Skip to main content
Skip main navigationClose Drawer MenuOpen Drawer Menu

MAINTENANCE ALERT: Our website management system will undergo essential maintenance on Monday and Tuesday, May 27-28. All articles and features will remain accessible during this period. Thank you for your patience as we work to enhance your user experience!

Intensive Blood Pressure Lowering in Patients With Malignant Left Ventricular HypertrophyFree Access

Original Investigation

J Am Coll Cardiol, 80 (16) 1516–1525
Topic(s):
Sections

Central Illustration

Abstract

Background

Left ventricular hypertrophy (LVH) combined with elevations in cardiac biomarkers reflecting myocardial injury and neurohormonal stress (malignant LVH) is associated with a high risk for heart failure and death.

Objectives

The aim of this study was to determine the impact of intensive systolic blood pressure (SBP) control on the prevention of malignant LVH and its consequences.

Methods

A total of 8,820 participants in SPRINT (Systolic Blood Pressure Intervention Trial) were classified into groups based on the presence or absence of LVH assessed by 12-lead ECG, and elevations in biomarker levels (high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro–B-type natriuretic peptide ≥125 pg/mL) at baseline. The effects of intensive vs standard SBP lowering on rates of acute decompensated heart failure (ADHF) events and death and on the incidence and regression of malignant LVH were determined.

Results

Randomization to intensive SBP lowering led to similar relative reductions in ADHF events and death across the combined LVH/biomarker groups (P for interaction = 0.68). The absolute risk reduction over 4 years in ADHF events and death was 4.4% (95% CI: −5.2% to 13.9%) among participants with baseline malignant LVH (n = 449) and 1.2% (95% CI: 0.0%-2.5%) for those without LVH and nonelevated biomarkers (n = 4,361). Intensive SBP lowering also reduced the incidence of malignant LVH over 2 years (2.5% vs 1.1%; OR: 0.44; 95% CI: 0.30-0.63).

Conclusions

Intensive SBP lowering prevented malignant LVH and may provide substantial absolute risk reduction in the composite of ADHF events and death among SPRINT participants with baseline malignant LVH.

Introduction

Pathological left ventricular hypertrophy (LVH), which can be detected by 12-lead electrocardiography (ECG) or cardiac imaging, most often occurs in response to hypertension and has strong associations with incident heart failure (HF) and death.1,2 Individuals who progress from asymptomatic LVH to HF are hypothesized to have maladaptive cardiac remodeling resulting from chronic myocardial cell injury, inflammation, and fibrosis, accompanied by neurohormonal activation caused by increased diastolic wall stress.3-5 Recent observational data demonstrate that LVH subphenotypes exist with markedly different risks for HF and death. LVH accompanied by biomarker evidence of chronic myocardial injury, as measured by high-sensitivity cardiac troponin T (hs-cTnT) or I, and neurohormonal activation, as measured by N-terminal pro–B-type natriuretic peptide (NT-proBNP), identifies a subgroup known as malignant LVH that is at particularly high risk for HF and death.6-9

Among individuals with hypertension and at high cardiovascular disease (CVD) risk, SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated that targeting a systolic blood pressure (SBP) <120 mm Hg compared with <140 mm Hg led to significant reductions in acute decompensated heart failure (ADHF) events and death.10 SPRINT and other randomized clinical trials have also shown that intensive SBP lowering leads to the prevention and regression of LVH.11-13 However, it is unknown whether intensive SBP lowering can prevent or reverse malignant LVH, or impact the risk of ADHF events and death when malignant LVH is present.

Our objectives were to evaluate in SPRINT whether intensive vs standard SBP lowering would: 1) prevent the development of malignant LVH; and 2) reduce ADHF events and death among individuals with malignant LVH present at baseline.

Methods

Study design

The design and protocol of SPRINT have been reported previously.10,14 In brief, SPRINT was a National Institutes of Health–funded open-label clinical trial that randomized participants with hypertension to an “intensive” SBP target (<120 mm Hg) vs a “standard” SBP target (<140 mm Hg). Inclusion criteria were age ≥50 years, systolic BP 130 to 180 mm Hg, and high CVD risk (defined as prior clinical or subclinical CVD other than stroke, chronic kidney disease [estimated glomerular filtration rate (eGFR) 20-59 mL/min/1.73 m2], age ≥75 years, or 10-year CVD risk >15% based on the Framingham risk score). Key exclusion criteria included diabetes mellitus, prior stroke or transient ischemic attack, eGFR <20 mL/min/1.73 m2, symptomatic heart failure, or a left ventricular ejection fraction <35%. A total of 9,361 participants were enrolled between November 2010 and March 2013 across 102 sites in the United States and Puerto Rico. The SPRINT study was approved by the Institutional Review Board at each participating study site, and all participants provided written informed consent.

