Trends and Outcomes of Pulmonary Arterial Hypertension–Related Hospitalizations in the United States: Analysis of the Nationwide Inpatient Sample Database From 2001 Through 2012

Key Points

Question  What are the recent trends and outcomes of pulmonary arterial hypertension (PAH)–related hospitalization in the United States?

Findings  This cross-sectional study of the National Inpatient Sample database found that PAH-related hospitalizations in the United States have decreased significantly, but hospital charges have increased substantially and are increasingly being borne by Medicare. In-hospital mortality remains unchanged, but length of hospitalization has increased.

Meaning  These data highlight the increasing clinical and economic burden of PAH-related hospitalizations and should help identify patients with PAH who are at increased risk of prolonged hospitalization and in-hospital mortality.

Importance  Recent trends and outcomes of pulmonary arterial hypertension (PAH)–related hospitalization in adults in the United States are unknown.

Objective  To examine the characteristics of PAH-related hospitalizations.

Design, Setting, and Participants  We analyzed the National Inpatient Sample database for all adult patients (≥18 years old) with PAH as the principal discharge diagnosis from January 1, 2001, through December 31, 2012.

Main Outcomes and Measures  We analyzed the temporal trends in hospitalization rate, hospital charges, in-hospital mortality, length of hospitalization, and comorbidities pertaining to PAH-related hospitalizations. We also evaluated the predictors of in-hospital mortality and length of hospitalizations.

Results  The number of PAH-related hospitalizations per year in adults decreased significantly from 2001 through 2012 (3177 vs 1345, P for trend <.001). However, the mean hospital charge per admission increased 2.7-fold from 2001 through 2012 ($29 507 vs $79 607, P for trend <.001). There was a significant increase in each of these associated comorbid conditions: diabetes (4.6%-7.8%), hypertension (5.1%-17.1%), coronary artery disease (15.6%-22.3%), chronic obstructive pulmonary disease (14.4%-20.1%), anemia (12.4%-20.4%), cardiac dysrhythmias (21.7%-29.0%), congestive heart failure (40.7%-56.1%), acute (5.9%-20.1%) or chronic kidney disease (1.1%-16.4%), fluid and electrolyte imbalance (18.9%-35.3%), pneumonia (4.4%-6.3%), cardiogenic shock (0.5%-1.5%), and acute respiratory failure (4.3%-20.8%) from 2001 through 2012. The length of hospitalization increased (mean [SE], 7.0 [0.5] days in 2001 vs 7.6 [0.6] days in 2012, P for trend = .009), but in-patient mortality remained unchanged (7.8% [1.1%] in 2001 vs 6.3% [1.7%] in 2012, P for trend = .54). Admission to a teaching hospital (β coefficient for length of hospitalization, 2.0; 95% CI, 1.3-1.6; odds ratio [OR] for mortality, 1.5; 95% CI, 1.1-2.1), cardiac dysrhythmias (β coefficient, 1.8; 95% CI, 1.1-2.6; OR, 1.8; 95% CI, 1.4-2.4), acute kidney injury (β coefficient, 5.0; 95% CI, 3.9-6.1; OR, 2.3; 95% CI, 1.7-3.2), acute cerebrovascular accident (β coefficient, 6.6; 95% CI, 1.9-11.3; OR, 6.7; 95% CI, 2.1-21.1), and acute respiratory failure (β coefficient, 6.2; 95% CI, 5.1-7.4; OR, 5.6; 95% CI, 4.2-7.5) were associated with increased length of hospitalization and in-hospital mortality. Congestive heart failure (OR, 1.7; 95% CI, 1.3-2.2), cardiogenic shock (OR, 5.4; 95% CI, 2.7-10.9), and fluid and electrolyte imbalance (OR, 1.9; 95% CI, 1.5-2.4) were associated with increased in-hospital mortality but not length of hospitalization.

