Pulmonary Vascular Distensibility Research Articles

Chronic e-cigarette use in young adults is associated with reduced cardiopulmonary function at rest and during exercise

E-cigarette aerosols produce contaminant particles that have the potential to impair cardiopulmonary function. However, the current understanding of the impact of e-cigarette use on cardiopulmonary function remains inconclusive. Exercise represents a stress on the cardiopulmonary system and may help identify cardiopulmonary dysfunction in chronic e-cigarette users. Consequently, the purpose of this study was to investigate if e-cigarette users exhibit cardiopulmonary abnormalities under physiological stress of exercise. To further investigate pulmonary vascular responses, the secondary purpose of the study was to examine how diffusing capacity (DLCO), pulmonary capillary blood volume (VC), and membrane diffusing capacity (DM) respond to positional changes, as the transition from the upright to supine position should increase DLCO, VC, and DM, secondarily to increased perfusion pressure. We hypothesized that e-cigarette users would exhibit impaired cardiopulmonary function during exercise and reduced pulmonary vascular responsiveness to postural changes. Six chronic e-cigarette (e-cig) users (age: 24±5yrs, 5±2 years of e-cigarette use) with <5 pack years of traditional cigarette smoking history and six non-smoking controls who were age-, height-, and sex-matched completed two experimental trials. Day 1: Pulmonary function test and cardiopulmonary exercise test. Day 2: multiple fraction of inspired oxygen DLCO technique to quantify DLCO, VC, and DM at rest in the upright and supine positions. Resting pulmonary function was not significantly different between groups. The change in DLCO from upright to supine was significantly lower in e-cig users compared to controls (Control: 7.61±2.32 ml/min/mmHg vs. E-cig: 3.17±2.09 ml/min/mmHg; p=0.01), due to a smaller change in VC ( p=0.03), which suggests reduced pulmonary vascular distention in e-cig users. V̇O2peak was significantly lower in e-cig users compared to controls (Control: 4.4±1.2 L/min vs. E-cig: 2.6 ±0.7 L/min; p=0.01). E-cig users exhibited significantly elevated V̇E/ V̇CO2nadir ( p=0.02) indicating worse ventilatory effciency, and greater dyspnea relative to power output ( p=0.02) compared to controls. Preliminary findings suggest that e-cigarette use is associated with normal resting lung function but reduced pulmonary vascular distensibility. Further, e-cigarette users demonstrate ventilatory ineffciency and greater exertional dyspnea along with exercise intolerance. Canadian Institutes of Health Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

ICPET Calculator: A Web-Based Application to Standardize the Calculation of Alpha Distensibility in Patients With Pulmonary Arterial Hypertension.

Background Pulmonary vascular distensibility associates with right ventricular function and clinical outcomes in patients with unexplained dyspnea and pulmonary hypertension. Alpha distensibility coefficient is determined from a nonlinear fit to multipoint pressure-flow plots. Study aims were to (1) create and test a user-friendly tool to standardize analysis of exercise hemodynamics including distensibility, and (2) investigate changes in distensibility following treatment in patients with pulmonary arterial hypertension. Methods and Results Participants with an exercise right heart catherization were retrospectively identified from the University of Arizona Pulmonary Hypertension (UA PH) registry and split into a pulmonary arterial hypertension group, a comparator group, and a control group. Right ventricular function was quantified using the coupling ratio and diastolic stiffness. Prototypes of the invasive cardiopulmonary exercise testing (iCPET) calculator were developed using Matlab, Python, and RShiny to analyze exercise hemodynamics and alpha distensibility coefficient, α (%/mm Hg) from multipoint pressure flow plots. Interclass correlation coefficients were calculated for interplatform and interobserver variability in alpha. No significant bias in the intraplatform (Matlab versus RShiny; intraclass correlation coefficient: 0.996) or interobserver (intraclass correlation coefficient: 0.982) comparison of alpha values. Afterload significantly decreased (P<0.05) with no change in alpha distensibility in the pulmonary arterial hypertension group at follow-up. The comparator group had no change in pressure, resistance or alpha distensibility. There were no significant changes in RV diastolic stiffness at follow-up. Conclusions The interactive user interface in the iCPET calculator allows exploration of alpha distensibility using standardized methods. No significant change in alpha distensibility at follow-up suggests that alpha may be less modifiable in patients with long-standing pulmonary arterial hypertension.

