Jennie Newman

Causes and Circumstances of Death in Pulmonary Arterial Hypertension

RATIONALE The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). OBJECTIVES We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. METHODS All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. MEASUREMENTS AND MAIN RESULTS PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. CONCLUSIONS Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

Plasma Levels of High-Density Lipoprotein Cholesterol and Outcomes in Pulmonary Arterial Hypertension

RATIONALE High-density lipoprotein cholesterol (HDL-C) promotes healthy vascular function, and it is decreased in insulin resistance. Insulin resistance predisposes to pulmonary vascular disease. OBJECTIVES We hypothesized that HDL-C is associated with clinical outcomes in pulmonary arterial hypertension (PAH). METHODS Plasma HDL-C concentrations were measured in 69 patients with PAH (age, 46.7 +/- 12.9 yr; female, 90%) and 229 control subjects (age, 57 +/- 13 yr; female, 48%). Clinical outcomes of interest included hospitalization for PAH, lung transplantation, and all-cause mortality. Survival and time to clinical worsening curves were derived by the Kaplan-Meier method. Cox regression modeling of outcome versus HDL-C with individual covariate adjustments was performed. MEASUREMENT AND MAIN RESULTS HDL-C was low in subjects with PAH compared with control subjects (median, interquartile range: PAH: 36, 29-40 mg/dl; control subjects: 49, 40-60 mg/dl; P < 0.001). An HDL-C level of 35 mg/dl discriminated survivors from nonsurvivors, with a sensitivity of 100% and specificity of 60%. After a median follow-up of 592 days, high HDL-C was associated with decreased mortality (hazard ratio for every 5-mg/dl increase in HDL-C, 0.643; 95% confidence interval, 0.504-0.822; P = 0.001) and less clinical worsening (hazard ratio for every 5-mg/dl increase in HDL-C, 0.798; 95% confidence interval, 0.663-0.960; P = 0.02). HDL-C remained a significant predictor of survival after adjusting for cardiovascular risk factors, C-reactive protein, indices of insulin resistance, and severity of PAH (all P < 0.05). CONCLUSIONS Low plasma HDL-C is associated with higher mortality and clinical worsening in PAH. This association does not appear to be explained by underlying cardiovascular risk factors, insulin resistance, or the severity of PAH.

Prognostic Value of Echocardiographic Changes in Patients with Pulmonary Arterial Hypertension Receiving Parenteral Prostacyclin Therapy

BACKGROUND It is unknown whether the echocardiographic changes observed after treatment of patients with pulmonary arterial hypertension have prognostic value. METHODS Subjects with pulmonary arterial hypertension, confirmed by right heart catheterization, who underwent Doppler echocardiography before (baseline) and after 1 year of treatment (follow-up) with parenteral prostacyclin analogues were retrospectively identified. Echocardiographic parameters were measured offline by two investigators. RESULTS A total of 48 patients were included (mean age, 45 ± 14 years; 83% women). Compared with baseline, follow-up echocardiography showed reductions in right atrial area (mean percentage change, 12 ± 25%; P < .001), right ventricular (RV) basal and middle cavity dimensions (mean percentage change, 8.5 ± 14% [P < .001] and 6.8 ± 17% [P = .005], respectively), and peak tricuspid regurgitant velocity (mean percentage change, 10 ± 14%; P < .001). Tricuspid annular plane systolic excursion (mean percentage change, 36 ± 43%; P < .001) and RV outflow tract time-velocity integral (mean percentage change, 48 ± 66%; P < .001) increased. During a median follow-up period of 52.5 months (interquartile range, 20.5-80 months), 18 patients (37.5%) died, mostly (n = 15 [83%]) from progression of pulmonary arterial hypertension. The changes in RV end-diastolic area (hazard ratio [HR per 10% decrease, 0.73; 95% confidence interval [CI], 0.57-0.93), tricuspid valve regurgitation velocity (HR per 10 cm/sec decrease, 0.58; 95% CI, 0.37-0.89), RV outflow tract velocity-time integral (HR per 10% increase, 0.90; 95% CI, 0.83-0.98), and subjective RV function (HR per 1 unit of improvement [e.g., from moderate to mild], 0.55; 95% CI, 0.31-0.96) were associated with overall mortality. CONCLUSIONS Echocardiographic parameters that estimate RV systolic pressure and assess RV morphology and function improve after 1 year of prostacyclin analogue treatment, and the degree of change has prognostic implications.

Breath Analysis in Pulmonary Arterial Hypertension

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive and devastating condition characterized by vascular cell proliferation and is associated with several metabolic derangements. We hypothesized that metabolic derangements in PAH can be detected by measuring metabolic by-products in exhaled breath. METHODS We collected breath and blood samples from patients with PAH at the time of right-sided heart catheterization (n=31) and from healthy control subjects (n=34). Breath was analyzed by selected ion flow tube-mass spectrometry in predetermined training and validation cohorts. RESULTS Patients with PAH were 51.5±14 years old, and 27 were women (85%). Control subjects were 38±13 years old, and 22 were women (65%). Discriminant analysis in the training set identified three ion peaks (H3O+29+, NO+56+, and O2+98+) and the variable age that correctly classified 88.9% of the individuals. In an independent validation cohort, 82.8% of the individuals were classified correctly. The concentrations of the volatile organic compounds 2-propanol, acetaldehyde, ammonia, ethanol, pentane, 1-decene, 1-octene, and 2-nonene were different in patients with PAH compared with control subjects. Exhaled ammonia was higher in patients with PAH (median [interquartile range]: 94.7 parts per billion (ppb) [70-129 ppb] vs 60.9 ppb [46-77 ppb], P<.001) and was associated with right atrial pressure (ρ=0.57, P<.001), mean pulmonary artery pressure (ρ=0.43, P=.015), cardiac index by thermodilution (ρ=-0.39, P=.03), pulmonary vascular resistance (ρ=0.40, P=.04), mixed venous oxygen (ρ=-0.59, P<.001), and right ventricular dilation (ρ=0.42, P=.03). CONCLUSIONS Breathprint is different between patients with PAH and healthy control subjects. Several specific compounds, including ammonia, were elevated in the breath of patients with PAH. Exhaled ammonia levels correlated with severity of disease.

Value of Impedance Cardiography during 6-Minute Walk Test in Pulmonary Hypertension

Methods that predict prognosis and response to therapy in pulmonary hypertension (PH) are lacking. We tested whether the noninvasive estimation of hemodynamic parameters during 6‐minute walk test (6MWT) in PH patients provides information that can improve the value of the test.

Novel methods in pulmonary hypertension phenotyping in the age of precision medicine (2015 Grover Conference series)

Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

Evaluation of left ventricular diastolic function profile in patients with pulmonary hypertension due to heart failure with preserved ejection fraction

Echocardiography plays an important role in the diagnostic work up of heart failure with preserved ejection fraction (HFpEF). We sought to determine the left ventricular (LV) diastolic profile by echocardiography in patients diagnosed with pulmonary hypertension (PH) due to PH‐HFpEF.

Hypoxemia in patients with idiopathic or heritable pulmonary arterial hypertension

Background The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. Objectives We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. Methods Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. Results A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54–3.98)) Conclusions Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival.