John N. Booth

N-terminal proBNP—Marker of Cardiac Dysfunction, Fluid Overload, or Malnutrition in Hemodialysis Patients?

BACKGROUND AND OBJECTIVES N-terminal probrain type natriuretic peptide (NTproBNP) has been proven to be a valuable biomarker for predicting cardiac events and mortality in the hemodialysis population. However recent reports have suggested that NTproBNP is a marker of volume overload rather than one of cardiac dysfunction. Therefore this study investigated the effect of fluid volume status on NTproBNP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Volume status was determined pre- and postdialysis in 72 stable hemodialysis outpatients by multifrequency bioimpedance, and the relationship to NTproBNP values was examined. RESULTS The mean and median NTproBNP values were 931.9 +/- 230 and 242 (90 to 688) pmol/L, respectively. On simple correlation, NTproBNP was associated with markers of volume overload and cardiac dysfunction. However, on logistical regression analysis, the strongest association was with the predialysis ratio of extracellular water/total body water (beta 26.6, F29.6, P = 0.000), followed by postdialysis mean arterial blood pressure (beta 0.14, F17.1, P = 0.000), dialysate calcium concentration (beta -1.19, F14.1, P = 0.002), and change in extracellular fluid volume with dialysis (beta 0.27, F7.4, P = 0.009) CONCLUSIONS In this study, NTproBNP was not associated with cardiac dysfunction as assessed by transthoracic echo or nuclear medicine scintigraphy but was dependent on factors associated with volume overload. However, because bioimpedance results can also be affected by malnutrition with loss of cell mass, NTproBNP may be elevated not only in patients with volume overload, but also those with malnutrition.

Refractory Hypertension: Determination of Prevalence, Risk Factors, and Comorbidities in a Large, Population-Based Cohort

Refractory hypertension is an extreme phenotype of antihypertensive treatment failure. Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a large (n=30 239), population-based cohort were evaluated to determine the prevalence of refractory hypertension and associated cardiovascular risk factors and comorbidities. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic, ≥140/90 mm Hg) on ≥5 antihypertensive drug classes. Participants with resistant hypertension (systolic/diastolic, ≥140/90 mm Hg on ≥3 or <140/90 mm Hg on ≥4 antihypertensive classes) and all participants treated for hypertension served as comparator groups. Of 14 809 REGARDS participants receiving antihypertensive treatment, 78 (0.5%) had refractory hypertension. The prevalence of refractory hypertension was 3.6% among participants with resistant hypertension (n=2144) and 41.7% among participants on ≥5 antihypertensive drug classes. Among all participants with hypertension, black race, male sex, living in the stroke belt or buckle, higher body mass index, lower heart rate, reduced estimated glomerular filtration rate, albuminuria, diabetes mellitus, and history of stroke and coronary heart disease were associated with refractory hypertension. Compared with resistant hypertension, prevalence ratios for refractory hypertension were increased for blacks (3.00; 95% confidence interval, 1.68–5.37) and those with albuminuria (2.22; 95% confidence interval, 1.40–3.52) and diabetes mellitus (2.09; 95% confidence interval, 1.32–3.31). The median 10-year Framingham risk for coronary heart disease and stroke was higher among participants with refractory hypertension when compared with those with either comparator group. These data indicate that although resistant hypertension is relatively common among treated patients with hypertension, true antihypertensive treatment failure is rare.

Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of three or more antihypertensive medication classes or controlled hypertension while treated with four or more antihypertensive medication classes. We evaluated the association of aTRH with incident stroke, coronary heart disease (CHD), and all-cause mortality. Participants from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) Study treated for hypertension with aTRH (n = 2043) and without aTRH (n = 12,479) were included. aTRH was further categorized as controlled aTRH (≥4 medication classes and controlled hypertension) and uncontrolled aTRH (≥3 medication classes and uncontrolled hypertension). Over a median of 5.9, 4.4, and 6.0 years of follow-up, the multivariable adjusted hazard ratio for stroke, CHD, and all-cause mortality associated with aTRH versus no aTRH was 1.25 (0.94-1.65), 1.69 (1.27-2.24), and 1.29 (1.14-1.46), respectively. Compared with controlled aTRH, uncontrolled aTRH was associated with CHD (hazard ratio, 2.33; 95% confidence interval, 1.21-4.48), but not stroke or mortality. Comparing controlled aTRH with no aTRH, risk of stroke, CHD, and all-cause mortality was not elevated. aTRH was associated with an increased risk for coronary heart disease and all-cause mortality.

