Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function

Jessica H Huston; Bradley A Maron; John French; Shi Huang; Timothy Thayer; Eric H Farber-Eger; Quinn S Wells; Gaurav Choudhary; Anna R Hemnes; Evan L Brittain

doi:10.1001/jamacardio.2019.3345

. 2019 Sep 18;4(11):1112–1121. doi: 10.1001/jamacardio.2019.3345

Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function

Jessica H Huston ¹, Bradley A Maron ^2,³, John French ⁴, Shi Huang ⁵, Timothy Thayer ¹, Eric H Farber-Eger ⁶, Quinn S Wells ^1,⁶, Gaurav Choudhary ^7,⁸, Anna R Hemnes ⁹, Evan L Brittain ^1,^6,^✉

¹Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

²Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

³Department of Cardiology, Boston VA Healthcare System, West Roxbury, Massachusetts

⁴Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

⁵Department of Biostatistics, Vanderbilt University, Nashville, Tennessee

⁶Vanderbilt Translational and Clinical Research Center, Vanderbilt University Medical Center, Nashville, Tennessee

⁷Vascular Research Laboratory, Providence VA Medical Center, Providence, Rhode Island

⁸Division of Cardiovascular Medicine, Department of Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island

⁹Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

Accepted for Publication: July 28, 2019.

^✉

Corresponding Author: Evan L. Brittain, MD, MSCI, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Ste 300-A, Nashville, TN 37203 (evan.brittain@vumc.org).

Published Online: September 18, 2019. doi:10.1001/jamacardio.2019.3345

Author Contributions: Dr Brittain had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Huston, Hemnes, Brittain.

Acquisition, analysis, or interpretation of data: Huston, Maron, French, Huang, Thayer, Farber-Eger, Wells, Choudhary, Brittain.

Drafting of the manuscript: Huston, Maron, Thayer, Brittain.

Critical revision of the manuscript for important intellectual content: Huston, French, Huang, Thayer, Farber-Eger, Wells, Choudhary, Hemnes, Brittain.

Statistical analysis: French, Huang, Thayer, Brittain.

Obtained funding: Brittain.

Administrative, technical, or material support: Huston, French, Thayer, Farber-Eger, Wells.

Study supervision: Huston, Hemnes, Brittain.

Conflict of Interest Disclosures: Dr Choudhary has received grants from Novartis. Dr Hemnes has received grants from the Cardiovascular Medical Research and Education Fund and the National Institutes of Health as well as personal fees from Actelion Pharmaceuticals, Bayer, Complexa, and United Therapeutics and has a patent issued for Annamometer. Dr Brittain has received personal fees from Bayer. No other disclosures were reported.

Funding/Support: This research was supported by grants U01 HL125212-01 (Dr Hemnes), K08HL111207-01A1 (Dr Maron), and R01HL146588 (Dr Brittain) from the National Institutes of Health, grants 13FTF16070002 (Dr Brittain) and 15GRNT25080016 (Dr Maron) from the American Heart Association, the Gilead Scholars Program in Pulmonary Arterial Hypertension (Dr Brittain), the Cardiovascular Medical Research and Education Foundation (Dr Maron), and the Klarman Foundation at Brigham and Women’s Hospital (Dr Maron). The datasets used for the analyses described were obtained from Vanderbilt University Medical Center’s Synthetic Derivative, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Clinical and Translational Science Award grant UL1TR000445 from the National Center for Advancing Translational Sciences and National Institutes of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

^✉

Corresponding author.

PMCID: PMC6751783 PMID: 31532457

Key Points

Question

Do patients with mild echocardiographic pulmonary hypertension have worse right ventricular function and mortality than patients with pulmonary pressures in the normal range?

Findings

In this cohort study of 47 784 patients, those with mild echocardiographic pulmonary hypertension (right ventricular systolic pressure of 33 to 39 mm Hg) had higher mortality, reduced right ventricular function, and impaired right ventricular–pulmonary arterial coupling compared with patients with right ventricular systolic pressure less than 33 mm Hg.

Meaning

In a clinical referral population, mildly elevated pulmonary pressures were associated with adverse right ventricular compensation and increased adjusted mortality.

This cohort study evaluates if mild echocardiographic pulmonary hypertension is associated with reduced right ventricular function and increased risk of mortality.

Abstract

Importance

Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk.

Objectives

To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality.

Design, Setting, and Participants

In this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019.

Exposures

Mild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV–pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP.

Main Outcomes and Measures

Associations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines.

Results

Of the 47 784 included patients, 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV–pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value.

Conclusions and Relevance

Mild ePH was associated with RV dysfunction and worse RV–pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.

