Abstract
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.
Keywords: African American, blood pressure, heart failure, hypertension, left ventricular hypertrophy, subclinical hypertensive heart disease, urban
Hypertension (HTN) has long been associated with asymptomatic geometric and functional changes of the heart.1,2 Absent symptoms, such as early stage remodeling has been termed “subclinical hypertensive heart disease” (SHHD)—a condition that is strongly associated with subsequent development of cardiovascular disease (CVD), especially heart failure (HF).3,4 Appropriate secondary prevention, primarily by blood pressure (BP) control, has been shown to reverse the pathological changes seen with SHHD and prevent the development of HF.5 Although there have been several prior studies that have demonstrated the benefits of intensive BP control on CVD in the elderly, the recent SPRINT study group demonstrated significantly lower incident rates of fatal and nonfatal major CVD events and death with intense BP control6,7 with corresponding improvements in left ventricular hypertrophy (LVH) as determined by electrocardiogram.8 Similarly, patients with intensive BP control in the CABL study9 and in the SANDS trial10 had lower rates of 2D echocardiography-determined LVH.
While such literature supports the concept of more intensive BP control to reduce the rate of HF and cardiovascular morbidity, little is known on what effect this approach to BP control has on left ventricular (LV) remodeling in a high risk, predominantly African American (AA) population with a high prevalence of SHHD, and what role LV remodeling plays in populations at risk for developing complications associated with HTN. Urban-dwelling AAs are at tremendous risk for developing CVD morbidity associated with HTN and have the highest incidence of HTN in the United States.11,12 with the poorest rates of BP control.13–15 This translates to a greater likelihood of developing HF, and a higher CVD-specific mortality rate16–18 similar to the subgroup analysis of the SPRINT study that demonstrated increased risk of HF in AAs.7 Importantly, when AAs do develop HF, it occurs at a strikingly young median age of 39 years,19 which is tightly linked to a disproportionate occurrence of LVH in the population.20–22 The relative mortality risk among AAs with LVH (and equivalent to frankly impaired LV function) is greater than the relative risk of multivessel coronary artery obstruction (2.4 vs. 1.6, respectively).23 Based on this and other evidence, the International Society for Hypertension in Blacks (ISHIB) recommended BP goals of 135/85 mm Hg in the general black population, and 130/80 mm Hg in patients with end-organ damage24 before contemporary guidelines called for similar targets.
Despite these recommendations, appropriate BP targets to achieve clinically significant reductions in SHHD have not been clearly defined. We hypothesized that an intensive BP goal of <120/80 mm Hg, compared with standard goals (<140/90 mm Hg, and <130/80 for patients with chronic kidney disease or diabetes, according to the 7th Joint National Committee (JNC 7) on Prevention, Detection, Evaluation and Treatment of High Blood Pressure),25 would be associated with more significant regression of SHHD in our high risk, predominantly AA population with a high prevalence of SHHD.
METHODS
Overview
This was a longitudinal randomized controlled trial in a predominantly AA patient population with poorly controlled chronic HTN and echocardiographic evidence of SHHD22 designed to compare the effects of 2 BP targets: the standard BP therapy group, which used JNC 7 defined BP goals (<140/90 or <130/80 mm Hg if diabetes or chronic kidney disease was present), vs. <120/80 mm Hg in the intensive BP therapy group. As described in previous publications,26,27 patients were followed for 1-year postenrollment in a single HTN clinic with care delivered by a multidisciplinary team including a hypertension specialist physician. Antihypertensive medications were provided free of charge. In addition, patients received telephone reminders prior to scheduled visits and transportation to follow-up appointments was provided. This study was approved by The Institutional Review Board (IRB) at Wayne State University; all subjects signed a written consent form prior to enrollment. This study was registered with www.clinicaltrials.gov with identifier number NCT00689819.