This ancillary study included 8,820 (94.2%) SPRINT participants with a baseline standard 12-lead ECG and baseline measures of hs-cTnT and NT-proBNP, and was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center. In analyses of incidence and regression of malignant LVH, we excluded those without at least 1 follow-up ECG (n = 1,059). The data that support the findings of this study are available from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repositories and the corresponding author upon request.

ECG and cardiac biomarker measurements

LVH was determined using standard 12-lead ECGs obtained at baseline, year 2, year 4, and close-out visits. Digital ECG data were recorded using a GE MAC 1200 electrocardiograph at 10 mm/mV calibration and a speed of 25 mm/s. ECG reading was performed centrally at the Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina. All ECG tracings were initially inspected visually for technical errors and inadequate quality before being automatically processed using GE 12-SL Marquette version 2001.

Cardiac biomarkers were measured from blood samples obtained at the time of study entry and year 2 of the trial follow-up period. All blood samples were stored at −80°C until hs-cTnT and NT-proBNP measurements were performed at the SPRINT Central Laboratory (University of Minnesota). Both hs-cTnT and NT-proBNP were measured from freshly thawed serum samples using an electrochemiluminescence immunoassay on the Roche Cobas 6000 platform (Roche Diagnostics) as previously described.15 The hs-cTnT assay (5th generation) has an imprecision of 3.4% at 28.3 ng/L and 2.3% at 2,076 ng/L, with a lower limit of quantitation of 6 ng/L. The NT-proBNP assay has an imprecision of 2.9% at 140.3 pg/mL and 2.7% at 4,563 pg/mL, with a lower limit of detection of 5 pg/mL.

Combined LVH and cardiac biomarker groups

Consistent with previous studies in SPRINT, LVH was defined using Cornell voltage criteria (RaVL amplitude + SV3 amplitude) with sex-specific thresholds of ≥2,200 μV in women and ≥2,800 μV in men, and elevated cardiac biomarkers was defined as hs-cTnT ≥14 ng/L and/or NT-proBNP ≥125 pg/mL.13,15,16 Participants were categorized into 4 groups: 1) no LVH with nonelevated cardiac biomarkers (LVH−, biomarker−); 2) no LVH with elevated cardiac biomarkers (LVH−, biomarker+); 3) LVH with nonelevated cardiac biomarkers (LVH+, biomarker−); and 4) LVH with elevated cardiac biomarkers (LVH+, biomarker+), which we defined as malignant LVH.6-8 In sensitivity analyses, we also defined LVH using Cornell voltage product ([RaVL amplitude + SV3 amplitude] × QRS duration) and Sokolow-Lyon (SV1 amplitude + RV5/V6 amplitude) LVH criteria.17,18

Outcomes

The primary outcome of this analysis was the composite of incident ADHF events and all-cause mortality. We selected this outcome because elevated cardiac biomarkers and LVH are most strongly associated with these endpoints.15 Additionally, the effect of intensive SBP lowering on the primary CVD composite outcome in SPRINT was primarily driven by reductions in these endpoints.10 The definition, ascertainment, and formal adjudication of these events have been previously described in detail.10,14,19 Incident ADHF events were defined as hospitalization or emergency department visit requiring treatment with infusion therapy (diuretic or inotropic agents) for a clinical syndrome that presented with multiple signs and symptoms consistent with ADHF. Chronic stable HF during a hospitalization, reduced left ventricular ejection fraction in the absence of symptoms, right-sided HF, volume overload caused by inadequate dialysis, and new outpatient HF were not considered incident ADHF endpoints in SPRINT.19 We also evaluated all-cause mortality as a secondary clinical outcome. Secondary subclinical outcomes included the following: 1) incidence and regression of malignant LVH; 2) incidence and regression of LVH; and 3) annual change in Cornell voltage index.

Malignant LVH incidence and regression were restricted to the first 2 years of the trial follow-up period, when both cardiac biomarker and ECG measurements were available. Incident malignant LVH occurred when individuals without baseline malignant LVH subsequently met Cornell voltage criteria on ECG and had elevated cardiac biomarkers at year 2 of follow-up. Malignant LVH regression occurred when individuals with baseline malignant LVH no longer met either LVH or cardiac biomarker criteria for malignant LVH at year 2 of follow-up.

LVH incidence and regression were assessed during the total trial follow-up period. Incident LVH occurred when individuals without baseline LVH met Cornell voltage criteria for LVH on a follow-up ECG, and LVH regression occurred when individuals with baseline LVH no longer met Cornell voltage criteria for LVH on a follow-up ECG. In addition to binary LVH outcomes, we evaluated annual change in the Cornell voltage index as a continuous variable, defined as the annualized difference between the Cornell voltage index on the last available ECG and the baseline ECG.

Statistical analyses

Baseline characteristics were compared across LVH/biomarker categories using analysis of variance or Kruskal-Wallis test for continuous variables, and chi-square test for categorical variables. We replaced undetectable hs-cTnT levels (21% <6 ng/L) and NT-proBNP levels (3.4% <5 pg/mL) as the lower limit of detection divided by 2.

