Effect of Lower Blood Pressure Goals on Left Ventricular Structure and Function in Patients With Subclinical Hypertensive Heart Disease.

BACKGROUND: Subclinical hypertensive heart disease (SHHD) is a precursor to heart failure. Blood pressure (BP) reduction is an important component of secondary disease prevention in patients with SHHD. Treating patients with SHHD utilizing a more intensive BP target (120/80 mm Hg), may lead to improved cardiac function but there has been limited study of this, particularly in African Americans (AAs). METHODS: We conducted a single center, randomized controlled trial where subjects with uncontrolled, asymptomatic hypertension, and SHHD not managed by a primary care physician were randomized to standard (<140/90 mm Hg) or intensive (<120/80 mm Hg) BP therapy groups with quarterly follow-up for 12 months. The primary outcome was the differences of BP reduction between these 2 groups and the secondary outcome was the improvement in echocardiographic measures at 12 months. RESULTS: Patients (95% AAs, 65% male, mean age 49.4) were randomized to the standard (n = 65) or the intensive (n = 58) BP therapy groups. Despite significant reductions in systolic BP (sBP) from baseline (-10.9 vs. -19.1 mm Hg, respectively) (P < 0.05), no significant differences were noted between intention-to-treat groups (P = 0.33) or the proportion with resolution of SHHD (P = 0.31). However, on post hoc analysis, achievement of a sBP <130 mm Hg was associated with significant reduction in indexed left ventricular mass (-6.91 gm/m2.7; P = 0.008) which remained significant on mixed effect modeling (P = 0.031). CONCLUSIONS: In post hoc analysis, sBP <130 mm Hg in predominantly AA patients with SHHD was associated with improved cardiac function and reverse remodeling and may help to explain preventative effects of lower BP goals. CLINICAL TRIALS REGISTRATION: Trial Number NCT00689819.

Screening and Treatment for Subclinical Hypertensive Heart Disease in Emergency Department Patients With Uncontrolled Blood Pressure: A Cost-effectiveness Analysis.

OBJECTIVES: Poorly controlled hypertension (HTN) is extremely prevalent and, if left unchecked, subclinical hypertensive heart disease (SHHD) may ensue leading to conditions such as heart failure. To address this, we designed a multidisciplinary program to detect and treat SHHD in a high-risk, predominantly African American community. The primary objective of this study was to determine the cost-effectiveness of our program. METHODS: Study costs associated with identifying and treating patients with SHHD were calculated and a sensitivity analysis was performed comparing the effect of four parameters on cost estimates. These included prevalence of disease, effectiveness of treatment (regression of SHHD, reversal of left ventricular hypertrophy [LVH], or blood pressure [BP] control as separate measures), echocardiogram costs, and participant time/travel costs. The parent study for this analysis was a single-center, randomized controlled trial comparing cardiac effects of standard and intense (<120/80 mm Hg) BP goals at 1 year in patients with uncontrolled HTN and SHHD. A total of 149 patients (94% African American) were enrolled, 133 (89%) had SHHD, 123 (93%) of whom were randomized, with 88 (72%) completing the study. Patients were clinically evaluated and medically managed over the course of 1 year with repeated echocardiograms. Costs of these interventions were analyzed and, following standard practices, a cost per quality-adjusted life-year (QALY) less than $50,000 was defined as cost-effective. RESULTS: Total costs estimates for the program ranged from $117,044 to $119,319. Cost per QALY was dependent on SHHD prevalence and the measure of effectiveness but not input costs. Cost-effectiveness (cost per QALY less than $50,000) was achieved when SHHD prevalence exceeded 11.1% for regression of SHHD, 4.7% for reversal of LVH, and 2.9% for achievement of BP control. CONCLUSIONS: In this cohort of predominantly African American patients with uncontrolled HTN, SHHD prevalence was high and screening with treatment was cost-effective across a range of assumptions. These data suggest that multidisciplinary programs such as this can be a cost-effective mechanism to mitigate the cardiovascular consequences of HTN in emergency department patients with uncontrolled BP.

Blood pressure treatment and outcomes in hypertensive patients without acute target organ damage: a retrospective cohort.