Introduction

Pulmonary hypertension (PH) is associated with adverse clinical outcomes regardless of the underlying etiology.^1,2,3 Echocardiography permits noninvasive estimation of right ventricular systolic pressure (RVSP) based on the velocity of the tricuspid regurgitant jet (TRV) and is the screening test of choice for PH.⁴ Consensus guidelines based on expert opinion, not clinical risk, recommend consideration of further evaluation if RVSP is greater than 40 mm Hg or TRV is greater than 2.8 m/s in the setting of unexplained dyspnea or right ventricular (RV) dysfunction.^5,6,7

Emerging epidemiologic data suggest that invasively measured mean pulmonary arterial pressures (mPAPs) from 20 to 24 mm Hg are associated with increased risk of clinical events.^8,9,10 Existing data of echocardiographic cohorts, although from relatively small or disease-specific cohorts, also suggest that clinical risk is increased at RVSP estimates less than 40 mm Hg.^1,8,9,11 A missing piece in the epidemiology of mild or borderline PH is whether modestly elevated pressures are sufficient to cause RV dysfunction or whether the increase in adverse outcomes is solely driven by concomitant comorbid conditions. Understanding the effect of mild PH on RV function is important to clinicians because such knowledge may influence management strategies and identify individuals who may benefit from more aggressive therapy.

We examined the association of all-cause mortality with RVSP estimates in more than 43 000 individuals referred for echocardiography at a tertiary care center. We also examined the association of mildly elevated RVSP values with RV function and noninvasive RV–pulmonary artery (PA) coupling, a measurement that informs how the RV compensates for a given afterload.^{12,13,14,15,16,17,18} We hypothesized that clinical risk and RV dysfunction develop at RVSP values lower than 40 mm Hg.

Methods

Study Population

The Vanderbilt Institutional Review Board approved this study (IRB No. 140544). We developed a cohort of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 using Synthetic Derivative, Vanderbilt’s deidentified electronic medical record database. Informed consent was waived per institutional policy, as all patients consented to participate in the Synthetic Derivative at the time of consent to treatment. The design, implementation, and content of the Synthetic Derivative have been described previously.^19,20,21

Clinical Data

We identified patients referred for transthoracic echocardiography from March 1997 to February 2014 with a recorded RVSP or TRV value. If more than 1 qualifying echocardiogram was available, we analyzed the echocardiogram with the highest RVSP or TRV value to best capture a given patient’s potential for developing PH. Further details of clinical data collection and comorbidity phenotyping are given in the eMethods in the Supplement.

Echocardiographic Data

Echocardiographic data were extracted directly from reports in the Synthetic Derivative, as previously described.²¹ Study images are not available for review in the Synthetic Derivative; however, echocardiograms were interpreted clinically and reflect the expert opinion of a board-certified cardiologist and echocardiographer based on contemporary guidelines for interpretation. We used the reported RVSP value when available. When only TRV and right atrial pressure (RAP) values were reported, we calculated RVSP using the modified Bernoulli equation (RVSP = 4(TRV)² + RAP).²² Further details of echocardiographic data collection are given in the eMethods in the Supplement.

Outcomes

Follow-up time for all-cause mortality was calculated from the date of echocardiography. The Synthetic Derivative is linked to the Social Security Administration Death Master File and is updated monthly to ascertain vital status. Further details of outcome are given in the eMethods in the Supplement.

Statistical Analysis

Descriptive statistics of demographic and clinical characteristics were analyzed. Unless otherwise stated, data are expressed as means and standard deviations for continuous variables and as counts and percentages for categorical variables. Comparisons of demographic and clinical characteristics between PH groups were performed using nonparametric Wilcoxon tests for continuous variables and χ² tests for categorical variables. The reference threshold for group comparisons was an RVSP value of less than 33 mm Hg or a TRV value of less than 2.6 m/s. Cox proportional hazard models were used to examine the associations of RVSP or TRV with mortality. In Cox models, we adjusted for the following potential confounders a priori based on clinical knowledge: age, race, sex, body mass index, hypertension, heart failure (HF) with reduced ejection fraction (EF), HF with preserved EF, left-sided valve disease, left atrial dilation, interstitial lung disease, chronic obstructive pulmonary disease (COPD), connective tissue disease, coronary disease, atrial fibrillation, sleep apnea, and diabetes. We also adjusted by cohort of time in which echocardiography was performed. The nonlinear associations of RVSP or TRV with mortality hazard was assessed by restricted cubic spline with 4 knots. Hazard ratios (HRs) were determined by comparing RVSP or TRV values with reference values of 15 mm Hg for RVSP and 1.9 m/s for TRV based on prior studies examining pulmonary pressure as a continuous variable.^8,9 In additional analyses of mortality and RV function, we divided RVSP values into the following groups to correspond with invasive hemodynamic cutoffs: normal (reference group; RVSP value less than 33 mm Hg), mild echocardiographic PH (ePH; RVSP value of 33 to 39 mm Hg), and ePH (RVSP value of 40 mm Hg or greater).^8,9,23 These group definitions were influenced by the 2019 sixth World Symposium on Pulmonary Hypertension consensus document²⁴ acknowledging an mPAP of greater than 20 mm Hg as abnormal. An mPAP of 21 to 24 mm Hg on right heart catheterization has been called borderline or mild PH. Using the conversion equation of mPAP = systolic blood pressure × 0.62, these values correspond to an RVSP range of 33 to 39 mm Hg.^22,25,26,27 Further details of statistical methods can be found in the eMethods of the Supplement. A 2-sided P value less than .05 was considered statistically significant. All analyses were conducted using R version 3.3.1 (The R Foundation).