Conclusions and Relevance  Analyses of temporal changes in PAH care reveal a significant decrease in PAH-related hospitalizations in the United States, but hospital charges have increased substantially and are increasingly being borne by Medicare. In-hospital mortality remains unchanged, but length of hospitalization has increased. This study should help identify the characteristics of patients with PAH that are associated with increased risk of in-hospital mortality and longer length of hospitalization.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by obstructive vascular remodeling of the small resistance pulmonary arteries, resulting in elevated pulmonary artery pressure and pulmonary vascular resistance with decreased pulmonary vascular compliance, which eventually leads to right ventricular failure and death.^1,2 The estimated prevalence of PAH is 10 to 50 cases per 1 million people, with an annual incidence of 1 to 10 cases per 1 million.^3-8 Despite the availability of several PAH-specific vasodilator therapies in the current era, 1-year mortality remains high at 10% to 15%.^9,10 In addition to high mortality, PAH is associated with significant morbidity, often requiring frequent hospitalizations attributable to right heart failure.¹¹

Pulmonary arterial hypertension–related hospitalization is associated with a further increased risk of additional hospitalizations and decreased survival at 3 years.¹² Moreover, hospitalizations related to PAH create a significant economic burden.^11,13,14 Despite this clinical and economic relevance, little is known about the characteristics of PAH-related hospitalizations in the United States in the modern era of PAH-specific therapies. Prior studies^15-17 addressing PAH-related hospitalization were predominantly small, single-center studies from tertiary referral centers.

To address this knowledge gap, we investigated the national trends in PAH-related hospitalizations in the United States using the largest nationally representative database in the United States. We also sought to examine shifting demographics, hospitalization charges, associated comorbidities, in-hospital mortality, and length of hospitalization related to PAH. Finally, we determined the factors associated with in-hospital mortality and length of hospitalization.

The Healthcare Utilization Project (HCUP) is a family of databases sponsored by the Agency for Healthcare Research and Quality that provides the most comprehensive source of hospital data in the United States. In this study, we used the National Inpatient Sample (NIS) database, a HCUP database that is the largest all-payer database of inpatient hospitalizations in the United States. The NIS database contains data from 1000 hospitals and includes approximately 8 million hospitalizations per year. The database represents a random, 20% stratified sample of all inpatient hospitalizations from 46 states (representing >97% of the total US population).¹⁸ Patients admitted under observation status and those admitted to short-term rehabilitation hospitals, psychiatric hospitals, and alcoholism or chemical dependency units are not included. Discharge weights computed for the 20% sample were used to generate national estimates.¹⁸

The NIS database includes deidentified information on patient demographics, admission status, primary and secondary discharge diagnoses, comorbidities, procedures, and outcomes for each sampled hospitalization, including in-hospital mortality and length of hospitalization. All diagnoses, comorbidities, and procedures are available in the NIS database as International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Because this is an analysis of publicly available deidentified data, the University of Minnesota Institutional Review Board guidelines stipulate that board approval of the study and informed consent are waived.

We identified all patients 18 years or older in the NIS database from January 1, 2001, through December 31, 2012, with a primary discharge diagnosis of primary pulmonary hypertension using an ICD-9-CM primary diagnosis code of 416.0. Pulmonary hypertension is categorized in ICD-9-CM as primary pulmonary hypertension (code 416.0) or secondary pulmonary hypertension (code 416.8). Primary pulmonary hypertension represents current World Health Organization (WHO) category I PAH, and secondary pulmonary hypertension represents all other WHO categories of pulmonary hypertension (categories II–V). Throughout the rest of the article, we use the current term PAH rather than primary pulmonary hypertension.

Next, for each patient identified with a primary discharge diagnosis of PAH, we obtained the following variables: patient demographics, including age and sex; comorbidities, including hypertension, diabetes, coronary artery disease, chronic obstructive pulmonary disease, atrial fibrillation, cardiac arrhythmias, chronic kidney disease, anemia, liver disease, fluid and electrolyte imbalance, congestive heart failure, acute kidney injury, pneumonia, cardiogenic shock, acute respiratory failure, and acute cerebrovascular accident, using ICD-9-CM codes; and hospital characteristics, including hospital location (Northeast, Midwest, South, and West and metropolitan vs nonmetropolitan), hospital type (teaching vs nonteaching), and hospital bed size (small, medium, and large). The comorbidities included in the analyses were selected a priori based on their established clinical significance and relevance to outcomes in patients with left heart failure.¹⁹ The diagnosis and ICD-9-CM codes grouped under the definition of cardiac dysrhythmias in the NIS database are included in the eAppendix in the Supplement. Hospital size was defined as small, medium, and large as per HCUP criteria (eTable in the Supplement).¹⁸ In addition, we categorized the payer status for all admissions as Medicare, Medicaid, private insurance, uninsured, and others. Finally, we extracted data related to hospitalization, including inpatient length of hospitalization, hospital charges, and inpatient mortality.

