The relationships between home blood pressure (BP), masked hypertension defined by home BP, and integrated flow‐mediated vasodilation (FMD) response remain unclear. The authors enrolled 257 patients (mean age, 63.5 years; 51% men) who had at least one cardiovascular risk factor. FMD of the brachial artery was measured with a semiautomatic edge‐detection algorithm. The integrated FMD response was calculated as the area under the dilation curve during 120 seconds after deflation (FMD‐AUC ₁₂₀) and the FMD magnitude as the percentage change in peak diameter (ΔFMD). Masked hypertension was defined by office BP <140/90 mm Hg and home BP ≥135 mm Hg and/or 85 mm Hg. Home systolic BP was inversely correlated with FMD‐AUC ₁₂₀ and ΔFMD (FMD‐AUC ₁₂₀: r=−.23, P<.001; ΔFMD: r=−.13, P=.041), and office systolic BP was inversely associated with FMD‐AUC ₁₂₀ (r=−.16, P=.011), but not with ΔFMD. After adjusting for covariates, home systolic BP (β=−.27, P=.003), but not office BP, was inversely associated with FMD‐AUC ₁₂₀, whereas ΔFMD was not associated with office or home systolic BP. FMD‐AUC ₁₂₀ was significantly lower in patients with masked hypertension compared with those with normotension (7.7±6.7 vs 11.5±8.8 mm × s, P=.048). Home systolic BP and masked hypertension defined by home BP were associated with a decrease in FMD‐AUC ₁₂₀.

In recent years, the importance of out‐of‐office blood pressure (BP) measurement has been widely known,¹, ², ³, ⁴ and many reports have shown that self‐measured home BP could predict cardiovascular (CV) events better than office BP.⁵, ⁶, ⁷ When guided by only office BP, control of BP might be insufficient to prevent CV events.⁸ Masked hypertension defined by normal office BP and high ambulatory BP has been associated with CV events.⁹, ¹⁰ On the other hand, masked hypertension defined by normal office BP and high home BP has also been shown to be associated with an increased risk of CV events,¹¹, ¹², ¹³ hypertensive organ damage, and atherosclerosis.¹⁴, ¹⁵ Consequently, home BP has been established as the determinant of masked hypertension.¹⁶ A decrease in flow‐mediated vasodilation (FMD) has been shown to predict CV events¹⁷ and hypertensive organ damage.¹⁸ FMD analyses have been widely performed, and a decrease of FMD has been shown to reflect endothelial dysfunction.¹⁹, ²⁰, ²¹, ²² Two studies showed an association between a decrease in FMD and masked hypertension defined by normal office BP and high ambulatory BP.²³, ²⁴ To date, the integrated FMD response has been measured by time‐course analysis using continuous measurement in addition to the traditional FMD magnitude, which was calculated as the percentage change in peak diameter from the resting baseline diameter. Although there have also been some reports on the association between CV risk and the integrated FMD response,²⁵, ²⁶ previous reports did not investigate the association between masked hypertension and the integrated FMD response. Thus, the association between masked hypertension defined by home BP and the integrated FMD response remains unclear.In this study, we hypothesized that home BP and masked hypertension defined by home BP would be associated with integrated FMD response in patients with a CV risk factor.     

Obstructive Sleep Apnea Using Watch‐PAT 200 Is Independently Associated With an Increase in Morning Blood Pressure Surge in Never‐Treated Hypertensive Patients

This study aimed to examine the association between obstructive sleep apnea (OSA) and morning blood pressure surge in never‐treated patients with essential hypertension. This prospective study included a total of 58 patients (mean age, 51.7 years; 55.2% men) with never‐treated essential hypertension. The patients were divided into non‐OSA (n=23, 49.3±12.7 years) and OSA (n=35, 53.2±9.8 years) groups. The OSA group was defined as having an apnea‐hypopnea index level >5 as measured by the Watch‐PAT 200. The authors collected 24‐hour ambulatory BP, plasma aldosterone concentration, and plasma renin activity data from all of the patients. The measured sleep‐trough morning systolic blood pressure (SBP) increases were higher in the OSA group than in the non‐OSA group (28.7±11.8 mm Hg vs 19.6±12.8 mm Hg, P=.008). The sleep‐trough morning SBP increase was inversely correlated with the lowest oxygen saturation (r=−0.272, P=.039). OSA known to be associated with increased daytime and nocturnal sympathetic activity was associated with significantly higher sleep‐trough morning SBP levels in this study.

Obstructive sleep apnea (OSA) is a common disorder characterized by episodes of upper airway obstruction during sleep. The prevalence of OSA (apnea±hypopnea index [AHI] ≥5) in adults 30 to 69 years is estimated at 17%, increasing to 23% to 35% in relatively unselected hypertensive populations.¹, ² OSA is associated with endothelial dysfunction, metabolic syndrome, atherosclerosis, and cardiovascular disorders.³, ⁴, ⁵, ⁶, ⁷ Morning blood pressure (BP) surge (MS) is a normal physiological phenomenon; however, extreme MS is a risk factor for stroke and cardiovascular mortality.⁸, ⁹, ¹⁰ Sympathetic activity is suspected to play a role as an underlying mechanism in OSA and MS.⁷, ¹¹, ¹², ¹³ Few studies have evaluated the association between OSA and MS.¹⁴, ¹⁵ Peripheral arterial tone (PAT) is based on the pulsatile plethysmographic signal that is measured on a finger, which could serve as a single noninvasive substitute for sympathetic activity.¹⁶ This study aimed to examine the association of sleep parameters with WATCH^‐PAT 200 (WP200; (Itamar Medical Ltd, Caesarea, Israel) based on measurements of PAT variations and MS in never‐treated patients with essential hypertension.¹⁶, ¹⁷, ¹⁸, ¹⁹     

Efficacy/Safety of a Fixed‐Dose Amlodipine/Olmesartan Medoxomil–Based Treatment Regimen in Hypertensive Blacks and Non‐Blacks With Uncontrolled BP on Prior Antihypertensive Monotherapy

In this secondary analysis of a dose‐titration study of patients with hypertension uncontrolled on prior monotherapy, blacks (n=234) and non‐blacks (n=765) were switched to amlodipine (AML)/olmesartan medoxomil (OM) 5/20 mg, with uptitration every 4 weeks to AML/OM 5/40 mg and then AML/OM 10/40 mg to achieve a seated cuff blood pressure (SeBP) of <120/70 mm Hg. Hydrochlorothiazide 12.5 and 25 mg could be added if SeBP was ≥125/75 mm Hg. The cumulative proportions of patients achieving systolic SeBP <140 mm Hg (<130 mm Hg if diabetic) at 12 weeks were 71.6% for blacks and 77.2% for non‐blacks. Mean SeBP change from baseline in blacks (mean baseline BP: 153.0/93.7 mm Hg) ranged from −11.7/−6.1 mm Hg for AML/OM 5/20 mg to −23.6/−12.9 mm Hg for AML/OM 10/40 mg +hydrochlorothiazide 25 mg (all P<.0001). Antihypertensive efficacy was maintained throughout the 24‐hour dosing interval. An AML/OM‐based regimen was effective in blacks with hypertension uncontrolled on prior monotherapy.