Pulmonary vascular distensibility with passive leg raise is comparable to exercise and predictive of clinical outcomes in pulmonary hypertension

Pulmonary vascular distensibility (α) is a marker of the ability of the pulmonary vasculature to dilate in response to increases in cardiac output, which protects the right ventricle from excessive increases in afterload. α measured with exercise predicts clinical outcomes in pulmonary hypertension (PH) and heart failure. In this study, we aim to determine if α measured with a passive leg raise (PLR) maneuver is comparable to α with exercise. Invasive cardiopulmonary exercise testing (iCPET) was performed with hemodynamics recorded at three stages: rest, PLR and peak exercise. Four hemodynamic phenotypes were identified (2019 ECS guidelines): pulmonary arterial hypertension (PAH) (n = 10), isolated post‐capillary (Ipc‐PH) (n = 18), combined pre‐/post‐capillary PH (Cpc‐PH) (n = 15), and Control (no significant PH at rest and exercise) (n = 7). Measurements of mean pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output at each stage were used to calculate α. There was no statistical difference between α‐exercise and α‐PLR (0.87 ± 0.68 and 0.78 ± 0.47% per mmHg, respectively). The peak exercise‐ and PLR‐based calculations of α among the four hemodynamic groups were: Ipc‐PH = Ex: 0.94 ± 0.30, PLR: 1.00 ± 0.27% per mmHg; Cpc‐PH = Ex: 0.51 ± 0.15, PLR: 0.47 ± 0.18% per mmHg; PAH = Ex: 0.39 ± 0.23, PLR: 0.34 ± 0.18% per mmHg; and the Control group: Ex: 2.13 ± 0.91, PLR: 1.45 ± 0.49% per mmHg. Patients with α ≥ 0.7% per mmHg had reduced cardiovascular death and hospital admissions at 12‐month follow‐up. In conclusion, α‐PLR is feasible and may be equally predictive of clinical outcomes as α‐exercise in patients who are unable to exercise or in programs lacking iCPET facilities.

Association of obesity-related inflammatory pathways with lung function and exercise capacity

BackgroundObesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear.Research Question:To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance. MethodWe examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006–June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression. ResultsObesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV1 and FVC with a preserved FEV1/FVC ratio suggesting a restrictive physiology pattern (P ≤ 0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV1 and FVC (beta −4.8, s.e. 0.9 for FEV1; beta −4.9, s.e. 0.8 for FVC; P < 0.0001 for both). Obesity-related inflammatory pathways were associated with worse pulmonary vascular distensibility (adiponectin, IL-6, and CRP, P < 0.05 for all), as well as lower pulmonary artery compliance (IL-6 and CRP, P ≤ 0.01 for both). InterpretationOur findings highlight the importance of obesity-related inflammatory pathways including inflammation and insulin resistance on pulmonary spirometry and pulmonary vascular function. Specifically, systemic inflammation as ascertained by CRP, IL-6 and insulin resistance are associated with restrictive pulmonary physiology independent of BMI. In addition, inflammatory markers were associated with lower exercise capacity and pulmonary vascular dysfunction.

Systemic vascular distensibility relates to exercise capacity in connective tissue disease.

Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P=0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.

Exercise stress echocardiography of the pulmonary circulation and right ventricular-arterial coupling in healthy adolescents.

