Shorter Survival in Familial versus Idiopathic Pulmonary Arterial Hypertension is Associated with Hemodynamic Markers of Impaired Right Ventricular Function

Abstract

Although individuals with familial pulmonary arterial hypertension (FPAH) have more severe hemodynamics, compared to individuals with idiopathic PAH (IPAH), it is unclear whether this translates into a survival difference. The influence of right ventricular (RV) function on survival in these groups is also unknown. We reviewed hemodynamic data and health information from a prospective institutional database of 57 FPAH and 66 IPAH patients registered with the Vanderbilt Pulmonary Hypertension Research Cohort. We compared hemodynamics at the time of diagnosis between the two groups and calculated pulmonary arteriolar capacitance (PC) and RV stroke work index (RVSWI). Using survival analysis, we compared freedom from a 5-year composite of death or lung transplantation in FPAH and IPAH patients. The composite outcome of death or transplant at 5 years from diagnosis was significantly increased in FPAH (log rank P < 0.001). PC and RVSWI were significantly decreased in FPAH, compared to IPAH (P < 0.001 for both). In univariate analysis, PC (odds ratio [OR]: 0.17 [95% confidence interval (95% CI): 0.03–0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77–0.95]) were predictors of mortality, as were cardiac index (OR: 0.17 [95% CI: 0.06–0.51]) and PVR (OR: 1.1 [95% CI: 1.01–1.12]). Among FPAH patients, RVSWI was lower in those who died or received a transplant than in survivors (P = 0.006), while PC was not (P = 0.5). We found significantly worse event-free survival and significantly lower PC and RVSWI in FPAH than in IPAH. In FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting disproportionate RV dysfunction.

Keywords

pulmonary arterial hypertension familial pulmonary arterial hypertension right ventricular function hemodynamics

INTRODUCTION

Pulmonary arterial hypertension (PAH) results in progressive obliteration of the pulmonary vasculature and elevated pulmonary vascular resistance (PVR), leading to right heart failure and death. Differences in survival in PAH associated with the scleroderma spectrum of diseases and congenital heart disease–associated PAH are well described,^1,2 but whether familial PAH (FPAH) is associated with worse survival compared with idiopathic PAH (IPAH) is currently unclear. FPAH is usually associated with mutation in the type 2 bone morphogenetic protein receptor (BMPR2) gene, while the genetic etiology in the majority of patients with IPAH is unknown; there may be important molecular and phenotypic differences between these two conditions. Several studies have shown more-severe hemodynamic parameters in patients with FPAH than in those with IPAH.^3–5 Current data regarding survival differences between FPAH and IPAH are conflicting.^3,6

Right ventricular (RV) failure is the predominant cause of death in PAH, and survival closely correlates with noninvasive parameters of RV function.^7–10 However, survival in PAH is variable, and the ability to prognosticate using clinical and hemodynamic information is limited, particularly between subclasses of PAH.^6,11 RV- or pulmonary vascular-specific hemodynamic parameters may better predict survival in PAH patients. Pulmonary arteriolar capacitance (PC; stroke volume [SV] divided by pulmonary pulse pressure) measures the ability of the pulmonary vasculature to distend and store blood during RV systole and then recoil and expel blood from the pulmonary tree during diastole. Both invasively measured and noninvasively derived PC are strong predictors of survival in IPAH.^12,13 RV stroke work index (RVSWI) is a direct measurement of RV workload that predicts outcomes in patients with dilated cardiomyopathy, septic shock, and left ventricular assist device insertion and in a cohort with mixed etiologies of PH, but has not been studied in patients with FPAH or IPAH.^7,14–17

We hypothesized that survival is worse in patients with FPAH than in those with IPAH, on the basis of observations of decreased cardiac index and increased PVR in FPAH patients. We further hypothesized that survival differences would in part be explained by differences in RV function. We used the Vanderbilt Pulmonary Hypertension Research Cohort (VPHRC) to analyze survival and invasive hemodynamics in a large number of FPAH and IPAH patients.