Hypertension is more common among black individuals in the United States than in other ethnic groups, with an age‐adjusted prevalence rate of 40% compared with 27% for whites.¹ In addition, hypertension among black Americans is of greater severity and has an earlier onset, resulting in higher rates of cardiovascular disease (CVD) compared with non‐Hispanic whites.¹, ², ³ For example, rates for nonfatal stroke (1.3‐fold), fatal stroke (1.8‐fold), heart disease death (1.5‐fold), and end‐stage kidney disease (4.2‐fold) are higher among blacks compared with whites.³ The pattern of hypertension among black individuals in Africa is somewhat different. A study analyzing data from 17 population studies in sub‐Saharan African countries indicated an overall prevalence rate of 16.2% for 2008, with higher rates among urban than rural populations.⁴ The rural/urban difference was highlighted by data that demonstrate that migration from rural to urban areas and from African countries to the United States is associated with an increase in blood pressure (BP) among black individuals.⁵ The increased prevalence of hypertension and adverse clinical outcomes among blacks is likely related to a combination of genetic and environmental factors.⁶ For example, black patients, particularly in the southeastern United States, have a high prevalence of patient‐related risk factors for CVD such as obesity, diabetes mellitus, and hypercholesterolemia, and these risk factors are frequently clustered.⁷ Blacks also appear to have greater vascular resistance and/or disturbances in both endothelial‐dependent and ‐independent vasodilation compared with other populations.⁶ The Blood Pressure Control in All Subgroups With Hypertension (BP‐CRUSH) study was designed to evaluate improvements in BP control among patients previously uncontrolled on antihypertensive monotherapy who were switched to fixed‐dose amlodipine/olmesartan medoxomil (AML/OM) ±hydrochlorothiazide (HCTZ) combination therapy.⁸ This article reports the effectiveness of the AML/OM‐based treatment regimen in reducing BP and achieving BP goals in prespecified subgroups of black and non‐black patients in the BP‐CRUSH study.     

The Impact of Azilsartan Medoxomil Treatment (Capsule Formulation) at Doses Ranging From 10 to 80 mg: Significant,Rapid Reductions in Clinic Diastolic and Systolic Blood Pressure

In this phase 2, multicenter, parallel‐group, double‐blind, dose‐ranging study, hypertensive adults (n=449) were randomized to receive one of five doses of a capsule formulation of azilsartan medoxomil (AZL‐M; 5, 10, 20, 40, 80 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. AZL‐M provided rapid statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) vs placebo at all doses except 5 mg. Placebo‐subtracted changes were greatest with the 40 mg dose (DBP, −5.7 mm Hg; SBP, −12.3 mm Hg). Clinic changes with AZL‐M (all doses) were statistically indistinguishable vs OLM, although there were greater reductions with AZL‐M 40 mg using 24‐hour ambulatory blood pressure. Adverse event frequency was similar in the AZL‐M and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL‐M tablet in the dose range of 20 to 80 mg/d.

Despite the wide array of available antihypertensive drug options, blood pressure (BP) control remains suboptimal in many patients with hypertension, and most patients require multidrug therapy to achieve BP goals.¹, ² Consequently, the cardiovascular disease burden associated with hypertension remains substantial and there continues to be a real need for improved BP‐lowering strategies and better use of the most effective and well‐tolerated available antihypertensive therapies.³ As a class, the angiotensin II receptor blockers (ARBs) are generally considered to be among the more effective BP‐lowering drugs and among the best tolerated, albeit with some differences between individual agents.⁴, ⁵, ⁶, ⁷, ⁸, ⁹ Furthermore, along with other renin‐angiotensin system (RAS) inhibitors, there is good evidence to show that ARBs improve renal outcomes compared with other antihypertensive drug classes in patients with chronic kidney disease.¹⁰, ¹¹ Consequently, ARBs feature highly in hypertension treatment guidelines as a recommended first‐ or second‐line treatment option for many patients with hypertension, especially those with renal impairment.¹⁰, ¹¹ The latest ARB and eighth drug in the class, azilsartan medoxomil (AZL‐M), is approved for the treatment of hypertension at a dose of 20 to 80 mg once daily (40–80 mg in the United States), alone or in combination with other antihypertensive agents.¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸ This ARB is a prodrug that is rapidly hydrolyzed during absorption in the gut to form its active moiety azilsartan (AZL).¹⁹, ²⁰ The estimated absolute bioavailability of AZL following oral administration of AZL‐M is approximately 60%, with peak plasma concentrations achieved in 1.5 to 3.0 hours, a volume of distribution of around 16 L, and an elimination half‐life of approximately 11 hours.¹², ¹³ A nonprodrug formulation of AZL is available for clinical use in Japan.¹⁹, ²⁰ Similar to other ARBs, AZL has a high affinity for the angiotensin type 1 (AT₁) receptor and high selectivity relative to the type 2 (AT₂) receptor, although AZL appears to dissociate more slowly from the AT₁ receptor compared with other ARBs, which has the potential to confer greater and longer‐lasting antihypertensive effects.¹⁹, ²⁰, ²¹, ²² During its development, AZL was investigated using various formulations, including an AZL‐M (prodrug) capsule and an AZL (nonprodrug) tablet, which differ from the final commercially approved AZL‐M tablet formulation.²³ The AZL‐M capsule and AZL tablet provide approximately 60% and 162% systemic AZL exposure, respectively, compared with the commercial AZL‐M tablet under fasting conditions.²³ With the AZL‐M capsule, food increases AZL exposure and also increases variability in exposure, whereas the AZL‐M tablet has the advantage that it is unaffected by food.²³ Phase 2 dose‐ranging studies were performed using the AZL‐M capsule and AZL tablet formulations only, and these provided the basis for dosing in the subsequent phase 3 studies using the AZL‐M tablet. The current study evaluated the BP‐lowering dose‐response relationship of the AZL‐M capsule formulation in patients with essential hypertension. The phase 2 study evaluating the AZL tablet has been published separately.     

Relationships Between Blood Pressure and 24‐Hour Urinary Excretion of Sodium and Potassium by Body Mass Index Status in Chinese Adults

This study examined the impact of overweight/obesity on sodium, potassium, and blood pressure associations using the Shandong‐Ministry of Health Action on Salt Reduction and Hypertension (SMASH) project baseline survey data. Twenty‐four–hour urine samples were collected in 1948 Chinese adults aged 18 to 69 years. The observed associations of sodium, potassium, sodium‐potassium ratio, and systolic blood pressure (SBP) were stronger in the overweight/obese population than among those of normal weight. Among overweight/obese respondents, each additional standard deviation (SD) higher of urinary sodium excretion (SD=85 mmol) and potassium excretion (SD=19 mmol) was associated with a 1.31 mm Hg (95% confidence interval, 0.37–2.26) and −1.43 mm Hg (95% confidence interval, −2.23 to −0.63) difference in SBP, and each higher unit in sodium‐potassium ratio was associated with a 0.54 mm Hg (95% confidence interval, 0.34–0.75) increase in SBP. The association between sodium, potassium, sodium‐potassium ratio, and prevalence of hypertension among overweight/obese patients was similar to that of SBP. Our study indicated that the relationships between BP and both urinary sodium and potassium might be modified by BMI status in Chinese adults.

