Rise In Pulmonary Artery Pressure Research Articles

Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.

Maximal exercise capacity is reduced at altitude or during hypoxia at sea level. It has been suggested that this might reflect increased right ventricular afterload due to hypoxic pulmonary vasoconstriction. We have shown previously that the pulmonary vascular sensitivity to hypoxia is enhanced by sustained isocapnic hypoxia, and inhibited by intravenous iron. In this study, we tested the hypothesis that elevated pulmonary artery pressure contributes to exercise limitation during acute hypoxia. Twelve healthy volunteers performed incremental exercise tests to exhaustion breathing 12% oxygen, before and after sustained (8-h) isocapnic hypoxia at sea level. Intravenous iron sucrose (n = 6) or saline placebo (n = 6) was administered immediately before the sustained hypoxia. In the placebo group, there was a substantial (12.6 ± 1.5 mmHg) rise in systolic pulmonary artery pressure (SPAP) during sustained hypoxia, but no associated fall in maximal exercise capacity breathing 12% oxygen. In the iron group, the rise in SPAP during sustained hypoxia was markedly reduced (3.4 ± 1.0 mmHg). There was a small rise in maximal exercise capacity following sustained hypoxia within the iron group, but no overall effect of iron, compared with saline. These results do not support the hypothesis that elevated SPAP inhibits maximal exercise capacity during acute hypoxia in healthy volunteers.

Abstract 19002: Impact of Pulmonary Hypertension on Covid-19 Pneumonia Hospitalizations: Analysis of The National Inpatient Sample 2020

Background: SARS-CoV-2 swept across the globe, overwhelming healthcare systems across the world regardless of borders and socioeconomic factors. COVID pneumonia (CP) can result in ARDS and increased pulmonary artery pressures. Pulmonary hypertension (PHT) is generally a chronic cardiopulmonary disease that is associated with progressive vascular remodeling. We aimed to assess the impact of underlying PHT on CP patients with a large sample size. Methods: We utilized the National Inpatient Sample from 2020 to identify 1,058,815 hospitalized adults with CP. These hospitalizations were further stratified based on the presence of PHT. A multivariate regression model was used to adjust for confounders and analyze the variables. Results: Of those who were admitted for CP, 24,284 (2.3%) had PHT. In-hospital mortality was higher in those with PHT (19.6% vs 10.9%; p<0.001). Figure 1 shows the Forrest plot for multivariate analysis of in-hospital outcomes when adjusted for patient demographics, comorbidities, and hospital characteristics. When adjusted similarly, CP patients with PHT had longer length of stay (LOS) by 1.3 days (p<0.001) and had additional hospital costs (HC) of $23,232 (p<0.001). Conclusions: CP patients who had PHT had significantly worse outcomes in terms of in-hospital mortality, LOS, HC, cardiac arrest, arrhythmias, sepsis, cardiogenic shock, and being intubated. These patients are unable to tolerate the ventilation-perfusion mismatch and the rise in pulmonary arterial pressures seen in ARDS.

RGS5 as a Biomarker of Pericytes, Involvement in Vascular Remodeling and Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained rise in mean pulmonary artery pressure. Pulmonary vascular remodeling serves an important role in PAH. Identifying a key driver gene to regulate vascular remodeling of the pulmonary microvasculature is critical for PAH management. Differentially expressed genes were identified using the Gene Expression Omnibus (GEO) GSE117261, GSE48149, GSE113439, GSE53408 and GSE16947 datasets. A co-expression network was constructed using weighted gene co-expression network analysis. Novel and key signatures of PAH were screened using four algorithms, including weighted gene co-expression network analysis, GEO2R analysis, support vector machines recursive feature elimination and robust rank aggregation rank analysis. Regulator of G-protein signaling 5 (RGS5), a pro-apoptotic/anti-proliferative protein, which regulate arterial tone and blood pressure in vascular smooth muscle cells. The expression of RGS5 was determined using reverse transcription-quantitative PCR (RT-qPCR) in PAH and normal mice. The location of RGS5 and pericytes was detected using immunofluorescence. Compared with that in the normal group, RGS5 expression was upregulated in the PAH group based on GEO and RT-qPCR analyses. RGS5 expression in single cells was enriched in pericytes in single-cell RNA sequencing analysis. RGS5 co-localization with pericytes was detected in the pulmonary microvasculature of PAH. RGS5 regulates vascular remodeling of the pulmonary microvasculature and the occurrence of PAH through pericytes, which has provided novel ideas and strategies regarding the occurrence and innovative treatment of PAH.