We evaluated associations of LVH/biomarker categories with risk of the clinical outcomes using multivariable Cox proportional hazards models. There was no evidence that the proportional hazards assumptions were violated. Models were adjusted for demographics (age, sex, race, site), treatment assignment, and clinical characteristics (body mass index, smoking status, prevalent CVD, SBP, eGFR, and low-density lipoprotein cholesterol).

Event rates were then compared between the intensive SBP and standard SBP arms among participants in each LVH/biomarker category. Heterogeneity of treatment effect across LVH/biomarker categories was tested using a likelihood ratio test for multiplicative interaction terms (treatment assignment by LVH/biomarker category) in models that included main effects. Absolute risk differences over 4 years between randomized treatment groups and corresponding 95% CIs were estimated for each endpoint using the method described by Altman and Andersen.20

Logistic regression models were used to evaluate the effect of intensive vs standard SBP lowering on incident malignant LVH and malignant LVH regression, and on incident LVH and LVH regression stratified by baseline elevated vs nonelevated cardiac biomarkers. Linear regression models were used to evaluate the treatment effect on annual changes in Cornell voltage index, and were stratified by combined LVH/biomarker category.

In sensitivity analyses, we used Cornell voltage product and Sokolow-Lyon criteria instead of Cornell voltage index to define LVH to confirm our findings were insensitive to LVH criteria.

Underlying assumptions including linearity were assessed while building multivariable models for each outcome of interest. All analyses were conducted using SAS software, version 9.4 (SAS Institute).

Results

Study population and baseline characteristics

Among the 9,361 SPRINT participants, 8,820 (94.2%) had both hs-cTnT (median 9.4 ng/L [IQR: 6.4-14.1 ng/L]) and NT-proBNP (median 86 pg/L [IQR: 37-197 pg/mL]) measured at baseline. In the cardiac biomarker study sample, 4,361 (49.4%) had no LVH and nonelevated cardiac biomarkers at baseline (LVH−, biomarker−), 3,761 (42.6%) had no LVH and elevated cardiac biomarkers (LVH−, biomarker+), 249 (2.8%) had LVH with nonelevated cardiac biomarkers (LVH+, biomarker−), and 449 (5.1%) were categorized as malignant LVH (LVH+, biomarker+). LVH−, biomarker− participants had median hs-cTnT and NT-proBNP levels of 7.3 ng/L and 44 pg/mL, respectively, and a median Cornell voltage of 1,422 μV. The malignant LVH group had median hs-cTnT and NT-proBNP levels of 15.3 ng/L and 308 pg/mL, respectively, and a median Cornell voltage of 2,883 μV. Older age, African-American race, female sex, and a higher burden of comorbidities were also associated with baseline malignant LVH (Table 1).

Table 1 Baseline Characteristics of SPRINT Participants Stratified by Combined LVH and Cardiac Biomarker Categories

LVH−, Biomarker− (n = 4,361)LVH−, Biomarker+ (n = 3,761)LVH+, Biomarker− (n = 249)LVH+, Biomarker+ (n = 449)
Intensive BP arm2,168 (50)1,918 (51)121 (49)211 (47)
Age, y64 ± 872 ± 964 ± 870 ± 10
Female1,471 (34)1,346 (36)169 (68)260 (58)
African Americana1,493 (34)877 (23)146 (59)210 (47)
Hispanica581 (13)290 (8)32 (13)41 (9)
Current smoker670 (15)377 (10)43 (17)57 (13)
Prevalent CVD568 (13)994 (26)41 (16)147 (33)
Prevalent heart failurea67 (2)187 (5)5 (2)41 (9)
Systolic BP, mm Hg
 ≤132573 (13)448 (12)20 (8)28 (6)
 >132-<1451,864 (43)1,579 (42)72 (29)147 (33)
 ≥1451,924 (44)1,734 (46)157 (63)274 (61)
Diastolic BP, mm Hg
 ≤70471 (11)1,130 (30)25 (10)122 (27)
 >70-<801,148 (26)1,090 (29)61 (25)120 (27)
 ≥802,742 (63)1,541 (41)163 (65)207 (46)
Total med burden ≥52,070 (48)2,478 (66)111 (45)278 (62)
Number of BP meds2 (1-2)2 (1-3)2 (1-3)2 (2-3)
BMI, kg/m230.2 ± 5.529.3 ± 5.830.4 ± 6.029.3 ± 5.7
eGFR, mL/min/1.73 m277 ± 1965 ± 2081 ± 2065 ± 21
Urine ACR, mg/g8 (5-15)12 (7-32)9 (6-21)16 (8-45)
hs-cTnT, ng/L7.3 (3-9.7)14.4 (9.2-19.6)7.1 (3-9.9)15.3 (9.9-21.1)
NT-proBNP, pg/mL44 (22-74)198 (131-352)55 (29-86)308 (168-569)
Cornell voltage index, μV1,422 (1,071-1,782)1,409 (1,043-1,797)2,800 (2,373-3,073)2,883 (2,465-3,259)
Sokolow-Lyon, μV2,032 (1,610-2,508)2,034 (1,570-2,580)2,444 (2,063-3,088)2,661 (2,056-3,421)