Cardiovascular disease (CVD), including heart disease and stroke, accounted for 41% of all deaths and 23% of national healthcare spending in China in 2005.¹ Unfortunately, the prevalence of hypertension, the leading risk factor for CVD, has increased dramatically in China, from 5.1% in 1959 to 29.6% in 2009 among adults aged 18 years and older.², ³ High sodium intake, low potassium intake, and obesity all increase the risk of hypertension.⁴, ⁵, ⁶ In China, sodium intake decreased over the past two decades, but studies suggest that average daily intake in 2009 (4700 mg/d) was almost double the Chinese Nutrition Association recommendation (2400 mg/d).⁷ The average daily potassium intake among Chinese adults is very low, resulting in a high sodium‐potassium ratio, indeed one of the highest in the world.⁵, ⁷, ⁸ In addition, overweight and obesity have increased remarkably in China over the past two decades; in 2010, 30.6% of Chinese adults were overweight and 12% were obese.⁹, ¹⁰ The US Institute of Medicine recommended that analyses on the effects of dietary sodium on health outcomes should also examine potassium intake and account for potential confounding factors.¹¹ In addition, accumulating evidence has suggested that in humans the response of blood pressure (BP) to changes in sodium intake may vary by body weight/BMI or the presence of the metabolic syndrome.¹², ¹³, ¹⁴, ¹⁵, ¹⁶ In China, several population‐based studies have linked sodium and potassium intake and their ratio with BP and risk of hypertension.¹⁷, ¹⁸, ¹⁹ However, few studies have examined the relationship between sodium and potassium intake and BP in analyses stratified by BMI status.²⁰, ²¹ The INTERSALT study examined the Chinese subsample to assess the effect modification of BMI on the association of sodium and BP.²⁰ However, the sample was relatively small and was based on just three Chinese neighborhoods. In addition, the sample was collected 20 to 30 years ago, when the prevalence of hypertension and obesity in China were relatively low. Therefore, we sought to understand how the association of sodium and BP might be modified by BMI status among Chinese adults in the contemporary setting.We used baseline survey data from 2011 obtained as part of the Shandong and Ministry of Health Action on Salt and Hypertension (SMASH) project to examine the association between (1) urinary sodium, urinary potassium, and their ratio; and (2) BP and the prevalence of hypertension. We also explored whether the associations of sodium and potassium with BP and hypertension prevalence are modified by BMI.     

Medication Class Effects on Visit‐to‐Visit Variability of Blood Pressure Measurements: Analysis of Electronic Health Record Data in the “Real World”

Blood pressure (BP) visit‐to‐visit variability (VVV) influences the risk of vascular events and mortality. Research has suggested that antihypertensive medication classes may differentially impact VVV. This study evaluated whether antihypertensive medication class differentially impacted BP VVV among hypertensive individuals in a clinical, “real‐world” setting as well as the association between VVV and patient characteristics. Clinical observational data were extracted for adults (mean age, 63; 56% female, 86% Caucasian) with hypertension from the Mercy EpicCare EHR‐Derived Database (MEDD) (n=183,374) who had at least 4 outpatient visits with BP readings. A multilevel mixed model for change over time estimated between‐ and within‐subject effects on the absolute real VVV of systolic BP. Diuretics significantly lowered VVV (β=−0.32[−0.39 to−0.25]) and α‐/β‐blockers resulted in the highest VVV (β=0.89 [0.77–1.00]). Being older, female, and having a higher systolic BP and certain comorbid conditions significantly raised VVV (P<.001). The findings from the MEDD were consistent in general with other research on BP VVV. However, the magnitude of effect of antihypertensive medication class and patient characteristics was relatively low (<10% of the BP VVV variance for any one variable). More research is needed to evaluate the extent to which the class of antihypertensive medication class impacts BP VVV in the outpatient setting.

Long‐term poorly controlled blood pressure (BP) in hypertensive patients is associated with increased cardiovascular, renal, and cerebrovascular morbidity and mortality.¹, ², ³ Although the individual''s systolic BP level is considered of primary importance in assessing risk of vascular events, it is possible that other BP parameters might also be influential. One such parameter that has been proposed is BP visit‐to‐visit variability (VVV).⁴, ⁵, ⁶, ⁷ Although BP VVV has at times been considered a nuisance variable,⁸, ⁹, ¹⁰, ¹¹ there is burgeoning literature on the topic.⁶, ⁷, ¹² Rothwell and colleagues reported that in two large trials (United Kingdom Transient Ischaemic Attack [UK‐TIA aspirin] trial and the Anglo‐Scandinavian Cardiac Outcomes Trial‐Blood Pressure Lowering Arm [ASCOT‐BPLA]) systolic BP (SBP) VVV was found to be predictive of stroke and coronary events, including mortality (and was independent of mean SBP).⁶, ¹³ Munter and colleagues found that higher SBP VVV is associated with an increased risk of negative cardiovascular outcomes and end‐organ damage.⁷ BP VVV has been previously shown to be associated with adverse outcomes such as mortality and cardiovascular events,¹², ¹⁴ yet there remains a gap to demonstrate what factors may explain higher levels of VVV.Antihypertensive medications may have class‐specific effects on BP VVV.¹³, ¹⁵ A recent meta‐analysis considering VVV across multiple randomized trials reported that some antihypertensive classes (calcium channel blockers, diuretics) decrease VVV, while others (angiotensin‐converting enzyme inhibitors, β‐blockers) increase VVV.¹⁵ Within the ASCOT‐BPLA trial it was reported that using a calcium channel blocker resulted in a 24% decrease in cardiovascular mortality and a 23% decrease in stroke compared with β‐blocker therapy.¹⁶ In at least one study, VVV was associated with being older and female and a predictor of myocardial infarction.⁶ Given the potential impact of BP VVV on vascular events, it is important to evaluate whether certain patient characteristics are associated with BP VVV. Due to the evolving understanding of BP VVV on clinical outcomes, more work needs to be conducted to evaluate whether BP VVV is differentially influenced by the various classes of antihypertensive medications as well as patient characteristics.In order to appreciate these relationships in a “real‐world” setting, it would be beneficial to examine a clinical electronic health record (EHR)–derived database. The current study had two main objectives. The first objective was to investigate whether antihypertensive class differentially affected VVV among individuals in an EHR‐derived database, while the second objective was to investigate the effect of patient characteristics on VVV.     

Effect of Continuous Positive Airway Pressure on Blood Pressure Variability in Patients With Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a common risk factor for cardiovascular disease. Continuous positive airway pressure (CPAP) improves OSA symptoms and blood pressure (BP) control. The effect of CPAP on BP variability (BPV) in patients with and without hypertension treated with autotitrating CPAP (APAP) for 2 weeks was studied. A total of 78 participants (76.9% men, 49% hypertensive, mean body mass index 36.2 [6.9] kg/m², age 49.0 [12.9] years) underwent 2 weeks of APAP therapy. Office BP, BPV (standard deviation of three BP measurements), and pulse rate were measured before and after treatment. Systolic BPV (5.3±4.9 vs 4.2±3.4 mm Hg, P=.047) and pulse rate (78.0±14.5 vs 75.5±15.8 beats per minute, P=.032) decreased after treatment, particularly in hypertensive participants. Mask leak was independently associated with reduced changes in systolic BPV (r=−0.237, P=.048). Short‐term APAP treatment reduced BPV and pulse rate, particularly in hypertensive patients with OSA.