Hypoxic pulmonary vascular response can screen subclinical lifestyle disease in healthy population.

Subclinical life style disease can cause endothelial dysfunction associated with perfusion abnormalities and reduced vascular compliance. Subclinical elevated beta type natriuretic peptide (BNP) has been associated with altered fluid shift from extra to intracellular space during acute hypoxia. Therefore we measured vascular response and BNP levels during acute hypoxia to study endothelial functions among healthy individuals. Individuals were exposed to acute normobaric hypoxia of FiO2=0.15 for one hour in supine position and their pulmonary and systemic vascular response to hypoxia was compared. Individuals were divided into two groups based on either no response (Group 1) or rise in systolic pulmonary artery pressure to hypoxia (Group 2) and their BNP levels were compared. BNP was raised after hypoxia exposure in group 2 only from 18.52±7 to 21.56±10.82picogram/ml, p<0.05. Group 2 also showed an increase in mean arterial pressure and no fall in total body water in response to acute hypoxia indicating decreased endothelial function compared to Group 1. Rise in pulmonary artery pressure and BNP level in response to acute normobaric hypoxia indicates reduced endothelial function and can be used to screen subclinical lifestyle disease among healthy population.

COUNTERPOINT: Pulmonary Vascular Resistance 2.0— Shedding Light or Casting Shadows?

COUNTERPOINT: Pulmonary Vascular Resistance 2.0— Shedding Light or Casting Shadows?

Effect of acetazolamide on pulmonary vascular haemodynamics in patients with COPD going to altitude: a randomised, placebo-controlled, double-blind trial.

COPD may predispose to symptomatic pulmonary hypertension at high altitude. We investigated haemodynamic changes in lowlanders with COPD ascending to 3100 m and evaluated whether preventive acetazolamide treatment would attenuate the altitude-induced increase in pulmonary artery pressure (PAP). In this randomised, placebo-controlled, double-blind, parallel-group trial, patients with COPD Global Initiative for Chronic Obstructive Lung Disease grades 2-3 who were living <800 m and had peripheral oxygen saturation (S pO2 ) >92% and arterial carbon dioxide tension <6 kPa were randomised to receive either acetazolamide (125-250 mg·day-1) or placebo capsules, starting 24 h before ascent from 760 m and during a 2-day stay at 3100 m. Echocardiography, pulse oximetry and clinical assessments were performed at 760 m and after the first night at 3100 m. Primary outcome was PAP assessed by tricuspid regurgitation pressure gradient (TRPG). 112 patients (68% men, mean±sd age 59±8 years, forced expiratory volume in 1 s (FEV1) 61±12% pred, S pO2 95±2%) were included. Mean±sd TRPG increased from 22±7 to 30±10 mmHg in 54 patients allocated to placebo and from 20±5 to 24±7 mmHg in 58 patients allocated to acetazolamide (both p<0.05) resulting in a mean (95% CI) treatment effect of -5 (-9 to -1) mmHg (p=0.015). In patients assigned to placebo at 760/3100 m, mean±sd S pO2 was 95±2%/88±3%; in the acetazolamide group, the respective values were 94±2%/90±3% (both p<0.05), resulting in a treatment effect of +2 (1 to 3)% (p=0.001). In lowlanders with COPD travelling to 3100 m, preventive acetazolamide treatment attenuated the altitude-induced rise in PAP and improved oxygenation.

