Pulmonary Artery Pressure Response Research Articles

Pulmonary Artery Pressures During Cardiopulmonary Exercise Testing Using Cardiomems

<h3>Purpose</h3> Continuous pulmonary artery (PA) pressure monitoring has proven its value in reducing heart failure and all-cause hospitalizations. Invasive hemodynamic testing has shown that exercise in HFrEF leads to a steep increase in PA pressures and this steep rise is independently associated with reduced peak Vo₂. PA pressure response during exercise is likely more closely related to outcomes than resting hemodynamics in HF. The significance and potentially prognostic value of measuring PA pressures during CPET testing in AHF patients is currently unknown. In this feasibility-study we describe PA pressure curves during CPET in a cohort of advanced HF patients. <h3>Methods</h3> 7 advanced HF patients (Etiology: 4 NICM, 3 ICM; age 61 ± 12y; EF 28 ± 15%; 86% on beta blocker) with CardioMEMS device underwent standard stationary bike - CPET. PA pressures were measured at rest, every 2 minutes during exercise and during recovery. <h3>Results</h3> Max VO2 was 13.3±5.2 ml/kg/min; average duration of exercise was 8:56 min. Mean resting PA pressure was 12.5±5.2 mmHg. Mean peak PA pressure was 26.7±10 mmHg. Mean PA pressures increased on average by 2.5-fold (± 1.14) (Figure 1). The slope of mPAP rise was 3.33±2.1. mPAP uniformly returned to baseline values within 3 minutes of recovery. Pt. 3 was admitted 1 week after CPET testing with subacute worsening HF symptoms and underwent OHT, all other patients continue to follow at the centralized HF program at our institution. <h3>Conclusion</h3> PAP assessment using CardioMEMS is feasible during CPET. mPAP rose sharply during exercise. In HF patients with invasive PA pressure monitor devices, exercise PAP assessment may be a valuable tool to assess for functional capacity with possibly prognostic significance.

Pulmonary artery pressure response to percutaneous mitral valvuloplasty: Associated factors and clinical implications.

Pulmonary hypertension (PH) is a marker of poor outcome in mitral stenosis (MS), which improves after percutaneous mitral valvuloplasty (PMV). However, mechanical interventions for relief of valve obstruction often but not always reduce pulmonary pressures. This study aimed to assess the parameters associated with abnormal pulmonary artery pressure (PAP) response immediately after a successful PMV, and also its impact on long-term outcome. A total of 181 patients undergoing PMV for rheumatic MS were prospectively enrolled. Invasive hemodynamic and echocardiographic measures were examined in all patients. Abnormal PAP response was defined as the mean PAP (mPAP) values unchanged at the end of the procedure. Long-term outcome was a composite endpoint of death, mitral valve replacement, repeat PMV, new onset of atrial fibrillation (AF), or stroke. The mean age was 44.1 ± 12.6 years, and 157 patients were women (86.7%). In the overall population, mPAP decreased from 33.4 ± 13.1 mmHg pre to 27.6 ± 9.8 mmHg post (p < 0.001). Following PMV, 52 patients (28.7%) did not have any reduction of mPAP immediately after the PMV. Multivariable analysis adjusting for baseline values of PAP and mitral valve area revealed that AF (Odds ratio [OR] 2.7, 95% [confidence interval] CI 1.3 to 6.7), maximum mitral valve leaflets displacement (OR 0.8, 95% CI 0.7 to 0.9), and post-procedural left ventricular compliance (OR 0.7, 95% CI 0.5 to 0.9) were predictors of a lack of improvement in mPAP. During a median follow-up of 4.4 years, the endpoint was reached in 56 patients (31%). The pulmonary pressure response to PMV was not an independent predictor of long-term events. In patients with MS undergoing PMV, pulmonary pressures may not reduce immediately after the procedure, despite adequate opening of the valve. Abnormal PAP response can be predicted from baseline clinical and valvular characteristics as well as post-procedural left ventricular compliance. The lack of any immediate reduction in mPAP is not associated with long-term adverse outcomes.

Perinatal cardiopulmonary adaptation to the thin air of the Alto Andino by a native Altiplano dweller, the llama.