METHODS

This study was approved by the Institutional Review Board at Vanderbilt University Medical Center (IRB no. 9401). The VPHRC provided the data for this study. The VPHRC contains clinical and biologic specimens collected prospectively over 25 years, including detailed family pedigree and medical histories of patients with FPAH and IPAH. For the purposes of this study, only FPAH patients with BMPR2 mutation and at least one affected family member were included in analysis. IPAH patients known to have a BMPR2 mutation were excluded from analysis (n = 7). To avoid confounding by treatment era, cases were restricted to those with diagnostic hemodynamic and clinical data between January 1, 1996 (when intravenous prostaglandins became commercially available), and March 1, 2011.

Patients

Patients included in this study were enrolled in the VPHRC in one of two ways: (1) patients who had sought care at the Vanderbilt Pulmonary Hypertension Clinic for evaluation and management or (2) patients referred by outside institutions for research purposes at the time of pulmonary hypertension diagnosis for the purposes of inclusion in our observational research cohort. In patients followed at Vanderbilt University, the diagnosis of PAH was made according to consensus guidelines,¹⁸ including mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, PVR > 3 Wood units (WU), and pulmonary wedge pressure (PWP) ≤ 15 mmHg. The diagnosis of IPAH or FPAH was made by experienced physicians in accordance with published consensus guidelines.¹⁸ Vasodilator responsiveness was defined as a decrease in mPAP of ≥10 mmHg to an absolute mPAP of <40 mmHg, associated with a lack of change or an increase in cardiac output.¹⁹ Patients with FPAH had at least one confirmed family member within their bloodline with PAH. Patients with a clinical diagnosis of IPAH who were found to have a BMPR2 mutation but no known affected family members (i.e., FPAH) were excluded from analysis. The VPHRC includes subjects not directly treated for clinical care at Vanderbilt University. For those subjects with PAH, diagnostic data were reviewed by clinicians at Vanderbilt University to confirm the diagnosis. Because the VPHRC is an observational study, therapy was at the discretion of the treating physician and not according to a specific algorithm. Prostaglandins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists were used as they became available at the discretion of the treating physician.

Hemodynamics

Heart rate (HR), right atrial pressure (RAP), pulmonary artery pressure (PAP; mean, systolic, and diastolic), PWP, and cardiac index (CI) were recorded from the patient's diagnostic catheterization. CI, PVR, and SV were calculated from standard formulas. The Fick method was used to calculate cardiac output.

The physiologic rationale for the calculation of PC has been described in detail elsewhere,¹² and the formula has been validated in an in vivo model.²⁰ PC and RVSWI were calculated using the following formulas:

\begin{array}{l} PC (mL / mmHg) = \frac{SV}{pulmonary pulse pressure}, \\ \begin{array}{l} RVSWI (g m / m^{2} / beat) = (mean PAP - mean RAP) \\ \times CI / HR \times 0.0136. \end{array} \end{array}

Statistical analysis

Continuous data are expressed as mean ± standard deviation. Unpaired, two-tailed Student's t tests and Mann-Whitney U tests were used to measure differences in continuous variables between groups according to specifications. Categorical variables were compared between groups by means of the χ² test. Event-free survival was defined as freedom from death and lung transplantation within 5 years of the date of diagnostic catheterization. All-cause mortality was used because the cause of death could not always be confidently determined. Survival curves were constructed with the Kaplan-Meier method and survival differences compared with the log rank test. Univariate logistic regression was used to determine the odds ratios (ORs) and 95% confidence intervals for RVSWI and PC. A P value of <0.05 was considered statistically significant. Statistical analyses were performed with Prism 5.0 (Graph Pad Software, La Jolla, CA) and SPSS 20 (SPSS, Chicago) software.

RESULTS

Population

One hundred forty-three patients were identified from the VPHRC as having either FPAH or IPAH. Thirteen IPAH patients were excluded because they had PWP > 15 mmHg, and 7 additional IPAH patients were excluded because of the presence of a BMPR2 mutation. Fifty-seven patients with FPAH (mean age at diagnosis: 34.8 ± 14.4 years, 70% female) and 66 patients with IPAH (mean age at diagnosis: 44.2 ± 14.4 years, 76% female) were included in survival analysis (Table 1). Of the 123 patients included in the analysis, 98 (80%) were enrolled from Vanderbilt and 25 (20%) were enrolled from outside institutions. Patients with FPAH were significantly younger at the time of diagnosis than IPAH patients (P < 0.001). Patients with FPAH came from 30 different families, with a range of affected members per family of 2–14. A greater proportion of FPAH patients were treated with prostanoid therapy (Table 1). None of the FPAH patients and 11 IPAH patients (11/66, 17%) were vasodilator responsive at the time of diagnostic catheterization.