Results

Cohort Description and Clinical Characteristics

We identified a total of 91 376 patients who had echocardiography performed from March 1997 to February 2004. We excluded 37 418 patients who did not have RVSP or TRV measurements and 56 patients whose values were nonphysiologic. Of the resultant 47 784 patients, there were 43 246 patients who had reported RVSP values and 47 544 who had reported TRV values (Figure 1). There were 7116 of 47 784 patients (14.9%) who had multiple echocardiograms in which the study with the highest RVSP or TRV values was used in lieu of the incident study. The mean (SD) age at the time of echocardiography was 59 (18) years, and 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black. The 5 most common indications for echocardiography were coronary artery disease (13.0% [3337 of 25 664]), dyspnea (13.0% [3346 of 25 664]), arrhythmia (11.9% [3046 of 25 664]), HF (9.9% [2535 of 25 664]), and aortic valvular disease (7.4% [1920 of 25 664]) (eTable 1 in the Supplement). The mean (SD) RVSP and TRV values were 35 (15) mm Hg and 2.6 (0.6) m/s, respectively. In total, 8219 patients (19.0%) had RVSP values between 33 and 39 mm Hg, and 11 729 (27.1%) had values of 40 mm Hg or greater (eFigure 1 in the Supplement). When reported by sex, 3634 of 18 796 men (19.3%) and 4585 of 24 438 women (18.8%) had RVSP values between 33 and 39 mm Hg. Compared with the reference group, those with mild ePH were older (mean [SD] age, 63 [16] years vs 55 [18] years; P < .001) and had a higher prevalence of cardiometabolic and pulmonary comorbidities (Table 1). Patients with mild ePH also had evidence of myocardial remodeling on echocardiography (lower left ventricular EF, larger left atrial size), higher prevalence of any grade of diastolic dysfunction, and higher brain-type natriuretic peptide levels. The risk of developing mild ePH was increased in the presence of left atrial enlargement (4.2 cm vs 3.3 cm: odds ratio, 1.94; 95% CI, 1.78-2.11), left-sided valvular disease (odds ratio, 1.29; 95% CI, 1.17-1.41), and diastolic dysfunction (odds ratio, 1.25; 95% CI, 1.05-1.49). The distribution of demographic and clinical characteristics were similar when groups were defined on the basis of TRV values (eTable 2 in the Supplement).

Table 1. Demographic, Echocardiographic, and Laboratory Characteristics of Patients With Normal Right Ventricular Systolic Pressure (RVSP), Mild Pulmonary Hypertension, and Pulmonary Hypertension by Echocardiography.