Obstructive sleep apnea (OSA) is a well‐recognized risk factor for cardiovascular (CV) disease.¹ Its prevalence is rising as a result of the current obesity epidemic.² OSA is caused by recurrent obstructions of the upper airway when asleep. These obstructions result in apneas and hypopneas, which lead to repeated oxygen desaturations and arousals from sleep, and hence activation of the sympathetic nervous system.³ Increased sympathetic tone impacts on blood pressure (BP), heart rate,⁴ and importantly on the risk of CV morbidity.Continuous positive airway pressure (CPAP) maintains upper airway patency and abolishes or reduces obstructive events in patients with OSA,⁵ also reducing BP.⁶ Recent studies have revealed that optimal CPAP control reduces BP, with more marked effects in patients with resistant hypertension,⁷ implying a role of the autonom ous nervous system in relation to changes in BP.BP variability (BPV) is a marker of autonomic nervous system output and an independent predictor of CV morbidity and mortality.⁸ It is defined as the fluctuation of BP between different measurements over a defined time interval.⁹ Visit‐to‐visit BPV comparison is related to an increased risk of CV events.¹⁰, ¹¹ Patients with OSA are known to have an increased sympathetic tone, which causes increased BPV¹², ¹³ and leads to raised levels of absolute BP and increased risk of CV morbidity and mortality. Patients with hypertension exhibit higher BPV when compared with normotensives as expression of an enhanced sympathetic tone.⁹ We aimed to investigate how CPAP treatment modifies the risk of increased sympathetic activation, through its impact on BPV, in patients with obstructive sleep apnea.     

Orthostatic Blood Pressure Dysregulation and Polymorphisms of β‐Adrenergic Receptor Genes in Hypertensive Patients

The genetic susceptibility to orthostatic blood pressure dysregulation remains poorly understood. The association between polymorphisms of beta‐adrenergic receptor (β‐AR) genes and orthostatic blood pressure dysregulation in hypertensive patients was investigated. Two polymorphisms of β₁‐AR (Arg389/Gly) and β₂‐AR (Arg16/Gly) were genotyped in untreated hypertensive patients and normotensive patients. In patients with untreated hypertension, the frequency of β₁‐AR Gly389 homozygote was significantly higher in patients with orthostatic hypotension (OH) (P<.0001) and lower in patients with orthostatic hypertension (OHT) (P=.002) as compared with patients with orthostatic normotension (ONT) even after Bonferroni correction. After analysis by sex and adjustment for conventional risk factors, the β₁‐AR Gly389 homozygote conferred about a 3‐fold risk of OH and independently predicted a 6.5 mm Hg greater orthostatic SBP decrease (GG −8.9±13 mm Hg vs CC+CG −2.4±12 mm Hg, P<.001) only in female hypertensive patients. The association of β₂‐AR Arg16/Gly with OH was not significant after adjustment for conventional risk factors. In normotensive patients, no association was identified between these two polymorphisms and OHT or OH. These results indicated that the β₁‐AR Arg389/Gly polymorphism may be associated with increased risk of OH in female hypertensive patients.

Orthostatic blood pressure (BP) change is a common clinical problem in the real world of clinical practice. According to the updated consensus statement by the European Federation of Neurological Societies, orthostatic hypotension (OH) is defined as a sustained reduction in systolic BP (SBP) of at least 20 mm Hg or diastolic BP (DBP) of 10 mm Hg from the supine position to standing.¹ The most commonly used criterion for a diagnosis of orthostatic hypertension (OHT) appears to be an increase of SBP of 20 mm Hg with orthostatic change.² OH has been identified as an independent risk factor for cardiovascular disease,³ arterial stiffness,⁴ and ischemic stroke⁵ as a potential indicator underlying autonomic dysfunction.⁶ OHT is associated with cardiovascular disease,⁷ sustained hypertension,⁸ diabetes mellitus,⁹ and target organ damage.¹⁰ Hypertension, with estimates of heritability ranging from 31% to 68%,¹¹ has been associated with the increased risk of OH and OHT in many epidemiological studies.¹², ¹³ Therefore, better understanding of the underlying pathophysiology and genetic background may predict cardiovascular events and mortality independently of traditional risk factors and might have major clinical significance in hypertensive and normotensive patients.Many genetic variants have been suggested that partly contribute to the variation of BP response to postural change. Past studies indicate that genes on chromosome 13q and 18q are possibly associated with SBP response to postural change.¹⁴, ¹⁵ Some mitochondrial DNA mutations are also associated with idiopathic OH.¹⁶ The sympathetic nervous system (SNS) and the renin angiotensin system (RAS) may be involved in the pathogenesis of orthostatic dysregulation of BP.¹ Although the genetic variants in genes encoding components of the RAS have been associated with hypertension and BP variations, our previous study did not find any evidence for the role of angiotensin‐converting enzyme (ACE) and ACE2 in the genetic predisposition to OH or OHT in hypertensive and normotensive patients.¹⁷ β‐Adrenergic receptor (AR) is the important component of the SNS and it plays a crucial role in BP regulation.¹⁸ There are β₁‐, β₂‐, and β₃‐ARs. β₁‐ and β₂‐AR are the predominate receptors in the human heart.¹⁹ Some genetic variants in the β₁‐ and β₂‐AR genes have been associated with hypertension, OH, and orthostatic intolerance. However, few data are available on the genetic predisposition for OHT.Therefore, we hypothesized that polymorphisms of β₁/β₂‐AR may contribute to OH or OHT in hypertensive patients. To test our hypothesis, we investigated the association of orthostatic BP dysregulation with two common polymorphisms of β₁/β₂‐AR genes in 3630 untreated hypertensive patients and 826 normotensive patients.     

Trends in Hypertension Prevalence,Awareness, Treatment,and Control Among US Adults 80 Years and Older, 1988–2010

The authors examined trends in systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the prevalence, awareness, treatment, and control of hypertension in 1988–1994 (n=1164), 1999–2004 (n=1,026), and 2005–2010 (n=1048) among US adults 80 years and older in serial National Health and Nutrition Examination Surveys. Hypertension was defined as SBP ≥140 mm Hg, DBP ≥90 mm Hg, or use of antihypertensive medication. Awareness and treatment were defined by self‐report and control as SBP/DBP<140/90 mm Hg. Mean SBP decreased from 147.3 mm Hg to 140.1 mm Hg and mean DBP from 70.2 mm Hg to 59.4 mm Hg between 1988–1994 and 2005–2010. The prevalence, awareness, and treatment of hypertension each increased over time. Controlled hypertension increased from 30.4% in 1988–1994 to 53.1% in 2005–2010. The proportion of patients taking 3 classes of antihypertensive medication increased from 7.0% to 30.9% between 1988–1994 and 2005–2010. Increases in awareness, treatment, and control of hypertension and antihypertensive polypharmacy have been observed among very old US adults.