OBJECTIVES: The objective is of the study to evaluate the effect of antihypertensive therapy in emergency department (ED) patients with markedly elevated blood pressure (BP) but no signs/symptoms of acute target organ damage (TOD). METHODS: This is a retrospective cohort study of ED patients age 18 years and older with an initial BP greater than or equal to 180/100 mm Hg and no acute TOD, who were discharged with a primary diagnosis of hypertension. Patients were divided based on receipt of antihypertensive therapy and outcomes (ED revisits and mortality) and were compared. RESULTS: Of 1016 patients, 435 (42.8%) received antihypertensive therapy, primarily (88.5%) oral clonidine. Average age was 49.2 years, and 94.5% were African American. Treated patients more often had a history of hypertension (93.1% vs 84.3%; difference = -8.8; 95% confidence interval [CI], -12.5 to -4.9) and had higher mean initial systolic (202 vs 185 mm Hg; difference = 16.9; 95% CI, -19.7 to -14.1) and diastolic (115 vs 106 mm Hg; difference = -8.6; 95% CI, -10.3 to -6.9) BP. Emergency department revisits at 24 hours (4.4% vs 2.4%; difference = -2.0; 95% CI, -4.5 to 0.3) and 30 days (18.9% vs 15.2%; difference = -3.7; 95% CI, -8.5 to 0.9) and mortality at 30 days (0.2% vs 0.2%; difference = 0; 95% CI, -1.1 to 0.8) and 1 year (2.1% vs 1.6%; difference = -0.5; 95% CI, -2.5 to 1.2) were similar. CONCLUSIONS: Revisits and mortality were similar for ED patients with markedly elevated BP but no acute TOD, whether they were treated with antihypertensive therapy, suggesting relative safety with either approach.

Test characteristics of electrocardiography for detection of left ventricular hypertrophy in asymptomatic emergency department patients with hypertension.

OBJECTIVES: The objective was to evaluate the diagnostic test characteristics of three validated electrocardiographic (ECG) criteria for the diagnosis of left ventricular hypertrophy (LVH) in undifferentiated, asymptomatic emergency department (ED) patients with hypertension (HTN). METHODS: This was a prospective cohort study of ED patients with asymptomatic HTN at a single tertiary care facility. Patients 35 years of age or older with systolic blood pressure (sBP) ≥ 140 mm Hg or diastolic blood pressure (dBP) ≥ 90 mm Hg on two separate readings (at least 1 hour apart) were eligible for inclusion. At enrollment, ECGs were obtained for all patients. Presence of LVH on ECG was defined using Cornell voltage, Cornell product, and Minnesota Code 3.1/3.2 criteria. Echocardiography was then performed, with LVH defined by the presence of one or more of the following validated criteria: interventricular septal or posterior wall thickness ≥ 1.3 cm, LV mass ≥ 225 g (male) or ≥ 163 g (female), or LV mass indexed to height raised to the power of 2.7 ≥ 48 g/m(2.7) (male) or ≥ 45 g/m(2.7) (female). Descriptive statistics and diagnostic characteristics (i.e., sensitivity and specificity) with corresponding 95% confidence intervals (CIs) for each of the three ECG criteria were derived for both the composite and the individual echocardiographic determinants of LVH. Logistic regression was also used to model LVH before and after subsequent inclusion of clinically relevant variables. RESULTS: A total of 161 patients (93.8% African American; mean [±SD] age = 49.8 [±8.3] years) were enrolled, and LVH was present in 89 patients (55.2%, 95% CI = 47.6% to 62.8%). On ECG analysis, mean Cornell voltage (21.5 mV vs. 28.7 mV; difference = -7.2 mV, 95% CI = -3.8 to -10.7 mV) and Cornell product (1868.4 msec × mV vs. 2616.4 msec × mV; difference = -748.0 msec × mV, 95% CI = -401.2 to -1094.8 msec × mV) were significantly lower among those without LVH on echocardiography. Subjects without LVH on echocardiography were less likely to meet Cornell voltage (30.5% vs. 48.3%; difference = -17.8%, 95% CI = -2.5% to -31.7%) or Cornell product (26.4% vs. 49.4%; difference = -23.0%, 95% CI = -8.0% to -36.5%) criteria for LVH. The diagnosis of LVH by Minnesota Code was less common (18.1% vs. 25.8%; difference = -7.7%, 95% CI = -20.1% to 5.3%) with no difference by group. Sensitivity and specificity were as follows: for the Cornell voltage, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 50.0% (95% CI = 67.6% to 93.2%); for the Cornell product, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 75.0% (95% CI = 19.4% to 99.4%); and for the Minnesota code, sensitivity 26.9% (95% CI = 16.6% to 39.7%), specificity 75.0% (95% CI = 19.4% to 99.4%). On logistic regression, the c-statistics for Cornell voltage and Cornell product were equivalent (0.67), with only marginal improvement after the addition of body mass index (BMI; 0.69 and 0.70, respectively), B-type natriuretic peptide (BNP; 0.68 and 0.69, respectively), or both (0.71 and 0.72, respectively) to the models. CONCLUSIONS: In this cohort of predominately African American ED patients with asymptomatic HTN, sensitivity and specificity of standard ECG criteria were relatively poor for the diagnosis of LVH on echocardiography. Thus, ECG is of limited use for LVH risk stratification in asymptomatic ED patients with elevated blood pressure, with additional clinical information only modestly strengthening its predictive value.