Characteristic	RVSP, No./Total No. (%)
Characteristic	<33 mm Hg (n = 23 299)	33-39 mm Hg (n = 8219)	≥40 mm Hg (n = 11 728)
Demographic Characteristics
Deceased	901/23 229 (3.9)	617/8219 (7.5)^a	1582/11 728 (13.5)
Age, mean (SD), y	55 (18)	63 (16)^a	65 (16)
Sex^a
Male	9960/23 291 (42.7)	3634/8219 (44.3)	5202/11 724 (44.3)
Female	13 331/23 291 (57.2)	4585/8219 (55.8)	6522/11 724 (55.6)
Race^a
White	18 298/21 791 (83.9)	6526/7727 (84.5)	8934/11 724 (76.2)
Black	2708/21 791 (12.4)	998/7727 (12.9)	1822/11 724 (15.5)
Other	785/21 791 (3.6)	203/7727 (2.6)	220/11 724 (1.9)
BMI, mean (SD)^b	28.5 (6.9)	29.1 (7.6)^a	28.9 (7.9)
RVSP, mean (SD), mm Hg	26 (5)	36 (2)^a	54 (15)
TRV, mean (SD), m/s	2.2 (0.3)	2.7 (0.2)^a	3.3 (0.5)
Comorbidity
Hypertension	15 688/23 106 (67.9)	6436/8123 (79.2)^a	9262/11 425 (81.1)
COPD	2326/23 299 (9.9)	1365/8219 (16.6)^a	2591/11 728 (22.1)
CAD	8153/23 299 (34.9)	3879/8219 (47.2)^a	6193/11 728 (52.8)
Atrial fibrillation	4978/23 299 (21.4)	2692/8219 (32.8)^a	4792/11 728 (40.9)
Sleep apnea	2708/23 299 (11.6)	1053/8219 (12.8)^a	1462/11 728 (12.5)
HF	3182/23 299 (13.6)	1992/8219 (24.2)^a	4500/11 728 (38.4)
LVEF, %^a
<40	884/3089 (28.6)	573/1930 (29.7)	1440/4321 (33.3)
40-50	443/3089 (14.3)	324/1930 (16.8)	616/4321 (14.3)
>50	1762/3089 (57.0)	1033/1930 (53.5)	2265/4321 (52.4)
HF with reduced EF	1208/23 206 (5.2)	810/8157 (9.9)^a	1903/11 549 (16.5)
HF with preserved EF	506/23 279 (2.2)	271/8200 (3.3)^a	567/11 691 (4.8)
Left-sided valvular disease	1942/22 448 (8.6)	1253/7774 (16.1)^a	3087/11 728 (26.3)
Diabetes	7304/23 299 (31.3)	3047/8219 (37.1)^a	4769/11 728 (40.7)
Systemic sclerosis	151/23 299 (0.6)	62/8219 (0.8)	212/11 728 (1.8)
Echocardiographic Parameters
LVEF, mean (SD), %	55 (9)	53 (12)^a	49 (15)
Mitral inflow E/a ratio, mean (SD)	1.2 (0.6)	1.2 (0.9)	1.4 (0.8)
Left atrial diameter, mean (SD), mm	37 (7)	40 (8)^a	43 (9)
Left atrial volume index, mean (SD), mL/m²	25 (10)	32 (19)^a	41 (18)
Diameter, mean (SD), mm
Interventricular septal	12 (7)	13 (8)^a	13 (7)
Left ventricular posterior wall	10 (2)	11 (2)^a	11 (2)
RV end diastolic diameter, mean (SD), cm	2.9 (0.8)	3.0 (0.6)^a	3.2 (0.7)
TAPSE, mean (SD), cm	2.2 (0.5)	2.0 (0.6)^a	1.8 (0.6)
Diastolic dysfunction^a
Grade 1	3682/4280 (86.0)	1199/1606 (74.7)	1035/2134 (48.5)
Grade 2	520/4280 (12.1)	302/1606 (18.8)	604/2134 (28.3)
Grade 3	78/4280 (1.8)	105/1606 (6.5)	495/2134 (23.2)
RV size (qualitative)^a
Normal	12 686/13 415 (94.6)	3958/4408 (89.8)	4410/5913 (74.6)
Mildly dilated	602/13 415 (4.5)	367/4408 (8.3)	980/5913 (16.6)
Moderately dilated	107/13 415 (0.8)	77/4408 (1.7)	404/5913 (6.8)
Severely dilated	20/13 415 (0.1)	6/4408 (0.1)	119/5913 (2.0)
RV function (qualitative)^a
Normal	12 798/13 287 (96.3)	4053/4335 (93.4)	4635/5842 (79.3)
Mildly reduced	283/13 287 (2.1)	154/4335 (3.6)	616/5842 (10.5)
Moderately reduced	167/13 287 (1.3)	104/4335 (2.4)	423/5842 (7.2)
Severely reduced	39/13 287 (0.3)	25/4335 (0.6)	168/5842 (2.9)
Laboratory Values
BNP, median (IQR), pg/mL (n = 15 082)	140 (49-421)	234 (87-633)^a	386 (158-934)
Creatinine, mean (SD), mg/dL (n = 40 846)	1.1 (1.1)	1.3 (1.2)^a	1.6 (1.6)
CRP, median (IQR), mg/L (n = 10 352)	8 (2-51)	17 (4-88)^a	25 (5-101)
eGFR, mean (SD), mL/min/1.73 m² (n = 40 784)	84 (39)	75 (38)^a	68 (39)
Hemoglobin A_1c, mean (SD), % (n = 18 148)	6.2 (1.5)	6.3 (1.4)^a	6.4 (1.5)
HDL, mean (SD), mg/dL (n = 24 542)	50 (18)	48 (19)^a	45 (18)
LDL, mean (SD), mg/dL (n = 23 988)	101 (37)	95 (38)^a	89 (39)
Triglycerides, mean (SD), mg/dL (n = 25 366)	144 (116)	146 (138)	145 (117)
Hemoglobin, mean (SD), g/dL (n = 40 002)	12.7 (2)	12.1 (2)^a	11.7 (2)
Medications
β-Blocker	13 999/23 299 (60.0)	5966/8219 (72.5)^a	8580/11 728 (73.2)
ACE inhibitor	11 022/23 299 (47.3)	4685/8219 (57.0)^a	7010/11 728 (59.8)
CCB	10 386/23 299 (44.6)	4508/8219 (54.8)^a	6540/11 728 (55.8)
ARB	6097/23 299 (26.2)	2533/8219 (30.8)^a	3370/11 728 (28.7)
Loop diuretic	10 476/23 299 (44.9)	5257/8219 (63.9)^a	8876/11 728 (75.7)
Nonloop diuretic	8611/23 299 (36.9)	3651/8219 (44.4)^a	5184/11 728 (44.2)
Mineralocorticoid antagonist	3317/23 299 (14.2)	1611/8219 (19.6)^a	2993/11 728 (25.5)
α-Blocker	1074/23 299 (4.6)	519/8219 (6.3)^a	697/11 728 (5.9)
α₂ Agonist	3066/23 299 (13.2)	1439/8219 (17.5)^a	2135/11 728 (18.2)
Nitrates	7175/23 299 (30.8)	3171/8219 (38.5)^a	5114/11 728 (43.6)
Statins	11 830/23 299 (50.8)	4818/8219 (58.7)^a	6413/11 728 (54.7)
Nicotinic acid	1080/23 299 (4.6)	412/8219 (5.0)^a	452/11 728 (3.9)
Fibrates	4988/23 299 (21.4)	2199/8219 (26.8)^a	3070/11 728 (26.2)
Oral anticoagulant	6229/23 299 (26.7)	3032/8219 (36.9)^a	5335/11 728 (45.5)
Subcutaneous anticoagulant	5056/23 299 (21.7)	2277/8219 (27.7)^a	3560/11 728 (30.3)
Any PAH medication	10 271/23 299 (44.1)	4458/8219 (54.2)^a	6791/11 728 (57.9)
PAH CCB	9966/23 299 (42.8)	4343/8219 (52.8)^a	6317/11 728 (53.9)
Prostacyclin	293/23 299 (1.3)	175/8219 (2.1)^a	825/11 728 (7.0)
Endothelin receptor blocker	48/23 299 (0.2)	23/8219 (0.3)^a	337/11 728 (2.8)
Phosphodiesterase 5 inhibitor	644/23 299 (2.8)	247/8219 (3.0)	734/11 728 (6.3)
Guanylate cyclase stimulator	0	0	5/11 728 (<0.1)
Metformin	3590/23 299 (15.4)	1403/8219 (17.1)^a	1789/11 728 (15.3)
Insulin	7631/23 299 (32.8)	3533/8219 (42.9)^a	5716/11 728 (48.7)
Sulfonylurea	2140/23 299 (9.2)	1031/8219 (12.5)^a	1587/11 728 (13.5)
Thiazolidinedione	885/23 299 (3.8)	465/8219 (5.7)^a	697/11 728 (5.9)