Design
Study participants were recruited from the Emergency Department (ED) of a single academic, tertiary care institution with 90,000 annual visits. The facility’s electronic medical record (FirstNet by Cerner Corp., Kansas City, MO) was used by trained research assistants to identify eligible patients 35 years of age or older who had an initial and repeat (within 1 hour) BP >140/90, and normal exertional tolerance (defined as class 1 on the Goldman Specific Activity Scale28). Patients with acute illness requiring hospitalization, any history of cardiac disease, or any presentation with symptoms potentially attributable to hypertensive heart disease (i.e., dyspnea and chest pain) were excluded. So that patients’ BP could be managed exclusively by study practitioners, we also excluded patients with a usual source of health care (i.e., primary care physician actively managing BP medications).26
Although enrollment details have been published previously,26 patients were approached and consented in the ED and enrolled patients (n = 149) were invited to a post-ED secondary screening visit where an echocardiogram was performed and a detailed medical history was obtained. As defined by the 2009 American Society of Echocardiography, presence of LVH (LV mass indexed to height2.7 [males: ≥48 g/m2.7; females: ≥45 g/m2.7]), LV systolic dysfunction (ejection fraction <50%), LV diastolic dysfunction (combination of parameters based on validated criteria of LV stiffness and relaxation), or left atrial enlargement (left atrial volume indexed to body surface area [males or females: ≥29 ml/m2]) were considered to be indicative of SHHD.29 All echocardiograms were interpreted by a single, independent, cardiologist certified by the National Board of Echocardiography with more than 20 years’ experience who was blinded to clinical data. Patients with SHHD were then randomized to either the intensive BP therapy group or the standard BP therapy group.26
Intervention
Participants in each group had visits at baseline (initial visit), and then at 3, 6, 9, and 12 months. At each time-point visit, a trained research assistant who was blinded to randomized study group allocation obtained attended, automated oscillometric brachial cuff BP measurements using the same device each time (Welch Allyn, Chicago, IL), using the participant’s right arm while seated. The average reading of 3 independent measurements was recorded. Antihypertensive therapy was titrated as needed per BP goal of the respective treatment group assignment by a study practitioner in an open label fashion using principles based on JNC 7 recommendations.25 Details of the medication protocol have been described in detail previously.30 To enable between group comparison of antihypertensive therapy, therapeutic intensity score (TIS; a composite measure of therapy derived from the sum of individual medication’s intensity ratio [i.e., prescribed daily dose divided by maximum daily dose]) was calculated at each visit.26
Outcome measure
The primary outcome was BP differences between the standard therapy group and the intensive therapy group with a secondary outcome of improvement in echocardiographic measures of SHHD with intensive BP therapy over a 12-month study period.
Sample size
As our intervention was focused on differing BP targets by group, sample size was determined based on systolic BP (sBP) changes over time using a repeated measures design (baseline and 4 quarterly BP measurements), with a between-measurement correlation of 0.65 and an intraperson sBP SD of 10 mm Hg (both derived from our HTN clinic data). Using a 2-tail alpha error of 0.05, 90 total patients (45/group) were needed to have 80% power to detect a 6 mm Hg difference in change from baseline in sBP between the standard therapy and intensive therapy groups. We estimated a 15% dropout rate a priori, resulting in a target enrollment of 104 patients. Actual dropout rate was greater than expected (32/133; 24%), and thus additional subjects were recruited to maintain a stable study cohort.
Data analysis
First, descriptive analysis was conducted and the means, SDs, 95% confidence intervals, and medians with interquartile ranges were determined for continuous data while proportions and 95% confidence interval were used for categorical data. The distributions of continuous variables were examined for skewness/normality using Shapiro–Wilk statistic or Kolmogorov–Smirnov statistic with normalization using log transformations prior to analysis for any continuous variable that was far from normality assumption. Second, continuous and categorical data were compared using t-tests and chi-squared analysis; between group differences were also calculated along with corresponding 95% confidence intervals. Two-tailed alpha significance was set at 0.05, with the caveat that multiple comparisons were performed. Third, mixed linear models for repeated measures were performed adjusting for age, sex, baseline BP (with systolic and diastolic BP modeled as separate effects), antihypertensive TIS, and assigned treatment group for the primary outcome. All data were analyzed with SAS (Cary, NC) using both the intention-to-treat (ITT; n = 123) and on-treatment (OT; n = 88) cohorts. While the ITT cohort included all randomized subjects, the OT cohort included only those subjects who completed the study protocol. Missing data were imputed using a last observation carried forward strategy. Since BP goals were not uniformly attained in our randomized groups, post hoc modeling was performed for the 88 patients who completed the study comparing those who achieved a sBP goal of <130 mm Hg (n = 36; which consistent with prior guidelines24,31) vs. those who did not (n = 52).