Our primary outcomes were national temporal trends in the number of hospitalizations, mean charges per hospitalization, in-hospital mortality, and mean length of hospitalization. Secondary outcomes studied included assessment of factors associated with in-hospital mortality and length of hospitalization.

The hospital charges are the amount the hospital billed to private insurance, Medicaid, Medicare, and other sources for the entire hospital stay. Professional fees were not included in the hospital charges. The mean hospital charges reported are the raw charges and those adjusted to 2012 inflation dollars (total inflation rate of 29.7% from 2001 to 2012; http://www.bls.gov/data/inflation_calculator.htm).

The trends for total number of discharges with PAH as the primary discharge diagnosis code; distribution of patients by age, sex, and payer; mean length of hospitalization; mean total charges; and in-hospital mortality were analyzed from 2001 to 2012. National estimates were generated from the NIS sample using trend weights and published HCUP methods.²⁰ We also calculated the frequency of associated comorbidities in patients with a primary discharge diagnosis of PAH and compared the trends from 2001 to 2012. Continuous variables are presented as mean (SE), and categorical variables are presented as frequency (percentages). We used χ² tests to compare the categorical variables, and the 2-tailed t test was used for comparing continuous variables. The Cochran-Armitage test was used for temporal trend analysis of the categorical variables, and linear regression with a continuous term for year was used for continuous variables. In addition, we used logistic and linear regression analyses to create multivariable models to evaluate the factors associated with in-hospital mortality and length of hospitalization, respectively, while controlling for potential confounders. All covariates significantly associated with in-hospital mortality and length of hospitalization in the univariate analysis were included in the corresponding multivariable-adjusted models. All statistical analysis was completed using SAS statistical software, version 9.3 (SAS Institute Inc). P < .05 was considered significant.

The number of PAH-related hospitalizations decreased by 58% from 3177 in 2001 to 1345 in 2012 (P < .001) (Figure 1). In contrast, there was no significant change in the total number of hospitalizations for all causes in the United States (36 093 550 in 2001 to 36 484 846 in 2012, P = .54).

Table 1 lists the characteristics of PAH-related hospitalizations. Although the number of PAH-related hospitalizations in urban teaching hospitals, not-for-profit hospitals, and large bed-size hospitals decreased from 2001 through 2012, these hospitals remained the destination for most patients throughout the study period (Table 1). There was a decrease in the number of PAH-related hospitalizations in urban nonteaching hospitals and small- and medium-sized hospitals. The number of patients with PAH who underwent routine discharge (ie, discharge to home) decreased significantly from 2001 through 2012 (2192 [69.0%] to 840 [62.5%], P for trend <.001). However, there was a significant increase in use of home health care on discharge from 2001 through 2012 (404 [12.7%] to 250 [18.6%], P for trend <.001).

The mean (SE) charges for individual PAH-related hospitalization increased significantly over time (P for trend <.001) (Figure 1). Overall, there was a 2.7-fold increase in hospital charges from $29 507 ($3995) per hospitalization in 2001 to $79 607 ($8813) in 2012 (P < .001). After adjusting for inflation to 2012 dollars, there was still a 2.1-fold increase from $38 253 to $79 607. Medicare continued to be the largest payer of PAH-related admissions, followed by private insurance and Medicaid. From 2001 through 2012, the number of hospitalizations paid by Medicare increased substantially (39.8% vs 49.4%, P for trend <.001), whereas PAH-related hospitalizations paid by private insurance significantly decreased (38.0% vs 24.9%, P for trend <.001) (Table 1).