Values are n (%), mean ± SD, or median (IQR). All P values testing for differences in baseline characteristics across combined left ventricular hypertrophy (LVH) and biomarker groups were <0.001 except for intensive BP arm (P = 0.33). LVH+ is defined as Cornell voltage index on baseline electrocardiogram ≥2,200 μV in women and ≥2,800 μV in men. Biomarker+ is defined as baseline high-sensitivity cardiac troponin T (hs-cTnT) ≥14 ng/L or N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥125 pg/mL.

ACR = albumin-to-creatinine ratio; BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; SPRINT = Systolic Blood Pressure Intervention Trial.

a Race, ethnicity, and history of heart failure were self-reported.

Effects of intensive vs standard SBP lowering on ADHF events and all-cause mortality

The proportion of participants who experienced the composite of ADHF events and all-cause mortality varied across LVH/biomarker categories, occurring in 13.6% of participants with baseline malignant LVH compared with 8.2% of participants who were LVH−, biomarker+; 5.6% who were LVH+, biomarker−; and 1.9% who were LVH−, biomarker−. These findings persisted in multivariable-adjusted analyses, with malignant LVH participants having a 4-fold higher risk of the composite of incident ADHF events and all-cause mortality compared with LVH−, biomarker− participants (adjusted HR: 3.88; 95% CI: 2.44-6.18). Furthermore, LVH−, biomarker+ and LVH+, biomarker− participants had a 2-fold higher risk of incident ADHF events and all-cause mortality compared with LVH−, biomarker− participants (Figure 1). Similar patterns of results were noted for all-cause mortality (Figure 1).

Figure 1
Figure 1

Associations Between LVH/Biomarker Categories and Incident ADHF Events and Mortality

HRs with 95% CIs obtained from multivariable Cox proportional hazards models that included demographics (age, sex, race, site), treatment assignment, and clinical characteristics (body mass index, smoking status, prevalent cardiovascular disease, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein cholesterol). Combined left ventricular hypertrophy (LVH) and biomarker categories include: 1) no LVH and nonelevated cardiac biomarkers (LVH−, biomarker−); 2) no LVH and elevated cardiac biomarkers (LVH−, biomarker+); 3) LVH and nonelevated cardiac biomarkers (LVH+, biomarker−); and 4) LVH and elevated cardiac biomarkers (LVH+ biomarker+). Elevated cardiac biomarkers defined as high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro–B-type natriuretic peptide ≥125 pg/mL. ADHF = acute decompensated heart failure; LVH = left ventricular hypertrophy.

Randomization to intensive vs standard SBP lowering was associated with a similar relative risk reduction for the composite of incident ADHF events and all-cause mortality across all 4 LVH/biomarker categories (P for interaction = 0.68) (Table 2). Relative effects in each LVH/biomarker group also appeared similar among Black and White participants (data not shown). However, because of the much higher event rate in the malignant LVH group, the 4-year absolute risk reduction (ARR) was 4.4% (95% CI: −5.2% to 13.9%) compared with the 2.5% (95% CI: −0.3% to 5.3%) in the LVH−, biomarker+ group; 2.0% (95% CI: −6.6% to 10.7%) in the LVH+, biomarker− group; and 1.2% (95% CI: 0.0%-2.5%) in the LVH−, biomarker− group, with corresponding NNTs of 23, 41, 50, and 82, respectively. A similar pattern of results was noted for all-cause mortality (Table 2).

Table 2 Effect of Intensive SBP Lowering on Cardiovascular Outcomes Stratified by Combined LVH and Biomarker Categories

Standard SBPIntensive SBPHR (95% CI)P Valuea4-y ARR, % (95% CI)NNT
Incident ADHF events and all-cause mortality0.68
 LVH−, biomarker−54/2,193 (2.5)28/2,168 (1.3)0.52 (0.33 to 0.83)1.2 (0.0 to 2.5)82
 LVH−, biomarker+177/1,843 (9.6)133/1,918 (6.9)0.71 (0.57 to 0.89)2.5 (−0.3 to 5.3)41
 LVH+, biomarker−8/128 (6.3)6/121 (5.0)0.77 (0.27 to 2.23)2.0 (−6.6 to 10.7)50
 LVH+, biomarker+37/238 (15.5)24/211 (11.4)0.70 (0.42 to 1.16)4.4 (−5.2 to 13.9)23
All-cause mortality0.88
 LVH−, biomarker−42/2,193 (1.9)27/2,168 (1.2)0.65 (0.40 to 1.06)0.7 (−0.5 to 1.9)143
 LVH−, biomarker+126/1,843 (6.8)99/1,918 (5.2)0.75 (0.58 to 0.98)1.6 (−0.8 to 4.0)64
 LVH+, biomarker−6/128 (4.7)4/121 (3.3)0.69 (0.19 to 2.43)2.1 (−5.3 to 9.5)49
 LVH+, biomarker+28/238 (11.8)15/211 (7.1)0.58 (0.31 to 1.09)5.9 (−2.1 to 14.0)17

Values are events/total (%) unless otherwise indicated.

