Nadine Al-Naamani

Determinants of Right Ventricular Ejection Fraction in Pulmonary Arterial Hypertension

BACKGROUND Right ventricular function is a key determinant of exercise capacity and survival in pulmonary arterial hypertension (PAH). We aimed to study the predictors of right ventricular ejection fraction (RVEF) in patients with newly diagnosed PAH. METHODS We performed a cross-sectional analysis of a retrospective cohort of consecutive patients with idiopathic, familial, or anorexigen-associated PAH who underwent equilibrium radionuclide angiography for measurement of RVEF at baseline. RESULTS Of the 84 patients in the cohort, 63 underwent equilibrium radionuclide angiography and right heart catheterization and were included. The mean age was 41 +/- 13 years, and 79% of the patients were female. The mean RVEF was 30 +/- 8%. RVEF was directly associated with right ventricular stroke volume index and cardiac index, and inversely associated with pulmonary vascular resistance index from right heart catheterization (all p < 0.001). Older age and male sex were associated with lower RVEF (p < 0.05) after adjustment for pulmonary vascular resistance index and left ventricular ejection fraction. Higher plasma von Willebrand factor levels were also independently associated with lower RVEF (p = 0.01) (n = 55). Body size and type of PAH were not associated with RVEF. CONCLUSIONS Older patients and males with PAH had lower RVEF at baseline than younger patients and females, even after controlling for left ventricular function and hemodynamics. Higher plasma von Willebrand factor levels, a marker of endothelial dysfunction, were also associated with lower RVEF.

Risk Factors and Impact of Chronic Obstructive Pulmonary Disease in Candidates for Liver Transplantation

Chronic obstructive pulmonary disease (COPD) may cause significant symptoms and have an impact on survival. Smoking is an important risk factor for COPD and is common in candidates for liver transplantation; however, the risk factors for and outcomes of COPD in this population are unknown. We performed a prospective cohort study of 373 patients being evaluated for liver transplantation at 7 academic centers in the United States. COPD was characterized by expiratory airflow obstruction and defined as follows: prebronchodilator forced expiratory volume in 1 second/forced vital capacity < 0.70. Patients completed the Liver Disease Quality of Life Questionnaire 1.0, which included the Short Form‐36. The mean age of the study sample was 53 ± 9 years, and 234 (63%) were male. Sixty‐seven patients (18%, 95% confidence interval 14%‐22%) had COPD, and 224 (60%) had a history of smoking. Eighty percent of patients with airflow obstruction did not previously carry a diagnosis of COPD, and 27% were still actively smoking. Older age and any smoking (odds ratio = 3.74, 95% confidence interval 1.94‐7.23, P < 0.001) were independent risk factors for COPD. Patients with COPD had worse New York Heart Association functional class and lower physical component summary scores on the 36‐Item Short Form but had short‐term survival similar to that of patients without COPD. In conclusion, COPD is common and often undiagnosed in candidates for liver transplantation. Older age and smoking are significant risk factors of COPD, which has adverse consequences on functional status and quality of life in these patients. Liver Transpl 14:1357–1365, 2008.

Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension

RATIONALE Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary vasculature that is characterized by endothelial dysfunction, inflammation, and right ventricular dysfunction. OBJECTIVES The main objective was to determine whether endothelial, inflammatory, and cardiac biomarkers would be associated with the World Health Organization functional assessment and survival in patients with PAH. METHODS We performed a retrospective cohort study of patients with PAH enrolled in the Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension (ASA-STAT). Biomarkers (N-terminal fragment of pro-BNP [NT-pro-BNP], von Willebrand factor [vWF], soluble P selectin, C-reactive protein, total and high-density lipoprotein cholesterol, triglycerides, tumor necrosis factor, IL-6, β-thromboglobulin, and thromboxane B2) were measured at baseline. Patients from the study were followed until lung transplantation, death, or August 1, 2013. Ordinal logistic regression and Cox regression analyses were performed. MEASUREMENTS AND MAIN RESULTS Sixty-five patients with PAH were enrolled. The mean age was 51 years, and 86% were women. Higher vWF activity, lower high-density lipoprotein cholesterol, and higher thromboxane B2 levels were associated with worse World Health Organization functional class after adjustment for age, sex, and etiology of PAH. Higher NT-pro-BNP levels, lower vWF activity, and lower total cholesterol were associated with an increased risk of death or lung transplant after adjustment for age, sex, etiology of PAH, and 6-minute-walk distance. CONCLUSIONS In patients with PAH, lower vWF activity and cholesterol levels and higher NT-pro-BNP levels at baseline were associated with an increased risk of death or transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).