Exercise hemodynamics by echocardiography and right heart catheterization in patients with chronic thromboembolic pulmonary disease

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is an important cause of pulmonary hypertension (PH). A subclinical form of PH is referred to as exercise-induced pulmonary hypertension (EIPH), and its prevalence in patients with chronic thromboembolic pulmonary disease (CTEPD) without pulmonary hypertension at rest is unknown. Purpose To explore the occurrence of exercise-induced pulmonary hypertension (PH) in patients with CTEPD and compare exercise echocardiography with right heart catheterization (RHC). Methods In total, 16 patients with CTEPD, all diagnosed after pulmonary embolism, underwent exercise echocardiography and exercise RHC with dynamic supine leg exercise using a cycle ergometer. CTEPH at rest was defined as mean pulmonary artery pressure (mPAP) &amp;gt;20 mmHg and pulmonary vascular resistance (PVR) ≥3WU. EIPH by RHC was defined as mPAP &amp;gt;30 mmHg with total pulmonary resistance (TPR) ≥3 WU. Based on these criteria, our patients with CTEPD are presented by a flow chart (Figure 1). Systolic pulmonary artery pressure by echocardiography was calculated by tricuspid regurgitation peak velocity (TR V max) and the Bernoulli formula: 4 × (TR V)2. The RHC examination followed the exercise echocardiography within 2 hours. Groups were compared with independent sample t-test. Results Four patients (25%) were diagnosed with EIPH by exercise RHC. Patients with EIPH had a mean mPAP at peak exercise of 40.5 mmHg (range 38 to 43mmHg) and TPR of 3.7 WU (range 3.0 to 4.3 WU). The same patients also had a higher TR V max at peak exercise during exercise echocardiography compared to the patients without EIPH (Table 2). None of the patients had signs of elevated left-sided filling pressure during exercise by RHC, and none had left ventricular diastolic dysfunction during exercise by echocardiography. Conclusion In total, 4 of 16 patients with CTEPD were diagnosed with EIPH. The same four patients also had abnormal pulmonary artery pressure rise during exercise echocardiography and invasive RHC. These findings suggest that exercise echocardiography may be useful for screening patients with CTEPD and suspected EIPH. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Ostfold Hospital Trust

Single-Cell RNA-Sequencing Reveals the Active Involvement of Macrophage Polarizations in Pulmonary Hypertension.

Background Sustained hypoxia can trigger a progressive rise in pulmonary artery pressure and cause serious pulmonary diseases. Macrophages play important roles along the progression of pulmonary hypertension. However, the state of macrophage polarization during the early stage of pulmonary hypertension is unclear. Methods Unlike traditional sequencing method, single-cell sequencing can accurately distinguish among cell types and better understand cell-to-cell relationships. In this study, we investigated the polarization of macrophages in pulmonary hypertension via single-cell RNA-sequencing in a mice hypoxia model, which was then validated in patients with pulmonary hypertension. Results We identified that the intermittent exposure to hypoxic conditions could lead to the production of more M2-type macrophages than M1-type macrophages in a mouse model. Further validation analysis was performed by analyzing lung tissue of patients with pulmonary hypertension, revealing that the number of disease-associated M2 macrophages was substantially increased. Conclusions In this study, the active anti-inflammatory response of macrophage involved in pulmonary hypertension has been identified, suggesting that intervention against the polarization of macrophages to the M2 type may be a potential way to reduce chronic pulmonary inflammation, pulmonary vascular remodeling, and artery pressure. Thus, investigation of macrophage polarization associated with hypoxia could help us better understand disease mechanism and craft effective prevention strategies and approaches.

SIRT 1 Activator Loaded Inhaled Antiangiogenic Liposomal Formulation Development for Pulmonary Hypertension.