Table 1.

Baseline demographics and medication exposure

	FPAH patients (n = 57)	IPAH patients (n = 66)	P value
Age at diagnosis, years	34.8 ± 14.4	44.2 ± 14.4	0.001
Sex, % female	70	76	0.49
Treatment
Prostanoid, n (%)	41 (71.9)	30 (45.5)	0.003
Phosphodiesterase 5 inhibitor, n (%)	19 (33.3)	28 (42.4)	0.30
Endothelin receptor antagonist, n (%)	17 (29.8)	24 (36.4)	0.45

Note: FPAH: familial pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension.

Hemodynamics

Diagnostic hemodynamics are shown in Table 2. The mPAP was not significantly different between the two groups; however, the mean CI and HR were lower (P < 0.001 and P = 0.002, respectively) and the mean PVR was higher (P = 0.001) for FPAH than for IPAH patients. There was a borderline difference in pulse pressure between FPAH and IPAH patients (41.5 ± 11.0 vs. 46.4 ± 13.4 mmHg; P = 0.051). PC and RVSWI were significantly lower in FPAH than in IPAH patients (P < 0.001 for both; Figs. 1,2).

Figure 1.

Pulmonary arteriolar capacitance (PC) in FPAH versus that in IPAH at the time of diagnosis. PC is significantly lower in FPAH than in IPAH patients at the time of diagnosis. FPAH: familial pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension. Bars denote mean ± standard deviation. An asterisk denotes significant (P < 0.001) difference.

Figure 2.

Right ventricular stroke work index (RVSWI) in FPAH versus that in IPAH at the time of diagnosis. RVSWI is significantly lower in FPAH than in IPAH patients at the time of diagnosis. FPAH: familial pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension. Bars denote mean ± standard deviation. An asterisk denotes significant (P < 0.001) difference.

Table 2.

Hemodynamic parameters at diagnosis

Parameter	FPAH patients	IPAH patients	P value
Heart rate, beats per minute; n = 50, 57	84.8 ± 14.4	78.8 ±11.8	0.02
Mean RAP, mmHg; n = 57, 63	9.8 ± 6.0	8.8 ± 6.5	0.42
PA systolic pressure, mmHg; n = 57, 66	90.6 ± 20.5	86.9 ± 21.5	0.34
Mean PAP, mmHg; n = 57, 66	58.4 ± 12.5	54.3 ± 14.8	0.10
Pulmonary capillary pressure, mmHg; n = 56, 64	9.9 ± 4.3	8.8 ± 3.7	0.12
Pulmonary vascular resistance, WU; n = 54, 62	16.4 ± 9.1	11.0 ± 4.8	<0.001
Stroke volume, mL; n = 50, 57	39.4 ± 14.3	56.9 ± 14.7	<0.001
Cardiac index, L/min/m²; n = 54, 65	1.8 ± 0.4	2.3 ± 0.5	<0.001
Mixed venous oxygen saturation, %; n = 33, 54	57.0 ± 9.1	61.8 ± 8.3	0.01

Note: FPAH: familial pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension; RAP: right atrial pressure; PA: pulmonary artery; PAP: pulmonary artery pressure; WU: Wood units. n = x; y indicates the number of FPAH and IPAH patients, respectively, for each parameter.

Survival

Kaplan-Meier curves for the composite end point of death or lung transplantation at 5 years are shown in Figure 3A. Event-free survival was significantly reduced in FPAH, compared to IPAH (log rank P < 0.001). There were no differences in survival between males and females with FPAH (P = 0.8) and between males and females with IPAH (P = 0.1; Fig. 3B). There was also no outcome difference between males and females when the two cohorts were combined (P = 0.28). There was a modest correlation between age and outcome in FPAH (r = −0.33, P = 0.012) but no correlation between age and outcome in IPAH (P = 0.15).

Figure 3.