RESULTS
Following primary screening and subsequent enrollment, 149 patients were evaluated by echocardiogram of which 133 (89%) were found to have SHHD. Ultimately, 123 patients were randomized into the 2 treatment groups (standard BP therapy group (n = 65) and the intensive BP therapy group (n = 58)). In the standard BP therapy group, 45/65 patients (69%) completed the study with 18/65 patients (28%) dropping out and 2/65 (3%) who were withdrawn. These details, including a CONSORT figure, have been published previously.26 In the intensive BP therapy group, 43/58 patients (74%) completed the study with 14/58 patients (24%) dropping out and 1/58 (2%) were withdrawn. Patients who were withdrawn developed unrelated medical complications. Overall, of the patients that were randomized, 88/123 (72%) completed the study. There were no differences noted in any variables at baseline between patients who dropped out vs. those who completed the study (data not shown). The study cohort was predominantly AA (95.1%) and male (65.0%), with a mean age (SD) of 49.4 (8.2) years (Table 1). Mean (SD) ED screening BP was 181/105 (21/12) mm Hg on an average of 1.8 antihypertensive medications with no differences between groups regarding antihypertensive medication use, duration of use, or compliance (Table 1). Similarly, there were no statistically significant differences in the baseline characteristics of the standard BP therapy group vs. the intensive BP therapy group (Table 1) or between groups in the post hoc analysis (Table 2).
Table 1.
Comparison of patients’ characteristics at baseline between the standard BP therapy group and the intensive BP therapy group
| Baseline characteristic | Standard BP therapy (n = 65) | Intensive BP therapy (n = 58) | P value |
|---|---|---|---|
| Demographics | |||
| Gender, n (% male) | 21 (32.3) | 22 (37.9) | 0.51 |
| Race, n (% African American) | 59 (90.8) | 58 (100.0) | 0.06 |
| Age, mean (SD) | 49.3 (8.1) | 49.6 (8.3) | 0.83 |
| Education of high school or greater, n (%) | 49 (77.8) | 37 (67.3) | 0.32 |
| Body mass index (kg/m2), mean (SD) | 31.7 (6.3) | 32.8 (5.8) | 0.3 |
| sBP at recruitment (mm Hg), mean (SD) | 181.4 (21.0) | 181.5 (22.8) | 0.98 |
| dBP at recruitment (mm Hg), mean (SD) | 105.3 (13.3) | 105.3 (12.1) | 0.99 |
| sBP at randomization (mm Hg), mean (SD) | 153.2 (20.6) | 151.2 (25.1) | 0.63 |