Pulmonary hypertension (PH) is characterized by the rise in mean pulmonary arterial pressure (≥ 20mmHg at rest) due to the narrowing of the pulmonary arterial networks. Current treatments provide symptomatic treatment and the underlying progress of PH continues leading to higher mortality rates due to non-reversal of the disease. This warrants the need for drug therapies targeting angiogenesis and vascular remodeling mechanisms. Resveratrol, SIRT 1 activator, alters various signaling pathways, inhibits apoptosis, and negatively regulates angiogenesis either by increasing the production of anti-angiogenic factors or inhibiting pro-angiogenic factors. Our work describes the liposomal formulation development, physicochemical characterization, and in vitro aerosolization performance of resveratrol liposomal dry powder formulation. The resveratrol liposomal dry powder formulation reduces the right ventricular systolic pressure measured during right jugular vein catheterization and significantly reverses the PH disease pathological changes as demonstrated by histological observations of pulmonary arterial lumen and ventricular hypertrophy. The developed resveratrol liposomal dry powder formulation alleviates the pulmonary arterial remodeling through its antiangiogenic mechanism and indicates a promising therapeutic strategy for PH treatment.

Proteomic Profile Analysis of Pulmonary Artery in a Rat Model Under Hypoxic Pulmonary Hypertension

Aim: Proteomic profile analysis of pulmonary artery in a rat model under hypoxic pulmonary hypertension Background: Background: Hypoxic pulmonary hypertension (HPH) is a pathological condition exemplified by a constant rise in pulmonary artery pressure in high-altitudes. Objective: Objective: To investigated the proteome profile and response mechanisms of SD rats under hypoxia over a period of four-weeks. Method: Method: Proteomic profile analysis of pulmonary artery in a rat model under hypoxic pulmonary hypertension. Results: Results: With 3,204 proteins identified, 49 were up-regulated while 46 were down-regulated. Upregulated genes included Prolargin, Protein S100-A6 and Transgelin-2, whereas Nascent polypeptide-associated complex and Elongator complex protein 1 were down-regulated. KEGG enriched pathways had purine metabolism, cancer and lipolysis regulation as significantly enriched in hypoxic group. Conclusion: Conclusion: In conclusion, our findings submit basis for downstream studies on tissue hypoxia mechanisms alongside the associated physiological conditions. Hypoxic pulmonary hypertension (HPH) is a pathological condition exemplified by a constant rise in pulmonary artery pressure in high altitudes. Herein, we investigated the proteome profile and response mechanisms of Sprague-Dawley (SD) rats under hypoxia over a period of four weeks. Unbiased iTRAQ-based quantitative proteomics was utilized in proteome profile analysis of a rat model exposed to HPH. With 3,204 proteins identified, 49 were upregulated while 46 were downregulated. Upregulated genes included Prolargin, Protein, S100-A6 and Transgelin-2, whereas Nascent polypeptide-associated complex and Elongator complex protein 1 were downregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched pathways had purine metabolism, cancer, and lipolysis regulation as significantly enriched in hypoxic group. In conclusion, the findings from this study submit a basis for downstream studies on tissue hypoxia mechanisms alongside the associated physiological conditions.

Preservation of Right Ventricular Contractility After Transient Phenylephrine‐Induced Pressure Overload in Swine

