Pulmonary vascular disease in Veterans with post-deployment respiratory syndrome.

Exertional dyspnea has been documented in US military personnel after deployment to Iraq and Afghanistan. We studied whether continued exertional dyspnea in this patient population is associated with pulmonary vascular disease (PVD). We performed detailed histomorphometry of pulmonary vasculature in 52 Veterans with biopsy-proven post-deployment respiratory syndrome (PDRS) and then recruited five of these same Veterans with continued exertional dyspnea to undergo a follow-up clinical evaluation, including symptom questionnaire, pulmonary function testing, surface echocardiography, and right heart catheterization (RHC). Morphometric evaluation of pulmonary arteries showed significantly increased intima and media thicknesses, along with collagen deposition (fibrosis), in Veterans with PDRS compared to non-diseased (ND) controls. In addition, pulmonary veins in PDRS showed increased intima and adventitia thicknesses with prominent collagen deposition compared to controls. Of the five Veterans involved in our clinical follow-up study, three had borderline or overt right ventricle (RV) enlargement by echocardiography and evidence of pulmonary hypertension (PH) on RHC. Together, our studies suggest that PVD with predominant venular fibrosis is common in PDRS and development of PH may explain exertional dyspnea and exercise limitation in some Veterans with PDRS.

A medical odyssey of a 72-year-old man with Charcot-Marie-Tooth disease type 2 newly diagnosed with biallelic variants in SORD gene causing sorbitol dehydrogenase deficiency.

A 72-year-old man was referred to the Undiagnosed Diseases Network (UDN) because of gradual progressive weakness in both lower extremities for the past 45 years. He was initially diagnosed as having Charcot-Marie-Tooth disease type 2 (CMT2) without a defined molecular genetic cause. Exome sequencing (ES) failed to detect deleterious neuromuscular variants. Very recently, biallelic variants in sorbitol dehydrogenase (SORD) were discovered to be a novel cause of inherited neuropathies including CMT2 or distal hereditary motor neuropathy (dHMN) referred to as Sorbitol Dehydrogenase Deficiency with Peripheral Neuropathy (SORDD, OMIM 618912). The most common variant identified was c.757delG; p.A253Qfs*27. Through the Vanderbilt UDN clinical site, this patient was formally diagnosed with SORDD after the identification of homozygosity for the above SORD frameshift through UDN Genome Sequencing (GS). His medical odyssey was solved by GS and detection of extremely high levels of sorbitol. The diagnosis provided him the opportunity to receive potential treatment with an investigational drug in a clinical trial for SORDD. We suggest that similar studies be considered in other individuals thought to possibly have CMT2 or dHMN.

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male.

We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient's ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient's nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.

Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease.

BACKGROUND: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. OBJECTIVES: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. METHODS: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. RESULTS: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. CONCLUSIONS: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification. (Pulmonary Vascular Disease Phenomics Program PVDOMICS [PVDOMICS]; NCT02980887).

Personalized structural biology reveals the molecular mechanisms underlying heterogeneous epileptic phenotypes caused by de novo KCNC2 variants.

Whole-exome sequencing (WES) in the clinic has identified several rare monogenic developmental and epileptic encephalopathies (DEE) caused by ion channel variants. However, WES often fails to provide actionable insight for rare diseases, such as DEEs, due to the challenges of interpreting variants of unknown significance (VUS). Here, we describe a "personalized structural biology" (PSB) approach that leverages recent innovations in the analysis of protein 3D structures to address this challenge. We illustrate this approach in an Undiagnosed Diseases Network (UDN) individual with DEE symptoms and a de novo VUS in KCNC2 (p.V469L), the Kv3.2 voltage-gated potassium channel. A nearby KCNC2 variant (p.V471L) was recently suggested to cause DEE-like phenotypes. Computational structural modeling suggests that both affect protein function. However, despite their proximity, the p.V469L variant is likely to sterically block the channel pore, while the p.V471L variant is likely to stabilize the open state. Biochemical and electrophysiological analyses demonstrate heterogeneous loss-of-function and gain-of-function effects, as well as differential response to 4-aminopyridine treatment. Molecular dynamics simulations illustrate that the pore of the p.V469L variant is more constricted, increasing the energetic barrier for K+ permeation, whereas the p.V471L variant stabilizes the open conformation. Our results implicate variants in KCNC2 as causative for DEE and guide the interpretation of a UDN individual. They further delineate the molecular basis for the heterogeneous clinical phenotypes resulting from two proximal pathogenic variants. This demonstrates how the PSB approach can provide an analytical framework for individualized hypothesis-driven interpretation of protein-coding VUS.

