Impact of body position on hemodynamic measurements during exercise: A tale of two bikes.

The addition of exercise testing during right heart catheterization (RHC) is often required to accurately diagnose causes of exercise intolerance like early pulmonary vascular disease, occult left heart disease, and preload insufficiency. We tested the influence of body position (supine vs. seated) on hemodynamic classification both at rest and during exercise. We enrolled patients with exercise intolerance due to dyspnea who were referred for exercise RHC at the Cleveland Clinic. Patients were randomized (1:1) to exercise in seated or supine position to a goal of 60 W followed by maximal exercise in the alternate position. We analyzed 17 patients aged 60.3 ± 10.9 years, including 13 females. At rest in the sitting position, patients had significantly lower right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP) and cardiac index (CI). In every stage of exercise (20, 40, and 60 W), the RAP, mPAP, and PAWP were lower in the sitting position. Exercise in the sitting position allowed the identification of preload insufficiency in nine patients. Exercise in either position increased the identification of postcapillary pulmonary hypertension (PH). Body position significantly influences hemodynamics at rest and with exercise; however, mPAP/CO and PAWP/CO were not positionally affected. Hemodynamic measurements in the seated position allowed the detection of preload insufficiency, a condition that was predominantly identified as no PH during supine exercise.

Impact of Esophageal Pressure Measurement on Pulmonary Hypertension Diagnosis in Patients With Obesity.

BACKGROUND: Elevated intrathoracic pressure could affect pulmonary vascular pressure measurements and influence pulmonary hypertension (PH) diagnosis and classification. Esophageal pressure (Pes) measurement adjusts for the increase in intrathoracic pressure, better reflecting the pulmonary hemodynamics in patients with obesity. RESEARCH QUESTION: In individuals with obesity, what is the impact of adjusting pulmonary hemodynamic determinations for Pes on PH diagnosis and classification? Can Pes be estimated by positional or respiratory hemodynamic changes? STUDY DESIGN AND METHODS: In this prospective cohort study, we included patients with obesity who underwent right heart catheterization and demonstrated elevated pulmonary artery wedge pressure (PAWP; ≥ 12 mm Hg). After placement of an esophageal balloon, we performed pressure determination using an air-filled transducer connected to a regular hemodynamic monitor. We measured pulmonary pressures changes when sitting and the variations during the respiratory cycle. RESULTS: We included 53 patients (mean ± SD age, 59 ± 12 years; mean ± SD BMI, 44.4 ± 10.2 kg/m2). Supine end-expiratory pressures revealed a mean pulmonary artery pressure of > 20 mm Hg in all patients and a PAWP of >15 mm Hg in most patients (n = 50). The Pes adjustment led to a significant decrease in percentage of patients with postcapillary PH (from 60% to 8%) and combined precapillary and postcapillary PH (from 34% to 11%), at the expense of an increase in percentage of patients with no PH (0% to 23%), isolated precapillary PH (2% to 25%), and undifferentiated PH (4% to 34%). INTERPRETATION: Adjusting pulmonary hemodynamics for Pes in patients with obesity leads to a pronounced reduction in the number of patients who receive a diagnosis of postcapillary PH. Measuring Pes should be considered in patients with obesity, particularly those with elevated PAWP.

Effect of pulmonary artery catheter balloon inflation on pulmonary hemodynamics.

Background: Right heart catheterization (RHC), including a pulmonary artery wedge pressure (PAWP) determination, is necessary to categorize the hemodynamic type of pulmonary hypertension (PH). The potential hemodynamic implications of a pulmonary artery catheter (PAC) balloon inflation in PH have not been formally tested. Methods: We assessed the hemodynamic impact of the PAC balloon inflation during RHC by measuring systolic, diastolic, and mean pulmonary artery pressure (mPAP) in all patients, and cardiac output (CO) by thermodilution in a subgroup of patients. Hemodynamic measurements were obtained both with PAC balloon deflated and fully inflated (1.5 mL of air), while the PAC was free floating in the pulmonary artery before wedging. We calculated total pulmonary resistance (TPR). Results: We included 210 patients, age 58±14 years, 134 (64%) women. Patients had no PH (n: 12, 6%), PH group 1 (n: 68, 33%), 2 (n: 86, 41%), 3 (n: 11, 5%), 4 (n: 29, 14%), and 5 (n: 3, 1%). The mean ± standard deviation (SD) at end-expiration mPAP (balloon-up minus down) (n: 209) was -0.02±1.59 mmHg (range, -5.0 to 4.0 mmHg; P=0.84), while the TPR (n: 62) was -0.27±1.2 Wood units (WU) (range, -4.8 to 2.2 WU; P=0.08); without significant variation based on the type of PH group or degree of pulmonary vascular resistance (PVR). Interestingly, the change in mPAP at end-expiration with PAC balloon inflation was higher in women (mean ± SD: 0.31±1.43 mmHg) than men (mean ± SD: -0.61±1.70 mmHg) (P<0.001). Conclusions: Balloon inflation of the PAC in the main pulmonary artery had no significant impact on the mPAP or TPR, even when only including patients with group 1 PH or selecting a subgroup with a higher PVR.

Cutaneous iontophoresis of vasoactive medications in patients with scleroderma-associated pulmonary arterial hypertension.

BACKGROUND: It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). METHODS: We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naïve PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). RESULTS: The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naïve + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). CONCLUSIONS: Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

The breath print represents a novel biomarker of malnutrition in pulmonary arterial hypertension: A proof of concept study.

BACKGROUND: The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. METHODS: We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnoses and nutrition status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), control, and control with malnutrition (Control-Mal), based on the malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition. RESULTS: A total of 74 patients met inclusion criteria (PAH: 52; PAH-Mal: 10; control: 10; Control-Mal: 2). Levels of 1-octene (PAH-Mal, 5.1 ± 1.2; PAH, 12.5 ± 11.2; P = 0.005) and ammonia (PAH-Mal, 14.6 ± 15.8; PAH, 56.2 ± 64.2; P = 0.013) were reduced in PAH-Mal compared with PAH. The combination of 1-octene (P = 0.010) and 3-methylhexane (P = 0.045) distinguished malnutrition in PAH (receiver operating characteristic area under the curve: 0.8549). CONCLUSIONS: This proof of concept study provides the first evidence that the breath print is altered in malnutrition. Larger prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting.

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.

Comparison of volatile organic compound profiles in exhaled breath versus plasma headspace in different diseases.

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled breath and plasma samples from patients with pulmonary hypertension inflammatory bowel disease (IBD), and IBD patients after J-pouch surgery (pouch group). Half of the measured VOC's from exhaled breath were significantly associated with the VOC's from plasma headspace. Interestingly, six breath VOC's (trimethyl amine (FDR p = 0.02), hydrogen sulfide (FDR p = 7.64 × 10-30), ethanol (FDR p = 1.56 × 10-4), dimethyl sulfide (FDR p = 5.70 × 10-19), benzene (FDR p = 8.40 × 10-27), and acetaldehyde (FDR p = 4.27 × 10-17)) and two plasma headspace VOC's (1-Octene (FDR p = 0.02) and 2-propanol (FDR p = 2.47 × 10-9)) were able to differentiate between the three groups. Breath and plasma headspace share a similar signature with significant association in half of the measured VOCs. The disease discriminatory capacity of breath and plasma headspace appear to be different. Therefore, using the VOC's print from both breath and plasma headspace may better help diagnose patients.

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.