The trends in the characteristics of patients hospitalized for PAH from 2001 through 2012 are listed in Table 2. More than one-third of patients were 45 to 64 years of age. There was a slight increase in the percentage of patients in the 65- to 84-year age group, but this was not statistically significant (26.6% to 31.6%, P for trend = .19). Women continued to represent approximately 75% of the total patients admitted for PAH, consistent with the well-known female predominance in this syndrome.^3,4

During the study period, there was a temporal increase in each of the following comorbidities in patients admitted with PAH as the primary discharge diagnosis: diabetes (4.6% to 7.8%), hypertension (5.1% to 17.1%), coronary artery disease (15.6% to 22.3%), cardiac dysrhythmias (21.7% to 29.0%), atrial fibrillation (15.6% to 20.4%), congestive heart failure (40.7% to 56.1%), chronic obstructive pulmonary disease (14.4% to 20.1%), acute kidney injury (5.9% to 20.1%), chronic kidney disease (1.1% to 16.4%), fluid and electrolyte imbalance (18.9% to 35.3%), anemia (12.4% to 20.4%), pneumonia (4.4% to 6.3%), cardiogenic shock (0.5% to 1.5%), and acute respiratory failure (4.3% to 20.8%) (Table 2).

The in-hospital mortality of patients with PAH has remained unchanged over time despite an increase in the associated comorbidities (7.8% [1.1%] in 2001 vs 6.3% [1.7%] in 2012, P for trend = .54) (Figure 2). Table 3 lists the unadjusted predictors of in-hospital mortality. From multivariable logistic regression, each of the following factors was independently associated with increased in-hospital mortality: admission to teaching hospitals (odds ratio [OR], 1.5; 95% CI, 1.1-2.1), fluid and electrolyte imbalance (OR, 1.9; 95% CI, 1.5-2.4), cardiac dysrhythmias (OR, 1.8; 95% CI, 1.4-2.4), acute cerebrovascular accident (OR, 6.7; 95% CI, 2.1-21.1), congestive heart failure (OR, 1.7; 95% CI, 1.3-2.2), acute kidney injury (OR, 2.3; 95% CI, 1.7-3.2), cardiogenic shock (OR, 5.4; 95% CI, 2.7-10.9), and acute respiratory failure (OR, 5.6; 95% CI, 4.2-7.5) (eFigure 1 in the Supplement). Interestingly, the presence of anemia (OR, 0.6; 95% CI, 0.4-0.8) or diabetes (OR, 0.5; 95% CI, 0.3-0.97) was protective (eFigure 1 in the Supplement). As expected, in-patient mortality was substantially higher in patients with cardiogenic shock and acute respiratory failure.

The mean (SE) length of hospitalization increased over time (7.0 [0.5] days in 2001 vs 7.6 [0.6] days in 2012, P for trend = .009) (Figure 2). Table 3 lists the univariate predictors of increased length of hospitalization. Using multivariable linear regression, we found that patients with older age had a shorter length of hospitalization (β coefficient for per decade increase in age, −0.8; 95% CI, −0.9 to −0.6), whereas patients with admission to a teaching hospital (β coefficient, 2.0; 95% CI, 1.3-1.6), pneumonia (β coefficient, 7.6; 95% CI, 6.2-8.9), acute kidney injury (β coefficient, 5.0; 95% CI, 3.9-6.1), acute cerebrovascular accident (β coefficient, 6.6; 95% CI, 1.9-11.3), cardiac dysrhythmias (β coefficient, 1.8; 95% CI, 1.1-2.6), and acute respiratory failure (β coefficient, 6.2; 95% CI, 5.1-7.4) had a longer length of hospitalization. eFigure 2 in the Supplement shows the independent predictors of length of hospitalization with corresponding β coefficients with 95% CIs.

In a national sample, we found a significant decrease in the number of hospitalizations for PAH from 2001 through 2012; however, the hospitalization charges increased substantially during this period. There was a significant temporal increase in the number of associated comorbid conditions in patients admitted with PAH. Although the in-hospital mortality remained unchanged during the study period, length of hospitalization increased minimally. Admission to a teaching hospital, cardiac dysrhythmias, acute kidney injury, acute cerebrovascular accident, and acute respiratory failure were associated with increased length of hospitalization and in-hospital mortality. Congestive heart failure, cardiogenic shock, and fluid and electrolyte imbalance were associated with increased in-hospital mortality but not length of hospitalization. These data highlight the increasing clinical and economic burden of PAH-related hospitalizations and should help identify patients with PAH who are at increased risk of prolonged hospitalization and in-hospital mortality.