To explore the effects of age and sex in adolescents vs. young or middle-aged adults on pulmonary vascular function and right ventricular-arterial (RV-PA) coupling as assessed by exercise stress echocardiography. Forty healthy adolescents aged 12-15 years were compared with 40 young adults aged 17-22 years and 40 middle-aged adults aged 30-50 years. Sex distribution was equal in the three groups. All the subjects underwent an exercise stress echocardiography. A pulmonary vascular distensibility coefficient α was determined from multipoint pulmonary vascular pressure-flow relationships. RV-PA coupling was assessed by the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio, who has been previously validated by invasive study. While cardiac index and mean PAP were not different, adolescents compared to young and middle-aged adults, respectively had higher pulmonary vascular distensibility coefficients α (1.60 ± 0.31%/mmHg vs. 1.39 ± 0.29%/mmHg vs. 1.20 ± 0.35%/mmHg, P < 0.00001). Adolescents and young adults compared to middle-aged adults, respectively had higher TAPSE/PASP ratios at rest (1.24 ± 0.18 mm/mmHg and 1.22 ± 0.17 mm/mmHg vs. 1.07 ± 0.18 mm/mmHg, P < 0.008) and during exercise (0.86 ± 0.24, 0.80 ± 0.15 and 0.72 ± 0.15 mm/mmHg, P < 0.04). The TAPSE/PASP ratio decreased with exercise. There were no sex differences in α or TAPSE/PASP. Compared to adults, adolescents present with a sex-independent more distensible pulmonary circulation. Resting and exercise RV-PA coupling is decreased in middle-aged adults.

Noninvasive Pulmonary Hemodynamic Evaluation in Athletes With Exercise-Induced Hypoxemia

Pulmonary capillary stress failure is potentially involved in exercise-induced hypoxemia (ie, a significant fall in hemoglobin oxygen saturation [Spo2]) during sea level exercise in endurance-trained athletes. It is unknown whether there are specific properties of pulmonary vascular function in athletes exhibiting oxygen desaturation. Ten endurance-trained athletes with exercise-induced hypoxemia (EIH), nine endurance-trained athletes with no exercise-induced hypoxemia (NEIH), and 10 untrained control subjects underwent an incremental exercise stress echocardiography coupled with lung diffusion capacity for carbon monoxide (Dlco) and lung diffusion capacity for nitric oxide (Dlno) testing. Functional adaptation of the pulmonary circulation was evaluated with measurements of mean pulmonary arterial pressure (mPAP), pulmonary capillary pressure, pulmonary vascular resistance (PVR), cardiac output (Qc), and pulmonary vascular distensibility (alpha) mathematically determined from the curvilinearity of the multi-point mPAP/Qc relation. EIH athletes exhibited a lower exercise-induced PVR decrease compared with the untrained and NEIH groups (P< .001). EIH athletes showed higher maximal mPAP compared with NEIH athletes (45.4 ± 0.9mmHg vs41.6 ± 0.9mmHg, respectively; P= .003); there was no difference between the NEIH and untrained subjects. Alpha was lower in the EIH group compared with the NEIH group (P< .05). Maximal mPAP, Pcap, and alpha were correlated with the fall of Spo2 during exercise (P< .01, P< .01, and P< .05). Dlno and Dlco increased with exercise in all groups, with no differences between groups. Dlno/Qc was correlated to the exercise-induced Spo2 changes (P< .05). EIH athletes exhibit higher maximal pulmonary vascular pressures, lower vascular distensibility, or exercise-induced changes in PVR compared with NEIH subjects, in keeping with pulmonary capillary stress failure or intrapulmonary shunting hypotheses.

Decreased pulmonary vascular distensibility in adolescents conceived by in vitro fertilization.