| dBP at randomization (mm Hg), mean (SD) | 100.6 (13.2) | 97.9 (15.5) | 0.31 |
| Hypertensive history | |||
| Hypertension, n (%) | 50 (78.1) | 46 (82.1) | 0.6 |
| Duration of having HTN (in years), mean (SD) | 7.5 (9.9) | 8.1 (9.1) | 0.73 |
| Medical therapy for HTN, n (%) | 13 (20.0) | 15 (25.9) | 0.44 |
| Duration of HTN therapy (in years), mean (SD) | 10.1 (11.9) | 7.3 (9.5) | 0.42 |
| HTN medications missed per week, mean (SD) | 1.1 (2.0) | 0.6 (1.0) | 0.36 |
| Number of HTN medications, mean (SD) | 1.8 (0.8) | 1.8 (1.2) | 0.89 |
| Other medical history | |||
| Hyperlipidemia, n (%) | 6 (9.2) | 3 (5.3) | 0.7 |
| Stoke and/or TIA, n (%) | 2 (3.1) | 2 (3.5) | 0.89 |
| Diabetes, n (%) | 5 (7.7) | 3 (5.2) | 0.57 |
| Chronic kidney disease, n (%) | 1 (1.5) | 0 (0.0) | 0.54 |
| Any liver disease, n (%) | 1 (2.0) | 1 (2.6) | 0.54 |
| Health-related behaviors | |||
| Any exercise, n (%) | 32 (51.6) | 37 (64.9) | 0.14 |
| Tobacco use, n (%) | 38 (60.3) | 34 (59.6) | 0.94 |
| Alcohol use, n (%) | 35 (55.6) | 32 (56.1) | 0.63 |
| Illicit drug use, n (%) | 19 (30.2) | 14 (24.6) | 0..49 |
| Echocardiographic parameters | |||
| Ejection fraction, % (SD) | 64.8 (8.8) | 62.7 (11.0) | 0.25 |
| E, cm/s (SD) | 75.0 (18.5) | 75.3 (19.7) | 0.94 |
| A, cm/s (SD) | 74.0 (19.2) | 73.7 (18.8) | 0.93 |
| e′, cm/s (SD) | 7.1 (2.1) | 7.0 (2.3) | 0.94 |
| E/A ratio (SD) | 1.1 (0.4) | 1.1 (0.4) | 0.96 |
| E/e′ ratio (SD) | 11.5 (4.5) | 11.8 (4.6) | 0.72 |
| LV mass indexed to height2.7, in gm/m2.7 (SD) | 49.6 (14.6) | 51.0 (19.2) | 0.65 |
| LA volume indexed to BSA, in ml/m2 | 23.9 (7.2) | 22.8 (8.5) | 0.45 |
| Subclinical hypertensive heart disease (SHHD) parameters | |||
| Systolic dysfunction, n (%) | 7 (10.7) | 8 (13.7) | 0.32 |
| Diastolic dysfunction, n (%) | 33 (50.7) | 32 (55.1) | 0.45 |
| Left ventricular hypertrophy, n (%) | 41 (63.1) | 38 (65.5) | 0.4 |
| Left atrial enlargement, n (%) | 14 (21.5) | 9 (15.5) | 0.06 |
| >1 parameter of SHHD, n (%)a | 24 (36.9) | 25 (43.1) | 0.44 |
Abbreviations: A, late transmitral flow; BP, blood pressure; BSA, body surface area; dBP, diastolic blood pressure; E, early transmitral flow; e′, diastolic velocity at the medial mitral annulus; HTN, hypertension; LA, left atrial; LV, left ventricular; sBP, systolic blood pressure; TIA, transient ischemic attack.
a represents 2 or more of the other parameters of SHHD are present in the same individual.
Table 2.