Characterization of Immunopathology and Small Airway Remodeling in Constrictive Bronchiolitis.

Rationale: Constrictive bronchiolitis (ConB) is a relatively rare and understudied form of lung disease whose underlying immunopathology remains incompletely defined. Objectives: Our objectives were to quantify specific pathological features that differentiate ConB from other diseases that affect the small airways and to investigate the underlying immune and inflammatory phenotype present in ConB. Methods: We performed a comparative histomorphometric analysis of small airways in lung biopsy samples collected from 50 soldiers with postdeployment ConB, 8 patients with sporadic ConB, 55 patients with chronic obstructive pulmonary disease, and 25 nondiseased control subjects. We measured immune and inflammatory gene expression in lung tissue using the NanoString nCounter Immunology Panel from six control subjects, six soldiers with ConB, and six patients with sporadic ConB. Measurements and Main Results: Compared with control subjects, we found shared pathological changes in small airways from soldiers with postdeployment ConB and patients with sporadic ConB, including increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and lymphocyte infiltration. Using principal-component analysis, we showed that ConB pathology was clearly separable both from control lungs and from small airway disease associated with chronic obstructive pulmonary disease. NanoString gene expression analysis from lung tissue revealed T-cell activation in both groups of patients with ConB with upregulation of proinflammatory pathways, including cytokine-cytokine receptor interactions, NF-κB (nuclear factor-κB) signaling, TLR (Toll-like receptor) signaling, T-cell receptor signaling, and antigen processing and presentation. Conclusions: These findings indicate shared immunopathology among different forms of ConB and suggest that an ongoing T-helper cell type 1-type adaptive immune response underlies airway wall remodeling in ConB.

Identifying digenic disease genes via machine learning in the Undiagnosed Diseases Network.

Rare diseases affect millions of people worldwide, and discovering their genetic causes is challenging. More than half of the individuals analyzed by the Undiagnosed Diseases Network (UDN) remain undiagnosed. The central hypothesis of this work is that many of these rare genetic disorders are caused by multiple variants in more than one gene. However, given the large number of variants in each individual genome, experimentally evaluating combinations of variants for potential to cause disease is currently infeasible. To address this challenge, we developed the digenic predictor (DiGePred), a random forest classifier for identifying candidate digenic disease gene pairs by features derived from biological networks, genomics, evolutionary history, and functional annotations. We trained the DiGePred classifier by using DIDA, the largest available database of known digenic-disease-causing gene pairs, and several sets of non-digenic gene pairs, including variant pairs derived from unaffected relatives of UDN individuals. DiGePred achieved high precision and recall in cross-validation and on a held-out test set (PR area under the curve > 77%), and we further demonstrate its utility by using digenic pairs from the recent literature. In contrast to other approaches, DiGePred also appropriately controls the number of false positives when applied in realistic clinical settings. Finally, to enable the rapid screening of variant gene pairs for digenic disease potential, we freely provide the predictions of DiGePred on all human gene pairs. Our work enables the discovery of genetic causes for rare non-monogenic diseases by providing a means to rapidly evaluate variant gene pairs for the potential to cause digenic disease.

Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop.

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.

Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea.

