Relationships between nutritional status and markers of congestion in patients with pulmonary arterial hypertension

Cachexia is associated with a high risk of death in heart failure (HF) patients [1Anker S.D. Negassa A. Coats A.J. et al.Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study.Lancet. 2003; 361: 1077-1083Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar, 2Anker S.D. Ponikowski P. Varney S. et al.Wasting as independent risk factor for mortality in chronic heart failure.Lancet. 1997; 349: 1050-1053Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar]. Right ventricular dysfunction (RVD) reportedly often coexists with cachexia and is associated with accelerated weight loss, abnormal body composition, and a worsened prognosis in advanced HF [[3]Melenovsky V. Kotrc M. Borlaug B.A. et al.Relationships between right ventricular function, body composition, and prognosis in advanced heart failure.J. Am. Coll. Cardiol. 2013; 62: 1660-1670Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. Multiple mechanisms are thought to be involved in the development of cardiac cachexia. In particular, this condition is related to hemodynamics of HF including pulmonary hypertension [[4]Ghio S. Gavazzi A. Campana C. et al.Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure.J. Am. Coll. Cardiol. 2001; 37: 183-188Abstract Full Text Full Text PDF PubMed Scopus (1035) Google Scholar] as well as increased neurohumoral and cytokine responses [5Anker S.D. Ponikowski P.P. Clark A.L. et al.Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure.Eur. Heart J. 1999; 20: 683-693Crossref PubMed Scopus (324) Google Scholar, 6Kato T. Niizuma S. Inuzuka Y. et al.Analysis of liver metabolism in a rat model of heart failure.Int. J. Cardiol. 2012; 161: 130-136Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar], impaired gastrointestinal function [[7]Sandek A. Bauditz J. Swidsinski A. et al.Altered intestinal function in patients with chronic heart failure.J. Am. Coll. Cardiol. 2007; 50: 1561-1569Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar], and an increased metabolic rate [[8]Poehlman E.T. Scheffers J. Gottlieb S.S. Fisher M.L. Vaitekevicius P. Increased resting metabolic rate in patients with congestive heart failure.Ann. Intern. Med. 1994; 121: 860-862Crossref PubMed Scopus (182) Google Scholar]. However, only a few studies have investigated pulmonary arterial hypertension (PAH) and nutritional status [[9]Habedank D. Ewert R. Hetzer R. Anker S.D. Reversibility of cachexia after bilateral lung transplantation.Int. J. Cardiol. 2009; 133: 46-50Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. In the present study, we sought to examine the relationships among nutritional status, markers of congestion, and echocardiographic parameters in patients with stable PAH. Findings from the present study would provide insights on the mechanism underlying the effect of PAH alone on nutritional status. We enrolled 8 patients with stable (>6 months) pulmonary hypertension from our out-patient clinic prospectively, and written informed consent was obtained. The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethical committee of Kyoto University Hospital. Patients underwent the scored Patient-Generated Subjective Global Assessment (PG-SGA) for nutritional status, blood tests, and comprehensive echocardiography. After morning fasting, patients underwent blood testing for complete blood counts, chemistry, zinc, pre-albumin, transferrin, retinol-binding proteins, and brain natriuretic peptide (BNP) levels. Glomerular filtration rate (GFR) was estimated with the CKD-EPI Creatinine Equation. Spearman's rank correlation tests were conducted to assess relationships between nonparametric variables, and multiple regression analyses were performed to exclude multicollinearity. Data were analyzed with JMP 12 software (SAS Institute, Inc., Cary, NC). Patient characteristics are summarized in Table 1. The estimated systolic pulmonary artery pressure (ePAP) and BNP levels were 82.7 ± 15.7 (mean ± SD) mm Hg and 176 ± 146 ng/L, respectively. LV diastolic diameter (LVDd) was negatively correlated with ePAP (rs = −0.76, p = 0.04), which implied a dilated RV and compressed LV. Body mass index (BMI) was positively correlated with white blood cell count (WBC, rs = 0.84, p = 0.03) and fasting insulin levels (rs = −0.57, p = 0.03) and negatively correlated with aspartate aminotransferase concentration (AST, rs = −0.47, p = 0.02), serum sodium concentration (rs = −0.60, p = 0.03), and inferior vena cava (IVC) diameter (rs = −0.76, p = 0.04). Blood urea nitrogen, a marker of protein catabolism, was positively correlated with SGA scores (rs = 0.81, p < 0.01) and BNP (rs = 0.68, p = 0.04) and negatively correlated with LV diameter (rs = −0.87, p < 0.01). Serum pre-albumin – a rapid-turnover hepatic protein – was positively correlated with ePAP (rs = 0.70, p = 0.01) and negatively correlated with serum sodium concentrations (rs = −0.56, p = 0.02). Fig. 1 and supplementary Fig. 1 show the correlation map with clustering in which factors cluster more closely together based on how closely they