Comparison of patients’ baseline characteristics in post hoc cohort
| Baseline characteristic | Achieved BP <130 mm Hg (n = 36) | Did not achieve BP <130 mm Hg (n = 52) | P value |
|---|---|---|---|
| Demographics | |||
| Gender, n (% male) | 27 (75.0) | 32 (61.5) | 0.19 |
| Race, n (% African American) | 35 (97.2) | 49 (94.2) | 0.48 |
| Age, mean (SD) | 50.9 (6.2) | 48.9 (8.6) | 0.22 |
| Education of high school or greater, n (%) | 24 (72.7) | 39 (76.5) | 0.76 |
| Body mass index (kg/m2), mean (SD) | 34.0 (6.4) | 31.7 (5.5) | 0.08 |
| sBP at recruitment (mm Hg), mean (SD) | 178.5 (21.3) | 182.7 (20.1) | 0.35 |
| dBP at recruitment (mm Hg), mean (SD) | 103.4 (12.2) | 104.5 (2.2) | 0.66 |
| Hypertensive history | |||
| Hypertension, n (%) | 26 (74.3) | 42 (84.0) | 0.34 |
| Duration of having HTN (in years), mean (SD) | 7.7 (10.4) | 8.4 (8.5) | 0.76 |
| Medical therapy for HTN, n (%) | 8 (22.2) | 15 (28.8) | 0.49 |
| Duration of HTN therapy (in years), mean (SD) | 9.6 (11.4) | 5.8 (7.2) | 0.26 |
| HTN medications missed per week, mean (SD) | 0.3 (0.7) | 1.2 (2.1) | 0.13 |
| Number of HTN medications, mean (SD) | 1.8 (0.9) | 1.6 (0.9) | 0.44 |
| Other medical history | |||
| Hyperlipidemia, n (%) | 4 (11.4) | 4 (7.7) | 0.44 |
| Stoke and/or TIA, n (%) | 2 (5.7) | 2 (3.8) | 0.64 |
| Diabetes, n (%) | 3 (8.3) | 5 (9.6) | 0.84 |
| Chronic kidney disease, n (%) | 1 (2.9) | 0 (0.0) | 0.22 |
| Any liver disease, n (%) | 0 (0.0) | 2 (5.3) | 0.35 |
| Health-related behaviors | |||
| Any exercise, n (%) | 20 (58.8) | 27 (51.9) | 0.53 |
| Tobacco use, n (%) | 15 (44.1) | 34 (65.4) | 0.05 |
| Alcohol use, n (%) | 13 (38.2) | 31 (59.6) | 0.09 |
| Illicit drug use, n (%) | 8 (23.5) | 11 (21.2) | 0.8 |
| Echocardiographic parameters | |||
| Ejection fraction, % (SD) | 63.0 (9.5) | 64.4 (11.1) | 0.54 |
| E, cm/s (SD) | 71.2 (17.0) | 75.7 (19.8) | 0.22 |
| A, cm/s (SD) | 70.1 (16.3) | 73.7 (19.0) | 0.4 |
| e′, cm/s (SD) | 7.5 (2.5) | 7.0 (1.9) | 0.38 |
| E/A ratio (SD) | 1.1 (0.4) | 1.1 (0.3) | 0.75 |
| E/e′ ratio (SD) | 10.9 (4.8) | 11.3 (3.5) | 0.64 |
| LV mass indexed to height2.7, in gm/m2.7 (SD) | 48.3 (15.6) | 50.1 (16.7) | 0.61 |
| LA volume indexed to BSA, in ml/m2 | 23.0 (7.5) | 23.2 (6.5) | 0.88 |
Abbreviations: A, late transmitral flow; BP, blood pressure; BSA, body surface area; dBP, diastolic blood pressure; E, early transmitral flow; e′, diastolic velocity at the medial mitral annulus; HTN, hypertension; LA, left atrial; LV, left ventricular; sBP, systolic blood pressure; TIA, transient ischemic attack.
Although reductions in systolic and diastolic BPs (dBP) were significant in both groups from randomization baseline over time at the 12-month follow-up visit (sBP: standard: −10.9 mm Hg (P = 0.01), intensive: −19.1 mm Hg (P = 0.0008); dBP: standard: −5.8 mm Hg (P = 0.001), intensive: −11.3 mm Hg (P = 0.002)), only 32.3% of standard BP therapy patients (46.7% in the OT subgroup) and 17.2% of intensive BP therapy patients (23.3% in the OT subgroup) achieved their prespecified goal BP despite significantly higher use of antihypertensive agents by patients in the intensive BP therapy group (mean TIS scores: standard 0.74 vs. intensive 1.23; P < 0.008) (Figure 1). While there was some heterogeneity in the selection of antihypertensive agents, thiazide-like diuretics, renin–angiotensin–aldosterone system inhibitors, and calcium channel blockers were the most common medications used (52.9%, 26.4%, and 13.7%, respectively). There were no differences between proportion of medications used between the study groups in the randomized controlled trial or the post hoc analysis. BP changes over time in the OT and ITT groups are shown in Figure 2. Although body mass index, tobacco use, alcohol use, and medication compliance may contribute to successful achievement of BP control, they were not statistically significant (Table 2).