What is the functional relevance of decreased pulmonary vascular distensibility in adolescents conceived by IVF? Children born by IVF have a slight decrease in pulmonary vascular distensibility observed during normoxic exercise that is not associated with altered right ventricular function and aerobic exercise capacity. General vascular dysfunction and increased hypoxic pulmonary hypertension have been reported in ART children as compared to controls. Pulmonary hypertension or decreased pulmonary vascular distensibility may affect right ventricular function and thereby possibly limit maximal cardiac output and aerobic exercise capacity. This prospective case-control study enrolled 15 apparently healthy adolescents conceived by IVF/ICSI after fresh embryo transfer paired in a 2 to 1 ratio to 30 naturally conceived adolescents between March 2015 and May 2018. Fifteen IVF/ICSI adolescents and 30 controls from singleton gestations matched by age, gender, weight, height and physical activity underwent exercise echocardiography, lung diffusion capacity measurements and a cycloergometer cardiopulmonary exercise test. A pulmonary vascular distensibility coefficient α was determined from the pulmonary arterial pressure (PAP) versus cardiac output (Q) relationships. Pulmonary capillary volume (Vc) was calculated from single breath nitric oxide and carbon monoxide lung diffusion capacity measurements (DLCO and DLNO) at rest and during exercise (100W). Eight of the IVF subjects and eight controls underwent a 30min hypoxic challenge at rest with a fraction of inspired oxygen of 0.12 to assess hypoxic pulmonary vasoconstriction. In normoxia, oxygen uptake (VO2), blood pressure, DLCO, DLNO, echocardiographic indices of right ventricular function, Q and PAP at rest and during exercise were similar in both groups. However, IVF children had a lower pulmonary vascular distensibility coefficient α (1.2 ± 0.3 versus 1.5 ± 0.3%/mmHg, P= 0.02) and a blunted exercise-induced increase in Vc (24 versus 32%, P< 0.05). Hypoxic-induced increase in pulmonary vascular resistance in eight IVF subjects versus eight controls was similar. The IVF cohort was small, and thus type I or II errors could have occurred in spite of careful matching of each case with two controls. ART evolved over the years, so that it is not certain that the presently reported subtle changes will be reproducible in the future. As the study was limited to singletons born after fresh embryo transfers, our observations cannot be extrapolated to singletons born after frozen embryo transfer. The present study suggests that adolescents conceived by IVF have preserved right ventricular function and aerobic exercise capacity despite a slight alteration in pulmonary vascular distensibility as assessed by two entirely different methods, i.e. exercise echocardiography and lung diffusing capacity measurements. However, the long-term prognostic relevance of this slight decrease in pulmonary vascular distensibility needs to be evaluated in prospective large scale and long-term outcome studies. Dr Caravita was supported by an ERS PAH short term research training fellowship (STRTF2014-5264). Dr Pezzuto was funded by an Italian Society of cardiology grant. Dr Motoji was supported by a grant from the Cardiac Surgery Funds, Belgium. All authors have no conflicts of interests to declare.

Pulmonary Vascular Distensibility and Early Pulmonary Vascular Remodeling in Pulmonary Hypertension

Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects. A PV distensibility coefficient α (%/mmHg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption. The α coefficient decreased from 1.35 ± 0.58%/mmHg in control subjects and 1.1 ± 0.48%/mmHg in patients with passive HFpEF to 0.62 ± 0.32%/mmHg in exercise PH, 0.54 ± 0.27%/mmHg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed. PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity.

Supine, prone, right and left gravitational effects on human pulmonary circulation

BackgroundBody position can be optimized for pulmonary ventilation/perfusion matching during surgery and intensive care. However, positional effects upon distribution of pulmonary blood flow and vascular distensibility measured as the pulmonary blood volume variation have not been quantitatively characterized. In order to explore the potential clinical utility of body position as a modulator of pulmonary hemodynamics, we aimed to characterize gravitational effects upon distribution of pulmonary blood flow, pulmonary vascular distension, and pulmonary vascular distensibility.MethodsHealthy subjects (n = 10) underwent phase contrast cardiovascular magnetic resonance (CMR) pulmonary artery and vein flow measurements in the supine, prone, and right/left lateral decubitus positions. For each lung, blood volume variation was calculated by subtracting venous from arterial flow per time frame.ResultsBody position did not change cardiac output (p = 0.84). There was no difference in blood flow between the superior and inferior pulmonary veins in the supine (p = 0.92) or prone body positions (p = 0.43). Compared to supine, pulmonary blood flow increased to the dependent lung in the lateral positions (16–33%, p = 0.002 for both). Venous but not arterial cross-sectional vessel area increased in both lungs when dependent compared to when non-dependent in the lateral positions (22–27%, p ≤ 0.01 for both). In contrast, compared to supine, distensibility increased in the non-dependent lung in the lateral positions (68–113%, p = 0.002 for both).ConclusionsCMR demonstrates that in the lateral position, there is a shift in blood flow distribution, and venous but not arterial blood volume, from the non-dependent to the dependent lung. The non-dependent lung has a sizable pulmonary vascular distensibility reserve, possibly related to left atrial pressure. These results support the physiological basis for positioning patients with unilateral pulmonary pathology with the “good lung down” in the context of intensive care. Future studies are warranted to evaluate the diagnostic potential of these physiological insights into pulmonary hemodynamics, particularly in the context of non-invasively characterizing pulmonary hypertension.