ADHF = acute decompensated heart failure; ARR = absolute risk reduction; CVD = cardiovascular disease; LVH = left ventricular hypertrophy; NNT = number needed to treat; SBP = systolic blood pressure.

a P value for interaction on the relative hazard scale.

Effects of intensive vs standard SBP lowering on LVH outcomes

Among 7,431 participants without malignant LVH at baseline and with 1 or more follow-up ECG and cardiac biomarker measurements, 133 (1.8%) developed malignant LVH. Compared with standard SBP lowering, intensive SBP lowering led to a significant reduction in the incidence of malignant LVH (2.5% vs 1.1%; OR: 0.44; 95% CI: 0.30-0.63) (Figure 2). Among the 375 participants with malignant LVH at baseline who had 1 or more follow-up ECG and cardiac biomarker measurements, 216 (57.6%) experienced malignant LVH regression. Randomization to intensive vs standard BP lowering was associated with numerically greater malignant LVH regression (61.8% vs 53.4%; OR: 1.41; 95% CI: 0.94-2.13).

Figure 2
Figure 2

Intensive SBP-Lowering Effects on Incident LVH and Malignant LVH

ORs with 95% CIs obtained from logistic regression models. (A) Proportion without left ventricular hypertrophy (LVH) at baseline who developed LVH during follow-up stratified by randomized treatment assignment and baseline cardiac biomarker levels. Biomarker+ indicates high-sensitivity cardiac troponin T ≥14 ng/L or N-terminal pro–B-type natriuretic peptide ≥125 pg/mL. (B) Proportion without malignant LVH at baseline who developed malignant LVH during follow-up stratified by randomized treatment assignment. BP = blood pressure; LVH = left ventricular hypertrophy; SBP = systolic blood pressure.

Among 7,215 participants without LVH at baseline and with 1 or more follow-up ECGs, 310 (4.3%) developed LVH. Randomization to intensive vs standard SBP lowering reduced the risk of incident LVH similarly among biomarker− (OR: 0.51; 95% CI: 0.37-0.69) and biomarker+ participants (OR: 0.61; 95% CI: 0.43-0.88; P for interaction = 0.43) (Figure 2). Among 591 participants with LVH at baseline, 366 (61.9%) experienced LVH regression. Randomization to intensive vs standard SBP lowering led to more LVH regression and was similar among biomarker− (OR: 2.29; 95% CI: 1.29-4.06) and biomarker+ participants (OR: 1.71; 95% CI: 1.12-2.59; P for interaction = 0.42).

Compared with standard SBP lowering, intensive SBP lowering led to a greater reduction in Cornell voltage index during the follow-up period across all LVH/biomarker categories (Supplemental Table 1). The effect of intensive SBP lowering on reduction in Cornell voltage index was stronger among LVH−, biomarker+ participants compared with LVH−, biomarker− participants (P for interaction = 0.02).

In sensitivity analyses using Cornell voltage product and Sokolow-Lyon LVH criteria, the effects of intensive SBP lowering on clinical and LVH outcomes were overall similar to using Cornell voltage index in the main analyses (Supplemental Tables 2 to 4).

Discussion

In this ancillary analysis of SPRINT, participants with malignant LVH had markedly higher rates of ADHF events and all-cause death than those without LVH or biomarker elevation, as well as higher risk than those with either LVH or biomarker elevation. Intensive SBP lowering led to similar relative risk reductions in ADHF events and all-cause death across LVH/biomarker groups, and was compatible with large absolute risk reductions among those with baseline malignant LVH due to the high risk in this subgroup, although the finding did not reach statistical significance. We also observed that randomization to intensive vs standard SBP lowering reduced the incidence of malignant LVH. Taken together, these data highlight the importance of intensive SBP lowering in modifying the natural history of malignant LVH by preventing its development, and when present, decreasing the risk of ADHF events and death (Central Illustration).

Central Illustration
Central Illustration

Intensive SBP Lowering and the Natural History of Malignant LVH

Randomization to intensive SBP lowering (SBP <120 mm Hg) vs standard SBP lowering (SBP <140 mm Hg) not only prevents the development of malignant LVH (LVH with hs-cTnT ≥14 ng/L or NT-proBNP ≥125 pg/mL), but may also lead to substantial absolute risk reductions in the composite of ADHF events and all-cause mortality when malignant LVH is present. ADHF = acute decompensated heart failure; hs-cTnT = high-sensitivity cardiac troponin T; LVH = left ventricular hypertrophy; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SBP = systolic blood pressure; SPRINT = Systolic Blood Pressure Intervention Trial.