Effect of Sustaining Lifestyle Modifications (Nonsmoking, Weight Reduction, Physical Activity, and Mediterranean Diet) After Healing of Myocardial Infarction, Percutaneous Intervention, or Coronary Bypass (from the REasons for Geographic and Racial Differences in Stroke Study)

Guidelines recommend lifestyle modification for patients with coronary heart disease (CHD). Few data demonstrate which lifestyle modifications, if sustained, reduce recurrent CHD and mortality risk in cardiac patients after the postacute rehabilitation phase. We determined the association between ideal lifestyle factors and recurrent CHD and all-cause mortality in REasons for Geographic and Racial Differences in Stroke study participants with CHD (n = 4,174). Ideal lifestyle factors (physical activity ≥4 times/week, nonsmoking, highest quartile of Mediterranean diet score, and waist circumference <88 cm for women and <102 cm for men) were assessed through questionnaires and an in-home study visit. There were 447 recurrent CHD events and 745 deaths over a median 4.3 and 4.5 years, respectively. After multivariable adjustment, physical activity ≥4 versus no times/week and non-smoking versus current smoking were associated with reduced hazard ratios (HRs; 95% confidence interval [CI]) for recurrent CHD (HR 0.69, 95% CI 0.54 to 0.89 and HR 0.50, 95% CI 0.39 to 0.64, respectively) and death (HR 0.71, 95% CI 0.59 to 0.86 and HR 0.53, 95% CI 0.44 to 0.65, respectively). The multivariable-adjusted HRs (and 95% CIs) for recurrent CHD and death comparing the highest versus lowest quartile of Mediterranean diet adherence were 0.77 (95% CI 0.55 to 1.06) and 0.84 (95% CI 0.67 to 1.07), respectively. Neither outcome was associated with waist circumference. Comparing participants with 1, 2, and 3 versus 0 ideal lifestyle factors (non-smoking, physical activity ≥4 times/week, and highest quartile of Mediterranean diet score), the HRs (and 95% CIs) were 0.60 (95% CI 0.44 to 0.81), 0.49 (95% CI 0.36 to 0.67), and 0.38 (95% CI 0.21 to 0.67), respectively, for recurrent CHD and 0.65 (95% CI 0.51 to 0.83), 0.57 (95% CI 0.43 to 0.74), and 0.41 (95% CI 0.26 to 0.64), respectively, for death. In conclusion, maintaining smoking cessation, physical activity, and Mediterranean diet adherence is important for secondary CHD prevention.

Comparison of Volume Status in Asymptomatic Haemodialysis and Peritoneal Dialysis Outpatients

Background: The majority of haemodialysis (HD) patients gain weight between dialysis sessions and thereby become volume overloaded, whereas peritoneal dialysis (PD) is a more continuous technique. Cardiovascular mortality and hypertension is increased with both treatment modalities. We therefore wished to compare volume status in PD and HD to determine whether PD patients are chronically volume overloaded, as a risk factor for cardiovascular mortality. Study Design, Setting and Participants:We retrospectively audited 72 healthy HD patients and 115 healthy PD patients attending a university hospital dialysis centre for routine outpatient treatment, who had multi-frequency bioimpedance measurements of extracellular water to total body water (ECW/TBW). Results: The groups were well matched for age, sex, weight and ethnicity, PD patients had greater urine output [1,075 (485–1,613) vs. 42.5 (0–1,020) ml/day, p < 0.001], but there was no difference in antihypertensive prescription (63.5 vs. 76.4%), mean arterial blood pressure (post-dialysis 101.6 ± 1.5 mm Hg vs. pre-dialysis 102 ± 2.4 mm Hg), although post-dialysis arterial blood pressure was lower than in PD patients (96.4 ± 3.1 mm Hg, p < 0.05). The ratio of ECW/TBW fell after HD (pre-dialysis 0.394 ± 0.001 vs. post-dialysis 0.389 ± 0.004, p < 0.001) and was similar in the PD group to the group before HD (0.393 ± 0.001), and greater than that in the group after HD (p < 0.001). ECW/TBW was greater than the normal reference range in 30% PD patients, 28% patients before HD and 20% patients after HD. Conclusions: Overhydration is common in healthy stable PD outpatients, and ECW volumes in PD patients are not dissimilar to those of pre-dialysis HD patients. The role of chronic volume overload as a risk factor for cardiovascular disease needs further investigation.