Treatment of exercise pulmonary hypertension improves pulmonary vascular distensibility.

Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation. Despite normal resting pulmonary artery pressures, patients with ePH demonstrate early pulmonary vascular changes with reduced pulmonary arterial compliance (PAC) and vascular distensibility (α). Recent data suggest that targeted vasodilator therapy may improve hemodynamics in ePH, but it is not well-known whether such medications alter pulmonary vascular distensibility. Thus, we sought to evaluate if vasodilator therapy improved α a marker of early pulmonary vascular disease in ePH. Ten patients performed supine exercise right heart catheterization (exRHC) with bicycle ergometer to peak exercise. Patients diagnosed with ePH were treated with pulmonary vasodilators. A repeat symptom-limited exercise RHC was performed at least six months after therapy. Patients with ePH had evidence of early pulmonary vascular disease, as baseline PAC and α were reduced. After pulmonary vasodilator therapy, a number of peak exercise hemodynamics statistically improved, including a decrease of total pulmonary resistance and pulmonary vascular resistance, while cardiac output increased. Importantly, vasodilator therapy partially reversed the pathogenic decreases of α at the time of repeat exRHC. Pulmonary vascular distensibility, α, a marker of early pulmonary vascular disease, improves in ePH after therapy with pulmonary vasodilators.

Pulmonary Vascular Function and Aerobic Exercise Capacity at Moderate Altitude.

There has been suggestion that a greater "pulmonary vascular reserve" defined by a low pulmonary vascular resistance (PVR) and a high lung diffusing capacity (DL) allow for a superior aerobic exercise capacity. How pulmonary vascular reserve might affect exercise capacity at moderate altitude is not known. Thirty-eight healthy subjects underwent an exercise stress echocardiography of the pulmonary circulation, combined with measurements of DL for nitric oxide (NO) and carbon monoxide (CO) and a cardiopulmonary exercise test at sea level and at an altitude of 2250 m. At rest, moderate altitude decreased arterial oxygen content (CaO2) from 19.1 ± 1.6 to 18.4 ± 1.7 mL·dL, P < 0.001, and slightly increased PVR, DLNO, and DLCO. Exercise at moderate altitude was associated with decreases in maximum O2 uptake (V˙O2max), from 51 ± 9 to 43 ± 8 mL·kg⋅min, P < 0.001, and CaO2 to 16.5 ± 1.7 mL·dL, P < 0.001, but no different cardiac output, PVR, and pulmonary vascular distensibility. DLNO was inversely correlated to the ventilatory equivalent of CO2 (V˙E/V˙CO2) at sea level and at moderate altitude. Independent determinants of V˙O2max as determined by a multivariable analysis were the slope of mean pulmonary artery pressure-cardiac output relationship, resting stroke volume, and resting DLNO at sea level as well as at moderate altitude. The magnitude of the decrease in V˙O2max at moderate altitude was independently predicted by more pronounced exercise-induced decrease in CaO2 at moderate altitude. Aerobic exercise capacity is similarly modulated by pulmonary vascular reserve at moderate altitude and at sea level. Decreased aerobic exercise capacity at moderate altitude is mainly explained by exercise-induced decrease in arterial oxygenation.

Effects of body position on exercise capacity and pulmonary vascular pressure-flow relationships.