To our knowledge, no therapies have been established for the specific prevention or treatment of malignant LVH. Thus, our findings have important clinical implications. First, our novel findings that intensive SBP lowering prevents malignant LVH, prevents LVH similarly among individuals with both elevated and nonelevated cardiac biomarkers, and leads to greater voltage reductions among individuals with elevated cardiac biomarkers expand upon prior work demonstrating that achieving lower BP targets improves LVH outcomes.11-13 These results suggest that routine measurement of hs-cTnT and NT-proBNP levels among hypertensive individuals may be helpful for identifying persons for whom intensive BP control can delay the onset of structural heart disease. Second, these data provide direct trial evidence that the substantial risk associated with malignant LVH may be modifiable, suggesting that both individuals with LVH and individuals with malignant LVH appear to derive cardiovascular benefits from achieving lower BP targets.13,21 Previous work in SPRINT observed that ECG-LVH did not explain most of the reduction in the primary CVD composite from intensive SBP lowering, but the impact of SBP lowering on LVH may mediate effects on specific CVD outcomes, such as HF and death.13

Although routine cardiac imaging or ECG to screen for LVH is not currently recommended, our findings support the concept that a multimodality screening approach among select individuals with hypertension could distinguish those with elevated yet modifiable cardiovascular risk.15,22 Universal ECG screening for LVH is not recommended because of a lack of data on the value of ECG in assessing CVD risk to inform hypertension treatment decisions.23 However, we and others have shown that LVH is a heterogeneous phenotype with marked variation in natural history depending on the presence or absence of elevated cardiac biomarkers. Our findings suggest that ECG surveillance augmented by cardiac biomarkers to detect malignant LVH could be considered as an efficient strategy to identify those who may derive substantial absolute HF and mortality benefits from intensive SBP lowering.

Our finding that SPRINT participants with LVH and minimal elevations in cardiac biomarkers had a nearly 4-fold increased risk of ADHF events and all-cause death compared with LVH−, biomarker− participants is consistent with previous observational studies.6-9 LVH is common in the setting of hypertension, and numerous studies have established that both ECG- and imaging-derived measures of LVH are strong risk factors for HF and mortality.1,2 Although the natural history of LVH varies considerably between individuals, pathological cardiac remodeling is thought to be the key driver of LVH progression to HF. Cardiac biomarkers may reflect several mechanisms underlying this maladaptive process, including chronic myocardial cell injury, neurohormonal activation, and myocardial fibrosis.3-5,24,25

Study limitations

First, the relatively small proportion of SPRINT participants with baseline malignant LVH limited our ability to detect modest intensive SBP lowering effect sizes and to evaluate effect modification by race and sex subgroups.26 Second, LVH was defined using ECG, which may have been less accurate than echocardiography or cardiac magnetic resonance imaging. However, ECGs are widely available and are used in most patients with hypertension, and LVH by ECG is associated with CVD and mortality.27,28 Moreover, prior studies have shown similar risk of malignant LVH when defined using ECG and cardiac magnetic resonance imaging.6 LVH misclassification would have been nondifferential across randomized treatment groups and likely biased results to the null. Third, we used Cornell voltage to define LVH by ECG instead of other LVH criteria. We chose Cornell voltage because it is one of the most commonly used LVH criteria, and previous work in SPRINT demonstrated that the effect of intensive SBP lowering on LVH incidence and regression was similar using Cornell voltage or other LVH criteria.13 We also observed similar results in sensitivity analyses using 2 other commonly used LVH criteria (Sokolow-Lyon and Cornell voltage product). Finally, our findings may not be generalizable to individuals with malignant LVH who did not meet eligibility criteria for SPRINT, including those with diabetes, prior stroke, or at younger ages.

Despite these limitations, this analysis is the first report from a well-designed, large clinical trial describing the impact of intensive SBP lowering on outcomes in malignant LVH. As an ancillary study of SPRINT, this analysis benefited from inclusion of >8,000 participants with baseline ECG data and hs-cTnT and NT-proBNP measurements, the use of randomized data to minimize the impact of confounding, protocol-driven data collection including ECGs that were centrally read, and rigorously adjudicated HF and death outcomes.

Conclusions

This study reinforces the hypothesis that elevated cardiac biomarkers in the presence of LVH identify a subclinical, malignant LVH phenotype, and presents the best available evidence to date that intensive SBP lowering not only prevents malignant LVH, but may also provide large absolute risk reductions for ADHF events and death when malignant LVH is present. These findings support intensive SBP lowering as an effective treatment for patients with malignant LVH, and additionally provide preliminary support that intensive SBP lowering may prevent the development of malignant LVH.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Compared with lowering SBP to <140 mm Hg, more intensive lowering to <120 mm Hg reduces progression to malignant LVH and the development of heart failure or death in those with malignant LVH.