Kaplan-Meier curves of FPAH and IPAH. A shows survival difference between FPAH and IPAH patients, log rank P < 0.001. B shows survival difference between FPAH and IPAH patients by sex; P is not significant (within each group). FPAH: familial pulmonary arterial hypertension; IPAH: idiopathic pulmonary arterial hypertension.

In patients treated with prostanoids during the study period, there was significantly worse event-free survival in those with FPAH than in those with IPAH (log rank P = 0.001). When we used Cox regression to control for prostanoid use, the survival difference remained significant (P < 0.001; hazard ratio [HzR]: 5.3 [95% confidence interval (95% CI): 2.4–11.4). There was no significant survival difference within FPAH or IPAH patients when comparing those who were treated with prostanoids and those who were not. We performed Cox regression to control for vasodilator responsiveness, and the hazard for death in FPAH remained significant (P < 0.001; HzR: 6.2 [95% CI: 2.7–14.2]). In addition, when transplanted patients were excluded, the survival difference remained unchanged (P < 0.001). In the cohort as a whole, there were no differences in survival between patients treated at Vanderbilt and those recruited from outside institutions (log rank P = 0.58). When the analysis was confined separately to FPAH or IPAH patients, there was no difference in survival based on institution of care (FPAH log rank P = 0.47; IPAH log rank P = 0.42). At 5 years after diagnosis, 19 patients with FPAH (14 deaths, 5 transplants) and 4 patients with IPAH (4 deaths, 0 transplants) met the composite end point. Eleven of the 14 deaths (79%) in the HPAH group and 2 of the 4 (50%) in the IPAH group were due to right heart failure.

In order to compare outcomes among BMPR2 mutation types, we divided BMPR2 mutations into four categories: kinase binding (n = 20), ligand binding (n = 25), cytoplasmic tail (n = 7), and other (n = 5). There were no outcome differences among these groups.

Because treatment options have changed over the course of this study period, we subdivided each cohort into patients whose PAH was diagnosed between 1996 and 2001 and those whose PAH was diagnosed between 2002 and 2011. The survival difference remained significant when FPAH and IPAH patients who received diagnoses between 1996 and 2001 were compared (P = 0.005) and when those receiving diagnoses between 2002 and 2011 were compared (P = 0.002).

In univariate analysis, PC (OR: 0.17 [95% CI: 0.03–0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77–0.95]) were predictors of meeting the composite end point in both groups combined. The conventional prognostic hemodynamic parameters cardiac index (OR: 0.17 [95% CI: 0.06–0.51]) and PVR (OR: 1.1 [95% CI: 1.01–1.12]) were also univariate predictors of the composite end point. Among FPAH patients, there was no difference in mean PC between those who met the composite end point and survivors (0.9 ± 0.5 vs. 0.8 ± 0.3 mL/mmHg, P = 0.5), but RVSWI was significantly lower (11.2 ± 4.1 vs. 15.3 ± 4.7 g m/m²/beat, P = 0.006) in those who met the end point than in survivors (Fig. 4).

Figure 4.

Right ventricular stroke work index (RVSWI) and PC in FPAH. A shows RVSWI in FPAH patients who died, compared to that in survivors within 5 years of diagnosis; asterisk indicates P = 0.006. B shows PC in FPAH patients who died, compared to that in survivors within 5 years of diagnosis; P = 0.5. FPAH: familial pulmonary arterial hypertension; PC: pulmonary arteriolar capacitance. Bars denote mean ± standard deviation.

DISCUSSION

In addition to confirming worse hemodynamics at presentation in FPAH than in IPAH,^3,4 we found significantly worse outcomes in FPAH than in IPAH, as measured by a composite end point of death and lung transplantation at 5 years. We also showed that RV function, as measured by RVSWI, was depressed in FPAH, compared to that in IPAH, and that RVSWI was lower in FPAH patients who died or underwent transplant than in 5-year survivors. These data suggest that disproportional RV dysfunction may play a role in reduced survival in FPAH patients.

The molecular underpinnings of most cases of FPAH consist of a mutation in BMPR2; about 80% of patients with FPAH have an identified mutation in BMPR2. Although much research has focused on the pulmonary vascular effects of BMPR2 mutation, this germline mutation is universally expressed in the adult, including the RV. It is possible that BMPR2 mutation in FPAH plays a role in modifying disease phenotype through expression in tissues other than the pulmonary vasculature. It is currently unknown whether BMPR2 mutation has RV-specific effects in adults with FPAH.