ObjectiveWe have previously demonstrated that a transient phenylephrine (PE)‐induced rise in systemic arterial blood pressure leads to reversible left ventricular (LV) systolic dysfunction in the absence of ischemia (i.e., “stretch‐induced stunning”). However, the extent to which this phenomenon occurs in the right ventricle (RV) is unclear. Accordingly, the present study was designed to assess changes in pulmonary artery (PA) pressure and RV function during and after systemic administration of PE in swine.MethodsClosed‐chest propofol‐anesthetized swine (n=5) were instrumented with a Swan‐Ganz catheter and an admittance catheter for continuous measurement of PA pressure, RV pressure, and RV volume (ADV500; Transonic SciSense, Inc.). Ventricular end‐diastolic and end‐systolic volumes were assessed by multi‐detector computed tomography with iodinated contrast (1 mL/kg at 4 mL/s) before, during, and 30‐minutes after transient pressure overload elicited by a 1‐hour intravenous infusion of PE (18 mg/hour). Load‐independent RV systolic function was derived from RV pressure‐volume loops collected during inferior vena cava occlusion at baseline and 30 min after PE.ResultsPE elicited a significant rise in PA pressure (27±1/14±1 to 43±1/23±31mmHg; p&lt;0.05) and RV pressure (25±2/3±1 to 44±2/8±2 mmHg; p&lt;0.05) that normalized 30‐minutes after the end of the infusion period (PA: 28±1/11±1 mmHg; RV: 29±5/4±2 mmHg). This was accompanied by a significant increase in RV end‐diastolic and end‐systolic volumes and decrease in RV ejection fraction that tended to persist 30‐minutes after cessation of PE (Table; top panel). However, load‐dependent (dP/dtmax) and load‐independent (ESPVR and PRSW) parameters of RV systolic function were preserved after PE‐induced TPO (Table; bottom panel).ConclusionsDespite causing a significant rise in RV preload volume and pressure, transient PE‐induced pressure overload is not associated with RV contractile dysfunction during the post‐infusion period. The absence of stretch‐induced stunning in the RV may be linked to inherent differences in compliance relative to the LV as well as a diminished pressor response to PE in the pulmonary vs. systemic circulation.

Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.

The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

Exciter laser coronary atherectomy (ELCA) can be a powerful weapon in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH)

Chronic thromboembolic pulmonary hypertension (CTEPH) is mainly due to pulmonary vascular thrombosis causing pulmonary vasoconstriction and thrombosis, leading to pulmonary vascular remodeling, the formation of irreversible pulmonary arterial pressure rise, and ultimately producing serious right heart failure. It is the only curable subtype of pulmonary hypertension, mainly secondary to acute pulmonary embolism (PE), which is not rare but has a high disability rate and mortality rate. Early diagnosis and timely treatment can significantly improve the prognosis of CTEPH patients. However, the effective treatment of CTEPH has high requirements for patients, and most patients cannot be treated by surgery, resulting in high mortality.Excimer laser coronary atherectomy (ELCA) is a new percutaneous coronary intervention (PCI), which can decompose the blocking components in blood vessels through photochemical, photothermal, and photomechanical actions, and it can be used to remove thrombus, plaque, calcified lesions, and tissues. At present, it is mainly used in complex coronary artery disease, which not only improves the success rate but also reduces the incidence of complications. It showed significant advantages in the treatment of complex and refractory coronary artery disease. However, the clinical application of ELCA is limited to the coronary artery, and there is no report yet on the application of ELCA to other blood vessels in the human body, such as the pulmonary static artery.Based on the above situation, we made a basic review of ELCA and CTEPH and we discussed the hypothesis that ELCA, giving good results in complex coronary lesions, could also be applied to CTEPH.

Anesthetic Management in an Infant with Dandy–Walker Syndrome Presenting with Acyanotic Heart Disease and Hydrocephalous Post-COVID-19 Recovery: A Rare Experience

AbstractWe report a case of hydrocephalus with Dandy–Walker malformation in a 2-month-old girl child recently recovered from COVID-19. The child was detected to have acyanotic heart disease with left-to-right shunt and severe pulmonary arterial hypertension during the preoperative evaluation process for ventriculoperitoneal (VP) shunt placement. We share our experience of the perioperative management for pulmonary artery banding (PAB) and patent ductus arteriosus ligation as a part of staged cardiac corrective surgery, followed by VP shunt to relieve hydrocephalus in the single setting. Our management was focused on the preservation of the normal cerebral and cardiac physiology to prevent rise in intracranial pressure and pulmonary artery pressure. A multidisciplinary team, consisting of cardiac- and neuroanesthesiologists and cardiac and neurosurgeons, was involved in management of the case. Diligent maintenance of airway, stable hemodynamics, meticulous ventilation, along with postoperative ICU management helped in the successful outcome of this unique case.