The US population is aging and it is projected that the number of US adults 80 years and older will triple by 2050.¹ Hypertension is one of the most important risk factors for coronary heart disease, stroke, and heart failure, each of which has a high incidence in the very old patients.², ³, ⁴ A meta‐analysis of randomized trials that included participants 80 years and older found antihypertensive treatment to be associated with a reduced risk for stroke, cardiovascular events, and heart failure.⁵ Multi‐morbidity and functional impairment are common among the very old and the applicability of antihypertensive treatment trial results to this population has been questioned.⁶, ⁷, ⁸, ⁹ A major concern in using antihypertensive medications in the very old is the potential increased risk for adverse events including falls and myocardial infarction associated with low blood pressure (BP).¹⁰, ¹¹, ¹² Providers must often weigh potential cardiovascular benefits against the perceived risks of pharmacologic BP‐lowering among the very old. For these reasons, treatment patterns may be different for the very old vs the general US population.Given the anticipated growth of the very old population in the United States, there is a need to document the prevalence of hypertension and BP treatment patterns in this population. Such information could be used to guide the development and implementation of approaches for improving BP management in this group. Therefore, we examined secular changes in SBP and DBP and hypertension prevalence, awareness, treatment, and control from 1988–1994 through 2005–2010 among representative samples of US adults aged 80 and older. In addition, we examined trends in the use of different classes of antihypertensive medications and the prevalence of antihypertensive polypharmacy among very old US adults.     

Effect of Canagliflozin on Blood Pressure and Adverse Events Related to Osmotic Diuresis and Reduced Intravascular Volume in Patients With Type 2 Diabetes Mellitus

The effects of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis– and intravascular volume reduction–related adverse events (AEs) were evaluated using pooled data from four placebo‐controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (−4.3 mm Hg [−5.0 to −3.5], −5.0 mm Hg [−5.8 to −4.2], and −0.3 mm Hg [−1.2 to 0.5], respectively) and in diastolic BP (DBP; −2.5 mm Hg [−2.9 to −2.0], −2.4 mm Hg [−2.9 to −1.9], and −0.6 mm Hg [−1.1 to −0.02], respectively). Placebo‐subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were −4.0 mm Hg (−5.1 to −2.8) and −4.7 mm Hg (−5.8 to −3.5) and reductions in DBP were −1.9 mm Hg (−2.6 to −1.2) and −1.9 mm Hg (−2.6 to –1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (−12.8 mm Hg [−15.2 to −10.5], −14.2 mm Hg [−16.4 to −12.0], and −6.8 mm Hg [−9.1 to −4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (−5.9 mm Hg [−8.2 to −3.6], −9.0 mm Hg [−11.1 to −6.9], and −7.4 mm Hg [−9.6 to −5.1], respectively). In patients with elevated SBP at baseline, placebo‐subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were −6.0 mm Hg (−9.1 to −2.9) and −7.4 mm Hg (−10.4 to −4.4), respectively. Placebo‐subtracted changes in DBP were 1.5 mm Hg (−1.6 to 4.5) and −1.6 mm Hg (−4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis–related AEs (eg, pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction–related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction.

Hypertension is a common comorbidity in patients with type 2 diabetes mellitus (T2DM), with approximately 67% of adults with T2DM having blood pressure (BP) ≥140/90 mm Hg or taking antihypertensive medication.¹ Lowering BP could help reduce the risk of cardiovascular disease in patients with T2DM.¹, ² Current guidelines from the American Diabetes Association recommend a systolic BP (SBP) goal of <140 mm Hg for patients with diabetes and hypertension (or <130 mm Hg for certain individuals, including younger patients) and a diastolic BP (DBP) goal of <80 mm Hg for patients with diabetes.³ Canagliflozin is a sodium glucose co‐transporter 2 (SGLT2) inhibitor developed for the treatment of T2DM.⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹² Canagliflozin inhibits renal glucose reabsorption and increases urinary glucose excretion (UGE),¹³ thus reducing plasma glucose concentration in individuals with hyperglycemia. Increased UGE may lead to osmotic diuresis and intravascular volume reduction. In phase 3 studies, canagliflozin improved glycemic control and lowered body weight and BP in patients with T2DM on a variety of diabetes treatment regimens.⁴, ⁵, ⁶, ⁸, ⁹, ¹¹, ¹² Higher incidence of adverse events (AEs) related to osmotic diuresis (eg, pollakiuria [increased urine volume], polyuria [increased urine frequency]) and intravascular volume reduction (eg, orthostatic hypotension, postural dizziness) have been observed with canagliflozin vs placebo.⁴, ⁶, ⁹, ¹¹, ¹² To evaluate the effects of canagliflozin on BP and AEs related to osmotic diuresis and intravascular volume reduction in a general population of patients with T2DM, an analysis was performed based on pooled data from four randomized, double‐blind, placebo‐controlled phase 3 studies, as well as from subgroups of patients with elevated baseline SBP (≥140 mm Hg) or DBP (≥90 mm Hg) and those who were or were not taking antihypertensive medication at baseline.     

Effect of a Novel Calcium Channel Blocker on Abnormal Nocturnal Blood Pressure in Hypertensive Patients

The authors examined the effect of cilnidipine, a unique L/N‐type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE), a large‐scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24‐hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12‐week treatment with cilnidipine significantly reduced 24‐hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were −17.9 mm Hg from 154.6 mm Hg in risers and −11.9 mm Hg from 142.1 mm Hg, −6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but −7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (−0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

A number of studies have demonstrated that nocturnal nondipping¹, ², ³ and extreme dipping of blood pressure (BP)⁴, ⁵, ⁶ are associated with organ damage. A lack of nocturnal dipping has also been related to risk of cardiovascular events,⁷, ⁸, ⁹, ¹⁰, ¹¹ even if BP measured at the clinic or at home is normal. Diuretics, angiotensin‐converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists are partially effective in restoring normal BP dipping.¹², ¹³, ¹⁴ However, evidence‐based studies of antihypertensive medication for the treatment of abnormal nocturnal dipping are lacking. In current daily medical practice, antihypertensive medication for reducing 24‐hour BP as well as normalizing dipping status need to be individualized and optimized in each hypertensive patient with different backgrounds such as age and comorbidities.Cilnidipine is a unique L/N‐type calcium channel blocker (CCB) that inhibits norepinephrine release at sympathetic nerve endings by blocking N‐type calcium channels and directly dilates vascular vessels by blocking L‐type calcium channels.¹⁵, ¹⁶, ¹⁷, ¹⁸ Recently, we demonstrated that cilnidipine reduced BP and pulse rate (PR) in patients with morning hypertension suggested to be characterized by increased sympathetic activity using data measured at home obtained from the Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by the N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE) trial.¹⁹ The investigation is a large‐scale clinical study designed to evaluate the effects of cilnidipine in daily medical practice on BP and PR in patients with essential hypertension measured at the clinic and at home. In a portion of these patients, measurement was performed by 24‐hour ambulatory BP (ABP) monitoring (ABPM).In the present study, we examined the effects of cilnidipine on abnormal nocturnal dipping in hypertensive patients.     

Diuretics and Bioimpedance‐Measured Fluid Spaces in Hypertensive Patients

The authors examined the relationship between thiazide‐type diuretics and fluid spaces in a cohort of hypertensive patients in a retrospective study of 60 stable hypertensive patients without renal abnormalities who underwent whole‐body bioimpedance analysis. Overhydration was greater in the diuretic group, but only to a nonsignificant degree (5.9 vs 2.9%; P=.21). The total body water did not differ in the two groups (41.8 L vs 40.5 L; P=.64). Extracellular fluid volume (ECV) (19.7 L vs 18.5 L; P=.35) and intracellular fluid volume (ICV) spaces (20.8 L vs 21.3 L; P=.75) were also not significantly different in the two groups. The ratio of ICV:ECV, however, appeared different: 1.05 vs 1.15 (P=.017) and the effect was maintained in the linear regression–adjusted model (β coefficient: −0.143; P=.001). The diuretic‐related distortion of ICV:ECV ratio indicates potential fluid redistribution in hypertensive patients, with ICV participating in the process.