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Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, brain-type natriuretic peptide; CAD, coronary artery disease; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; HF, heart failure; IQR, interquartile range; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; PAH, pulmonary arterial hypertension; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; TRV, tricuspid regurgitant velocity.

SI conversion factor: To convert to BNP to nanograms per liter, multiply by 1; creatinine to micromoles per liter, multiply by 88.4; CRP to nanomoles per liter, multiply by 9.524; HDL to millimoles per liter, multiply by 0.0259; LDL to millimoles per liter, multiply by 0.0259; triglycerides to millimoles per liter, multiply by 0.0113; hemoglobin to grams per liter, multiply by 10.

^{^a}

P < .05 comparing RVSP of 33 to 39 mm Hg with RVSP less than 33 mm Hg.

^{^b}

Calculated as weight in kilograms divided by height in meters squared.

RV Function

Among 1994 patients with a tricuspid annular plane systolic excursion (TAPSE) measurement, mild ePH was associated with significantly reduced RV function compared with the reference group as a continuous measure (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) (Figure 2A; eFigure 2 in the Supplement). When dichotomized into normal and abnormal function, the prevalence of RV dysfunction (defined as TAPSE <1.7 cm) was nearly double in the mild ePH group vs the reference group (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). In the total cohort, we found that higher RVSP values were significantly associated with lower TAPSE values (χ² = 160; P < .001) (eFigure 3 in the Supplement). Compared with the reference group, patients with mild ePH had a higher prevalence of RV dilation both qualitatively (mild or greater dilation, 10.2% [450 of 4408] vs 5.4% [729 of 13 415]; P < .001) and quantitatively (mean [SD] RV end diastolic diameter, 3.0 [0.6] vs 2.9 [0.8]; P < .001). Right ventricular end diastolic diameter was largest (mean [SD] diameter, 3.2 [0.7] cm) and TAPSE values were lowest (mean [SD] excursion, 1.8 [0.6] cm) in those with RVSP values of 40 mm Hg or greater. Patients with mild ePH exhibited evidence of impaired RV-PA coupling compared with the reference group (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001) (Figure 2B; eFigure 2 in the Supplement). Using a previously published cutoff value of 0.36 mm/mm Hg for an abnormal ratio of TAPSE to RVSP,²⁸ the prevalence of impaired RV-PA coupling in the mild ePH group was 12.8% (36 of 282) compared with 1.7% (17 of 1015) in the reference group (P < .001). Coupling was most impaired in patients with an RVSP value of 40 mm Hg or greater (mean [SD] ratio of TAPSE to RVSP, 0.35 [0.14] mm/mm Hg).

Figure 2. — A, Right ventricular function as measured by tricuspid annular plane systolic excursion (TAPSE) was significantly lower in patients with mild ePH and ePH compared with the reference group. B, Right ventricular–pulmonary artery coupling as measured by the ratio of TAPSE to RVSP worsened with increasing pulmonary pressure. Boxes indicate the interquartile range; bisecting line, median; and error bars, 76.5th and 23.5th percentiles.

^aP < .001.

^bTwenty-one values fall outside the 76.5th percentile in the reference group and are not included.