TRANSLATIONAL OUTLOOK: Larger trials with longer follow-up of individuals with malignant LVH could provide better estimates of the benefit of intensive SBP lowering.

Funding Support and Author Disclosures

This ancillary study was supported by the National Heart, Lung, and Blood Institute (1R01HL144112-01 for Dr Berry). Analytical reagents for hs-cTnT and NT-proBNP measurements were donated by Roche. SPRINT was sponsored by the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13–002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, or the United States Government. Support was also received from the following CTSAs funded by the National Center for Advancing Translational Sciences: CWRU: UL1TR000439, OSU: UL1RR025755, U Penn: UL1RR024134 and UL1TR000003, Boston: UL1RR025771, Stanford: UL1TR000093, Tufts: UL1RR025752, UL1TR000073 and UL1TR001064, University of Illinois: UL1TR000050, University of Pittsburgh: UL1TR000005, UT Southwestern: 9U54TR000017–06, University of Utah: UL1TR000105–05, Vanderbilt University: UL1 TR000445, George Washington University: UL1TR000075, University of California, Davis: UL1 TR000002, University of Florida: UL1 TR000064, University of Michigan: UL1TR000433, Tulane University: P30GM103337 COBRE Award NIGMS, Wake Forest University: UL1TR001420. Dr de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; has received consulting fees from Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel Cardiovascular, Inc, and Siemen’s Health Care Diagnostics; and has been named a co-owner on a patent awarded to the University of Maryland (US Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr Kitzman has received honoraria as a consultant outside the present study from Bayer, Merck, Pfizer, Corvia Medical, Boehringer Ingelheim, Ketyo, Rivus, Novo Nordisk, AstraZeneca, and Novartis; has received grant funding from Novartis, Bayer, Pfizer, Novo Nordisk, and AstraZeneca; and has stock ownership in Gilead Sciences. Dr Berry has received grant support from the National Institutes of Health, Roche Diagnostics, and Abbott Diagnostics; and has received consulting fees from Roche Diagnostics and the Cooper Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

ADHF

acute decompensated heart failure

HF

heart failure

hs-cTnT

high-sensitivity cardiac troponin T

LVH

left ventricular hypertrophy

NT-proBNP

N-terminal pro-B-type natriuretic peptide

SBP

systolic blood pressure

References

  • 1. Levy D., Garrison R.J., Savage D.D., Kannel W.B., Castelli W.P. "Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study". N Engl J Med 1990;322:1561-1566.

    CrossrefMedlineGoogle Scholar
  • 2. Drazner M.H., Rame J.E., Marino E.K., et al. "Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study". J Am Coll Cardiol 2004;43:2207-2215.

    View ArticleGoogle Scholar
  • 3. Ahmed S.H., Clark L.L., Pennington W.R., et al. "Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease". Circulation 2006;113:2089-2096.

    CrossrefMedlineGoogle Scholar
  • 4. Zile M.R., Bennett T.D., St John Sutton M., et al. "Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures". Circulation 2008;118:1433-1441.

    CrossrefMedlineGoogle Scholar
  • 5. Drazner M.H. "The progression of hypertensive heart disease". Circulation 2011;123:327-334.

    CrossrefMedlineGoogle Scholar
  • 6. Neeland I.J., Drazner M.H., Berry J.D., et al. "Biomarkers of chronic cardiac injury and hemodynamic stress identify a malignant phenotype of left ventricular hypertrophy in the general population". J Am Coll Cardiol 2013;61:187-195.

    View ArticleGoogle Scholar
  • 7. Seliger S.L., de Lemos J., Neeland I.J., et al. "Older adults, “malignant” left ventricular hypertrophy, and associated cardiac-specific biomarker phenotypes to identify the differential risk of new-onset reduced versus preserved ejection fraction heart failure: CHS (Cardiovascular Health Study)". J Am Coll Cardiol HF 2015;3:445-455.

    Google Scholar
  • 8. Peters M.N., Seliger S.L., Christenson R.H., et al. "“Malignant” left ventricular hypertrophy identifies subjects at high risk for progression to asymptomatic left ventricular dysfunction, heart failure, and death: MESA (Multi-Ethnic Study of Atherosclerosis)". J Am Heart Assoc 2018;7:4: e006619 https://doi.org/10.1161/JAHA.117.006619.

    CrossrefGoogle Scholar
  • 9. Pandey A., Keshvani N., Ayers C., et al. "Association of cardiac injury and malignant left ventricular hypertrophy with risk of heart failure in African Americans: The Jackson Heart Study". JAMA Cardiol 2019;4:51-58.