Figure 1.
Therapeutic intensity scores (TISs) for the use of antihypertensive agents in (a) standard BP therapy group vs. (b) intensive BP therapy group over the 12-month study period. Data plotted at −0.5 and 0 months represent TIS scores at the time of recruitment in the emergency department (ED) and at time of randomization, respectively. Data illustrated are average TIS scores. Abbreviations: BP, blood pressure; RAAS, renin–angiotensin–aldosterone system inhibitors.
Figure 2.
Mean changes in systolic (top row) and diastolic (bottom row) blood pressures (BP) over time in the standard BP therapy group and the intensive BP therapy group from randomization (time = 0 month). Panels a and c represent the post hoc on-treatment group vs. panels b and d represent the intention-to-treat group. Dashed line represents BP data obtained during recruitment in the emergency department (ED) at −0.5 month. BP data are represented as mean ± SD (mm Hg) over the course of the 1-year study period. Abbreviations: dBP, diastolic blood pressure; sBP, systolic blood pressure.
The original randomized controlled trial lacked sufficient power (observed power was 0.15). Although group variation was minimal (F-test P = 0.92), and we recruited 88/90 of the projected number of patients, and we accurately estimated the observed difference in mean sBP between groups (6.3 vs. 6.0 mm Hg), the variability of the study was more than double the value used to originally estimate sample size (pooled SD in the observed data was 22.1 vs. an estimate of 10). Although an explanation is not entirely clear, we speculate that a major contributor to this phenomenon was that our initial power estimates were based on a stable cohort of HTN clinic patients vs. this study recruited patients directly from the ED.
At the end of the study the prevalence of SHHD remained high (91.8% and 88.7% in the ITT and OT groups, respectively), and there was no demonstrable association between randomization group and regression of SHHD (Table 3). However, on post hoc analysis, achievement of sBP <130 was associated with a significant reduction in LV mass index by −6.91 g/m2.7 (P = 0.008) and a corresponding increase (but not significant; P = 0.051) in ejection fraction over the course of the study at 12 months (Table 3). The post hoc group with sBP <130 had a lower prevalence of SHHD (76.2%) relative to the sBP >130 group (92.0%) but it was not significant (P > 0.05).
Table 3.
Comparison of changes between groups over 1 year in echocardiographic measures of subclinical hypertensive heart disease
| Echocardiographic parameter | Difference in echocardiographic changes between groups | |||||
|---|---|---|---|---|---|---|
| Intensive BP therapy vs. standard BP therapy | Achieved sBP <130 mm Hg vs. not | |||||
| Intention-to-treat | On-treatment | |||||
| n = 123 | n = 88 | n = 36 vs. 52 | ||||
| Mean (95% CI) | P value | Mean (95% CI) | P value | Mean (95% CI) | P value | |
| Ejection fraction, % | 1.70 (−4.3, 7.6) | 0.59 | −0.4 (3.9, −4.6) | 0.87 | 4.1 (8.3, −0.1) | 0.05 |
| E, cm/s | 0.03 (0.15, −0.09) | 0.60 | 0.01 (0.10, −0.07) | 0.74 | −0.04 (0.04, −0.12) | 0.30 |
| A, cm/s | −0.04 (0.08, −0.16) | 0.55 | −0.03 (0.05, −0.11) | 0.43 | 0.00 (0.08, −0.08) | 0.97 |
| e′’, cm/s | 0.00 (0.01, −0.02) | 0.84 | 0.00 (0.01, −0.01) | 0.41 | 0.00 (0.00, −0.01) | 0.37 |
| E/A ratio | 3.16 (9.17, −2.85) | 0.31 | 3.13 (9.12, −2.87) | 0.32 | −0.98 (0.39, −2.34) | 0.16 |
| E/e′ ratio | 0.40 (2.99, −2.19) | 0.76 | 0.23 (−1.57, 1.10) | 0.73 | −2.59 (3.52, −8.70) | 0.31 |
| LV mass indexed to height2.7, in g/m2.7 | 0.88 (10.64, −11.04) | 0.97 | 0.17 (5.74, −5.41) | 0.95 | −6.91 (−1.44, −12.39) | 0.008** |
| LA volume indexed to BSA, in ml/m2 | 4.18 (8.88, −0.52) | 0.08 | 2.22 (6.21, −1.78) | 0.27 | −1.6 (2.49, −5.7) | 0.42 |
Abbreviations: A, late transmitral flow; BP, blood pressure; BSA, body surface area; CI, confidence interval; E, early transmitral flow; e′, diastolic velocity at the medial mitral annulus; LA, left atrial; LV, left ventricular; sBP, systolic blood pressure.