Most mammals have a poor tolerance to hypoxia, and prolonged O2 restriction can lead to organ injury, particularly during fetal and early postnatal life. Nevertheless, the llama (Lama Glama) has evolved efficient mechanisms to adapt to acute and chronic perinatal hypoxia. One striking adaptation is the marked peripheral vasoconstriction measured in the llama fetus in response to acute hypoxia, which allows efficient redistribution of cardiac output toward the fetal heart and adrenal glands. This strong peripheral vasoconstrictor tone is triggered by a carotid body reflex and critically depends on α-adrenergic signaling. A second adaptation is the ability of the llama fetus to protect its brain against hypoxic damage. During hypoxia, in the llama fetus there is no significant increase in brain blood flow. Instead, there is a fall in brain O2 consumption and temperature, together with a decrease of Na+-K+-ATPase activity and Na+ channels expression, protecting against seizures and neuronal death. Finally, the newborn llama does not develop pulmonary hypertension in response to chronic hypoxia. In addition to maintaining basal pulmonary arterial pressure at normal levels the pulmonary arterial pressor response to acute hypoxia is lower in highland than in lowland llamas. The protection against hypoxic pulmonary arterial hypertension and pulmonary contractile hyperreactivity is partly due to increased hemoxygenase-carbon monoxide signaling and decreased Ca2+ sensitization in the newborn llama pulmonary vasculature. These three striking physiological adaptations of the llama allow this species to live and thrive under the chronic influence of the hypobaric hypoxia of life at high altitude.

Pulmonary Artery Systolic Pressure Response to Exercise in Patients with Rheumatic Mitral Stenosis: Determinants and Prognostic Value

Pulmonary hypertension in response to exercise is a marker of the hemodynamic severity of mitral stenosis (MS). However, the factors related to elevated pulmonary pressure with exercise are not well defined. The aim of this study was to assess the parameters associated with the pulmonary pressure response to exercise in patients with pure rheumatic MS. An additional aim was to determine the impact of exercise-induced pulmonary hypertension on clinical outcome. One hundred thirty patients with MS (94% women; mean age, 45±11years) underwent exercise echocardiography. A range of echocardiographic parameters were obtained at rest and at peak exercise. Symptom-limited graded ramp bicycle exercise was performed in the supine position. The primary end point was mitral valve intervention, either percutaneous or surgical. In the overall population, systolic pulmonary artery pressure (SPAP) increased from 38.3±13.4mm Hg at rest to 65.8±20.7mm Hg during exercise. Increases in mean mitral gradient, right ventricular function, left atrial volume, and net atrioventricular compliance were independently associated with SPAP at peak exercise, after adjusting for changes in heart rate. During the follow-up period (median, 17months; range, 1-45months), 46 adverse clinical events were observed. By multivariate Cox proportional-hazards analysis adjusted for age and sex, SPAP achieved at peak exercise was an important predictor of adverse outcome (adjusted hazard ratio, 1.025; 95% CI, 1.010-1.040; P=.001). New York Heart Association functional class (adjusted hazard ratio, 2.459; 95% CI, 1.509-4.006; P<.001) and the interaction between valve area and net atrioventricular compliance (P=.001) were also significant predictors of adverse events. Time-dependent areas under the receiver operating characteristic curve for the model with SPAP during exercise were better than for the model with SPAP at rest, with a significant improvement from 3years onward. In patients with MS, the pulmonary artery pressure response to exercise is determined by a combination of factors, including transmitral mean gradient at exercise, net atrioventricular compliance, left atrial volume, and right ventricular function. Pulmonary artery pressure at peak exercise is a predictor of clinical outcomes and adds incremental prognostic value beyond that provided by standard resting measurements, including valve area.

P1789 Stress echocardiography in patients with pulmonary arterial hypertension - a pilot study

Abstract INTRODUCTION Pulmonary arterial hypertension (PAH) is a rare, progressive disease with poor prognosis. Stress echocardiography (SE) gives an important data on hemodynamic response to exercise. In patients with PAH SE may be useful for the diagnosis and risk assessment but data are lacking. AIM OF STUDY The aim of the study was to analyze exercise-induced response of right heart function and pulmonary artery pressure in patients with PAH. MATERIALS AND METHODS Study group consisted of 15 hemodynamically stable patients, 9 women, aged 22-73 (median- 50), diagnosed with PAH treated at Cardiology Department. The patients were subjected to stress echocardiography on supine cycloergometer and underwent assessment before and at peak-exercise. Moreover the standard parameters of clinical assessment: NT-proBNP, WHO functional class, and 6-minute walk test were analyzed. RESULTS Nine patients were in WHO class III, 4 of them- WHO class II and 2- WHO class I. The median NT-proBNP concentration was 169.3 (IQR 151.2-989.5) pg/ml. 6-Minute Walk Test distance was 455 (428-489) meters. The median workload was 75 (IQR 50-100) Watts and it was the median 54% (IQR 37-62%) of predicted. The echocardiographic parameters assessed in SE at rest and shortly after peak-exercise revealed that RV systolic volume did not significantly differ: 70 (49.8-112.3) vs 71.5 (36.6-110) ml, p = 0.3. Right atrial area decreased from median 21.9 (17.4-27.3) to 19.8 (16.4-22.1) cm2, p = 0.05, whereas right atrial volume did not significantly changed - 80 (47.5-99.5) vs 68 (47.3-78.8) ml, p = 0.13. Further, shortly after exercise tricuspid regurgitation peak gradient (TRPG) significantly increased - 43 (25-76.5) vs 71 (50.5-102) mmHg, p = 0.002. CONCLUSIONS In stable PAH patients supine SE is feasible. Even in advanced WHO functional classes patients were able to exercise. Among echocardiographic parameters TRPG reflecting systolic pulmonary artery pressure showed the biggest difference between baseline and peak-exercise values. SE and seems to be a valuable tool in PAH patients’ assessment.

Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort

BackgroundAbnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear. ObjectivesThis study sought to investigate the association of exPH with clinical determinants and outcomes. MethodsThe authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality. ResultsAmong 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both). ConclusionsExercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

P4718Inadequate response of pulmonary artery pressure after percutaneous mitral valvuloplasty: determinant factors and prognostic impact

Abstract Introduction Pulmonary hypertension (HP) has long been known to be a marker of poor outcome in patients with mitral stenosis (MS). Percutaneous mitral valvuloplasty (PMV) is currently the treatment of choice for MS, which results in improvement in HP. However, despite the successful valve opening, the regression of PH may be incomplete. This has been attributed to irreversible morphologic changes within the pulmonary vasculature. Purpose To assess the clinical, echocardiographic and hemodynamic parameters associated with an inadequate response of the pulmonary artery pressure (PAP) immediately after a successful PMV, and also the impact of residual PH on long-term outcome in these patients. Methods 181 patients undergoing PMV for rheumatic MS were enrolled. Invasive hemodynamic and echocardiographic measures were examined in all patients. Inadequate response of PAP was defined as the mean pulmonary artery pressure (mPAP) values unchanged at the end of the procedure. Long-term outcome was a composite endpoint of death, mitral valve replacement, repeat PMV, new onset of atrial fibrillation (AF), or stroke. Results The mean age was 44.1±12.6 years, and 157 patients were women (86.7%). In the overall population, mPAP decreased from 33.4±13.1 mmHg pre to 27.6±9.8 mmHg post (p&lt;0.001), as mitral valve increased from 0.96±0.2 cm2 pre to 1.68±0.2 cm2 post (p&lt;0.001) PMV. Following PMV, 10 patients developed severe mitral regurgitation and were excluded from the analysis. Of the 171 patients analyzed, 52 (30%) did not present reduction of mPAP immediately after the PMV. Transmitral pressure gradients were significantly greater and mitral valve area was smaller in those patients with unchanged mPAP after PMV than in those whose PAP had decreased. Systolic, diastolic and mPAP pressures as well as left atrial pressure were higher in those patients who had improvement in pulmonary pressures after PMV. Multivariate analysis revealed the following independent predictors of unchanged mPAP: AF (Odds ratio [OR] 2.7, 95% [confidence interval] CI 1.1 to 6.4), mitral valve area (OR 1.3, 95% CI 1.1 to 1.5), maximum mitral valve leaflets displacement (OR 0.8, 95% CI 0.7 to 0.9), and left ventricular compliance after PMV (OR 0.8, 95% CI 0.6 to 0.9). During a mean follow-up of 28 months, the endpoint was reached in 48 patients (26%). The pulmonary pressure response to PMV was not predictor of long-term events. Conclusions In a large cohort of patients with MS undergoing PMV, mean pulmonary artery pressure values do not reduce immediately after the procedure in 30% of the cases, despite adequate opening of the valve. The factors associated with inadequate PAP response following PMV were presence of AF, larger mitral valve area, reduced valve leaflets mobility and post procedural low left ventricular compliance. The early non-reduction of mPAP after PMV is not associated with adverse outcome.