Creatinine Clearance in Patients with Obstructive Sleep Apnea

During an apnea, hemodynamic complications such as hypoxemia, a rise in systemic and pulmonary arterial pressure, and changes in heart rate occur in patients with obstructive sleep apnea (OSA). Potential mechanisms of OSA-associated renal dysfunction include renal hypoxia, hypertension, endothelial dysfunction. Hypertension is common in patients with OSA. This study aims to assess OSA patients' renal functions and investigate the creatinine clearance (CC) values across OSA patients with and without hypertension. The study included 530 individuals with OSA and 60 individuals with an apnea-hypopnea index (AHI) of &lt;5. CC calculated with the Cockcroft-Gault Equation. Patients with OSA divide into two groups as the group of patients with hypertension (HT) (group 1) and without HT (group 2). The study included 339 (64%) male and 191 (36%) female patients. It found that 32.4% of OSA patients had HT (Group 1). There was a significant difference in CC and urea levels between groups 1 and 2 (p&lt;0.001; p=0.005). While CC was low in the OSA group, CC values were not statistically significantly different between the OSA patients and the control group (p&gt;0.05). A statistically significant difference was detected in urea and creatinine levels between the OSA and control groups (p=0.005; p=0.012). Creatinine clearance decreases in patients with OSA in the presence of HT. Patients with OSA often experience cardiovascular disorders, and glomerular endothelial dysfunction occurs in OSA patients.

In Response.

We thank Dr A. K. Jha1 for his valuable comments regarding our article.2 Although there is a correlation between the relative perfusion to the operative lung as assessed by lung scans and the partial pressure of oxygen in arterial blood (Pao2), it is unclear whether this variable is clinically relevant for patients undergoing thoracic surgery.3 Because not all the patients enrolled in our trial underwent lung perfusion scans, we did not perform a between-group comparison. We also did not measure Pao2 levels by arterial blood gas analysis during 2-lung ventilation (TLV). Because the Pao2 level during 1-lung ventilation (OLV) strongly and positively correlates with Pao2 during TLV, we were able to predict hypoxemia during OLV for patients in both groups that presented with an average room air saturation of 93% before general anesthesia. Nonetheless, we acknowledge that the TLV parameters and preoperative perfusion scans may give more insight on the impact of OLV, peak inspiratory pressure (PIP) and Pao2/fractional inspiration of oxygen (Fio2) (P/F) ratio. Hypoxic pulmonary vasoconstriction (HPV) during OLV mitigates the shunt fraction. HPV is blunted by sevoflurane and suppressed by the pathologic effects of chronic obstructive pulmonary disease (COPD). Although we did measure sevoflurane concentrations, we administered balanced anesthesia that included a remifentanil infusion. Thus, the actual concentration of sevoflurane was probably less than 1 minimum alveolar concentration (MAC), a concentration thought to have limited impact on HPV.4 Also, the treatment of OLV-induced increase in pulmonary hypertension may have been beneficial, as Dr A. K. Jha1 commented in the letter. Unfortunately, as we mentioned in the limitation section, we can only speculate there was an OLV-induced rise in pulmonary artery pressure because it was not possible to obtain accurate measurements of pulmonary arterial pressure in our clinical practice. We agree with the view that iloprost-induced pulmonary arteriolar vasodilation in the ventilated lung resulted in blood diversion from nonventilated lung to the ventilated lung with physiological dead space reduction and P/F ratio augmentation. Indeed, as our study results indicate, inhaled iloprost improves oxygenation and dead space ventilation during OLV in COPD patients with poor lung oxygenation. Considering that atelectasis in the operated lung persists in the postoperative period,5 it can be deduced that the difference in P/F ratio in the postanesthetic care unit in both groups may be due to the residual intrapulmonary shunt fraction and the residual effects of iloprost inhalation, which ameliorates the ventilation/perfusion matching. In this regard, we speculate that the beneficial effects of iloprost during OLV may persist even after TLV or spontaneous ventilation is restored, but this needs to be clarified. We think that the comments provided by Dr A. K. Jha1 are valuable and should be considered when planning further studies. Namo Kim, MD, PhDDepartment of Anesthesiology and Pain MedicineAnesthesia and Pain Research InstituteYonsei University College of MedicineSeoul, Republic of Korea Su Hyun Lee, MDDepartment of Anesthesiology and Pain MedicineYonsei Sarang HospitalSeoul, Republic of Korea Young Jun Oh, MD, PhDDepartment of Anesthesiology and Pain MedicineAnesthesia and Pain Research InstituteYonsei University College of MedicineSeoul, Republic of Korea[email protected]