The Modification of Diet in Renal Disease (MDRD) and the Prediction of Kidney Outcomes After Lung Transplantation

BACKGROUND Chronic kidney disease (CKD) is prevalent after lung transplantation. This study evaluated the ability of the 24-hour urine creatinine clearance (CrCl) and the Modification of Diet in Renal Disease (MDRD) equation at the time of listing to predict CKD after lung transplantation and to determine risk factors for CKD. METHODS This was a retrospective cohort study of 122 patients who underwent lung transplantation at Columbia Presbyterian Medical Center between May 2002 and August 2006. The primary end point was CKD Stage 3 or higher, defined as glomerular filtration rate (GFR) </= 59 ml/min/1.73 m(2) or renal replacement therapy, for at least 3 months. RESULTS Patients were a mean age of 51 +/- 14 years, 55% women, and 83% non-Hispanic white. CKD developed in 62% by 1 year after lung transplantation. Older age, female gender, a diagnosis of sarcoidosis, and diabetes mellitus independently increased the risk of CKD (all p < 0.05). The MDRD equation was significantly better than CrCl at predicting CKD Stage 3 or higher at 1 year after transplantation, with an area under the receiver operating characteristic curve of 0.71 for MDRD (95% confidence interval [CI], 0.61-0.81) and 0.51 for CrCl (95% CI, 0.40-0.61) (P < 0.001). CONCLUSIONS Older age, female gender, and diabetes mellitus increased the risk of developing CKD after lung transplant. The MDRD estimate of GFR at listing was a better predictor of CKD than CrCl. MDRD estimates should be used during lung transplant evaluation for risk stratification for CKD.

Rationale and design of a Phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. Aspirin and simvastatin are highly effective and safe therapies for other cardiovascular diseases characterized by platelet activation and endothelial dysfunction, but have not been formally studied in PAH. METHODS ASA-STAT is a phase II, randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH. A total of 92 subjects were to be randomized to aspirin or aspirin placebo and simvastatin or simvastatin placebo. The primary outcome is the distance walked in 6 min at 6 months after randomization. Secondary measures include brachial artery flow-mediated dilation, circulating biomarkers of platelet and endothelial function, functional class, quality-of-life, and time to clinical end points. The incidence of adverse events will be compared between treatment groups. SCREENING AND ENROLLMENT: We screened a total of 712 individuals with PAH. Sixty-five subjects were enrolled when the trial was terminated for futility in reaching the primary end point for simvastatin. CONCLUSIONS This study aims to determine whether aspirin or simvastatin have beneficial biologic or clinical effects in patients with PAH. The safety and side effects of these commonly prescribed cardiovascular drugs will also be assessed.

Assessment of Kidney Function in Lung Transplant Candidates

BACKGROUND Glomerular filtration rate (GFR) is the best measure of kidney function; however, 24-hour creatinine clearance (CrCl) is the initial screening test used for lung transplant candidates at most centers. Although creatinine-based formulas that estimate GFR have been derived, none have been validated in patients with severe lung disease. METHODS We performed a retrospective cohort study of patients evaluated for lung transplantation at Columbia Presbyterian Medical Center and compared the GFR estimated from the Modification of Diet in Renal Disease (MDRD) and other formulas to the CrCl. We then validated these results in a cohort of patients evaluated at the Hospital of the University of Pennsylvania. RESULTS There were strong and statistically significant direct correlations between estimated GFR and CrCl. An estimated GFR of <95 ml/min by the MDRD was very sensitive at detecting kidney dysfunction by CrCl in the derivation cohort. In the validation cohort, the negative predictive value of this cut-off was 97%. CONCLUSIONS Established formulas for estimating GFR are highly discriminating for kidney dysfunction in patients being evaluated for lung transplantation and may actually have greater validity than CrCl in some instances.