There has been revival of interest in exercise testing of the pulmonary circulation for the diagnosis of pulmonary vascular disease, but there still is uncertainty about body position and the most relevant measurements. Doppler echocardiography pulmonary hemodynamic measurements were performed at progressively increased workloads in 26 healthy adult volunteers in supine, semirecumbent, and upright positions that were randomly assigned at 24-h intervals. Mean pulmonary artery pressure (mPAP) was estimated from the maximum tricuspid regurgitation jet velocity. Cardiac output was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility α-index, the percent change of vessel diameter per millimeter mercury of mPAP, was calculated from multipoint mPAP-cardiac output plots. Body position did not affect maximum oxygen uptake (Vo2max), maximum respiratory exchange ratio, ventilatory equivalent for carbon dioxide, or slope of mPAP-cardiac output relationships, which was on average of 1.5 ± 0.4 mmHg·l-1·min-1 Maximum mPAP, cardiac output, and total pulmonary vascular resistance were, respectively, 34 ± 4 mmHg, 18 ± 3 l/min, and 1.9 ± 0.3 Wood units. However, the semirecumbent position was associated with a 10% decrease in maximum workload. Furthermore, cardiac output-workload or cardiac output-Vo2 relationships were nonlinear and variable. These results suggest that body position does not affect maximum exercise testing of the pulmonary circulation when results are expressed as mPAP-cardiac output or maximum total pulmonary vascular resistance. Maximum workload is decreased in semirecumbent compared with upright exercise. Workload or Vo2 cannot reliably be used as surrogates for cardiac output.

Exercise pulmonary haemodynamics predict outcome in patients with systemic sclerosis.

The aim of the present study was to investigate the prognostic value of exercise haemodynamics measured during right heart catheterisation (RHC) in patients with systemic sclerosis (SSc) referred for evaluation of pulmonary hypertension.SSc patients undergoing RHC at rest and during maximal supine incremental cycle exercise were grouped into resting precapillary pulmonary hypertension (PHrest) (mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary artery wedge pressure <15 mmHg), exercise-induced pulmonary hypertension (PHex) (mPAP ≥30 mmHg and mPAP/cardiac output >3 mmHg·L-1·min-1 at maximal exercise), and without pulmonary hypertension (PHnone). Patients' characteristics, haemodynamics and follow up data were compared between groups.72 SSc patients were followed for median (interquartile range) 33 (15-55) months. Mean (95% CI) survival without transplantation estimated by Kaplan-Meyer analysis was 4.4 (0.8-2.9) years in PHrest (n=17), 5.2 (4.4-6.1) years in PHex (n=28) and 9.5(8.4-10.6) years in PHnone (n=27; p<0.05 versus others). In Cox regression models, the exercise-induced increase in mPAP (hazard ratio (HR) 1.097, 95% CI 1.002-1.200) and the coefficient of pulmonary vascular distensibility alpha (HR 0.100, 95% CI 0.012-0.871) controlled for age, but not resting haemodynamics predicted transplant-free survival.Among SSc patients with normal mPAP at rest, an excessive increase in mPAP during exercise and an impaired vascular distensibility may indicate an early stage of pulmonary vasculopathy, associated with reduced survival similar to resting pulmonary hypertension patients.

Pulmonary Vascular Distensibility Predicts Pulmonary Hypertension Severity, Exercise Capacity, and Survival in Heart Failure.

Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity. Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, ρ=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only. PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Effect of Exercise on Pulmonary Arterial Capacitance in Heart Failure