**P < 0.01.
Mixed effect linear modeling in both the ITT and OT cohorts found no effect of randomization to the intensive therapy group on change in systolic or diastolic BP or change in echocardiographic parameters when controlling for gender, age, baseline sBP, and TIS (data not shown). However, similar to the unadjusted post hoc analysis, on mixed effect linear modeling adjusting for randomized treatment group, gender, age, baseline sBP, and TIS, achievement of sBP <130 was associated with significant decrease in LV mass index by −4.56 g/m2.7 (P = 0.03) with a corresponding increase in ejection fraction by 2.4% (P = 0.04) (Table 4).
Table 4.
Mixed effect linear regression modeling of echocardiographic parameter change in post hoc cohort controlling for randomized treatment group, age, gender, baseline systolic blood pressure, and therapeutic intensity score
| Echocardiographic parameter | Change point estimate (95% CI) | P value |
|---|---|---|
| Ejection fraction, % | 2.4 (0.2, 4.6) | 0.04* |
| E, cm/s | −0.03 (−0.07, 0.02) | 0.23 |
| A, cm/s | −0.01 (−0.05, 0.03) | 0.61 |
| e′, cm/s | −0.00 (−0.01, 0.00) | 0.43 |
| E/A ratio | −0.67 (−3.80, 2.44) | 0.67 |
| E/e′ ratio | −0.59 (−1.27, 0.09) | 0.34 |
| LV mass indexed to height2.7, in gm/m2.7 | −4.56 (−7.37, −1.55) | 0.03* |
| LA volume indexed to BSA, in ml/m2 | −0.61 (−2.75, 1.53) | 0.57 |
Abbreviations: A, late transmitral flow; BSA, body surface area; CI, confidence interval; E, early transmitral flow; e′, diastolic velocity at the medial mitral annulus; LA, left atrial; LV, left ventricular.
*P < 0.05.
DISCUSSION
Our study was designed to screen and treat patients with HTN who had echocardiographic evidence of SHHD—a meaningful and early intervention point that is consistent with recommendations related to prevention of HTN mediated complications in relevant guidelines.24,25,32 In this randomized controlled trial of a high risk and predominantly AA population with SHHD we found no association between assignment to an intensive BP therapy group and regression of SHHD. However, both groups did achieve reductions in BP and on post hoc analysis utilizing a measure of actual achievement of sBP <130 mm Hg, regardless of treatment group, we demonstrated an association between lower sBP, reverse cardiac remodeling, and improved LV ejection fraction despite no statistical improvement in SHHD.
The results on LVH are consistent with other studies that have compared standard BP therapy to intensive BP therapy as assessed by electrocardiogram33–35 and echocardiography.9 However, a follow-up study used cardiac magnetic resonance imaging and did not demonstrate any effect of intensive BP therapy on LVH, function, or fibrosis despite an increase in LV end-diastolic volume36 suggesting alternative factors beyond just LV mass are contributing to improved outcomes. The strength of our study was the incorporation of additional echocardiographic parameters which not only provided quantification of LV mass but also assessment of systolic and diastolic function37 where we identified improvements in LV mass and function with sBP control <130 mm Hg—a finding that is consistent with secondary CVD prevention, particularly for high-risk patients such as those included in this study with evidence of SHHD.
Diastolic dysfunction has been identified in several prospective studies38 as a risk factor for predicting cardiovascular mortality among hypertensive patients, independent of LVH and intensive BP control has been shown to improve diastolic dysfunction.9,36 For instance, in a previous study of AA patients with SHHD there was a high prevalence of diastolic dysfunction (90%) but only 61% of the patients had LVH.22 These findings are consistent with the pathophysiologic process of hypertrophy leading to impaired diastolic relaxation during diastole that is believed to cause hypertensive HF. As LV compliance deteriorates, LV filling pressure increases, ultimately leading to pulmonary vascular congestion and symptomatic HF. It appears that physiologic changes in the LV (i.e., impaired relaxation) occur prior to the development of structural changes, and thus it is essential to target diastolic dysfunction as a separate entity to prevent HF. However, we did not find an effect of lower BP on diastolic function. Though several small, nonrandomized studies39 have noted this association, results from larger trials, including those mentioned above, are conflicting.34 However, the patient populations are diverse and our patient cohort has been shown to be particularly vulnerable and susceptible to developing HTN, SHHD, and subsequently HF.22
Our study was designed to evaluate the effects of an intensive BP goal in a predominantly AA population with preexisting echocardiographic evidence of LV pathology. Similar to several of the preceding studies, patients in our study did not attain BP goals in either treatment group. Clinical inertia on the side of the providers and suboptimal adherence by the subjects likely contributed to this outcome. Our post hoc analysis of subjects who achieved a sBP goal of <130 mm Hg is consistent with findings of previous studies that targeted BP control has the potential to reduce cardiovascular complications through LV mass reduction, improved diastolic relaxation, or both. However, because of the multiple confounders that exist across these studies, including study population differences, comorbidities, concurrent medication use, choice of antihypertensive agent, BP target, and presence of SHHD, the exact mechanisms by which these benefits are conferred remains unclear.
As has been observed in other similar studies, this study failed to achieve the specified BP goals in either treatment group. Furthermore, the primary objective was underpowered and the majority of our study findings were derived from nonrandomized post hoc analysis and susceptible to confounding. Although our study did not address cardiovascular outcomes, the use of improvements in LV mass as a surrogate measure has been employed in previous trials40 and may be applicable to a patient population with an exceedingly high rate of SHHD.22 Moreover, our finding of improved ejection fraction on post hoc analysis with achieved sBP <130 suggests that, at the least, tangible benefit on both cardiac structure and function are related to achievement of lower BP in those with SHHD.
In summary, we have studied the relationship between SHHD, a precursor of HF, and the impact of BP reduction. While we were unable to achieve randomized treatment goals, on post hoc analysis predominantly AA patients with a sBP <130 mm Hg exhibited improvements in echocardiographic parameters of cardiac structure and function.
ACKNOWLEDGMENTS
The authors thank all students and research technicians that were involved with the data collection and retention of participants enrolled in the study.
FUNDING
P.D.L. was supported by Robert Wood Johnson Foundation Physician Faculty Scholars Program.
DISCLOSURE
Phillip D. Levy: National Heart, Lung, and Blood Institute (R01 HL146059 and R01 HL127215), National Institutes of Health Admin (U24 NS100680), Michigan Department of Health and Human Services (Centers for Disease Control and Prevention 1815 and 1817); Michigan Health Endowment Fund (R-1907-144972); research contracts: CardioSounds, Edwards Lifescience; consulting: BMS, Roche Diagnostic, Ortho Clinical Diagnostics, Baim Institute; Aerpio Therapeutics. Robert Ehrman: grants: Society for Academic Emergency Foundation, Emergency Medicine Foundation, National Heart, Lung, and Blood Institute (1 R34 HL136986 and 1 R01HL144624-01); research contracts: CAN Diagnostics. Michael J. Burla, Michael Twiner, Alexander L. Marinica, James J. Mahn, Brian Reed, Aaron Brody, Allie Brodsky, Samar A. Nasser, and John M. Flack declared no conflict of interest.
This manuscript was sent to Guest Editor, Hillel W. Cohen, MPH, DrPH for editorial handling and final disposition.
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