Impact of arterial location, pressure wave indicators, and measurement devices on arterial form factor and mean and central arterial pressure.

Mean arterial pressure (MAP) is often estimated from cuff systolic (S) and diastolic (D) blood pressure (BP) using a fixed arterial form factor (FF, usually 0.33). If MAP is measured directly, a true FF can be calculated: FF = [MAP-DBP]/[SBP-DBP]. Because waveform shapes vary, true FF should also vary and MAP accuracy will be affected. We studied factors affecting FF using radial tonography (SphygmoCor, n = 376) or brachial oscillometry (Mobil-O-Graph, n = 157) and to compare devices, 101 pairs were matched precisely for SBP and DBP. SphygmoCor brachioradial FF correlated strongly with central FF (r2 = 0.75), central augmentation index (cAI, r2 = 0.39), and inversely with pulse pressure amplification (PPA) ratio (r2 = 0.44) [all p < 0.000]; brachioradial FF was lower than central (c) FF (0.34 vs. 0.44, 95% CI's [0.23,0.46] and [0.34,0.54], p < 0.000). On forward stepwise regression, brachioradial FF correlated with PPA ratio, age, heart rate, and cAI (multiple-r2 0.63, p < 0.000). With Mobil-O-Graph: brachial FF was fixed, lower than the corresponding cFF [mean(SD)] 0.46(0.00098) vs. 0.57(0.048), p < 0.000], and uncorrelated with clinical characteristics; MAP and cSBP were higher than SphygmoCor by 6.3 and 2.2 mmHg (p < 0.005) at the midpoint with systematic negative biases. We conclude that FF derived from radial tonometry (SphygmoCor) varies with pulse wave morphology within and between individuals and by measurement site, age, and heart rate. With oscillometry (Mobil-O-Graph), brachial FF was fixed and high and unrelated to other clinical variables; MAP and cSBP were higher than tonometry, with systematic negative biases.

Cardiovascular Health in a Single Community in Rural Haiti: A Cross-sectional Study.

INTRODUCTION: There is a growing burden of cardiovascular disease in low- and middle-income countries and assessment of cardiovascular health (CVH) may identify populations at risk for poor CVH. METHODS: Between July 2014 and August 2014, we performed a household survey from a convenience sample among adult community members in rural northern Haiti. We used a modified World Health Organization STEPwise approach to chronic disease questionnaire to capture self-reported data on tobacco, diet, physical activity, and diabetes, and measured blood pressure and body mass index. We used an adapted American Heart Association definition and thresholds for determining ideal, intermediate, and poor cardiovascular health. We used linear and logistic regression to examine associations between socio-demographic characteristics with CVH score and ideal CVH. RESULTS: Among 540 participants (mean [SD] age = 40.3 [17.1] years, 67% women), there was a high prevalence of poor CVH (n=476, 88.1%) compared with intermediate (n=56, 10.4%) and ideal (n=41, 7.6%) CVH. Ideal metrics for blood pressure (47%) and diet (26%) were least often met, while body weight (84%), physical activity (83%), and smoking (90%) were most often met. Men were associated with better CVH score (0.31, [0.04-0.59]; P=0.03), and being a farmer was associated with ideal CVH (P=0.006). CONCLUSION: In this community-based sample of a farming community in rural Haiti, very few adults had ideal CVH. Higher CVH score was associated with male sex, and farming as a primary occupation. Women and non-farmers may represent at-risk subgroups within this population. Blood pressure and diet may represent possible areas for improvement.

Maintenance of long-term blood pressure control and vascular health by low-dose amiloride-based therapy in hyperaldosteronism.

Whether aldosterone itself contributes directly to macro- or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long-term single-practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid-remediable aldosteronism, GRA) treated with low-dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5-10 (mean 7) mg daily for 14-28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1-4 weeks after starting amiloride and office BP's remained well controlled throughout the next two decades. 24-hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle-brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient-years total), no cardiovascular or renal event occurred. We conclude that long-term ENaC blockade with amiloride can normalize BP and protect macro- and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age-dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

Long-term BP control and vascular health in patients with hyperaldosteronism treated with low-dose, amiloride-based therapy.