Plasma 12- and 15-Hydroxyeicosanoids are Predictors of Survival in Pulmonary Arterial Hypertension

This study aimed to characterize alterations in select eicosanoids in experimental and human pulmonary arterial hypertension (PAH) and to assess their potential utility as predictors of outcome. Using liquid chromatography–mass spectrometry, we performed targeted lipidomic analyses of the lungs and right ventricles (RVs) of chronically hypoxic rats and plasma of consecutive PAH patients and healthy controls. In rat lungs, chronic hypoxia was associated with significantly decreased lung prostacyclin (PGI2)/thromboxane B2 (TXB2) ratio and elevated lung 8-hydroxyeicosanoid (HETE) acid concentrations. RV eicosanoids did not exhibit any changes with chronic hypoxia. PAH treatment–naïve patients had significantly increased plasma concentrations of TXB2 and 5-, 8-, 12-, and 15-HETE. The PGI2/TXB2 ratio was lower in PAH patients than in controls, especially in the treatmentnaïve cohort (median: 2.1, 0.3, and 1.3 in controls, treatmentnaïve, and treated patients, respectively, P = 0.001). Survival was significantly worse in PAH patients with 12-HETEhigh (≥57 pg/mL) and 15-HETEhigh (≥256 pg/mL) in unadjusted and adjusted analyses (hazard ratio [HR]: 2.8 [95% confidence interval (CI): 1.1–7.3], P = 0.04 and HR: 4.3 [95% CI: 1.6–11.8], P = 0.004, respectively; adjustment was performed with the REVEAL [Registry to Evaluate Early and Long-Term PAH Disease Management] risk score). We demonstrate significant alterations in eicosanoid pathways in experimental and human PAH. We found that 12- and 15-HETE were independent predictors of survival in human PAH, even after adjusting for the REVEAL score, suggesting their potential role as novel biomarkers.

Imatinib as Rescue Therapy in a Patient With Pulmonary Hypertension Associated With Gaucher Disease

Pulmonary hypertension (PH) is a known complication of Gaucher disease (GD) and splenectomy. Although it resembles World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH), PH due to GD or splenectomy is part of WHO group 5. There are no clinical trials testing therapies in PH due to GD or splenectomy. Several reports suggest that PAH-specific therapies are beneficial in patients with PH due to GD, although data are insufficient to formulate a treatment algorithm for these patients. The tyrosine kinase inhibitor imatinib has been investigated in the treatment of severe PAH, but not in PH WHO group 5. We report a patient with GD and splenectomy who developed PH that progressed while on conventional PAH-specific therapy and improved once imatinib was added to her treatment regimen. This is the first report, to our knowledge, describing significant subjective and objective improvements in response to imatinib in a patient with WHO group 5 PH.

The prognostic significance of pulmonary arterial capacitance in pulmonary arterial hypertension: single-center experience

This study explores the prognostic utility of pulmonary arterial capacitance (PAC) in a diverse cohort of patients with pulmonary arterial hypertension (PAH) from a tertiary referral center and compares it with the prognostic utility of other hemodynamic parameters. PAC is a strong independent predictor of mortality in patients with PAH.

Racial and ethnic differences in pulmonary arterial hypertension

This study explores the racial and ethnic differences in presentation, severity, and treatment of patients with pulmonary arterial hypertension (PAH) in a large multicenter registry. African American and Hispanic patients are more likely to present with associated PAH compared to non-Hispanic whites. Hispanic patients with PAH were less likely to be treated with PAH-specific medications compared to non-Hispanic whites.