Pulmonary arterial response to Angiostrongylus vasorum in naturally infected dogs: echocardiographic findings in two cases

BackgroundAngiostrongylus vasorum is a nematode living in the pulmonary arteries of canids. Infected dogs develop severe pulmonary lesions which can potentially lead to pulmonary hypertension (PH). However, reports of PH in natural infected dogs are scant. One of the possible causes of the low prevalence of PH in A. vasorum-infected dogs could be the establishment of large diameter intrapulmonary arteriovenous anastomoses (IPAVAs), which attenuate pulmonary vascular resistance, thus reducing the pulmonary arterial pressure. The present report describes the pulmonary arterial pressure (PAP) response to A. vasorum natural infection in two dogs, assessed by echocardiography and by the saline contrast echocardiographic test (SCE).ResultsBoth dogs showed clinical signs of respiratory disease. At presentation, case 1 did not show echocardiographic signs of PH and the SCE test was positive proving the presence of IPAVAs. However, at the follow-up visit, despite A. vasorum infection resolution, the same dog showed PH and the SCE test resulted negative, which ruled out the presence of IPAVAs. Case 2 suffered from severe pulmonary arterial hypertension and right-side congestive heart failure since the day of presentation. Saline contrast echocardiography was negative both at the time of presentation and at the follow-up visit.ConclusionsIn the two cases described above, the PH was not associated with IPAVAs. During A. vasorum infection, IPAVAs recruitment mechanism is able to contrast the rise of PAP until a certain level. It probably represents an initial escape mechanism of PH that, over time, exhausts its compensatory capacities allowing PAP to rise and to be detectable on echocardiography.

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD.

Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses.

BackgroundHypertension is the major risk factor for cardiovascular disease, the most common cause of death worldwide. Resistance arteries are capable of adapting their diameter independently in response to pressure and flow‐associated shear stress. Ryanodine receptors (RyRs) are major Ca2+‐release channels in the sarcoplasmic reticulum membrane of myocytes that contribute to the regulation of contractility. Vascular smooth muscle cells exhibit 3 different RyR isoforms (RyR1, RyR2, and RyR3), but the impact of individual RyR isoforms on adaptive vascular responses is largely unknown. Herein, we generated tamoxifen‐inducible smooth muscle cell–specific RyR2‐deficient mice and tested the hypothesis that vascular smooth muscle cell RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.Methods and ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of sarcoplasmic reticulum–mediated Ca2+‐release events and associated Ca2+‐activated, large‐conductance K+ channel currents in peripheral arteries, leading to increased myogenic tone and systemic blood pressure. In the absence of RyR2, the pulmonary artery pressure response to sustained hypoxia was enhanced, but flow‐dependent effects, including blood flow recovery in ischemic hind limbs, were unaffected.ConclusionsOur results establish that RyR2‐mediated Ca2+‐release events in VSCMs specifically regulate myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. They further suggest that vascular smooth muscle cell–expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.

Preservation of Cardiopulmonary Function in Patients Treated with Ultrasound-Accelerated Thrombolysis in the Setting of Submassive Pulmonary Embolism

PurposeTo evaluate the clinical effectiveness of ultrasound-assisted thrombolysis (USAT) in resolution of right ventricular dysfunction (RVD), preservation of cardiopulmonary function, and quality of life (QoL) in patients with acute submassive pulmonary embolism (PE). Materials and MethodsA single-center prospective study of patients presenting with acute PE and signs of RVD, as determined by right ventricle-to-left ventricle diameter ratio (RV:LV) > 0.9 on computed tomographic angiography of the thorax, was performed. Patients underwent USAT with recombinant tissue plasminogen activator. Primary endpoints measured were RV:LV by echocardiogram at baseline presentation and at 72 hours and 90 days after treatment. Secondary endpoints were QoL scores assessed by SF-36 Health Surveys at baseline and at 90 days, cardiopulmonary exercise test (CPET) parameters at 90 days, and procedural outcomes, including response of pulmonary artery pressure (PAP) and procedural complications. ResultsTwenty-five patients were treated between June 17, 2013, and September 15, 2014, with mean reduction of RV:LV by echocardiogram from 1.38 ± 0.28 at presentation to 0.92 ± 0.14 (P < .0001) at 72 hours and 0.84 ± 0.25 (P < .0001) at 90 days. SF-36 Health Survey scores demonstrated no long-term self-perceived adverse physical or mental effects as a result of PE. CPET parameters, including VO2max, weight-adjusted VO2, VE/VCO2, and VD/VT demonstrated no pulmonary vascular impairment at 90 days. PAP significantly improved after USAT, with mean initial systolic pressure of 50.46 ± 13.98 mmHg reduced to 39.64 ± 8.66 mmHg (P = .0001). There were no deaths, recurrent venous thromboembolism, hemodynamic decompensation, or hemorrhage. ConclusionsUSAT resulted in significant reduction of RV:LV at 72 hours, which was preserved at 90 days. QoL and objective measures of cardiopulmonary function are preserved at 90 days in this population. Further studies with long-term follow-up are needed to determine the potential value of USAT for the prevention of post-PE syndrome in patients with submassive PE.