The 58% decrease in number of admissions during the study period likely reflects an overall improvement in the outpatient care of these patients and likely favorable disease course with the availability of PAH-specific vasodilator therapies.²¹ Consistent with this outcome, newer PAH-specific therapies decrease PAH-related hospitalization by altering disease progression. For example, there was a 50% reduction in hospitalizations and annual hospital days with macitentan compared with placebo in the Study With Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome.²¹ Furthermore, in 2001, parenteral prostacyclins (epoprostenol and treprostinil) were the only therapies approved by the US Food and Drug Administration (FDA) for PAH. Initiation of treatment with parenteral prostacyclins in general requires hospitalization. However, since 2002, the FDA has approved 8 oral and 2 inhaled vasodilator therapies for treatment of PAH. It is likely that later in the study patients were being prescribed these nonparenteral therapies as outpatients, with only those who were acutely ill being admitted to the hospital.

Our results are different from the study by Mehari et al,²² which found increasing national hospitalization and mortality rates for pulmonary hypertension from 1999 to 2008. This discrepancy is likely because the study by Mehari et al²² included patients with all WHO categories of pulmonary hypertension, including pulmonary hypertension caused by left heart disease, which is much more prevalent than PAH. In contrast, our study included only patients with a principal discharge diagnosis of primary pulmonary hypertension, which represents WHO category I PAH.

We found that the hospital charges for individual PAH-related hospitalizations have increased significantly from 2001 through 2012. There are several possible explanations. Patients with PAH currently being hospitalized are more frequently acutely ill and have increasing comorbidities. In fact, in our present analysis, there was a significant trend toward increased frequency of cardiogenic shock, cardiac dysrhythmias, acute respiratory failure, and acute renal failure in patients with PAH hospitalized during the study period. These outcomes are also supported by our findings that there was a significant increase in the use of home health care on discharge, another indicator of illness severity. In addition, it is likely that the increased cost of PAH-related hospitalization is driven by the use of expensive PAH-specific vasodilator therapies while patients are being admitted in the hospital.

Our findings of increased length of hospitalization and high inpatient costs for PAH-related hospitalizations are consistent with findings previously reported by Lacey et al²³ using the Optum Research Database from 2007 to 2011, with a mean cost of initial hospitalization of $30 286 and a mean length of hospitalization of 11 days. Their study also found high rates of readmission (up to 75% of patients within 1 year). In addition, of those who were readmitted, 20% were readmitted within 30 days of hospital discharge. The mean cumulative cost of additional hospitalization per patient was $71 622, representing a substantial economic burden of PAH-related hospitalizations.

In terms of patient demographics, there was a trend toward admission of patients in the higher age groups (65-84 years old), consistent with a prior study¹¹ using a Medicare database, which is also in line with reports^4,7,24,25 from multiple registries that found a shift in the diagnosis of PAH to an older age. Similar to other PAH registry data, most patients continued to be women. We also observed an increased burden of comorbidities, including diabetes, hypertension, coronary artery disease, atrial fibrillation, and chronic obstructive pulmonary disease.^4,5,12,26 It is unclear whether these patients are truly a different phenotype of PAH or whether their inclusion reflects a clinical misclassification of other WHO groups of pulmonary hypertension as PAH. Although the exact reason for the striking increase in the prevalence of chronic kidney disease, acute kidney injury, and fluid and electrolyte imbalance in patients admitted for PAH is unclear, it is likely that patients who are being admitted for PAH in the current era are sicker with right heart failure and cardiogenic shock. Consistent with this occurrence, there is also a striking increase in the prevalence of acute respiratory failure in patients admitted for PAH. Less sick patients, in the current era, are probably being managed as outpatients because of the availability of nonparenteral therapies.

Although the overall survival in patients with PAH has improved significantly in the last decade, we found that in-hospital mortality remained unchanged between 2001 and 2012. In addition, we found that the length of hospitalization has increased significantly, albeit less than 1 day on average. Pulmonary arterial hypertension is a rare disease, and treatment of patients critically ill with PAH symptoms, especially acute right heart failure, is mainly based on consensus rather than evidence-based recommendations. The persistence of high mortality rates in the modern era illustrates the need to better understand and improve management of acute right heart failure and other critical illnesses in patients with PAH. In-hospital mortality rates for PAH-related hospitalizations in our study are slightly higher than the reported in-hospital mortality for first-time hospitalization in the Registry to Evaluate Early and Long-term PAH Disease Management registry patients (6.3% vs 5.4%).¹² This finding is probably attributable to the lack of differentiation between first hospitalizations and readmissions in the NIS database. Patients admitted with cardiogenic shock and acute respiratory failure had very high in-patient mortality as expected. We found that the presence of diabetes or anemia was associated with lower in-hospital mortality. The reason for this unexpected association is unclear. Although diabetes and anemia are associated with overall poor long-term survival in patients with PAH,^27,28 no prior studies have evaluated their effect on in-patient, short-term mortality. In our analysis, older age was independently associated with shorter length of hospitalization. For every 10-year increase in age, the length of hospitalization decreased by 0.8 days. The exact reason for shorter length of hospitalization in older patients with PAH is unclear.