Nutraceuticals in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

Early hours in the development of high-altitude pulmonary edema: time course and mechanisms.

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1-2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5-10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2-8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

P4509The cardiopulmonary vicious cycle in patients with heart failure, a mechanism for accelerated decompensation

Abstract Background Hemodynamic congestion appears days prior to the development of clinical congestion. Lung congestion is associated with increased respiratory effort and dyspnoea. The effects of increased respiratory effort on pulmonary circulation were not well-defined. Purpose The study investigates the cardiopulmonary interactions and the role of the respiratory effort in the development of decompensation. It is well-accepted that lung congestion affects the lung mechanics and increases the respiratory effort. On the other hand, changes in the intrathoracic and alveolar pressures, due to the increase in the respiratory effort, may have detrimental effects on the pulmonary circulation and the workloads of the heart. Methods We have simultaneously measured the hemodynamic indices and the respiratory mechanics in patients undergoing right heart catheterization (n=56) for the diagnosis of dyspnoea. The patients were classified either as heart failure (HF) or lung disease, according to their clinical history, symptoms and signs. The pulmonary capillary wedge pressure (PCWP) was decomposed into cardiac and respiratory waves. The respiratory effort (Presp) was defined as the respiratory wave amplitude that modulates the PCWP. Lung compliance was calculated as the ratio of the tidal volume to Presp. Results and discussion The HF patients (n=35) exhibited huge Presp of 9.6±3.7 mmHg [2.6–16.7], ∼4 fold the normal Presp, of about 2–3 mmHg (figure below). Their lung compliance decreased with increasing PCWP (2.0±0.4%/mmHg of PCWP). Both PCWP and pulmonary artery pressure (PAP) rose with Presp, by 0.92±0.36 mmHg and 1.68±0.47 mmHg, for 1 mmHg of Presp, respectively (Figure below). Interestingly, PCWP always exceeded Presp, leading to the stipulation of a novel fundamental constraint/law: the continuous pulmonary flow throughout the respiratory cycle requires that PCWP &gt; Presp (above the identity line in figure A), otherwise the capillary pressure will decrease below the surrounding alveolar pressure and the pulmonary circulation will collapse, especially during inspiration. This constraint imposes a positive feedback of Presp on the pulmonary circulatory pressures. It is also supported by the increase in PWCP with Presp in the patients with lung diseases (Figure A). The bigger rise in PAP than in PWCP is attributed to the increase in the pulmonary vascular resistance (PVR) with Presp (0.3±0.06 wood units for 1mmHg Presp). The latter constructs additional positive feedback of Presp on the cardiac workload. A decrease in the intrathoracic pressure that surrounds the heart increases the LV apparent afterload. The increase in PAP and PVR elevates the right ventricle afterload. PCWP (A) and PAP (B) vs. Presp Conclusions The respiratory effort is not just a hallmark of HF but plays a pivotal role in the cardiopulmonary vicious cycle. An increase in the respiratory effort increases the PWCP, PAP, PVR, and the afterloads of both ventricles, and thereby may accelerate cardiac decompensation.

Intravenous iron delivers a sustained (8-week) lowering of pulmonary artery pressure during exercise in healthy older humans.

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left‐heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double‐blind placebo‐controlled physiology study in 32 healthy participants aged 50–80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min−1) and a change in maximal cycling exercise capacity (V˙O2max). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V˙O2max remained unaffected in the iron‐replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.