There are several possible explanations for the differences in outcomes between FPAH and IPAH patients. The simplest explanation is that FPAH represents an extreme phenotype within PAH, with a worse degree of pulmonary vascular involvement; however, this would not explain the depressed RVSWI in FPAH. Differences in treatment could underlie these findings, but survival among FPAH patients remained worse despite a greater proportion being treated with prostaglandins. Referral bias to transplant is possible among FPAH patients, but survival differences persisted when these patients were excluded. A final factor may be a detrimental RV-specific effect of mutation in the BMPR2 or other germline mutations associated with familial disease.^22,23 The fact that FPAH patients present with more advanced disease may be attributable to impaired RV compensation and is an important clinical observation. This may influence referral for lung transplant, referral to a pulmonary hypertension center, and choice of therapy. These observations may also provide the rationale for detailed study of the RV in the context of BMPR2 mutation.

Our outcome data confirm findings from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL), the largest PAH registry, and have facilitated multiple observations on different forms of PAH. The REVEAL registry found an HzR of 2.2 for mortality in patients with FPAH, higher than that for connective tissue disease–associated PAH (HzR: 1.6), 6-minute walk distance (HzR: 1.7), or RAP > 20 mmHg (HzR: 1.8).⁶ Indeed, one of the strongest factors identified in the REVEAL risk calculator is the presence of FPAH.^6,24 The French registry, despite demonstrating worse hemodynamics in FPAH, did not find a survival difference between BMPR2 mutation carriers and noncarriers;³ however, there was worse survival among males in a cohort of mixed-etiology PAH patients.²⁵ When pure cohorts of FPAH and IPAH patients were compared in the French registry, there was no difference in survival between sexes, supporting our findings of no survival difference between sexes in pure cohorts.³ In our cohort, there was no difference in survival between sexes in the FPAH or IPAH cohorts or the two groups combined. Patients with FPAH were significantly younger at diagnosis than IPAH patients. This age difference has been observed in other cohorts of FPAH and IPAH patients and may support data indicating a more extreme phenotype in patients with FPAH.³ Unfortunately, we did not have B-type natriuretic peptide or 6-minute walk data on enough patients to determine the utility of the REVEAL risk score in this population.^6,24 Although epoprostenol has been shown to significantly improve survival in PAH patients,^26–28 we found a greater use of prostanoids in the FPAH group despite worse survival; this may strengthen the hypothesis that FPAH patients have more severe disease. Five of the 19 patients with FPAH, compared to none of the IPAH patients, underwent transplantation, possibly reflecting that the younger age at diagnosis in FPAH led to more aggressive listing or reflecting clinicians' perceptions of a worse disease trajectory in FPAH. In order to keep the comparison between FPAH and IPAH as clear as possible, we excluded 7 patients with IPAH who were found to have a sporadic BMPR2 mutation but did not have any affected family members. When these patients were included in the FPAH cohort, the survival and hemodynamic differences remained significant.

In order to test the hypothesis that RV function contributed to earlier mortality in FPAH patients, we calculated the RV-specific hemodynamic parameter RVSWI. This parameter is derived from mPAP, RAP, and cardiac index (CI) and can be calculated quite easily. RVSWI may be a more direct measure of the RV function than is CI, and differences between various PAH subpopulations are not described. Both FPAH and IPAH patients in our study had a supranormal RVSWIs (normal value: 7–12 g m/m²/beat), consistent with a compensatory increase in RV workload due to increased pulmonary resistance.²⁹ However, FPAH patients had a significantly lower RVSWI, which may indicate failure of appropriate RV compensation and a greater degree of intrinsic RV dysfunction. It is likely that differences in CI between groups drive the differences in RVSWI. The main components of CI are SV and HR. Given that there was a numerical but not clinically significant difference in HR between groups (~6 bpm), the main difference was therefore in SV, which is due to differences in RV contractility. This supports the hypothesis that there are intrinsic differences in RV function between groups. Moreover, RVSWI was lower in FPAH patients who died or underwent transplantation than in event-free survivors, suggesting a lesser degree of RV compensation in patients who met this end point. The natural history of RVSWI has not been described and may mirror that of mean pulmonary pressure, which begins to fall as the RV begins to fail.