The contributions of unhealthy lifestyle factors to apparent resistant hypertension: findings from the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study

Objectives: Unhealthy lifestyle factors may contribute to apparent treatment resistant hypertension (aTRH). We examined associations of unhealthy lifestyle factors with aTRH in individuals taking antihypertensive medications from three or more classes. Methods: Participants (n = 2602) taking three or more antihypertensive medication classes were identified from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was defined as having SBP/DBP at least 140/90 mmHg despite the use of three or more antihypertensive medication classes or the use of four or more classes to achieve blood pressure control. Lifestyle factors included obesity, physical inactivity, current smoking, heavy alcohol consumption, a low Dietary Approaches to Stop Hypertension (DASH) diet score and high sodium-to-potassium (Na/K) intake. Results: Among participants taking three or more antihypertensive medication classes, 1293 (49.7%) participants had aTRH. The prevalence of unhealthy lifestyle factors in participants with and without aTRH was 55.2 and 51.7%, respectively, for obesity, 42.2 and 40.5% for physical inactivity, 11.3 and 11.5% for current smoking, 3.1 and 4.0% for heavy alcohol consumption, 23.1 and 21.5% for low-DASH diet score, and 25.4 and 24.4% for high Na/K intake. After adjustment for age, sex, race, and geographic region of residence, none of the unhealthy lifestyle factors were associated with aTRH. The associations between each unhealthy lifestyle factor and aTRH remained nonsignificant after additional adjustment for education, income, depressive symptoms, total calorie intake, and comorbidities. Conclusions: Unhealthy lifestyle factors did not have independent associations with aTRH among individuals taking three or more antihypertensive medication classes.

Masked Hypertension and Incident Clinic Hypertension Among Blacks in the Jackson Heart Study

Masked hypertension, defined as nonelevated clinic blood pressure (BP) and elevated out-of-clinic BP may be an intermediary stage in the progression from normotension to hypertension. We examined the associations of out-of-clinic BP and masked hypertension using ambulatory BP monitoring with incident clinic hypertension in the Jackson Heart Study, a prospective cohort of blacks. Analyses included 317 participants with clinic BP <140/90 mm Hg, complete ambulatory BP monitoring, who were not taking antihypertensive medication at baseline in 2000 to 2004. Masked daytime hypertension was defined as mean daytime blood pressure ≥135/85 mm Hg, masked night-time hypertension as mean night-time BP ≥120/70 mm Hg, and masked 24-hour hypertension as mean 24-hour BP ≥130/80 mm Hg. Incident clinic hypertension, assessed at study visits in 2005 to 2008 and 2009 to 2012, was defined as the first visit with clinic systolic/diastolic BP ≥140/90 mm Hg or antihypertensive medication use. During a median follow-up of 8.1 years, there were 187 (59.0%) incident cases of clinic hypertension. Clinic hypertension developed in 79.2% and 42.2% of participants with and without any masked hypertension, 85.7% and 50.4% with and without masked daytime hypertension, 79.9% and 43.7% with and without masked night-time hypertension, and 85.7% and 48.2% with and without masked 24-hour hypertension, respectively. Multivariable-adjusted hazard ratios (95% confidence interval) of incident clinic hypertension for any masked hypertension and masked daytime, night-time, and 24-hour hypertension were 2.13 (1.51–3.02), 1.79 (1.24–2.60), 2.22 (1.58–3.12), and 1.91 (1.32–2.75), respectively. These findings suggest that ambulatory BP monitoring can identify blacks at increased risk for developing clinic hypertension.

