Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Rationale:: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries. Objective:: We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium. Methods and Results:: RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r ² =0.838 and r ² =0.818, respectively; P <0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10 ^{−7,−6,−5} mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner ( P <0.01). Conclusions:: Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.

Introduction: In medical and surgical intensive care units, clinical risk prediction models for readmission have been developed; however, studies reporting the risks for cardiovascular intensive care unit (CVICU) readmission have been methodologically limited by small numbers of outcomes, unreported measures of calibration or discrimination, or a lack of information spanning the entire perioperative period. The purpose of this study was to derive and validate a clinical prediction model for CVICU readmission in cardiac surgical patients. Methods: A total of 10,799 patients more than or equal to 18 years in the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry who underwent cardiac surgery (coronary artery bypass or valvular surgery) between 2004 and 2012 and were discharged alive from the first CVICU admission were included. The full cohort was used to derive the clinical prediction model and the model was internally validated with bootstrapping. Discrimination and calibration were assessed using the AUC c index and the Hosmer-Lemeshow tests, respectively. Results: A total of 479 (4.4%) patients required CVICU readmission. The mean CVICU length of stay (19.9 versus 3.3 days, P <0.001) and in-hospital mortality (14.4% versus 2.2%, P <0.001) were higher among patients readmitted to the CVICU. In the derivation cohort, a total of three preoperative (age ≥70, ejection fraction, chronic lung disease), two intraoperative (single valve repair or replacement plus non-CABG surgery, multivalve repair or replacement), and seven postoperative variables (cardiac arrest, pneumonia, pleural effusion, deep sternal wound infection, leg graft harvest site infection, gastrointestinal bleed, neurologic complications) were independently associated with CVICU readmission. The clinical prediction model had robust discrimination and calibration in the derivation cohort (AUC c index = 0.799; Hosmer-Lemeshow P = 0.192). The validation point estimates and confidence intervals were similar to derivation model. Conclusions: In a large population-based dataset incorporating a comprehensive set of perioperative variables, we have derived a clinical prediction model with excellent discrimination and calibration. This model identifies opportunities for targeted therapeutic interventions aimed at reducing CVICU readmissions in high-risk patients.

Ex vivo lung perfusion (EVLP) protocols generally limit metabolic supplementation to insulin and glucose. We sought to determine whether the addition of total parenteral nutrition (TPN) would improve lung function in EVLP. Ten porcine lungs were perfused using EVLP for 24 hours and supplemented with insulin and glucose. In the treatment group (n = 5), the perfusate was also supplemented with a continuous infusion of TPN containing lipids, amino acids, essential vitamins, and cofactors. Physiologic parameters and perfusate electrolytes were continuously evaluated. Perfusate lactate, lipid and branch chain amino acid (BCAA) concentrations were also analyzed to elucidate how substrates were being utilized over time. Lungs in the TPN group exhibited significantly better oxygenation. Perfusate sodium was more stable in the TPN group. In the control group, free fatty acids (FFA) were quickly depleted, reaching negligible levels early in the perfusion. Alternatively, BCAA in the control group rose continually over the perfusion demonstrating a shift toward proteolysis for energy substrate. In the TPN group, both FFA and BCAA concentrations remained stable at in vivo levels after initial stabilization. TNF-α concentrations were lower in the TPN group. The addition of TPN in EVLP allows for better electrolyte composition, decreased inflammation, and improved graft performance.