Diuretics are a cornerstone of most antihypertension guidelines, including the Joint National Committee on the management of hypertension in adults¹ and the European Society of Hypertension and the European Society of Cardiology.¹ While both recommendations clearly endorse the use of diuretics, their current recommendations seem somewhat less vocal than previous editions of the same. These newer guidelines take a much more cautionary approach both in treatment goals and in the unequivocal endorsement of one agent over another for the primary treatment of essential hypertension. For example, while the 2013 version of the European Societies'' recommendation discusses controversies of thiazide diuretic use in detail in section 5.2.1.2, the 2003 version simply makes the recommendations of grade 2B diuretics only.² Potential side effects of diuretic therapy include new‐onset diabetes and hyperuricemia,³ polypharmacy in the elderly,⁴ hypokalemia,⁵ and even adverse cardiac outcome.⁶ Clearly, some but not all of the untoward side effects associated with diuretics, such as dehydration and the increased risk of falls in the elderly,⁷ may be related to the changes of extracellular fluid volume (ECV) induced by diuretics.⁸, ⁹ However, classic methods for measuring total‐body water space,¹⁰, ¹¹ estimation of the extracellular and intracellular water spaces (with sodium bromide and potassium isotopes, respectively),¹² inulin‐based volume measurements,¹³ and the gold standard measurement of fat tissue content¹⁴, ¹⁵, ¹⁶ are not conducive to daily practice. Bioimpedance is an emerging technology to measure the body''s fat content and both ECV and intracellular fluid volume (ICV) spaces¹⁷ and may have the potential to optimize diuretic therapy.¹⁸, ¹⁹ In this current paper, we sought to evaluate the influence of diuretics on the various fluid compartments in a treated hypertensive cohort with predominantly normal kidney function.     

Correlation of 24‐Hour Blood Pressure and Heart Rate Variability to Renal Function Parameters in Hypertensive Patients. The Effect of Smoking

Intrarenal hemodynamics depend on blood pressure (BP), heart rate (HR), and smoking. Although BP levels have been associated with kidney function, the effect of HR levels, BP, and HR variability on renal function are less well clarified. This cross‐sectional study sought to determine the association of 24‐hour BP and HR variability with kidney function in hypertensive patients, stratified by smoking. The study comprised 9600 nondiabetic, never‐treated hypertensive individuals without evident renal impairment examined from 1985 to 2014 (aged 53.3±13.4 years, 55.3% males). The 24‐hour systolic BP (SBP) and HR variability were estimated via their coefficient of variation (C_V=standard deviation×100/mean value) derived from ambulatory recording. The C_VSBP‐to‐C_VHR ratio (C_VR) was used as a marker of the interplay between 24‐hour SBP and HR variability. Renal function was estimated via 24‐hour urine creatinine clearance (CrCl), estimated glomerular filtration rate (eGFR), albumin‐to‐creatinine ratio (ACR), and 24‐hour urine α₁‐microglobulin. After adjustment for age, sex, and smoking, C_VSBP was found to be weakly correlated to eGFR (r=−0.017, P=.1) and somewhat more strongly to CrCl, ACR, and α₁‐microglobulin (r=−0.032, 0.072, and 0.065; P=.002, <.001 and <.001, respectively). C_VHR was much better related to renal function, with stronger adjusted correlations to CrCl, eGFR, ACR, and α₁‐microglobulin (r=0.185, 0.134, −0.306, −0.247; all P<.001, respectively). C_VR also showed equally good adjusted correlations (r=−0.175, −0.125, 0.336, 0.262; all P<.001, respectively). Most adjusted correlations for C_VHR and C_VR were even better in smokers (r=0.213, 0.158, −0.332, −0.272 and −0.183, −0.118, 0.351, 0.275, respectively; all P<.001). C_VHR and C_VR emerge as better related to kidney function than C_VSBP, especially in smokers. The correlation of C_VHR and C_VSBP to renal function is inverse to each other. ACR and α₁‐microglobulin are better related to variability indices than CrCl and eGFR. However, causal relations cannot be proved.

Renal blood flow, and thus renal function, are largely dependent on cardiac output,¹ which, in turn, is directly related to systemic blood pressure (BP) and heart rate (HR).² Although high BP (hypertension) and low BP (hypotension) are established risk factors for renal dysfunction,³ the effect of HR levels as well as the isolated and cumulative effect of BP and HR variability on kidney function has not been well clarified.Some pilot studies in hypertensive patients have recently indicated that ambulatory BP and HR profile are closely related to renal function.⁴, ⁵, ⁶, ⁷ Moreover, improvement in the circadian measures of 24‐hour HR variability follows kidney transplantation.⁸ However, these preliminary studies conclude that further research is needed to define the role of BP and HR variability as diagnostic or prognostic markers of renal impairment.⁴, ⁶ On the other hand, in recent years, it has become apparent that smoking has a negative impact on renal function, even in patients without evident renal disease, being one of the most important remediable renal risk factors.⁹, ¹⁰, ¹¹, ¹² The risk for microalbuminuria is increased in smokers in the general population.⁹, ¹⁰, ¹¹, ¹² Smoking is particularly “nephrotoxic” in older individuals, patients with essential hypertension, and patients with pre‐existing renal disease.¹⁰, ¹¹ Smoking cessation has been shown to reduce the rate of progression of renal impairment both in patients with renal disease and in patients with a renal transplant.¹⁰ The mechanisms of smoking‐induced renal damage are still only partly understood.¹⁰ To shed light on the various issues mentioned above, the present study aimed to determine the association of 24‐hour BP variability, 24‐hour HR variability, and their interplay with renal function in a large cohort of 9600 adult nondiabetic, never‐treated hypertensive patients without evident renal impairment stratified by their smoking status.     

Estimating 24‐Hour Urine Sodium From Multiple Spot Urine Samples

The authors developed an equation to estimate 24‐hour urine sodium (24HUNa) using the average of three spot urine (SU) samples (morning‐first, morning, and evening) from 74 individuals and validated this equation using the average of three SU samples (morning‐first, daytime, and evening) from 174 additional individuals. Compared with previously published equations using a single SU sample, the currently developed equation using the average of three SU samples showed much lower bias from measured 24HUNa (−2.9 vs >10 mmol/24 h). The intraclass and concordance correlation coefficients of the proposed equation using the average of three SU samples were 0.909 and 0.832, respectively. The limits of agreement were −64.1–58.3 mmol/24 h and approximately 100 mmol/24 h for the currently developed and previously published equations, respectively. All equations showed a tendency to overestimate or underestimate 24HUNa in a manner dependent on the level of 24HUNa but irrespective of the number of SU samples considered. Nonetheless, among the currently tested equations, our equation using the average of three SU samples provided the best estimation of 24HUNa at a population level.