PURPOSE: Heart failure is often associated with abnormal pulmonary hemodynamics. Pulmonary arterial capacitance (PAC) is a measure of the distensibility of the pulmonary vasculature and is a determinant of right ventricular afterload. Previously it has been shown that, at rest, PAC demonstrates a hyperbolic relationship with pulmonary vascular resistance (PVR) in heart failure (HF) patients and is an independent predictor of mortality. Our aim was to determine how exercise affects PAC and its relationship with exercise capacity and indices of respiratory gas exchange. METHODS: 39 HF patients undergoing right heart catheterization performed incremental exercise to exhaustion. Pulmonary arterial systolic pressure (PAPs), pulmonary arterial diastolic pressure (PAPd), mean pulmonary artery pressure (PAPm), and mean pulmonary wedge pressure (PWPm) were measured invasively at rest and at peak exercise. Ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), and heart rate (HR) were continuously collected at rest and during exercise. Arterial and mixed venous blood samples were collected for determination of cardiac output (Q) via direct Fick. The following variables were then calculated: stroke volume (SV)=Q/HR; PAC=SV/(PAPs-PAPd); PVR=(PAPm-PWPm)/Q. RESULTS: PAC significantly decreased from rest to peak exercise (2.6 vs. 1.6 ml/mmHg, p<0.01). At peak exercise, PAC was correlated with VO2max (PAC=0.29*VO2max-0.87, R=0.74). PAC was negatively correlated to PVR at rest (R=0.85) and during exercise (R=0.82) according to a hyperbolic fit. PAC was negatively correlated to VE/VCO2 at rest (R=0.53) and during exercise (R=0.52) according to a hyperbolic fit. CONCLUSIONS: In patients with classic systolic HF, PAC is reduced and falls further with exercise. In addition, subjects with the greatest capacitance to accept increases in pulmonary blood volume have a better exercise capacity. This increased pulmonary vascular distensibility during exercise yields lower resistance to forward flow. The gas exchange measure ventilatory efficiency, a marker of disease severity and prognosis in HF patients, is also related to reduced PAC. Supported by NIH grant HL71478.

Loss of Vascular Distensibility During Exercise Is an Early Hemodynamic Marker of Pulmonary Vascular Disease

Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH). Distensibility α during exercise (percentage change in vessel diameter per mm Hg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n = 33) were compared with control subjects (n = 26) and PVD with overt resting PH (PVD-PH) (n = 31). Resting mean pulmonary artery pressure (mPpa) levels were 14 ± 4, 20 ± 3, and 34 ± 10 mm Hg with corresponding exercise mPpa-cardiac output slopes of 1.5 ± 0.6, 3.5 ± 0.9, and 5.7 ± 3.2 mm Hg/L/min for control subjects and the PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of -4.5 to 4.5 mm Hg between calculated and measured mPpa. Distensibility α was lowest in the PVD-PH group, intermediate in the PVD-noPH group, and highest in control subjects (0.25 ± 0.14%/mm Hg vs 0.45 ± 0.24%/mm Hg vs 1.40 ± 0.45%/mm Hg, P < .0001). Distensibility α discriminated PVD-noPH from control subjects with a sensitivity of 88% and a specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH, with a strictly normal resting mPpa ≤ 20 mm Hg. Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The usefulness of α as a novel vascular index for the early detection of PVD warrants further validation.

Abstract 10940: Distensibility of the Pulmonary Circulation During Exercise in Heart Failure

Background: Pulmonary vascular distensibility (PVD) permits the pulmonary arteries to increase in size to accommodate increased blood flow and is measured as the percent increase in pulmonary vessel diameter per mmHg increase in pressure. We hypothesized that impaired PVD is related to reduced functional capacity in patients with heart failure (HF) or pulmonary arterial hypertension (PAH). Methods and Results: Patients with HF and preserved ejection fraction (HFpEF, n=48), HF and reduced ejection fraction (HFrEF, n=55), PAH (n=18), and age matched controls (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PVD was lowest in the PAH group (mean±SD 0.36±0.25% per mmHg) and intermediate in the HFpEF and HFrEF groups (0.92±0.39 and 0.84±0.33% per mmHg, respectively) compared to controls (1.39±0.32, P&lt;0.0001 for all three, Fig. 1A). PVD was strongly associated with measurements of right ventricular-pulmonary vascular function during exercise including change in RVEF (ρ=0.39, P&lt;0.0001, Fig. 1B) and change in pulmonary vascular resistance (ρ=-0.51, P&lt;0.0001) with exercise. PVD was an independent predictor of peak VO2 in a multivariate model that included age, gender, hemoglobin, resting cardiac index, resting LVEF, and resting mean pulmonary artery pressure. 14 out of 26 HFrEF patients who were treated with sildenafil (25-75 mg orally TID) for 12 weeks demonstrated a 24.6% increase in PVD (p=0.015) compared to no change in PVD in those treated with placebo (n=12). Conclusions: Pulmonary vascular distensibility is reduced in patients with HF and PAH and is closely related to functional capacity and RV systolic function during exercise. Furthermore, distensibility was modifiable with selective pulmonary vasodilator therapy, suggesting that distensibility of the pulmonary vessels may be an important therapeutic target in the treatment of HF and pulmonary hypertension.