Our study has several important limitations. This study is a retrospective analysis of the US claims database using the ICD-9-CM code 416.0 (primary pulmonary hypertension). Although this code is intended to be specific, it is possible that patients with other WHO categories of pulmonary hypertension were classified under this ICD-9-CM code. The standards used to diagnose patients with PAH are not identified in this database. The NIS database does not capture laboratory, echocardiographic, and hemodynamic data to independently confirm the diagnosis. Next, follow-up data are not available, which prevents understanding of the overall disease course and mortality attributable to PAH. Moreover, the NIS database does not differentiate between first-time hospitalization and subsequent hospitalization; thus, we could not identify multiple hospitalizations for the same patient. In addition, the drug therapy received by the patients during the particular hospitalization and as an outpatient is not available in the NIS database. It is possible that patients admitted with PAH, who then die with a different discharge diagnosis, are not captured in this database. However, given our large sample size, this scenario is not likely to affect our results significantly. Finally, cause of death is not available in the NIS database, limiting us from ascertaining whether the in-hospital mortality is related to PAH or not. Nonetheless, unlike registries, which are associated with significant referral bias, the NIS database allows a larger, diverse sampling of the real-world experience. The NIS database is the largest inpatient national database, with data from 46 states in the United States, making it an ideal tool for real-world analysis of trends and outcomes of hospitalizations of a rare disease, such as PAH.

We found a significant decrease in PAH-related hospitalizations in the United States, but the cost has increased substantially and is increasingly being borne by Medicare. There is a significant temporal increase in the associated comorbid conditions in patients admitted with PAH. In-hospital mortality remains unchanged, with a minimal increase in the length of hospitalization despite availability of PAH-specific therapies. Admission to a teaching hospital, cardiac dysrhythmia, acute kidney injury, acute cerebrovascular accident, and acute respiratory failure were associated with increased length of hospitalization and in-hospital mortality. Congestive heart failure, cardiogenic shock, and fluid and electrolyte imbalance were associated with increased in-hospital mortality but not length of hospitalization. Taken together, these data highlight the increasing clinical and economic burden of PAH-related hospitalizations and should help identify patients with PAH who are at increased risk of prolonged hospitalization and in-hospital mortality.

Corresponding Author: Thenappan Thenappan, MD, Division of Cardiovascular Medicine, Department of Medicine, University of Minnesota School of Medicine, 420 Delaware St SE, Mayo Mail Code 508, Minneapolis, MN 55455 (tthenapp@umn.edu).

Accepted for Publication: August 1, 2016.

Published Online: November 16, 2016. doi:10.1001/jamacardio.2016.3591

Author Contributions: Dr Anand and Mr Roy had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Anand, Thenappan.

Acquisition, analysis, or interpretation of data: Anand, Roy, Garg, Duval, Thenappan.

Drafting of the manuscript: Anand, Roy, Garg, Thenappan.

Critical revision of the manuscript for important intellectual content: Anand, Roy, Archer, Weir, Duval.

Statistical analysis: Anand, Roy, Garg, Duval.

Administrative, technical, or material support: Anand, Thenappan.

Study supervision: Thenappan.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by scientist development grant 15SDG25560048 from the American Heart Association and a High Risk and High Reward grant from the Lillehei Heart Institute (Dr Thenappan) and by a grant from the Canadian Institutes of Health Research Foundation, grants NIH-RO1-HL071115 and 1RC1HL099462 from the National Institutes of Health, Tier 1 Canada Research Chair in Mitochondrial Dynamics funding, and the William J. Henderson Foundation (Dr Archer).

Role of the Funder/Sponsor: The funding sources 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.