Pulmonary Arterial Wedge Pressure at Rest and During Exercise in Healthy Adults: A Systematic Review and Meta-analysis

The pulmonary arterial wedge pressure (PAWP) response to exercise may unmask latent heart failure with preserved ejection fraction. There remains a lack of consensus over threshold values for PAWP during exercise. A systematic review of studies examining PAWP by means of right heart catheterization at rest and during exercise in healthy individuals was performed. Relevant data derived from healthy volunteers were stratified by age (older than 40 years vs 40 years or younger) and sex. Three exercise intensities were predefined: light, moderate, and strenuous. Weighted means and weighted 95% confidence intervals (CIs) for the aggregate data were calculated. A total of 424 individuals from 32 unique studies were included, of which 19% (n = 82) were female. PAWP reached weighted mean and 95% CI values of 19 (17-21) and 17 (16-18) mm Hg at light and moderate exercise, respectively. The PAWP response to exercise was similar between men and women >40 years of age. However, exercise intensities were lower in women. PAWP increases during exercise, reaching up to 20 mm Hg in adults >40 years of age. Older women achieve PAWP values similar to those of older men, but at lower intensities. Findings support a threshold of at least 25 mm Hg as an absolute cutoff value for "normal" PAWP response to exercise in individuals >40 years old.

“WHY WARM UP?”: EXERCISE ONSET AND THE EARLY PEAK IN PULMONARY ARTERY WEDGE PRESSURE IN HEALTHY OLDER ADULTS

Knowledge gaps exist regarding the pulmonary artery (PA) and pulmonary artery wedge pressure (PAWP) responses to exercise in healthy older adults that may contribute to exertional intolerance. A relatively precipitous rise in pressures occur early after exercise onset in older adults and is time-variant: an early peak in PAWP is followed by a decline as exercise becomes sustained. Our objective was to analyze the PAWP response to early exercise and its relationship to demographic, echocardiographic and hemodynamic characteristics. A retrospective analysis was performed using data from 36 healthy sedentary volunteers (18 men and 18 women, no medications, cardiac disease or cardiac risk factors) with a mean age of 56±7 years, who participated in an exercise study undergoing right heart catheterization. Subjects were studied at rest and during two stages of semi-upright cycle ergomety. Work rate was adjusted during the first stage of Light Exercise to achieve a target heart rate (HR) of 100bpm (Early Light, 2min), and then further adjusted to maintain this HR (Sustained Light, five min). Work rate in the second stage was similarly adjusted to achieve a target HR of 120bpm (Early Moderate, two min) and to sustain it (Sustained Moderate, five min). PAWP was measured at each stage. The early peak and sustained PAWP and PA pressure responses during exercise are shown in Table 1. We confirmed that the rise in PAWP occurs early but then declines with sustained light exercise. Neither the early PAWP peak nor the magnitude of change were correlated to any demographic or baseline echocardiographic variables. The early peak PAWP was significantly negatively correlated with resting HR as well as the magnitude of change in HR from rest to early exercise (R2 0.165, p<0.05, Figure). The magnitude of change in the peak PAWP from rest to early light exercise was positively related to the decay in PAWP with sustained exercise (R2 0.391, p<0.05, Figure). The PAWP response to exercise has a negative relationship to resting HR, which may reflect the adjustment to a particular work rate to achieve a HR of 100bpm in early light exercise. We speculate that the PAWP peak with early light exercise observed in this study may be explained by a rapid increase in left ventricular filling pressure as HR increases abruptly with the initiation of exercise. The latent decay in PAWP suggests delayed diastolic accommodation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses

ObjectiveCardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Resistance arteries can adapt their vessel diameter independently by pressure and by flow. Ryanodine receptors (RyRs) are major Ca2+ release channels in the sarcoplasmic reticulum (SR) membrane of myocytes contributing to contractility. Vascular smooth muscle cells (VSMCs) exhibit three different RyR isoforms (RyR1, 2, 3), but the impact of individual RyR isoforms on vascular adaptive responses is largely unknown.MethodsWe generated tamoxifen‐inducible smooth muscle cell (SM) specific RyR2 deficient mice and tested the hypothesis that VSMC RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of SR released Ca2+ sparks and the associated Ca2+ activated potassium (BKCa) channel currents, leading to increased myogenic arterial tone in peripheral arteries and systemic blood pressure. RyR2 deficiency enhanced the pulmonary artery pressure response to sustained hypoxia, but had no effect on flow‐dependent effects, including blood flow recovery in ischemic hind limbs.ConclusionOur results identify a specific contribution of RyR2 in mediating VSMC Ca2+ sparks relevant for regulating myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. VSMC expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.Support or Funding InformationThis study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to M.G and M.W. (SFB‐TR84 C3 and C6), and the Deutsche Akademische Austauschdienst (DAAD) to M.G. and I.S, and the NIH (R37 DK053832, R01 HL121706, PO1 HL095488, R01 HL131181), Fondation Leducq, and the Totman Medical Research Trust to M.T.N., and by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) to M.G. and M.K. We thank Dr. Kirill Essin for help in Ca2+ spark recordings using line scan imaging. CFG‐P is recipient of Ministerio de Educación Cultura y Deporte, Fundación San Pablo‐CEU and Banco Santander fellowships.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas.

Perinatal hypoxia causes pulmonary hypertension in neonates, including humans. However, in species adapted to hypoxia, such as the llama, there is protection against pulmonary hypertension. Nitric oxide (NO) is a vasodilatator with an established role in the cardiopulmonary system of many species, but its function in the hypoxic pulmonary vasoconstrictor response in the newborn llama is unknown. Therefore, we studied the role of NO in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. We show that high- compared to lowland newborn llamas have a reduced pulmonary vasoconstrictor response to acute hypoxia. Protection against excessive pulmonary vasoconstriction in the highland llama is mediated via enhancement of NO pathways, including increased MYPT1 and reduced ROCK expression as well as Ca2+ desensitization. Blunting of pulmonary hypertensive responses to hypoxia through enhanced NO pathways may be an adaptive mechanism to withstand life at high altitude in the newborn llama. Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of nitric oxide (NO) in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. The cardiopulmonary function of newborn llamas born at low (580m) or high altitude (3600m) was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and sodium nitroprusside (SNP), and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20. Pulmonary vascular remodelling was evaluated by morphometry and based on α-actin expression. High- compared to lowland newborn llamas showed lower in vivo pulmonary arterial pressor responses to acute hypoxia. This protection involved enhanced NO function, as NO blockade reverted the effect and the pulmonary arterial dilatator response to SNP was significantly enhanced in highland neonates. The pulmonary expression of ROCK2 and the phosphorylation of MLC20 were lower in high-altitude llamas. Conversely, MYPT1 was up-regulated whilst PSer695-MYPT1 and PThr695-MYPT1 did not change. Enhanced NO-dependent mechanisms were insufficient to prevent pulmonary arterial remodelling. Combined, the data strongly support that in the highland newborn llama reduced ROCK, increased MYPT1 expression and Ca2+ desensitization in pulmonary tissue allow an enhanced NO biology to limit hypoxic pulmonary constrictor responses. Blunting of hypoxic pulmonary hypertensive responses may be an adaptive mechanism to life at high altitude.

Changes in acute pulmonary vascular responsiveness to hypoxia during a progressive ascent to high altitude (5300m).