The Application of Intravascular Ultrasound to Evaluate Pulmonary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension

The aim of this study was to explore the application of intravascular ultrasound (IVUS) to evaluate pulmonary vascular properties and mortality in patients with pulmonary arterial hypertension (PAH). Patients (n=51) with systolic pulmonary artery pressures≥40mm Hg on echocardiography were prospectively enrolled. All patients underwent right-heart catheterization and IVUS and were divided into three groups: PAH associated with connective tissue diseases (group 1, n=25), PAH due to other causes (group 2, n=15), and patients with connective tissue diseases without pulmonary hypertension (group 3, n=11). PAH groups (groups 1 and 2) were divided into distal (n=22) and proximal (n=18) remodeling subtypes on the basis of IVUS results. All patients were followed (19±10months) to compare the differences among clinical variables, pulmonary vascular properties, and survival rates. A total of 408 segments of pulmonary arteries were studied. The PAH groups demonstrated a greater mean wall thickness than group 3 (P<.01 for all). Pulmonary vascular mechanical properties, including compliance, distensibility, elastic modulus, and stiffness index β, were found to be worse in the PAH groups than in group 3 (P<.01 for all), but they tended to be better in group 1 than in group 2. An inverse exponential association was found between pulmonary vascular mechanical properties and hemodynamics, with R(2) values ranging from 0.54 to 0.78 (P<.001). In the PAH groups, the mortality in group 1 was similar to that in group 2 (12% vs 13%, P>.05), while the distal remodeling subtype had higher mortality than the proximal remodeling subtype (23% vs 0%, P<.05). IVUS is useful in PAH assessment by evaluating pulmonary vascular properties and predicting mortality. The classification of the proximal and distal remodeling type of PAH may be proposed to predict mortality and evaluate the prognosis of patients with PAH in clinical practice.

Pulmonary vascular function and exercise capacity in black sub-Saharan Africans.

Sex and age affect the pulmonary circulation. Whether there may be racial differences in pulmonary vascular function is unknown. Thirty white European Caucasian subjects (15 women) and age and body-size matched 30 black sub-Saharan African subjects (15 women) underwent a cardiopulmonary exercise test and exercise stress echocardiography with measurements of pulmonary artery pressure (PAP) and cardiac output (CO). A pulmonary vascular distensibility coefficient α was mathematically determined from the natural curvilinearity of multipoint mean PAP (mPAP)-CO plots. Maximum oxygen uptake (V̇o2max) and workload were higher in the whites, while maximum respiratory exchange ratio and ventilatory equivalents for CO2 were the same. Pulmonary hemodynamics were not different at rest. Exercise was associated with a higher maximum total pulmonary vascular resistance, steeper mPAP-CO relationships, and lower α-coefficients in the blacks. These differences were entirely driven by higher slopes of mPAP-CO relationships (2.5 ± 0.7 vs. 1.4 ± 0.7 mmHg·l(-1)·min; P < 0.001) and lower α-coefficients (0.85 ± 0.33 vs. 1.35 ± 0.51%/mmHg; P < 0.01) in black men compared with white men. There were no differences in any of the hemodynamic variables between black and white women. In men only, the slopes of mPAP-CO relationships were inversely correlated to V̇o2max (P < 0.01). Thus the pulmonary circulation is intrinsically less distensible in black sub-Saharan African men compared with white Caucasian Europeans men, and this is associated with a lower exercise capacity. This study did not identify racial differences in pulmonary vascular function in women.