Blood pressure control and perceived health status in African Americans with subclinical hypertensive heart disease.

The role of antihypertensive therapy in reducing the risk of cardiovascular complications such as heart failure is well established, but the effects of different blood pressure goals on patient-perceived health status has not been well defined. We sought to determine if adverse effects on perceived health status will occur with lower blood pressure goals or more intensive antihypertensive therapy. Data were prospectively collected as a part of a single center, randomized controlled trial designed to evaluate standard (Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure-compliant) versus intense (<120/80 mm Hg) blood pressure goals for patients with uncontrolled hypertension and subclinical hypertensive heart disease. Blood pressure management was open label, and health status was measured at 3-month intervals over 1 year of follow-up using the short-form (SF)-36. Mixed linear models were constructed for each of the SF-36 summary scores. One hundred twenty-three (mean age 49.4 ± 8.2; 65% female; 95.1% African American) patients were randomized, 88 of whom completed the protocol. With the exception of a decrease in perceived health transition, health status did not change significantly on repeat measurement. Lower blood pressure goals and more intensive antihypertensive therapy appear to be well tolerated with limited effects on patients' perception of health status.

Generating an unfoldase from thioredoxin-like domains.

Protein-disulfide isomerase (PDI), an endoplasmic reticulum (ER)-resident protein, is primarily known as a catalyst of oxidative protein folding but also has a protein unfolding activity. We showed previously that PDI unfolds the cholera toxin A1 (CTA1) polypeptide to facilitate the ER-to-cytosol retrotranslocation of the toxin during intoxication. We now provide insight into the mechanism of this unfoldase activity. PDI includes two redox-active (a and a') and two redox-inactive (b and b') thioredoxin-like domains, a linker (x), and a C-terminal domain (c) arranged as abb'xa'c. Using recombinant PDI fragments, we show that binding of CTA1 by the continuous PDIbb'xa' fragment is necessary and sufficient to trigger unfolding. The specific linear arrangement of bb'xa' and the type a domain (a' versus a) C-terminal to bb'x are additional determinants of activity. These data suggest a general mechanism for the unfoldase activity of PDI: the concurrent and specific binding of bb'xa' to particular regions along the CTA1 molecule triggers its unfolding. Furthermore, we show the bb' domains of PDI are indispensable to the unfolding reaction, whereas the function of its a' domain can be substituted partially by the a' domain from ERp57 (abb'xa'c) or ERp72 (ca degrees abb'xa'), PDI-like proteins that do not unfold CTA1 normally. However, the bb' domains of PDI were insufficient to convert full-length ERp57 into an unfoldase because the a domain of ERp57 inhibited toxin binding. Thus, we propose that generating an unfoldase from thioredoxin-like domains requires the bb'(x) domains of PDI followed by an a' domain but not preceded by an inhibitory a domain.