Outcomes

A total of 3492 deaths occurred over a median (interquartile range) duration of 6.8 (4.7-11.6) years. Adjusted risk of all-cause mortality was more than 50% higher in the mild ePH group than the reference group when the model was not adjusted for HF with reduced EF, HF with preserved EF, and left-sided valve disease (HR, 1.50; 95% CI, 1.39-1.74; P < .001). After further adjusting for prevalent HF with reduced EF, HF with preserved EF, and left-sided valvular disease, the association of mild ePH with all-cause mortality persisted (HR, 1.65; 95% CI, 1.46-1.86; P < .001). Compared with an RVSP value of 15 mm Hg and a TRV value of 1.9 m/s, increased risk of mortality began at an RVSP value of 27 mm Hg (HR, 1.32; 95% CI, 1.02-1.70) and a TRV value of 2.3 m/s (HR, 1.14; 95% CI, 1.02-1.27), respectively, after adjusting for relevant clinical covariates (Figure 3A; eFigure 4 and eTable 3 in the Supplement). Additionally, mortality risk was doubled at an RVSP value of 35 mm Hg (HR, 2.08; 95% CI, 1.59-2.72) and a TRV value of 2.8 m/s (HR, 2.08; 95% CI, 1.83-2.37). There was no significant difference in mortality in patients with mild ePH stratified by normal vs impaired RV function by TAPSE (χ² = 2; P = .15).

Figure 3. — A, Mortality increased significantly as RVSP increased. B, Women had a higher risk of mortality compared with men at any given RVSP value (P < .001). The reference value was an RVSP value of 15 mm Hg. See eTables 1 and 2 in the Supplement for hazard ratios. Hazard ratios were adjusted for the following potential confounders a priori based on clinical knowledge: age, race, sex, body mass index, hypertension, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, left-sided valve disease, left atrial dilation, interstitial lung disease, chronic obstructive pulmonary disease, connective tissue disease, coronary disease, atrial fibrillation, sleep apnea, and diabetes as well as by cohort of time in which the echocardiography was performed. The shaded regions indicate 95% CIs.

In prespecified subgroup analyses, we compared patients with known or suspected PH risk factors and mild ePH with those with RVSP values less than 33 mm Hg. We observed a significant increase in mortality among patients with HF or COPD with mild ePH vs those with normal RVSP values (Table 2). Black patients with mild ePH had higher adjusted mortality compared with those with normal RVSP values (HR, 1.81; 95% CI, 1.29-2.54). Female sex was associated with higher adjusted mortality at any given RVSP or TRV value (Figure 3B; eFigure 4 and eTable 4 in the Supplement). When analyzed as a group, female patients with mild ePH had higher adjusted all-cause mortality compared with male patients (female: HR, 1.78; 95% CI, 1.49-2.13; male: HR, 1.55; 95% CI, 1.32-1.82; P < .001).

Table 2. Association of Mild Echocardiographic Pulmonary Hypertension With Mortality in Patients With Specific Pulmonary Hypertension Risk Factors.

Variable	RVSP, HR (95% CI)
Variable	33-39 mm Hg	≥40 mm Hg
Heart failure	1.27 (1.06-1.54)^a	1.91 (1.64-2.23)^a
COPD	1.47 (1.11-1.95)^a	2.12 (1.66-2.71)^a
OSA	1.17 (0.84-1.64)	1.87 (1.39-2.51)^a
Systemic sclerosis	0.73 (0.06-8.66)	11.79 (2.67-61.37)
Black race	1.81 (1.29-2.54)^a	2.87 (2.14-3.84)^a

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Abbreviations: COPD, chronic obstructive pulmonary disease; HR, hazard ratio; OSA, obstructive sleep apnea; RVSP, right ventricular systolic pressure.

^{^a}

P < .05.

Discussion

In this clinical cohort study of more than 43 000 patients referred for echocardiography, we found that the adjusted risk of mortality began at RVSP values less than 40 mm Hg. The adjusted hazard for mortality was increased by 65% in patients with RVSP values between 33 and 39 mm Hg and nearly doubled at RVSP values of 35 mm Hg compared with a reference value of 15 mm Hg. Parallel analyses in a cohort with TRV values yielded similar results. By convention, the upper limit of normal has been defined as 2 SDs above the mean (or greater than the 95th percentile); in our study, this equates to an RVSP value of 65 mm Hg and a TRV value of 3.8 m/s, missing an at-risk population. Moreover, RVSP values that are currently considered normal (those between 33 and 39 mm Hg) are associated with RV dysfunction and dilation on a population level. These findings are important for patients and their clinicians because they suggest that the current echocardiographic thresholds for defining PH and triggering further evaluation do not adequately capture clinical risk related to rising RVSP values. To our knowledge, no prior studies have examined the association of mild PH with quantitative measures of RV function or RV-PA coupling in a racially mixed referral population.