are associated and multiple scattered maps with correlation coefficients, respectively. In multiple regression analyses, BMI was associated by WBC count (p = 0.008), ePAP (P = 0.0008), serum sodium (p = 0.001), and AST concentrations (p = 0.0005), and IVC diameter (p = 0.0042; supplementary Table 1).Table 1Patients characteristics.SexMale 4Mean ± SDMean ± SDFemale 4WBC (/μL)5.6 ± 0.9Blood sugar (mg/dL)96.3 ± 6.3HGB (g/dL)14.9 ± 1.7Na (mEq/L)142.3 ± 2.6Mean ± SDLymph (/mm3)1831 ± 622C-reactive protein (g/dL)0.1 ± 0.1Age62.4 ± 2.4AST (IU/L)26.5 ± 11.7Zinc (μg/dL)72.9 ± 4.7BMI22.1 ± 2.1ALT (IU/L)17.3 ± 8.5Pre-albumin (mg/dL)23.8 ± 5.6Total protein (g/dL)7.1 ± 0.6RBP (mg/dL)3.0 ± 0.8SGA score2.6 ± 2.5Albumin (g/dL)3.8 ± 0.2Transferrin (mg/dL)255.7 ± 28.6Choline esterase (IU/L)281 ± 59HbA1c (NGSP %)5.6 ± 0.3LVDd (mm)40.8 ± 5.1Total bilirubin (mg/dL)1.1 ± 0.6Insulin (μU/mL)24.7 ± 18.4LVDs (mm)22.6 ± 3.1Creatinine (mg/dL)0.8 ± 0.2BNP (pg/mL)176.9 ± 149.4EF (%)75.8 ± 5.2eGFR67.0 ± 7.0TR-PG (mm Hg)72.8 ± 15.8BUN (mg/dL)15.6 ± 4.1Estimated PAP (mm Hg)82.3 ± 15.7Total cholesterol (mg/dL)198 ± 15IVC max (mm)18.6 ± 8.1HDL-chol (mg/dL)58 ± 9LDL-chol (mg/dL)119 ± 16Triglycerides (mg/dL)122 ± 55TG/HDL2.3 ± .3BMI: body mass index; HbA1c: hemoglobin A1c; SGA: subjective global assessment; LVDd/s: left ventricular diastolic/systolic dimension; EF: ejection fraction; TR-PG: pressure gradient of tricuspid regurgitation; PAP: pulmonary artery pressure; IVC: inferior vena cava; WBC: white blood cell; HGB: hemoglobin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; RBP: retinol binding protein; BNP: brain natriuretic peptide; SD, standard deviation; NGSP, National Glycohemoglobin Standardization Program; eGFR, estimate glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; and TG, triglycerides. Open table in a new tab BMI: body mass index; HbA1c: hemoglobin A1c; SGA: subjective global assessment; LVDd/s: left ventricular diastolic/systolic dimension; EF: ejection fraction; TR-PG: pressure gradient of tricuspid regurgitation; PAP: pulmonary artery pressure; IVC: inferior vena cava; WBC: white blood cell; HGB: hemoglobin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; eGFR: estimated glomerular filtration rate; RBP: retinol binding protein; BNP: brain natriuretic peptide; SD, standard deviation; NGSP, National Glycohemoglobin Standardization Program; eGFR, estimate glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; and TG, triglycerides. As previously reported [[8]Poehlman E.T. Scheffers J. Gottlieb S.S. Fisher M.L. Vaitekevicius P. Increased resting metabolic rate in patients with congestive heart failure.Ann. Intern. Med. 1994; 121: 860-862Crossref PubMed Scopus (182) Google Scholar], increased right heart filling pressure and tricuspid regurgitation have been associated with body fat depletion and low BMI in HF patients. RV function and degree of pulmonary hypertension may play a critical role in the nutritional status in patients with PAH by maintaining cardiac output and by possibly causing congestion of splanchnic organs. Liver congestion was estimated from the correlation between pre-albumin and ePAP. In our study, BMI was in association with nutritional factors, liver enzymes, serum sodium, ePAP, and IVC diameter, indicating the presence of a close relationship between pulmonary hypertension with IVC dilatation, poor nutritional status, and low BMI. Valentova et al. reported that cachexia in HF patients is associated with RVD, liver markers, and albumin levels [[10]Valentova M. von Haehling S. Krause C. et al.Cardiac cachexia is associated with right ventricular failure and liver dysfunction.Int. J. Cardiol. 2013; 169: 219-224Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. With regard to PAH, nutritional status may be surrogate markers for PAH. Although cachexia due to pulmonary disease was reversible after lung transplantation [[9]Habedank D. Ewert R. Hetzer R. Anker S.D. Reversibility of cachexia after bilateral lung transplantation.Int. J. Cardiol. 2009; 133: 46-50Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar], it is unclear whether interventions targeting nutritional status would improve PAH or its prognosis. The limitations of the present study are that the sample size was small and all patients were from a single institution. Moreover, we did not monitor the therapeutic effect on liver function sequentially nor did we monitor body weight, and analyses of RVD were not performed in all cases. However, the ejection fraction was maintained, and the decrease in LV diastolic dimension might consequently suggest that the RV compresses the LV. In conclusion, there were strong correlations among markers of nutritional status, markers of congestion, and PAH severity. These results suggest that poor nutritional status may be surrogate markers for PAH severity. Further study is needed that it would be therapeutic targets for PAH. None declared. This work is supported by the grants from Uehara Memorial Foundation (201310180) and the Tazuke Kofukai Medical Research Institute (2014-2BR). Download .docx (1.15 MB) Help with docx files Supplementary material.