    CrossrefMedlineGoogle Scholar
  • 10. Wright J.T., Williamson J.D., Whelton P.K., et al.for the SPRINT Research Group. "A randomized trial of intensive versus standard blood-pressure control". N Engl J Med 2015;373:2103-2116. https://doi.org/10.1056/NEJMoa1511939.

    CrossrefMedlineGoogle Scholar
  • 11. Verdecchia P., Staessen J.A., Angeli F., et al.for the Cardio-Sis Investigators. "Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial". Lancet 2009;374:525-533.

    CrossrefMedlineGoogle Scholar
  • 12. Soliman E.Z., Byington R.P., Bigger J.T., et al. "Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with diabetes mellitus: Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial". Hypertension 2015;66:1123-1129.

    CrossrefMedlineGoogle Scholar
  • 13. Soliman E.Z., Ambrosius W.T., Cushman W.C., et al. "Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with hypertension: SPRINT (Systolic Blood Pressure Intervention Trial)". Circulation 2017;136:440-450.

    CrossrefMedlineGoogle Scholar
  • 14. Ambrosius W.T., Sink K.M., Foy C.G., et al. "The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT)". Clin Trials 2014;11:532-546.

    CrossrefMedlineGoogle Scholar
  • 15. Berry J.D., Nambi V., Ambrosius W.T., et al. "Associations of high-sensitivity troponin and natriuretic peptide levels with outcomes after intensive blood pressure lowering: findings from the SPRINT randomized clinical trial". JAMA Cardiol 2021;6:1397-1405.

    CrossrefMedlineGoogle Scholar
  • 16. Casale P.N., Devereux R.B., Kligfield P., et al. "Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria". J Am Coll Cardiol 1985;6:572-580.

    View ArticleGoogle Scholar
  • 17. Molloy T.J., Okin P.M., Devereux R.B., Kligfield P. "Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage-duration product". J Am Coll Cardiol 1992;20:1180-1186.

    View ArticleGoogle Scholar
  • 18. Sokolow M., Lyon T.P. "The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads". Am Heart J 1949;37:161-186.

    CrossrefMedlineGoogle Scholar
  • 19. Upadhya B., Rocco M., Lewis C.E., et al. "Effect of intensive blood pressure treatment on heart failure events in the Systolic Blood Pressure Reduction Intervention Trial". Circ Heart Fail 2017;10:e003613.

    CrossrefMedlineGoogle Scholar
  • 20. Altman D.G., Andersen P.K. "Calculating the number needed to treat for trials where the outcome is time to an event". BMJ 1999;319:1492-1495. https://doi.org/10.1136/bmj.319.7223.1492.

    CrossrefMedlineGoogle Scholar
  • 21. Lee H.-H., Lee H., Cho S.M.J., Kim D.-W., Park S., Kim H.C. "On-treatment blood pressure and cardiovascular outcomes in adults with hypertension and left ventricular hypertrophy". J Am Coll Cardiol 2021;78:1485-1495.

    View ArticleGoogle Scholar
  • 22. de Lemos J.A., Ayers C.R., Levine B.D., et al. "Multimodality strategy for cardiovascular risk assessment: performance in 2 population-based cohorts". Circulation 2017;135:2119-2132.

    CrossrefMedlineGoogle Scholar
  • 23. Whelton P.K., Carey R.M., Aronow W.S., et al. "2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". J Am Coll Cardiol 2018;71:19: e127-e248.

    View ArticleGoogle Scholar
  • 24. Seliger S.L., Hong S.N., Christenson R.H., et al. "High-sensitive cardiac troponin T as an early biochemical signature for clinical and subclinical heart failure: MESA (Multi-Ethnic Study of Atherosclerosis)". Circulation 2017;135:1494-1505.

    CrossrefMedlineGoogle Scholar
  • 25. Liu C.-Y., Heckbert S.R., Lai S., et al. "Association of elevated NT-proBNP with myocardial fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA)". J Am Coll Cardiol 2017;70:3102-3109.

    View ArticleGoogle Scholar
  • 26. Lewis A.A., Ayers C.R., Selvin E., et al. "Racial differences in malignant left ventricular hypertrophy and incidence of heart failure: a multicohort study". Circulation 2020;141:957-967.

    CrossrefMedlineGoogle Scholar
  • 27. Okin P.M., Hille D.A., Kjeldsen S.E., Devereux R.B. "Combining ECG criteria for left ventricular hypertrophy improves risk prediction in patients with hypertension". J Am Heart Assoc 2017;6:e007564.

    CrossrefGoogle Scholar
  • 28. Bang C.N., Soliman E.Z., Simpson L.M., et al.ALLHAT Collaborative Research Group. "Electrocardiographic left ventricular hypertrophy predicts cardiovascular morbidity and mortality in hypertensive patients: the ALLHAT study". Am J Hypertens 2017;30:914-922.

    CrossrefMedlineGoogle Scholar

Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.