The current recommended threshold for prompting further evaluation for PH is an RVSP value of 40 mm Hg, which approximates an mPAP of 25 mm Hg. This recommendation is based on expert consensus opinion. Emerging epidemiologic data consistently demonstrate a strong association of mortality with invasively measured pulmonary pressure values less than 25 mm Hg.^8,9,10,29 Given the weight of this evidence from invasive studies, PH was recently suggested to be defined as an mPAP greater than 20 mm Hg.²⁴ The goal of our study was to understand the association of corresponding noninvasive estimates with outcomes because most patients at risk of PH (eg, with HF and COPD) are never referred for invasive measurements. Prior studies have made similar observations using echocardiographic estimates of pulmonary pressure in populations at high risk of PH.^23,30,31,32 Important strengths of our study include the large sample size, racially diverse cohort representative of the United States, unselected population, and density of clinical and laboratory data, which are lacking from similar published cohorts.^33,34,35 Unlike prior studies, we specifically analyzed RVSP as a continuous variable to determine at what pressure clinical risk emerges.³¹ When patients had multiple studies with RVSP or TRV values, we chose the highest reported value under the presumption that this would be the point in time that represented a given patient’s highest risk. In 2018, Marra et al³⁶ found a 95% upper limit of 2.55 m/s for TRV in healthy participants. This corresponds to an RVSP value of approximately 29 mm Hg in the setting of normal RAP, which is very similar to the threshold we identified at which adjusted mortality risk begins (27 mm Hg). Thus, the threshold we identified is consistent with normative data on the upper limit of normal TRV values identified by Marra et al.³⁶ More recently, Strange et al³⁷ found that an RVSP threshold of 30 mm Hg is associated with increased risk of mortality, which is also largely consistent with our results. Our work adds to these findings by examining quantitative RV function and RV-PA coupling, including additional adjustments for established PH risk factors, and by examining risk in a racially diverse population. The latter point is particularly important given our finding of increased risk of mortality among black individuals with mild ePH. We have identified substantial risk at RVSP values that have historically been considered normal or not of clinical consequence.

We observed an increased risk of mortality among both women and black individuals with mild ePH. The findings with respect to sex are consistent with our prior report of an unselected population referred for invasive catheterization but contrasts with the epidemiology of pulmonary arterial hypertension in which men have increased mortality.^8,38 Our population differs substantially from the pulmonary arterial hypertension population in which men present later and with poor RV compensation and women respond better to vasodilator therapy. We have previously observed an increased risk of both PH and PH-related mortality among black individuals.^8,39,40 These findings do not appear to be fully driven by differences in comorbidity burden or treatment intensity, which raises the possibility of a molecular or genetic predisposition to develop pulmonary vascular disease.^8,39

Echocardiographic estimation of pulmonary pressure is recommended as a screening tool for patients at risk of PH but correlates imperfectly with invasive measurements.^22,41 Despite the relative imprecision of echocardiographic estimates, clinicians use these values to inform management decisions in clinical practice and help to guide therapy.^42,43 We urge that clinicians continue to interpret echocardiographic estimates with appropriate caution. However, based on our results, we emphasize that values greater than 27 mm Hg may not be benign and, at minimum, warrant consideration for further evaluation.

Prior population-based studies of echocardiographic pulmonary pressure estimates have not examined the association of mildly elevated RVSP values with RV function, to our knowledge. Our findings suggest that even modest elevations in pulmonary pressure are sufficient to adversely affect RV size and function. We found reduced RV function, near doubling in the prevalence of RV dysfunction, and evidence of impaired RV-PA coupling among patients with mild ePH compared with those with lower values. Although the definitive assessment of RV-PA coupling generally uses invasive measurements,⁴⁴ the noninvasive metric of TAPSE to RVSP ratio approximates the relationship between function and pressure and has strong prognostic value in a variety of clinical populations.^13,28,45 Our findings are consistent with a report from Lamia et al⁴⁶ in which RV dyssynchrony was prolonged among 13 patients with mPAP values between 20 and 25 mm Hg, suggesting early RV-PA uncoupling. These observations suggest that the increased risk of clinical events among patients with mild PH is not driven solely by an increased burden of comorbidities but rather a pathologic response of the RV to increase pulmonary pressures.

One inference from these data is that using an RVSP threshold of 40 mm Hg to prompt further clinical evaluation may identify patients with relatively advanced disease. The value of any screening test is the detection of incipient disease at a stage where early treatment could be more effective.^47,48 Our data suggest that mild ePH is not benign and may be a reasonable therapeutic target, particularly among some high-risk groups. Such a finding should prompt clinicians to seek an underlying cause, which most commonly would involve investigation for HF with preserved EF, obstructive sleep apnea, or COPD. Importantly, our findings do not support initiation of pulmonary vasodilators in patients with mild ePH. Future studies should focus on identifying patient subgroups who may benefit from invasive hemodynamic measurements and aggressive risk factor management. Future studies need to examine whether behavioral interventions or tight management of underlying comorbidities have an effect on outcomes among patients with mild ePH. We do not interpret our findings to suggest that all patients with mild ePH should be referred for invasive catheterization; we simply wish to raise awareness among clinicians that identification of mild ePH may warrant more aggressive management. Regardless, the finding that patients have increased mortality starting at an RVSP value of 27 mm Hg is striking. Although we do not have cause of death data, it is unlikely that patients die specifically from mildly elevated pulmonary pressures. Rather, mild ePH is a marker of prognosis that is likely driven by a higher burden of comorbidities.

