American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
Background Hyponatremia is the most common electrolyte abnormality in hospitalized patients and is associated with adverse outcomes, but its prevalence and significance in the general U.S. population is unknown. Our aims were to determine the prevalence of hyponatremia and its association with mortality in the population. Methods We performed a population-based cross-sectional study of 14,697 adults aged ≥ 18 years who participated in the nationally representative National Health and Nutrition Examination Survey for 1999 – 2004. Using measurements of serum sodium corrected for dilutional effect of hyperglycemia, we determined the association of hyponatremia with patient characteristics, comorbidities, and prescription medications, and performed unadjusted and adjusted Cox proportional hazards regression to find the association of hyponatremia with all-cause mortality. Results We provide the first estimate of the prevalence of hyponatremia in the U.S. population, which in our weighted analysis was 1.72%. Prevalence of hyponatremia was significantly higher in females (2.09%, p=0.004) and increased with age. Hyponatremia was more common in subjects with hypertension, diabetes, coronary artery disease, stroke, chronic obstructive pulmonary disease, cancer, and psychiatric disorders, and less common with those with no comorbidities (1.04%, p<0.001). There was a significant risk of death associated with hyponatremia in unadjusted (HR 3.61, p<0.001) and adjusted Cox models controlling for demographics, smoking, comorbidities and insurance status (HR 2.43, p<0.001). There was a U-shaped relationship between serum sodium and hazard ratio for mortality. Conclusions Our findings suggest that hyponatremia is a predictor of mortality in the general population independent of age, gender, and comorbid conditions.
Altered metabolism in pulmonary artery smooth muscle cells (pASMcs) and endothelial cells (pAecs) contributes to the pathology of pulmonary hypertension (pH), but changes in substrate uptake and how substrates are utilized have not been fully characterized. We hypothesized stable isotope metabolomics would identify increased glucose, glutamine and fatty acid uptake and utilization in human pASMcs and pAecs from pH versus control specimens, and that tGf-β treatment would phenocopy these metabolic changes. We used 13 c-labeled glucose, glutamine or a long-chain fatty acid mixture added to cell culture media, and mass spectrometry-based metabolomics to detect and quantify 13 c-labeled metabolites. We found pH pASMcs had increased glucose uptake and utilization by glycolysis and the pentose shunt, but no changes in glutamine or fatty acid uptake or utilization. Diseased pAecs had increased proximate glycolysis pathway intermediates, less pentose shunt flux, increased anaplerosis from glutamine, and decreased fatty acid β-oxidation. tGf-β treatment increased glycolysis in pASMcs, but did not recapitulate the pAec disease phenotype. in tGf-β-treated pASMcs, glucose, glutamine and fatty acids all contributed carbons to the tcA cycle. in conclusion, pASMcs and pAecs collected from pH subjects have significant changes in metabolite uptake and utilization, partially recapitulated by TGF-β treatment. Changes in cellular metabolism are increasingly recognized as a hallmark of pulmonary hypertension (PH) pathobiology 1-4. Shifts in the uptake of metabolic substrates and how they are utilized downstream enables the disease phenotype of vascular cells in PH, including increased proliferation, apoptosis resistance, hypertrophy and vasoconstriction 3. One critical metabolic shift observed in PH is an increase in glycolysis, which is thought to occur in resident vascular wall cells including pulmonary artery smooth muscle cells (PASMCs), endothelial cells (PAECs) and fibroblasts 5-7. Increased glucose uptake can be demonstrated in vivo by increased uptake of the glucose analog 18 F-fluorodeoxyglucose in the lung parenchyma of PH subjects 6,8. The concept that glycolysis in PH is detrimental has led to investigation of the potential utility of dichloroacetate (DCA), which by blocking pyruvate dehydrogenase kinase causes increased glucose flux into the TCA cycle, and less glycolysis 9. Glutamine uptake and metabolism by PAECs has also been shown to contribute to their disease phenotype 10. However, comprehensive assessment of substrate uptake and how the substrates are utilized by pulmonary vascular cells in PH is lacking. A potential driver of altered cellular metabolism is transforming growth factor β (TGF-β) signaling, which underlies many forms of heritable (through mutations in BMPR2 and other members of the TGF-β signaling superfamily) and idiopathic PAH, and PAH etiologies associated with other conditions such as autoimmune
in situ Smad3 expression in the lungs of patients with idiopathic PAH and control subjects, PAs were laser microdissected, followed by qPCR. Smad3 mRNA (trend, statistically not significant) and miR-130a/301b (P , 0.01) expression was higher in the PAs and plexiform lesions of patients with idiopathic PAH compared with control subjects (Figure 1E). Thus, our human data support the notion that boosted signaling of TGF-b1 and its canonical downstream effector Smad3 in human PAs is crucial for PAH development and severity.We designed this focused study to address the controversy regarding TGF-b1-mediated Smad3 signaling in PAH. We show that chronic TGF-b1 signaling in vivo leads to spontaneous PAH in mice; is associated with canonical Smad3 activation (Smad3 phosphorylation) but not Smad3 downregulation; and drives PAH by means of proliferation, inflammation, and metabolism in the lung. Our results are supported by several other important publications (2,(6)(7)(8)10). In contrast to the study by Zabini and colleagues (9), we cannot confirm a loss of Smad3 with chronic TGF-b1 signaling in our PAH rodent models (TG-TGF-b1 mouse and SuHx rat). Zabini and colleagues focused only on total Smad3 expression and did not investigate Smad3 phosphorylation, which is the hallmark of canonical TGF-b1 activation. It is certainly possible that in PAH, downregulation of Smad3 mRNA and/or protein expression occurs in pulmonary arterial endothelial cells or other non-SMCs, such as pericytes and fibroblasts; however, experimental evidence is currently lacking, and resolving this issue would require additional studies.A better understanding of the functional antagonism of TGF-b1 and BMP2 (2) (and other BMPs) and their downstream pathways is crucial for our understanding of PAH. Emerging discoveries in this field will guide the future development of more efficient therapies for PAH, which currently is incurable. Taken together, our results indicate that chronic TGF-b1 signaling in PAH induces sustained canonical Smad3 signaling in PASMCs, and that such signals correlate with the hemodynamic and morphological PAH phenotype in rodents. n Author disclosures are available with the text of this letter at www.atsjournals.org.
Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions. These changes lead to increased right ventricular afterload, which often progresses to maladaptive right ventricular remodelling and eventually death. Pulmonary arterial hypertension represents one of the most severe and best studied types of pulmonary hypertension and is consistently targeted by drug treatments. The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterised by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle. Current treatments for pulmonary arterial hypertension and some other types of pulmonary hypertension target pathways involved in the control of pulmonary vascular tone and proliferation; however, these treatments have limited efficacy on patient outcomes. This review describes key features of pulmonary hypertension, discusses current and emerging therapeutic interventions, and points to future directions for research and patient care. Because most progress in the specialty has been made in pulmonary arterial hypertension, this review focuses on this type of pulmonary hypertension. The review highlights key pathophysiological concepts and emerging therapeutic directions, targeting inflammation, cellular metabolism, genetics and epigenetics, sex hormone signalling, bone morphogenetic protein signalling, and inhibition of tyrosine kinase receptors.
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