What is the central question of this study? Do the pulmonary vascular responses to hypoxia change during progressive exposure to high altitude and can alterations in these responses be related to changes in concentrations of circulating biomarkers that affect the pulmonary circulation? What is the main finding and its importance? In our field study with healthy volunteers, we demonstrate changes in pulmonary artery pressure suggestive of remodelling in the pulmonary circulation, but find no changes in the acute responsiveness of the pulmonary circulation to changes in oxygenation during 2 weeks of exposure to progressive hypoxia. Pulmonary artery pressure changes were associated with changes in erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. We sought to determine whether changes in pulmonary artery pressure responses to hypoxia suggestive of vascular remodelling occur during progressive exposure to high altitude and whether such alterations are related to changes in concentrations of circulating biomarkers with known or suspected actions on the pulmonary vasculature during ascent. We measured tricuspid valve transvalvular pressure gradients (TVPG) in healthy volunteers breathing air at sea level (London, UK) and in hypoxic conditions simulating the inspired O2 partial pressures at two locations in Nepal, Namche Bazaar (NB, elevation 3500m) and Everest Base Camp (EBC, elevation 5300m). During a subsequent 13day trek, TVPG was measured at NB and EBC while volunteers breathed air and hyperoxic or hypoxic mixtures simulating the inspired O2 partial pressures at the other locations. For each location, we determined the slope of the relationship between TVPG and arterial oxygen saturation (SaO2) to estimate the pulmonary vascular response to hypoxia. Mean TVPG breathing air was higher at any SaO2 at EBC than at sea level or NB, but there was no change in the slope of the relationship between SaO2 and TVPG between locations. Nitric oxide availability remained unchanged despite increases in oxidative stress (elevated 8-isoprostane). Erythropoietin, pro-atrial natriuretic peptide and interleukin-18 levels progressively increased on ascent. Associations with TVPG were observed only with erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. Although the increased TVPG for any given SaO2 at EBC suggests that pulmonary vascular remodelling might occur during 2weeks of progressive hypoxia, the lack of change in the slope of the relationship between TVPG and SaO2 indicates that the acute pulmonary vascular responsiveness to changes in oxygenation does not vary within this time frame.

High Intensity Interval Training is Superior to Continuous Training in a Pulmonary Hypertension Rat Model

Exercise appears to have overall benefit in pulmonary arterial hypertension (PAH); however, studies to date indicate little effect on the elevated pulmonary artery pressure (PAP) or RV hypertrophy (RVH) and dysfunction associated with the disease. We investigated if the greater endothelial stimulation of high intensity interval training (HIIT) would provide superior benefit over the more customary prolonged continuous exercise training (CExT) protocol in a rat model of PAH. We further sought to characterize acute PAP responses to HIIT and CExT in a PAH rat. METHODS: Six wks of treadmill training was performed 5x/wk in male Sprague-Dawley rats (250-300g) with monocrotaline- (MCT, 40 mg/kg) induced mild PAH. Training sessions were either HIIT (2 min at ~90% VO2 reserve [VO2R] + 3 min at 30% VO2R, for 5 cycles; n=8), or low intensity CExT (60 min at 50% VO2R; n=7). In an additional rat, telemetric recording of simultaneous PAP and systemic pressures were obtained during HIIT and CExT running, serially at pre- and 2, 4, 6, and 8 wks post-MCT. Values are means±SE. RESULTS: MCT-induced decrement in VO2max was ameliorated by both HIIT and CExT (p≤0.01 vs. sedentary MCT rats, MCT-SED, n=6), and were similar to healthy sedentary controls (CON, n=6). Most importantly, RV systolic pressure (in mmHg) and RVH (ratio of RV to LV+S mass) were lowered (p<0.05) only by HIIT (28.7±2, and 0.32±0.02) and not by CExT (44.1±3, and 0.43±0.01) vs. MCT-SED (40.2±3.2, and 0.41±0.02). Echocardiography performed pre- and post-HIIT also indicated reduced RVH ([INCREMENT] wall thickness 0.11±8 mm) and improved RV function ([INCREMENT] cardiac output 117±28 μl) vs. MCT-SED (0.79±8 mm, and 6±42 μl, p<0.05). RV fibrosis was less only for HIIT (p<0.05 vs. MCT-SED), and no training effect was observed on RV inflammation and apoptosis or pulmonary vascular remodeling. Pulmonary endothelial nitric oxide synthase was increased (p<0.05) only with HIIT, consistent with enhanced endothelial stimulation. Implantable telemetry revealed repeated ‘surging’ of PAP during HIIT running, followed by more pronounced PAP reduction during recovery. CONCLUSIONS: HIIT may be superior to CExT for improving hemodynamics and RV dysfunction in PAH and may be explained by greater sheer-stress mediated vascular endothelial adaptation to HIIT stimulus. Funding: Amer. Heart Assoc. SDG to Brown.

Pulmonary Arterial Pressure Response During Exercise in COPD: A Correlation with C-Reactive Protein (hsCRP).