Limitations

Our study has limitations. Our study reports outcomes in a population of patients referred for echocardiography, which may not be generalizable to the community. By virtue of our deidentified electronic health record interface, we were unable to directly review echocardiographic images related to pressure estimates or RV function. As such, we relied on accurate data input by physicians into echocardiographic reports and accurate coding of diagnoses. However, we used the same definitions to capture comorbidities that are used by other electronic health record–based cohorts (eg, the Precision Medicine Initiative and the Million Veterans Project). Another limitation of electronic health record cohorts is nonrandom missing data because the available clinical data reflect information specific to an individual’s medical history. Moreover, the use of International Classification of Diseases–based comorbidity definitions did not allow us to account for comorbidity severity. Echocardiographic estimates of pulmonary pressure correlate imperfectly with invasive measurements, particularly at very high pressures.^49,50 As a result, some patients in our cohort will have overestimated or underestimated pressure estimates, resulting in misclassification. However, the size of our cohort likely reduces noise related to imprecise estimates. Additionally, given we are using echocardiographic data, we cannot confidently differentiate between precapillary, postcapillary, and mixed PH. Although imperfect, echocardiographic RVSP estimates are clinically valuable because they are used as a screening tool, and only a minority of individuals with ePH undergo criterion-standard assessment by right heart catheterization. Despite these limitations, clinicians routinely make management decisions based on echocardiographic estimates of RVSP. Our assessment of RV function was limited to a single metric (TAPSE). Tricuspid annular plane systolic excursion is easy to measure and highly reproducible but only reports on RV function at the base, which may overestimate or underestimate global RV function. We determined vital status using the Social Security Administration Death Master File, which does not report the cause of death and may substantially underestimate the number of deaths owing to reporting delays and underreporting.⁵¹

Conclusions

The results of this study suggest that the current thresholds for defining ePH do not adequately capture risk of mortality and RV dysfunction related to RVSP. These findings should prompt reconsideration of RVSP values at which clinicians should consider clinical action and motivate future studies to determine whether more aggressive management of risk factors in individuals with mildly elevated RVSP values (and corresponding TRV values) reduces risk of clinical outcomes.

Supplement.

eMethods.

eTable 1. Most frequent indications for echocardiography.

eTable 2. Demographic, echocardiographic, and laboratory differences between patients with normal, mild ePH, and ePH by TRV.

eTable 3. Adjusted risk of mortality according to RVSP and TRV extracted from Figure 4A and eFigure 3A in the Supplement.

eTable 4. Adjusted risk of mortality according to RVSP and TRV stratified by sex extracted from Figure 4B and eFigure 3B in the Supplement.

eFigure 1. Frequency distribution of RVSP and TRV values reported.

eFigure 2. Whisker plots of RV function by TAPSE and RV-PA coupling by TAPSE/RVSP ratio stratified by degree of PH by TRV.

eFigure 3. Relationship between TAPSE and RVSP.

eFigure 4. Adjusted risk of Mortality by TRV and stratified by sex.

eReferences.

Click here for additional data file.^{(152.7KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eMethods.

eTable 1. Most frequent indications for echocardiography.

eTable 2. Demographic, echocardiographic, and laboratory differences between patients with normal, mild ePH, and ePH by TRV.

eTable 3. Adjusted risk of mortality according to RVSP and TRV extracted from Figure 4A and eFigure 3A in the Supplement.

eTable 4. Adjusted risk of mortality according to RVSP and TRV stratified by sex extracted from Figure 4B and eFigure 3B in the Supplement.

eFigure 1. Frequency distribution of RVSP and TRV values reported.

eFigure 2. Whisker plots of RV function by TAPSE and RV-PA coupling by TAPSE/RVSP ratio stratified by degree of PH by TRV.

eFigure 3. Relationship between TAPSE and RVSP.

eFigure 4. Adjusted risk of Mortality by TRV and stratified by sex.

eReferences.

Click here for additional data file.^{(152.7KB, pdf)}

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PERMALINK

Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function

Jessica H Huston, MD

Bradley A Maron, MD

John French, MD

Shi Huang, PhD

Timothy Thayer, MD

Eric H Farber-Eger, MS

Quinn S Wells, MD, MSCI

Gaurav Choudhary, MD

Anna R Hemnes, MD

Evan L Brittain, MD, MSCI

Key Points

Question

Findings

Meaning

Abstract

Importance

Objectives

Design, Setting, and Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Population

Clinical Data

Echocardiographic Data

Outcomes

Statistical Analysis

Results

Cohort Description and Clinical Characteristics

Figure 1. Flowchart of Patients With Echocardiography Measurements of Right Ventricular Systolic Pressure (RVSP) or Tricuspid Regurgitant Velocity (TRV) Included in the Analysis.

Table 1. Demographic, Echocardiographic, and Laboratory Characteristics of Patients With Normal Right Ventricular Systolic Pressure (RVSP), Mild Pulmonary Hypertension, and Pulmonary Hypertension by Echocardiography.

RV Function

Figure 2. Whisker Plots of Right Ventricular (RV) Function and Right Ventricular–Pulmonary Artery (RV-PA) Coupling Stratified by Degree of Echocardiographic Pulmonary Hypertension (ePH) Estimated by Right Ventricular Systolic Pressure (RVSP).

Outcomes

Figure 3. Adjusted Risk of Mortality by Right Ventricular Systolic Pressure (RVSP).

Table 2. Association of Mild Echocardiographic Pulmonary Hypertension With Mortality in Patients With Specific Pulmonary Hypertension Risk Factors.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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