PC measures the ability of the pulmonary vasculature to store blood during RV systole and then expel blood from the pulmonary tree during diastole. Lung vascular capacitance has two inputs: vascular resistance and elastic recoil (the inverse of compliance). In the normal lung, PVR is so low that much of the capacitance measure is likely due to elastic recoil, but in advanced PAH, where there is reduction in lumen size, dropout of vessels, and thickening of large arteries, PVR probably exceeds compliance as responsible for capacitance data. Mahapatra et al.¹² found an HzR for mortality of 17 per mL/mmHg decrease in PC in a cohort of 104 incident patients with IPAH. In receiver operator curve analysis, PC outperformed the National Institutes of Health–predicted survival, CI, and PVR as predictors of survival. Our study found an HzR of 0.17 for survival per mL/mmHg increase in PC for both cohorts combined, and PC in our study was similar to that found by Mahapatra et al. (1.0 ± 0.5 vs. 1.4 ± 0.7).¹² However, in our study there was no difference in PC between FPAH survivors and those who met the composite end point, while RVSWI was lower in those who met the composite end point, demonstrating disproportionate RV dysfunction in FPAH patients with a poor outcome.

Limitations

Our study has a relatively small sample size, compared to REVEAL and the French registry,^3,6,30 but is one of the largest survival cohorts of FPAH patients. While we did not find any impact of prostanoid use on survival between groups, the duration of drug exposure was not captured in this database. This study focused on hemodynamic predictors of survival in patients with FPAH and IPAH. RVSWI is an imperfect measure of RV function that is not wholly divorced from the effect of afterload. Echocardiographic data would have provided an additional measure of RV function but were not available for analysis in our cohort over the extended period of the study.

The VPHRC primarily enrolls patients seen and treated at Vanderbilt but also enrolls patients from multiple other institutions and across time. Patients are entered into the database at the time of enrollment, thus representing consecutive cases; however, because there is variability in the amount and quality of patient data collected, this cohort is not as rigorous as a single-institution cohort. Our research cohort is particularly enriched for FPAH patients relative to other pulmonary hypertension research cohorts, because our research center has a long tradition of interest in studying subjects with familial disease.

Our hemodynamic data are only a snapshot at the time of diagnosis. Follow-up data describing the natural history of conventional hemodynamic parameters and RVSWI would better describe how RV function changes over time and in response to treatment. Serial data would also shed light on the direct contribution of RV dysfunction to survival. Survival was high in patients with IPAH, which may reflect milder disease. However, several recent publications also report historically high survival in IPAH and mixed cohorts, which may signal a trend toward improved survival in IPAH.^31–33 More FPAH patients were treated with prostaglandins, which would bias to the null hypothesis. Multivariate analysis was not performed because of the relatively small sample size and low event rate.

Our research cohort has a large familial component; the subjects in this study represented 30 families, and 8 families were represented with more than one PAH patient. After careful analysis of the included subjects, as well as of pedigrees from each family included in the study, it was concluded that the genetic relatedness of this cohort was not sufficient or appropriate to justify the use of family-based association tests that model genotypic risks. However, for verification of this conclusion, we compared hemodynamic parameters and outcomes among different FPAH families in the study cohort and found no differences according to family representation.

Conclusions

In our cohort of FPAH and IPAH patients, we found significantly worse survival in FPAH patients, with no survival difference between sexes in either FPAH or IPAH. Further, we found that FPAH patients have lower PC and RVSWI at the time of diagnosis and that in FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting possible intrinsic RV dysfunction in FPAH.

Footnotes

Source of Support: This work was supported by National Institutes of Health (NIH; grants K08 HL093363 [ARH], K23 HL0987431 [EDA], and NCRR/NIH [1 UL1 RR024975 (Vanderbilt University)]) and the American College of Cardiology Foundation/Merck Fellowship in Cardiometabolic Diseases (ELB).

Conflict of Interest: ARH has received grants from Pfizer and the NIH and consulting fees from Pfizer and United Therapeutics. All other authors have no conflicts of interest to declare.

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