Excessive sodium intake is associated with high blood pressure (BP) and a greater risk for cardiovascular disease and stroke.¹, ² Thus, reducing sodium intake is important to prevent and treat cardiovascular disease. Moreover, accurate assessment of sodium intake is crucial in the evaluation and management of diseases associated with high sodium intake. Although measurement of 24‐hour urine sodium (24HUNa) is considered the most reliable method,³ 24‐hour urine collection is cumbersome in many patients and often results in incomplete samples. For this reason, various equations to estimate 24HUNa from a single spot urine (SU) sample have been suggested by Kawasaki and colleagues,⁴ Tanaka and colleagues,⁵ and Brown and colleagues,⁶ as SU samples are convenient to collect. However, the amount of bias affecting the reported relationship⁷, ⁸ between cardiovascular disease and sodium intake estimated on the basis of equations using a single SU sample remains unclear, as validation against measured 24HUNa values revealed that most such equations provide significantly biased estimates of 24HUNa.⁹, ¹⁰, ¹¹ Therefore, when interpreting the association found between high sodium levels and cardiovascular events, the measurement method should always be considered as a potential bias‐inducing factor.¹² In our previous study, we suggested that using multiple SU samples to estimate 24HUNa may improve predictive capabilities.⁹ In the present study, we developed an equation to estimate 24HUNa using the average of three SU samples. We validated the developed equation on a study population different from that used in its development. Finally, we compared the predictive capability of the currently developed equation with that of previously published equations using a single SU sample.     

Fixed‐Combination Olmesartan/Amlodipine Was Superior to Perindopril + Amlodipine in Reducing Central Systolic Blood Pressure in Hypertensive Patients With Diabetes

This post hoc analysis from the Sevikar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate‐to‐Severe Hypertension (SEVITENSION) study assessed the efficacy and tolerability of olmesartan (OLM) and amlodipine (AML) in reducing central systolic blood pressure (CSBP) compared with perindopril (PER) plus AML in hypertensive patients with type 2 diabetes. Patients were randomized to OLM/AML 40/10 mg or PER/AML 8/10 mg for 24 weeks. The primary efficacy endpoint was the absolute change in CSBP from baseline to week 24, which was greater with OLM/AML (−13.72±1.14 mm Hg) compared with PER/AML (−10.21±1.11 mm Hg). The between‐group difference was −3.51±1.60 mm Hg (95% confidence interval, −6.66 to −0.36 mm Hg) and was within the noninferiority margin (2 mm Hg) as well as the superiority margin (0 mm Hg). In addition, OLM/AML was associated with a higher proportion of patients achieving blood pressure normalization. In hypertensive patients with diabetes, the fixed‐dose combination of OLM/AML was superior to PER/AML in reducing CSBP, as well as other secondary endpoints.

Recently, a number of studies have demonstrated that central systolic blood pressure (CSBP) measurements could provide a better estimate of cardiovascular (CV) risk compared with the traditional method of measuring brachial blood pressure (BP). Indeed, CSBP provides valuable insights into arterial stiffness and organ damage.¹, ², ³, ⁴ Studies comparing different treatment regimens have found that patients in parallel treatment groups may display comparable levels of brachial BP measurements while at the same time showing major differences in CSBP, which may relate to differences seen in organ damage and CV outcomes.² This phenomenon was highlighted by the Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo‐Scandinavian Cardiac Outcomes Trial‐Blood Pressure Lowering Arm (ASCOT‐BPLA).⁵ ASCOT‐BPLA was an outcomes study which found that patients treated with a combination of the calcium channel blocker (CCB) amlodipine (AML) plus the angiotensin‐converting enzyme (ACE) inhibitor perindopril (PER) showed lower rates of CV outcomes, such as stroke and death, compared with patients treated with the β‐blocker atenolol plus the diuretic bendroflumethiazide. The substudy CAFE found that patients treated with AML/PER showed significantly greater reductions in CSBP compared with patients treated with atenolol plus bendroflumethiazide, despite similar reductions in brachial BP. These findings raise the possibility that the lower rates of CV outcomes seen in patients treated with AML/PER in ASCOT‐BPLA may be the result of larger reductions in CSBP.The ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)⁶ showed that compared with ACE inhibitors, angiotensin II receptor blockers (ARBs) are as effective at lowering BP and reducing CV risk and show improved tolerability. The results from ONTARGET suggested that it would be possible to use an ARB to provide the renin‐angiotensin system (RAS) blockade component and to combine this with AML to deliver effective lowering of CSBP free from the tolerability issues associated with the use of ACE inhibitors.The results from the SEVIkar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate‐to‐Severe HyperTENSION (SEVITENSION) study⁷ confirmed that a combination of the ARB olmesartan (OLM) plus AML was not only noninferior to PER/AML in reducing CSBP, but was also superior for this endpoint, as well as a range of other hemodynamic variables that included measurements of office and ambulatory BP. The SEVITENSION study included patients with a range of factors that put them at increased risk of CV disease, including a substantial proportion of patients with diabetes.Hypertension and diabetes commonly occur together. It is estimated that between 40% and 80% of diabetic patients may also be hypertensive.⁸, ⁹, ¹⁰ Patients who have both diabetes and hypertension are at a higher risk for CV events than patients with hypertension or diabetes alone.¹¹, ¹², ¹³ Indeed, diabetic patients with hypertension are at approximately a two‐fold risk for CV‐related events compared with those with normal BP.⁹ Furthermore, between 60% and 80% of patients with type 2 diabetes mellitus (T2DM) die as a result of CV complications, and high BP is associated with approximately 75% of these deaths.¹⁴, ¹⁵ RAS inhibitors have been found to be effective in preventing CV complications in diabetic patients.¹⁶, ¹⁷, ¹⁸ Because of the increased risk of CV events in hypertensive patients with diabetes, it is important to assess the effects of dual RAS‐calcium channel blockade on arterial stiffness in these patients. The aim of the present post hoc analysis was to assess the effects of OLM/AML compared with PER/AML in reducing CSBP and other hemodynamic variables in patients with diabetes who took part in the SEVITENSION study.     

Two‐Year Outcomes of Patients Treated With Aliskiren Under Clinical Practice Conditions: Non‐Interventional Prospective Study

The authors investigated the long‐term effectiveness and safety of aliskiren (ALIS) with particular attention on its association with dual blockade of the renin‐angiotensin system (RAS). The open, prospective 3A Registry (N=8723) in Germany assigned patients in a 4:1:1 ratio to ALIS, angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or non‐RAS drugs. Patients taking ALIS compared with those taking ACE inhibitors/ARBs or non‐RAS had more comorbidities and risk factors, were taking more antihypertensive agents, and had higher blood pressure (BP) values at entry. At 2 years, BP reduction from baseline was similar in all groups (mean, −20.5/−9.9 mm Hg). A total of 2.3% of patients died, 0.5% had myocardial infarction, 0.6% had stroke, 2.9% were hospitalized, and 5.5% had any event (not significant between groups). ALIS alone or combined with another RAS inhibitor was well tolerated and effective in lowering BP in typical unselected patients with hypertension. Given the methodical limitations of the design, the study cannot be used to confirm or refute safety concerns for dual RAS blockade as suggested by the Aliskiren Trial in Type 2 Diabetes Using Cardio‐Renal Endpoints (ALTITUDE) trial.

