Causes and Circumstances of Death in Portopulmonary Hypertension.

The causes and circumstances surrounding death are poorly studied in patients with portopulmonary hypertension (PoPH). We sought to determine the specific reasons for dying and characteristics surrounding this process in patients with PoPH. METHODS: All deaths of patients with PoPH followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the pulmonary hypertension team between 1996 and 2020. RESULTS: A total of 69 patients with PoPH (age 56.0 ± 8.9 y), with 49% females, were included. Causes of death were available in 52 (75%) patients, of these PoPH either directly or indirectly contributed to death in 13 of 52 (25%) of patients, meanwhile 39 of 52 (75%) of the patients died because of progressive liver disease and its related complications. Decompensated liver disease was the leading cause of death in this cohort 20 of 52 (38%), whereas 19 of 52 (37%) died because of conditions associated with liver disease. About half, 36 of 69 (52%) of patients died in a healthcare environment and 23 of 36 (64%) during a hospitalization at Cleveland Clinic. A total of 59 of 69 (74%) of patients received pulmonary arterial hypertension (PAH)-specific therapies. Six patients died after liver transplantation (in 3 death was related to PAH-related complications). Most of the patients in this cohort of PoPH patients were considered unsuitable for liver transplantation for a variety of reasons. Advanced healthcare directives were available in only 28% of patients. CONCLUSIONS: Most patients with PoPH died because of complications of their liver disease. PAH directly or indirectly contributed to death in a third of them. A quarter of them did not receive PAH-specific therapy before their death.

Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension.

Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology.

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.

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

BACKGROUND: 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. HYPOTHESIS: The study of LV diastolic function by echocardiography has limitations in patients with HFpEF and PH, and certain LV diastolic determinations convey a worse prognosis. METHODS: We included patients with postcapillary PH and diagnosis of PH-HFpEF. Investigators reviewed Doppler echocardiograms completed within 3 months of the diagnostic right heart catheterization. RESULTS: We included 149 patients with a mean ± standard deviation age of 63 ± 14 years; 58% were women. LV diastolic function profile was determined as normal (41%), grade I (34%), and grade II and grade III (25%). Pulmonary artery pressure and pulmonary vascular resistance were higher and cardiac output lower in patients with LV diastolic dysfunction profile; however, pulmonary artery wedge pressure was not significantly different among grades of LV diastolic function. Although there was an association between the presence of LV diastolic dysfunction profile and long-term survival (P = 0.03), it disappeared when adjusting for age and gender. Right ventricular (RV) dysfunction, paradoxical septal motion, and higher RV systolic pressure remained the only variables significantly associated with poor survival. CONCLUSIONS: The profile of LV diastolic dysfunction by conventional echocardiography is highly variable in patients with PH-HFpEF and has no significant impact on long-term survival. A more severe RV function and higher right ventricle systolic pressure were associated with worse survival.

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.

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.

BACKGROUND: 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. METHODS: We estimated hemodynamic parameters during the 6MWT using a portable, signal-morphology-based, impedance cardiograph (PhysioFlow Enduro) with real-time wireless monitoring via a bluetooth USB adapter. RESULTS: We recruited 48 subjects in the study (30 with PH and 18 healthy controls). PH patients had significantly lower maximum stroke volume (SV) and CI and slower cardiac output (CO) acceleration and decelerations slopes during the test when compared with healthy controls. In PH patients, CI change was associated with total distance walked (R = 0.62; P < 0.001) and percentage of predicted (R = 0.4, P = 0.03), HR recovery at 1 minute (0.57, P < 0.001), 2 minutes (0.65, P < 0.001), and 3 minutes (0.66, P < 0.001). Interestingly, in PH patients CO change during the test was predominantly related to an increase in SV instead of HR. CONCLUSIONS: Estimation of hemodynamic parameters such as cardiac index during 6-minute walk test is feasible and may provide useful information in patients with PH. Clin Trans Sci 2013; Volume #: 1-7.

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.

CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival.

CXC-chemokine ligand 10 (CXCL10) inhibits angiogenesis and attracts activated T lymphocytes. Abnormal angiogenesis and lymphocytic infiltration participate in the pathobiology of pulmonary arterial hypertension (PAH). We hypothesized that serum CXCL10 is elevated in idiopathic PAH and that it is associated with clinical outcomes. This was a cohort study that included 40 idiopathic PAH patients (age = 44 +/- 14 years, 37 females) and 22 healthy controls (age = 35 +/- 6 years, 18 females). It took place at the Pulmonary Vascular Program at the Cleveland Clinic. Serum CXCL10 levels were measured by an enzyme-linked immunosorbent assay. A cutoff value of CXCL10 for best distinguishing alive and dead patients was obtained from a receiver operating characteristic curve (ROC). Survival and time to clinical worsening curves according to the appropriate CXCL10 level were derived by the Kaplan-Meier method and compared by means of the log-rank test. The prognostic value of CXCL10 and of other variables of interest was tested by Cox proportional hazards regression analysis. Serum CXCL10 levels were elevated in PAH subjects compared to controls [CXCL10 pg/ml (mean +/- SEM) for PAH: 306 +/- 73, and for controls: 92 +/- 10; p < 0.0001]. CXCL10 levels higher than 111 pg/ml discriminated survivors from nonsurvivors with a sensitivity of 81% and a specificity of 75% (area under the ROC curve = 0.74). After a mean follow-up of 23.5 +/- 13.5 months since the day of venous sampling, higher CXCL10 levels were associated with improved survival (hazard ratio for mortality = 0.10, 95% confidence interval = 0.01-0.97; p = 0.01). Serum CXCL10 is elevated in PAH and this is associated with improved survival.