After deployment to Southwest Asia, some soldiers develop persistent respiratory symptoms, including exercise intolerance and exertional dyspnea. We identified 50 soldiers with a history of deployment to Southwest Asia who presented with unexplained dyspnea and underwent an unrevealing clinical evaluation followed by surgical lung biopsy. Lung tissue specimens from 17 age-matched, nonsmoking subjects were used as controls. Quantitative histomorphometry was performed for evaluation of inflammation and pathologic remodeling of small airways, pulmonary vasculature, alveolar tissue and visceral pleura. Compared with control subjects, lung biopsies from affected soldiers revealed a variety of pathologic changes involving their distal lungs, particularly related to bronchovascular bundles. Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content. In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers. Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles. In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects. In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers. Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity. Susceptible soldiers develop a postdeployment respiratory syndrome that includes exertional dyspnea and complex pathologic changes affecting small airways, pulmonary vasculature, alveolar tissue, and visceral pleura.

Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants.

OBJECTIVE: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure. METHODS: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure. RESULTS: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex. CONCLUSIONS: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.

Vascular homeostasis at high-altitude: role of genetic variants and transcription factors.

High-altitude pulmonary edema occurs most frequently in non-acclimatized low landers on exposure to altitude ≥2500 m. High-altitude pulmonary edema is a complex condition that involves perturbation of signaling pathways in vasoconstrictors, vasodilators, anti-diuretics, and vascular growth factors. Genetic variations are instrumental in regulating these pathways and evidence is accumulating for a role of epigenetic modification in hypoxic responses. This review focuses on the crosstalk between high-altitude pulmonary edema-associated genetic variants and transcription factors, comparing high-altitude adapted and high-altitude pulmonary edema-afflicted subjects. This approach might ultimately yield biomarker information both to understand and to design therapies for high-altitude adaptation.

Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL).

CONTEXT: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the ALPL gene or its regulatory regions, individual pathogenic variants are often not tightly correlated with clinical symptomatology. We sought to better understand the genotype/phenotype correlation in HPP by examining the clinical and biochemical data of 37 subjects with 2 rare variants in ALPL. METHODS: Through BioVU, a DNA biobank that pairs individuals' genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects' de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant. RESULTS: Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. CONCLUSIONS: Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention.

Six-minute walk distance in healthy young adults.

BACKGROUND: The 6-min walk test (6MWT) is a commonly used clinical assessment of exercise capacity in patients with cardiopulmonary or neuromuscular disease, but normal values are lacking for young adults, who are frequent subjects of testing. METHODS: In a two-center study, 272 young adults, ages 18-50, underwent American Thoracic Society protocolized 6-min walk testing, and 56 underwent repeat testing. A linear regression model was developed based on anthropomorphic data. This model was compared to existing prediction equations. RESULTS: Median 6MWD for the cohort was 637 m (IQR 584-686 m) and was not significantly impacted by age. This is in contrast to existing equations extrapolated from older subjects that predict increasing 6MWD in younger subjects. We found weak correlation of 6MWD with height, weight, BMI, and resting heart rate. Heart rate at completion correlated most strongly with 6MWD (rho 0.53 p < 0.0001). Repeat 6MWD was surprisingly variable, with a median difference between tests of 32.5 ± 31.9 m. Established reference equations performed poorly in this population, largely because age has much less effect on 6MWD in this group than in older adults. CONCLUSIONS: Established reference equations should be reconfigured to include data from young adults, as age has minimal effect on 6MWD in this population. Heart rate response may be a valuable measure of effort in normal subjects. Six-minute walk distance, as with pulmonary function and exercise testing, should have predictive equations across the spectrum of age to allow for accurate assessment of exercise limitation.

Limitations of exome sequencing in detecting rare and undiagnosed diseases.