Whether aldosterone itself contributes directly to macro- or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long-term single-practice experience in 5 patients with chronic hyperaldosteronism (HA, including 3 with glucocorticoid remediable aldosteronism, GRA) treated with low-dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5-10 (mean 7) mg daily for 14-28 (mean 20) years. Except for 1 GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normal or near-normal within 1-4 weeks after starting amiloride and office BP's were well controlled for 20 years thereafter. Vascular studies and 24-hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, and reflection magnitude) were assessed after a mean of 18 years as were regional pulse wave velocities, pulse stiffening ratio, ankle-brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio. All indicators were completely normal in all patients after 18 years of amiloride, and none had a cardiovascular event during the 20-year mean follow-up. We conclude that long-term ENaC blockade can normalize BP and protect macro- and microvascular function in patients with HA. This suggests that (a) any vasculopathic effects of aldosterone are mediated via ENaC, not MR activation itself, and are fully preventable or reversible with ENaC blockade or (b) aldosterone may not play a major BP-independent role in human macro- and microcirculatory diseases. These and other widely divergent results in the literature underscore the need for additional studies regarding aldosterone, ENaC, and vascular disease.

Pulse Wave Velocities Derived From Cuff Ambulatory Pulse Wave Analysis.

Pulse wave velocity (PWV), a measure of arterial stiffness, is an independent risk factor for cardiovascular morbidity and mortality. We investigated the relationship of ambulatory brachial cuff-based oscillometric PWV (oPWV) to 2 known correlates: age and brachial systolic blood pressure (SBP). In 234 participants in the Masked Hypertension Study, we analyzed 7284 validated hourly ambulatory SBP and oPWV readings using the Mobil-O-Graph monitor, which uses a proprietary pulse wave analysis algorithm to determine oPWV. Carotid-femoral PWV (cfPWV) was also measured. Mixed linear models were developed to estimate oPWV from age and ambulatory SBP. Participants were 34% male, with mean (SD) age 52.8 (9.9) years, SBP 123.8 (18.4) mm Hg, and oPWV 7.6 (1.3) m/s and cfPWV of 7.7 (1.7) m/s. The relationship of oPWV to age and SBP is given below: [Formula: see text] Age uniquely accounted for an estimated 75% of the total variation of oPWV, whereas SBP uniquely accounted for 20%; these findings were confirmed in an external validation dataset. Together, age and SBP accounted for 99.1% of the total variance of oPWV but (only) 40.2% of the variance of cfPWV. The correlation between oPWV and cfPWV was 0.58 but was only 0.11 after controlling for age and SBP. We conclude that the Mobil-O-Graph's oPWV is nearly completely explained by age and SBP and its relationship to cfPWV is because of their shared associations with age and SBP. Other hemodynamic variables derived from oscillometric pulse wave analysis may be useful and deserve additional scrutiny.

Antihyperglycemic and Blood Pressure Effects of Empagliflozin in Black Patients With Type 2 Diabetes Mellitus and Hypertension.

BACKGROUND: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor indicated for type 2 diabetes mellitus (T2DM), can lower blood pressure (BP) and reduce cardiovascular mortality in patients with T2DM and preexisting cardiovascular disease. Its effects in blacks have been understudied. METHODS: In this 24-week study, 150 blacks with T2DM and hypertension had glycohemoglobin (primary end point), office and 24-hour ambulatory BP, body weight, and safety assessments. After a 2-week, open-label, placebo run-in, patients were randomly assigned to once daily empagliflozin (10 mg for the first 4 weeks, then force-titrated to 25 mg until week 24) or placebo. A mixed-effects model for repeated measures was performed on the primary and 2 key secondary end points, and an analysis of covariance for nonrepeated measures with last observation carried forward was performed for 2 other key secondary end points. Hierarchical testing was applied for these end points. RESULTS: Overall, 52.7% of participants were men, mean (SD) age, 56.8 (9.3) years; mean duration of T2DM, 9.3 (7.1) years. The baseline values of key parameters (mean [SD]) were as follows: glycohemoglobin, 8.59 (1.02)%; ambulatory systolic BP, 146.3 (11.0) mm Hg; and ambulatory diastolic BP, 89.4 (8.1) mm Hg. By week 24, the mean (standard error) change in glycohemoglobin in the empagliflozin group was -0.77 (0.15%) in comparison with an increase of 0.07 (0.16%) in the placebo group; placebo-corrected difference, -0.78% (95% CI, -1.18 to -0.38; P=0.0002). Reductions in body weight by week 24 were -2.38 (0.38) empagliflozin and -0.80 (0.47) placebo; the placebo-corrected difference was -1.23 kg (95% CI, -2.39 to -0.07; P=0.0382). Empagliflozin significantly reduced 24-hour ambulatory systolic BP versus placebo by weeks 12 and 24 (placebo-corrected difference, -5.21 mm Hg [95% CI, -9.24 to -1.18; P=0.0117] and -8.39 mm Hg [95% CI, -13.74 to -3.04; P=0.0025], respectively). Diastolic BP was also reduced. CONCLUSIONS: In blacks with T2DM, empagliflozin reduced glycohemoglobin, body weight, and BP. The effect of empagliflozin on BP increased from 12 to 24 weeks, suggesting a full antihypertensive effect takes ≥6 months to be fully realized. At week 24, the placebo-subtracted BP effect was similar to standard antihypertensive monotherapies, suggesting that empagliflozin may be beneficial for this high-risk population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02182830.

Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study.

We compared the systolic blood pressure (SBP)-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office SBP 150-179 mm Hg). Primary-dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24-hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily (1) is superior to valsartan 320 mg daily for lowering SBP, (2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, (3) represents the optimal dosage for systolic hypertension in patients of any age, and (4) is safe and well tolerated.

Influence of Age and Race on 24-Hour Ambulatory Blood Pressure Responses to Valsartan, Hydrochlorothiazide, and Their Combination: Implications for Clinical Practice.

The effects of race and age on 24-hour mean ambulatory systolic blood pressure (maSBP) responses to sequential 4-week periods of angiotensin receptor blocker therapy (valsartan [VAL] 160 mg/d then 320 mg/d and combination VAL/hydrochlorothiazide [HCTZ] 320/12.5 mg/d) were compared in 304 patients with stage 1 or 2 hypertension. There were lesser blood pressure (BP) responses from baseline with VAL monotherapy in black than Caucasian patients (-2.9 and -4.0 mm Hg vs -8.2 and -9.3 mm Hg, respectively; P<.001 each) but VAL/HCTZ BP responses were similar in both groups (-12 vs -15 mm Hg). Participants 65 years and older had lower BP responses with VAL 160 mg/d and 320 mg/d than those younger than 65 years (-2.8 and -4.5 mm Hg vs -6.5 and -7.5 mm Hg, respectively; P<.001) but similar responses to VAL/HCTZ (-14 vs -17 mm Hg). No BP response differences were found between those older than and those younger than 55 years. The authors conclude that: (1) adding low-dose HCTZ (12.5 mg daily) to VAL is more effective than VAL titration, irrespective of age or race, (2) VAL BP efficacy is lower in blacks than Caucasians, and (3) ARB responses are diminished in patients older than 65 years. Guidelines for stage 1 or 2 hypertension that suggest age 55 should determine initial monotherapy choice (eg, ARB vs thiazide diuretic) or that fail to recommend initial ARB-thiazide combination therapy should be reconsidered.

Arterial Stiffness: Going a Step Beyond.

Interest in arterial stiffness has been fueled by the scientific and clinical implications of its "vicious cycle" relationship with aging and systolic blood pressure. In physical terms, stiffness is the slope of the relationship between an artery's distending pressure and its cross-sectional area or volume. Pulse wave velocity (PWV, in m/s), the most common arterial stiffness indicator, is usually measured by the foot-to-foot time and distance method and is proportional to [stiffness × area (or volume)]1/2 at a given pressure. Its intrinsic pressure dependency and other flaws in current PWV methods limit its utility. In contrast, the arterial stiffness-arterial pressure relationship is near-linear, with a slope ß, the exponent of the curvilinear arterial pressure-arterial volume relationship. The concept of arterial stiffening is related to ß and describes a more functionally relevant aspect of arterial behavior: the change in stiffness for a given change in pressure. Arterial stiffening can be estimated from the variability of within-individual BP measurements (24-h ambulatory, home BP, or BP measured at different arm heights) and can be expressed as the pulse stiffening ratio (PSR) = [systolic stiffness]/[diastolic stiffness] or the ambulatory arterial stiffness index (AASI or its symmetric form, sAASI). High arterial stiffness (PWV) and stiffening (ß, stiffness index, cardio-ankle vascular index, AASI, and PSR) are associated with increased cardiovascular disease risk, but it remains unclear whether these indicators are useful in improving medical care quality; the standard of care remains stringent BP control.

Renal denervation for human hypertension: is there a future?