Background: The non-invasive assessment of pulmonary haemodynamics during exercise provides complementary data for the evaluation of exercise tolerance in patients with COPD. Methods: Exercise echocardiography in the semi-supine position was performed in 27 patients with COPD (C) with a forced expiratory volume in one second (FEV1) of 36±12% predicted and 13 age and gender-matched non-COPD subjects (NC). COPD patients also underwent cardiopulmonary exercise testing with gas exchange detection (CPET). Furthermore, serum high sensitive C-reactive protein (hsCRP), a marker of systemic inflammation, was also measured. Results: The maximal work rate (WRmax) and aerobic capacity (VO2peak) were significantly reduced (WRmax: 77±33 Watt, VO2peak: 50±14 %pred) in COPD. Pulmonary arterial systolic pressure (PAPs) was higher in COPD versus controls both at rest (39±5 vs. 31±2 mmHg, p<0.001), and at peak exercise (72±12 vs. 52±8 mmHg, p<0.001). In 19 (70%) COPD patients, the increase in PAPs was above 22 mmHg. The change in pressure (dPAPs) correlated with hsCRP (r2=0.53, p<0.0001) and forced vital capacity (FVC) (r2=0.18, p<0.001). Conclusion:PAPs at rest and during exercise were significantly higher in COPD patients and correlated with higher hsCRP. This may indicate a role for systemic inflammation and hyperinflation in the pulmonary vasculature in COPD. The study was registered at ClinicalTrials.gov webpage with NCT00949195 registration number.

Pulmonary Artery Pressure Response to Simulated Air Travel in a Hypobaric Chamber.

Hypoxia-induced elevation in pulmonary artery pressure during air travel may contribute to the worldwide burden of in-flight medical emergencies. The pulmonary artery pressure response may be greater in older passengers, who are more likely to require flight diversion due to a medical event. Understanding these effects may ultimately improve the safety of air travel. We studied 16 healthy volunteers, consisting of a younger group (aged <25 yr) and an older group (aged >60 yr). Using a hypobaric chamber, subjects undertook a 2-h simulated flight at the maximum cabin pressure altitude for commercial airline flights (8000 ft; 2438 m). Higher and lower altitudes within the aeromedical range were also explored. Systolic pulmonary artery pressure (sPAP) was assessed by Doppler echocardiography. There was a progressive increase in sPAP which appeared to be biphasic, with a small initial increase and a larger subsequent rise. Overall, sPAP increased by 5±1 mmHg from baseline to 35±1 mmHg at 8000 ft, an increase of 18%. The sPAP response to 8000 ft was greater in the older group than the younger group. This study confirms that pulmonary artery pressure increases during simulated air travel, and provides preliminary evidence that this response is greater in older people. Advancing age may increase in-flight susceptibility to adverse pulmonary vascular responses in passengers, aircrew, and aeromedical patients.

Pulmonary vascular response patterns during exercise in interstitial lung disease

When overt pulmonary hypertension arises in interstitial lung disease (ILD), it contributes to exercise intolerance. We sought to determine the functional significance of abnormal pulmonary arterial pressure (PAP) responses to exercise in ILD.27 ILD patients and 11 age-matched controls underwent invasive cardiopulmonary exercise testing (iCPET). Mean PAP (mPAP) was indexed to cardiac output (Q'T) during exercise, with a mPAP-Q'T slope ≥3 mmHg·min·L(-1) defined as an abnormal pulmonary vascular response.All control subjects had mPAP-Q'T slopes <3 mmHg·min·L(-1) (mean±sem 1.5±0.1 mmHg·min·L(-1)). 15 ILD patients had mPAP-Q'T slopes ≥3 mmHg·min·L(-1) (4.1±0.2 mmHg·min·L(-1)) and were labelled as having ILD plus pulmonary vascular dysfunction (PVD). Subjects without pulmonary hypertension and with mPAP-Q´T slopes <3 mmHg·min·L(-1) (1.9±0. 2 mmHg·min·L(-1)) were labelled as ILD minus PVD (n=12). ILD+PVD and ILD-PVD patients did not differ in terms of age, sex, body mass index, pulmonary function testing or degree of exercise oxygen desaturation. Peak oxygen consumption was lower in ILD+PVD than in ILD-PVD (13.0±0.9 versus 17±1.1 mL·kg(-1)·min(-1), p=0.012) and controls (19.8±1.7 mL·kg(-1)·min(-1), p=0.003). ILD+PVD patients had increased dead space volume (VD)/tidal volume (VT) and minute ventilation/carbon dioxide production at the anaerobic threshold.In ILD, mPAP-Q'T slope ≥3 mmHg·min·L(-1) is associated with lower peak oxygen consumption, increased VD/VT and inefficient ventilation. While noninvasive parameters were unable to predict those with abnormal pulmonary vascular responses to exercise, iCPET-derived mPAP-Q'T slope may aid in identifying physiologically significant, early pulmonary vascular disease in ILD.