While exome sequencing (ES) is commonly the final diagnostic step in clinical genetics, it may miss diagnoses. To clarify the limitations of ES, we investigated the diagnostic yield of genetic tests beyond ES in our Undiagnosed Diseases Network (UDN) participants. We reviewed the yield of additional genetic testing including genome sequencing (GS), copy number variant (CNV), noncoding variant (NCV), repeat expansion (RE), or methylation testing in UDN cases with nondiagnostic ES results. Overall, 36/54 (67%) of total diagnoses were based on clinical findings and coding variants found by ES and 3/54 (6%) were based on clinical findings only. The remaining 15/54 (28%) required testing beyond ES. Of these, 7/15 (47%) had NCV, 6/15 (40%) CNV, and 2/15 (13%) had a RE or a DNA methylation disorder. Thus 18/54 (33%) of diagnoses were not solved exclusively by ES. Several methods were needed to detect and/or confirm the functional effects of the variants missed by ES, and in some cases by GS. These results indicate that tests to detect elusive variants should be considered after nondiagnostic preliminary steps. Further studies are needed to determine the cost-effectiveness of tests beyond ES that provide diagnoses and insights to possible treatment.

Pulmonary Hypertension by the Method of Paul Wood.

A physiological approach to the analysis of hemodynamic data in pulmonary hypertension (PH) has the advantage of reducing the large number (well over 100) of potential causal illnesses into four simple mechanisms. A fifth condition is composed of mixtures of the four basic mechanisms. This approach was beautifully described by Paul Wood, the great cardiologist whose name is given to the units of pulmonary vascular resistance (PVR), Wood units. This approach uses well understood physiological contributions to pulmonary vascular pressure. It is powerful, the major uncertainty being in determination of the magnitude of each mechanism in patients that have mixed PH of several causes. It also makes sense of the occasionally awkward clustering of conditions in the clinical classification of the World Symposium, which omits pulmonary vasoconstriction, hyperkinetic states, and the highly prevalent condition of "mixed" PH. This method of analysis is described and demonstrated, much as Wood did in his writings. The method is useful in the office, the ICU, and in consultation. A basic message from this approach is that correct assessment requires measurement of each of the three major inputs, pulmonary arterial pressure (Ppa), pulmonary artery wedge pressure (Pwedge) and cardiac output (CO). Some cases also need left ventricular end diastolic pressure (LVEDP). Other data contributing to analysis will be discussed in each condition. A key to avoiding mistakes is to always remember that PH is simply an elevation in pressure and is not inherently diagnostic of cause.

Minimum 10-year outcomes of a fixed bearing all-polyethylene unicompartmental knee arthroplasty used to treat medial osteoarthritis.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) accounts for 8.9% of knee arthroplasty procedures in England, Wales and Northern Ireland. Fixed bearing UKA designs have shown favourable survivorship in registries when compared with mobile bearings but some studies suggest poor survival of all-polyethylene fixed tibial bearings. This study analyses long-term follow-up of patients with a medial fixed all-polyethylene tibial bearing UKA and reports survivorship and 10-year clinical outcomes. METHODS: Data was collected prospectively for 214 medial unicompartmental all-polyethylene tibial bearing UKAs implanted in 184 patients at our tertiary referral centre between November 2002 and December 2007. The indication was osteoarthritis in all but one patient. Patient reported outcome scores were documented pre-operatively and at five, eight, 10 and 12 years of follow-up. The mean patient age was 70 years (range 41-87). RESULTS: Outcome and survivorship data were collected for 214 medial all-polyethylene tibial bearing UKAs. There were outcomes recorded for 83 UKAs with at least 10-year follow-up. Twenty-four patients underwent revision of their UKA at an average of 5.84 years after the primary procedure. Kaplan-Meier analysis demonstrated survivorship of 89.1% at 10 years and the OKS, AKSS and WOMAC patient reported outcomes remained significantly improved in comparison to preoperatively. For those 70 years or older, 10-year survivorship was 92.4%, compared to 85.0% for those under 70 years old. CONCLUSION: Medial fixed all-polyethylene tibial bearing UKA demonstrates acceptable long-term survivorship and patient outcomes. It appears to be a suitable option for the treatment of medial compartment OA, particularly in older patients.

BMPR2 dysfunction impairs insulin signaling and glucose homeostasis in cardiomyocytes.

Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating AktSer473 via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.