The sympathetic nervous system plays a permissive, if not primary causal role in the genesis and maintenance of human essential hypertension. Excessive sympathetic nervous system activity in man is most apparent in early forms of hypertension (prehypertension and white-coat type). Renal nerves are of particular interest because of their roles in modulating the activity of the renin-angiotensin system and renal sodium excretion. Renal denervation substantially ameliorates the development of hypertension in animal models such as renovascular, spontaneously hypertensive, and steroid-induced hypertension in rats and aortic coarctation in dogs. In man, catheter ablation of renal nerves has been undertaken in the late phases of hypertension; in a rigorously controlled trial in resistant hypertension (SYMPLICITY HTN-3), renal denervation did not reduce blood pressure over the long term. Is this because renal denervation is more appropriate to prevent than treat late-stage hypertension? Are there anatomical or technical barriers yet to be overcome in the procedure? These and other issues are addressed by two experts in this issue of the controversies series: Deepak L. Bhatt and Murray Epstein.

Is there a preferred diuretic class for patients with renal impairment and hypertension?

It is widely believed that "high-ceiling" loop diuretics are required in patients with renal impairment and that "low-ceiling" thiazides are not sufficiently potent to cause meaningful natriuresis and diuresis. If this statement is true, at what level of renal function do thiazides lose their punch? Another related issue is the enlightened use of diuretic combinations. Use of diuretics in chronic kidney disease and hypertension has been addressed in the many guidelines, but further insight is provided in this installment of the "Controversies" series by two well-known authorities, William Elliott, M.D. Ph.D. and Rajiv Agarwal, M.D.

Should age determine hypertension management? Recommendations from current guidelines.

Age is the most powerful of risk factors and is related continuously to systolic BP and cardiovascular disease risk. Yet current guidelines have dichotomized age groups around a cutoff value of 55-60 years and some guidelines now suggest that age should affect diagnostic thresholds and drug choices. These choices are not supported directly by scientific evidence but are based on expert opinion, the value of which is uncertain. This initial topic of the new Controversies in Hypertension series highlights important differences among current U.S., European, and Canadian practice guidelines, then moves on to editorial commentaries with different perspectives.

Ambulatory 24-hour cardiac oxygen consumption and blood pressure-heart rate variability: effects of nebivolol and valsartan alone and in combination.

We compared an angiotensin receptor blocker (valsartan; VAL), a beta-blocker (nebivolol; NEB) and the combination of NEB/VAL with respect to 24-hour myocardial oxygen consumption (determined by 24-hour ambulatory heart rate-central systolic pressure product [ACRPP]) and its components. Subjects with hypertension (systolic blood pressure >140 or diastolic blood pressure >90; n = 26) were studied in a double-blinded, double-dummy, forced-titration, crossover design with 3 random-order experimental periods: VAL 320 mg, NEB 40 mg, and NEB/VAL 320/40 mg daily. After 4 weeks of each drug, ambulatory pulse wave analysis (MobilOGraph) was performed every 20 minutes for 24 hours. All three treatments resulted in nearly identical brachial and central systolic blood pressures. NEB alone or in combination with VAL resulted in lower ACRPP (by 11%-14%; P < .001 each) and heart rate (by 18%-20%; P < .001 each) compared with VAL, but stroke work (ACRPP per beat) was lower with VAL. Relative and adjusted variability (standard deviation and coefficient of variation) of heart rate were also lower with NEB and NEB/VAL than VAL. Results in African Americans, the majority subpopulation, were similar to those of the entire treatment group. We conclude that the rate-slowing effects of NEB cause ambulatory cardiac myocardial oxygen consumption to be lower with NEB monotherapy or NEB/VAL combination therapy than with VAL monotherapy. NEB/VAL is not superior to NEB alone in controlling heart rate, blood pressure, or ACRPP. Heart rate variability but not ACRPP variability is reduced by NEB or the combination NEB/VAL. There is no attenuation of beta-blocker-induced rate-slowing effects of in African Americans.

Brachial vs. central systolic pressure and pulse wave transmission indicators: a critical analysis.

This critique is intended to provide background for the reader to evaluate the relative clinical utilities of brachial cuff systolic blood pressure (SBP) and its derivatives, including pulse pressure, central systolic pressure, central augmentation index (AI), and pulse pressure amplification (PPA). The critical question is whether the newer indicators add sufficient information to justify replacing or augmenting brachial cuff blood pressure (BP) data in research and patient care. Historical context, pathophysiology of variations in pulse wave transmission and reflection, issues related to measurement and model errors, statistical limitations, and clinical correlations are presented, along with new comparative data. Based on this overview, there is no compelling scientific or practical reason to replace cuff SBP with any of the newer indicators in the vast majority of clinical situations. Supplemental value for central SBP may exist in defining patients with exaggerated PPA ("spurious systolic hypertension"), managing cardiac and aortic diseases, and in studies of cardiovascular drugs, but there are no current standards for these possibilities.