Masked Hypertension and Cardiovascular Disease Events in a Prospective Cohort of Blacks: The Jackson Heart Study

Masked hypertension, defined as nonelevated clinic blood pressure (BP) with elevated out-of-clinic BP, has been associated with increased cardiovascular disease (CVD) risk in Europeans and Asians. Few data are available on masked hypertension and CVD and mortality risk among blacks. We analyzed data from the Jackson Heart Study, a prospective cohort study of blacks. Analyses included participants with clinic-measured systolic/diastolic BP <140/90 mm Hg who completed ambulatory BP monitoring after the baseline examination in 2000 to 2004 (n=738). Masked daytime (10:00 AM–8:00 PM) hypertension was defined as mean ambulatory systolic/diastolic BP ≥135/85 mm Hg. Masked nighttime (midnight to 6:00 AM) hypertension was defined as mean ambulatory systolic/diastolic BP ≥120/70 mm Hg. Masked 24-hour hypertension was defined as mean systolic/diastolic BP ≥130/80 mm Hg. CVD events (nonfatal/fatal stroke, nonfatal myocardial infarction, or fatal coronary heart disease) and deaths identified through December 2010 were adjudicated. Any masked hypertension (masked daytime, nighttime, or 24-hour hypertension) was present in 52.2% of participants; 28.2%, 48.2% and 31.7% had masked daytime, nighttime, and 24-hour hypertension, respectively. There were 51 CVD events and 44 deaths during a median follow-up of 8.2 and 8.5 years, respectively. CVD rates per 1000 person-years (95% confidence interval) in participants with and without any masked hypertension were 13.5 (9.9–18.4) and 3.9 (2.2–7.1), respectively. The multivariable adjusted hazard ratio (95% confidence interval) for CVD was 2.49 (1.26–4.93) for any masked hypertension and 2.86 (1.59–5.13), 2.35 (1.23–4.50), and 2.52 (1.39–4.58) for masked daytime, nighttime, and 24-hour hypertension, respectively. Masked hypertension was not associated with all-cause mortality. Masked hypertension is common and associated with increased risk for CVD events in blacks.

Prevalence of Masked Hypertension and Its Association With Subclinical Cardiovascular Disease in African Americans: Results From the Jackson Heart Study

Background Studies consisting mostly of whites have shown that the prevalence of masked hypertension differs by prehypertension status. Using data from the Jackson Heart Study, an exclusively African American population‐based cohort, we evaluated the association of masked hypertension and prehypertension with left ventricular mass index and common carotid intima media thickness. Methods and Results At the baseline visit, clinic blood pressure (CBP) measurement and 24‐hour ambulatory blood pressure monitoring were performed. Masked hypertension was defined as mean systolic/diastolic CBP <140/90 mm Hg and mean daytime systolic/diastolic ambulatory blood pressure ≥135/85 mm Hg. Clinic hypertension was defined as mean systolic/diastolic CBP ≥140/90 mm Hg. Normal CBP was defined as mean systolic/diastolic CBP <120/80 mm Hg and prehypertension as mean systolic/diastolic CBP 120 to 139/80 to 89 mm Hg. The analytic sample included 909 participants. Among participants with systolic/diastolic CBP <140/90 mm Hg, the prevalence of masked hypertension and prehypertension was 27.5% and 62.4%, respectively. The prevalence of masked hypertension among those with normal CBP and prehypertension was 12.9% and 36.3%, respectively. In a fully adjusted model, which included prehypertension status and antihypertensive medication use as covariates, left ventricular mass index was 7.94 g/m2 lower among those without masked hypertension compared to participants with masked hypertension (P<0.001). Left ventricular mass index was also 4.77 g/m2 lower among those with clinic hypertension, but this difference was not statistically significant (P=0.068). There were no significant differences in left ventricular mass index between participants with and without masked hypertension, or clinic hypertension. Conclusions Masked hypertension was common among African Americans with prehypertension and also normal CBP, and was associated with subclinical cardiovascular disease.

Healthy Lifestyle Factors and Risk of Cardiovascular Events and Mortality in Treatment-Resistant Hypertension The Reasons for Geographic and Racial Differences in Stroke Study

Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68–1.21), 0.80 (0.57–1.14), and 0.63 (0.41–0.95), respectively (P-trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment-resistant hypertension.