The renin‐angiotensin‐aldosterone system (RAS) plays a pivotal role in the regulation of fluid balance and blood pressure (BP), and RAS blockade is an established principle in the treatment of hypertension.¹ Further, RAS inhibition exerts a renoprotective effect independent of BP reduction.² Three drug classes are available that inhibit the RAS at various stages, namely angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and the direct renin inhibitor aliskiren (ALIS), which controls the RAS directly at the point of activation.³ ALIS has been extensively investigated in randomized controlled trials as monotherapy and in various free and single‐pill combinations.⁴, ⁵, ⁶, ⁷ However, the drug is less well documented with regard to its effectiveness and safety under clinical practice conditions.⁸, ⁹, ¹⁰ Particular interest has been given to the combination of ALIS with an ACE inhibitor or ARB, ie, dual RAS blockade, as ALIS was expected to block the compensatory rise of plasma renin activity (PRA) induced by RAS inhibitors acting downwards in the cascade. Although recent results of both the Valsartan in Acute Myocardial Infarction Trial (VALIANT)¹¹ and the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)¹² showed no clinical benefits of the combination of effective doses of an ACE inhibitor and ARB, the combination with ALIS could probably offset potential deleterious effects of compensating renin activation––a well‐known risk factor for cardiovascular and renal events¹³, ¹⁴––and exert substantial renoprotective effects.¹⁵ Against this background, the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) was studying ALIS on top of ACE inhibitor or ARB therapy in optimally treated patients with type 2 diabetes and renal impairment compared with a placebo add‐on. However, the active‐treatment group experienced an increase in renal complications, hyperkalemia, and hypotension over 18 to 24 months of follow‐up.¹⁶ There was also a slight increase in cardiovascular events (death or stroke) in the ALIS group; however, the US Food and Drug Administration (FDA) did not reach a definite conclusion regarding an actual link between these drugs and death or stroke.¹⁷ Nonetheless, the described events led to early termination of the study in 2011 as recommended by the Data and Safety Monitoring Board.The 3A Project is one of the largest contemporary registries documenting management of unselected patients with hypertension by primary care physicians.¹⁸, ¹⁹ As it documents predominantly ALIS over the long term, it provides the largest and most current dataset on the utilization and effects of the drug in clinical practice. Here, we report the 2‐year outcomes of unselected patients with hypertension treated with various antihypertensive regimens. Particular focus was put on the effectiveness and safety of ALIS without other RAS inhibitors and in combination with other RAS blockers (ALIS plus an ACE inhibitor/ARB), including the outcomes of the drug in a patient population similar to ALTITUDE.     

Anti‐Inflammatory Effects and Prediction of Blood Pressure Response by Baseline Inflammatory State in Catheter‐Based Renal Denervation

This retrospective analysis aimed to examine off‐target effects on inflammatory and renal function parameters in n=78 subsequent patients treated with renal denervation (RDN) for resistant hypertension. Ambulatory and office blood pressure (ABP/OBP), serum creatinine, glomerular filtration rate (GFR), cystatin C, C‐reactive protein (CRP), interleukin‐6 (IL‐6), and white blood cell count (WBC) were assessed before, 6 and 12 months after RDN. ABP was significantly reduced by −8.2/−3.8 mm Hg (P=.002/.021) at 1 year after RDN, while an initial OBP reduction was not sustained during follow‐up. IL‐6 levels significantly decreased by −0.5 pg/mL (P=.042) and by −1.7 pg/mL (P<.001) at 6 and 12 months, baseline IL‐6 levels possibly predicting ABP response to RDN (r=−0.295; P=.020). Concurrently, leukocyte count was reduced by −0.5 × 10³/μL (P=.017) and −0.8 × 10³/μL (P<.001), respectively. Serum creatinine and GFR remained unchanged, but we observed a significant increase in cystatin C by 0.04 mg/L (P=.026) and 0.14 mg/L (P<.001) at 6 and 12 months after the intervention.

Renal sympathetic denervation (RDN) using radiofrequency ablation has been introduced as a novel technique to target hypertension (HTN) that is resistant to drug treatment. Although first publications were auspicious,¹, ², ³, ⁴ more recent studies on RDN have raised concerns about the efficacy of the procedure.⁵, ⁶ However, recently published post hoc analyses of SYMPLICITY HTN‐3 data revealed several potential confounding factors, including weakness in procedural performance, which may partially explain the lower‐than‐anticipated response to RDN.⁷, ⁸ Despite the ongoing discussion on RDN, directly targeting the sympathetic nervous system (SNS) still appears to be a promising therapeutic approach. Elevated SNS activity is not only present in resistant HTN, but also in obesity and the metabolic syndrome,⁹, ¹⁰ chronic kidney disease,¹¹ and other states of chronic inflammation.¹²     

Blood Pressure Control in a Hypertension Telemedicine Intervention: Does Distance to Primary Care Matter?

Although telemedicine may help overcome geographic access barriers, it is unknown whether rural patients receive greater benefits. In a secondary analysis of 503 veterans participating in a hypertension telemedicine study, the authors hypothesized that patients with greater travel distances would have greater improvements in 18‐month systolic blood pressure (SBP). Patients were categorized by telemedicine exposure and travel distance to primary care, derived from zip codes. Comparisons were (1) usual care (UC), distance <30 miles (reference); (2) UC, distance ≥30 miles; (3) telemedicine, distance <30 miles; (4) telemedicine, distance ≥30 miles. Compared with patients receiving UC, distance <30 miles (intercept=127.7), no difference in 18‐month SBP was observed in patients receiving UC, distance ≥30 miles (0.13 mm Hg, 95% confidence interval [−6.6 to 6.8]); telemedicine, distance <30 miles (−1.1 mm Hg [−7.3 to 5.2]); telemedicine, distance ≥30 miles (−0.80 mm Hg [−6.6 to 5.1]). Although telemedicine may help overcome geographic access barriers, additional studies are needed to identify patients most likely to benefit.

Primary care providers manage the majority of the 65 million individuals with hypertension in the United States.¹ However, the primary care workforce is currently unable to meet the demand for clinic visits to manage patients with chronic diseases.², ³ The demand for primary care is expected to increase further with expansion of healthcare availability under the 2010 Patient Protection and Affordable Care Act (PPACA).⁴ Furthermore, our current healthcare system is designed to deliver services primarily through face‐to‐face encounters between a patient and healthcare provider. This model, however, is likely unsustainable as the demand for healthcare services continues to grow.³, ⁵ Telemedicine is the use of telecommunication technologies and the exchange of electronic medical information between different sites to improve patients'' health status.⁶ Telemedicine can support the delivery of health services over geographic distances⁷ and increase access to healthcare services for patients who live in rural areas.⁸ Telemedicine may also provide an alternative to traditional face‐to‐face clinic‐based encounters by increasing the capacity to manage chronic diseases through non–face‐to‐face visits.⁹ Hypertension telemedicine interventions have been shown to improve blood pressure (BP) control in individuals with hypertension.¹⁰, ¹¹ However, in order to optimize the effectiveness of telemedicine interventions in chronic disease management, it is critical to identify characteristics of patients most likely to benefit from this service.Although telemedicine may increase access to healthcare for patients who live in rural areas, it remains unknown whether those patients with greater travel distances to primary care have improved outcomes with telemedicine interventions compared with those with shorter travel distances. Thus, we sought to determine whether distance to primary care modified the response to a telemedicine intervention designed to improve hypertension control among veterans. We hypothesized that greater travel distance to primary care would be associated with a greater reduction in systolic BP (SBP) among veterans enrolled in a hypertension telemedicine study.