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Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. Are risk scores originally developed for PAH predictive in PH groups 1 through 4? We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including the Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, European Society of Cardiology/European Respiratory Society 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata. Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups. ClinicalTrials.gov; No.: NCT05329714; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

The article discusses the concept of disease modification in pulmonary arterial hypertension (PAH) and proposes a framework for its definition and evaluation in clinical trials. It defines disease modification as therapy-induced changes in clinical manifestations, disease trajectory, and outcomes due to an effect on the underlying pathophysiology. It proposes a randomized-withdrawal trial design to evaluate disease-modifying therapies effectively.

Decline in muscle mass, protein synthesis, and mitochondrial function occurs with age, and amino acids are reported to enhance both muscle protein synthesis and mitochondrial function. It is unclear whether increasing dietary protein intake corrects postabsorptive muscle changes in aging. We determined whether a 10-day diet of high [HP; 3.0 g protein x kg fat-free mass [(FFM).sup.-1] x [day.sup.-1]] vs. usual protein intake (UP; 1.5 g protein x kg [FFM.sup.-1] x [day.sup.-1]) favorably affects mitochondrial function, protein metabolism, and nitrogen balance or adversely affects insulin sensitivity and glomerular filtration rate (GFR) in 10 healthy younger (24 [+ or -] 1 yr) and 9 older (70 [+ or -] 2 yr) participants in a randomized crossover study. Net daily nitrogen balance increased equally in young and older participants, but postabsorptive catabolic state also increased, as indicated by higher whole body protein turnover and leucine oxidation with no change in protein synthesis. Maximal muscle mitochondrial ATP production rate was lower in older people, with no change occurring in diet. GFR was lower in older people, and response to HP was significantly different between the two groups, with a significant increase occurring only in younger people, thus widening the differences in GFR between the young and older participants. In conclusion, a short-term high-protein diet increased net daily nitrogen balance but increased the postabsorptive use of protein as a fuel. HP did not enhance protein synthesis or muscle mitochondrial function in either young or older participants. Additionally, widening differences in GFR between young and older patients is a potential cause of concern in using HP diet in older people. dietary protein; protein metabolism; mitochondrial function; kidney function; aging

There are several features of the metabolism of the indispensable BCAAs that set them apart from other indispensable amino acids. BCAA catabolism involves 2 initial enzymatic steps that are common to all 3 BCAAs; therefore, the dietary intake of an individual BCAA impacts on the catabolism of all 3. The first step is reversible transamination followed by irreversible oxidative decarboxylation of the branched-chain [alpha]-keto acid transamination products, the branched chain [alpha]-keto acids (BCKAs). The BCAA catabolic enzymes are distributed widely in body tissues and, with the exception of the nervous system, all reactions occur in the mitochondria of the cell. Transamination provides a mechanism for dispersing BCAA nitrogen according to the tissue's requirements for glutamate and other dispensable amino acids. The intracellular compartmentalization of the branched-chain aminotransferase isozymes (mitochondrial branched-chain aminotransferase, cytosolic branched-chain aminotransferase) impacts on intra- and interorgan exchange of BCAA metabolites, nitrogen cycling, and net nitrogen transfer. BCAAs play an important role in brain neurotransmitter synthesis. Moreover, a dysregulation of the BCAA catabolic pathways that leads to excess BCAAs and their derivatives (e.g., BCKAs) results in neural dysfunction. The relatively low activity of catabolic enzymes in primates relative to the rat may make the human more susceptible to excess BCAA intake. It is hypothesized that the symptoms of excess intake would mimic the neurological symptoms of hereditary diseases of BCAA metabolism. KEY WORDS: * branched-chain aminotransferases * nitrogen cycles * glutamate * alanine * mitochondria

We have examined the localization of the first two enzymes in the branched-chain amino acid (BCAA) catabolic pathway: the branched-chain aminotransferase (BCAT) isozymes (mitochondrial BCATm and cytosolic BCATc) and the branched-chain [alpha]-keto acid dehydrogenase (BCKD) enzyme complex. Antibodies specific for BCATm or BCATc were used to immunolocalize the respective isozymes in cryosections of rat tissues. BCATm was expressed in secretory epithelia throughout the digestive tract, with the most intense expression in the stomach. BCATm was also strongly expressed in secretory cells of the exocrine pancreas, uterus, and testis, as well as in the transporting epithelium of convoluted tubules in kidney. In muscle, BCATm was located in myofibrils. Liver, as predicted, was not immunoreactive for BCATm. Unexpectedly, BCATc was localized in elements of the autonomic innervation of the digestive tract, as well as in axons in the sciatic nerve. The distributions of BCATc and BCATm did not overlap. BCATm-expressing cells also expressed the second enzyme of the BCAA catabolic pathway, BCKD. In selected monkey and human tissues examined by immunoblot and/or immunohistochemistry, BCATm and BCATc were distributed in patterns very similar to those found in the rat. The results show that BCATm is in a position to regulate BCAA availability as protein precursors and anabolic signals in secretory portions of the digestive and other organ systems. The unique expression of BCATc in neurons of the peripheral nervous system, without coexpression of BCKD, raises new questions about the physiological function of this BCAT isozyme. digestive system; human; leucine; monkey; rat

Pulmonary artery smooth muscle cells (PASMCs) and pericytes are NG2+ mural cells that provide structural support to pulmonary arteries and capillaries. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization, but whether similar mechanisms are responsible for their behavior is unknown. RNA-seq was used to compare the gene profile of pericytes and PASMCs from PAH and healthy lungs. NG2-Cre-ER mice were used to generate NG2-selective reporter mice (NG2tdT) for cell lineage identification and tamoxifen-inducible mice for NG2-selective SDF1 knockout (SDF1NG2-KO). Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is highly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that, similar to PAH, tdT1 cells accumulate in muscularized microvessels and demonstrate significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared with control mice, SDF1NG2-KO mice in chronic hypoxia had reduced muscularization and lower abundance of NG2+ cells around microvessels. SDF1 stimulation in healthy pericytes induced greater contractility and impaired their capacity to establish endothelial-pericyte communications. In contrast, SDF1 knockdown reduced PAH pericyte contractility and improved their capacity to associate with vascular tubes in coculture. SDF1 is upregulated in NG2+ mural cells and is associated with PA muscularization. Targeting SDF1 could help prevent and/or reverse muscularization in PAH. [ABSTRACT FROM AUTHOR]