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To evaluate the effect of aging on pulmonary vessels based on computed tomography (CT) quantification and analyse the correlation between quantitative pulmonary vascular volume and pulmonary function during aging. A total of 330 healthy adult volunteers, including 161 men (53 aged 20–39 years, 61 aged 40–59 years, and 47 aged ≥60 years) and 169 women (53 aged 20–39 years, 63 aged 40–59 years, and 53 aged ≥60 years) were recruited in this study. AVIEW software was used to quantitatively measure pulmonary vascular volume, including pulmonary total blood vessel volume (TBV) and small blood vessel volume with a cross-sectional area of <5 mm2 (BV5). Pulmonary vascular volume parameters were standardised using the ratio of vascular volume to the body surface area (BSA; TBV/BSA and BV5/BSA). Subsequently, the effect of aging on the pulmonary vessels was analysed. The pulmonary vascular volume parameters TBV/BSA and BV5/BSA of the whole lung, right lung, and left lung decreased significantly with increasing age (p< 0.05). Additionally, TBV/BSA and BV5/BSA of the whole lung were higher in men than in women. The declining trend of pulmonary vascular volume was consistent in men and women and increased with age. The pulmonary vascular volume parameters, TBV/BSA and BV5/BSA, decreased with age and were weakly positively correlated with pulmonary function. • Aging affects the pulmonary vascular structure. • With the increase in age, the pulmonary vascular volume decreased significantly. • The declining trend of the pulmonary vascular volume was consistent in both sexes. • The pulmonary vascular volume was weakly correlated with pulmonary function. [ABSTRACT FROM AUTHOR]

A mild pneumocoelom was diagnosed by computed tomography in a stranded juvenile loggerhead sea turtle (Caretta caretta). After gas extraction by ultrasound-guided puncture, the animal did not improve and was subjected to hyperbaric oxygen therapy (HBOT). After HBOT, the turtle developed marked subcutaneous emphysema and was found dead the following morning. Gross lesions included a distended right atrium with numerous gas bubbles within the epicardium, gas bubbles in the hepatic, gastric and mesenteric veins, a small gas-filled bulla in the left lung and diffuse haemorrhages in the encephalon. Histological lesions included gas-like emboli in the lumen of the right atrium with myocardial necrosis, gas-like emboli in the lumina of intestinal, pulmonary and renal blood vessels and severe meningeal haemorrhages. From a forensic pathology perspective, the subcutaneous emphysema of immediate onset after HBOT and the greater severity of the histological lesions in blood vessels, heart, lung and brain differentiate this case from other cases of gas embolism in turtles due to incidental capture. Two factors contributed to this outcome: the existence of a probably unresolved pneumocoelom and the application of HBOT without an initial diagnosis that accurately indicated its use. Therefore, as in human medicine, the use of HBOT in sea turtles with lung lesions and pneumocoelom is discouraged. This is the first description of an iatrogenic gas embolism in a sea turtle. [Display omitted] [ABSTRACT FROM AUTHOR]

• Mixed pulmonary hypertension in patients with left heart disease from chronic heart failure is related to a constellation of underlying pathologies: left ventricular dysfunction, valvular heart disease, and chronic pressure/volume overload. • Recently, several biomarkers with potential diagnostic and prognostic significance in pulmonary arterial hypertension have been identified, encompassing heart failure indicators, endothelial and platelet function impairment, cardiac myocyte harm, and oxidative stress. • Current methods of assessing pulmonary hypertension reversal may prohibit suitable candidates from being considered for heart transplantation and routed toward left ventricular assist device placement. • Future optimization may include the use of combination therapy with temporary mechanical circulatory support at home and concomitant medical therapy. Pulmonary arterial hypertension (PAH) is characterized by persistently increased pressure in the pulmonary arteries. New defining criteria for the different hemodynamic types of pulmonary hypertension (PH) that occur with left heart disease have been proposed by the task force on PH. After consideration of the changes in the general definition of PH in left heart disease, the proposed hemodynamic definition was: (1) isolated postcapillary PH: pulmonary artery wedge pressure >15 mm Hg and mean pulmonary arterial pressure (mPAP) >20 mm Hg and pulmonary vascular resistance (PVR) <3 Woods units (WU); and (2) combined post- and precapillary PH: pulmonary artery wedge pressure >15 mm Hg, mPAP >20 mm Hg, and PVR ≥3 WU. Secondary PH is initially reversible, but eventually, it can become fixed because of the remodeling process of the pulmonary vascular system. Limitations in defining both the time for and amount of reversibility lack clarity. We discuss a case of PH as a framework to better understand these key principles in addressing patients' candidacy for heart or heart-lung transplantation. We performed a literature search for all available contemporary data with the following terms: "pulmonary hypertension," "reversal," "Impella 5.5," "temporary mechanical support," and "LVAD" using the National Library of Medicine – PubMed and PubMed Central between 2019 and 2023. A total of 14 published papers were found with these search. From these, 3 addressed the issue of PH and reversibility in the setting of LHD after durable LVAD placement. No papers were found using Impella 5.5 and PH during this timeframe. Given the paucity of data in the field regarding temporary mechanical circulatory support and pulmonary hypertension, we present a case-based discussion to guide the reader in understanding the potential impact of this method in patients with WHO Class 2 Pulmonary hypertension. A 49-year-old woman with a medical history of acute on chronic biventricular systolic and diastolic heart failure, American College of Cardiology stage D, Stevenson profile C, New York Heart Association class IV (ejection fraction 18%) secondary to nonischemic cardiomyopathy after cardiac resynchronization therapy, pulmonary hypertension, bilateral deep vein thrombosis, and segmental pulmonary embolism presented for heart transplant evaluation. Her cardiac output and central hemodynamics were measured, and she was found to have a pulmonary artery (PA) pressure of 78/38 with a mean PA pressure of 51, pulmonary capillary wedge pressure (PCWP) 30, transpulmonary pressure gradient (TPG) 21, thermodilution cardiac output (CO) 3.35 L/min, and cardiac input (CI) 1.75 L/min/m2. Her PVR was 6.2 WU. Provocative pharmacologic testing for reversibility of PH was performed using sodium nitroprusside, which resulted in a blood pressure of 83/57 (92), heart rate 92/min, and PA pressure of 71/31, with a mean PA pressure of 44 PCWP 22, TPG 22, CO 4.8 L/min, and CI of 2.48 L/min/m2 with a PVR of 4.5 WU. Following this, the patient underwent Impella 5.5 placement through the right axillary artery to optimize afterload reduction and improve end-organ perfusion. Post-Impella hemodynamics on milrinone 0.5 mcg/kg/min demonstrated the following: blood pressure 90/66 (74), heart rate 53/min, and PA pressure of 56/29, with a mean PA pressure of 38, PCWP 24, TPG 14, CO 6 L/min, and CI of 2.9 L/min/m2 with a PVR of 2.3 WU. Left ventricular assist device support with Impella 5.5 is associated with a reduction in mPAP and PVR over weeks to months and thus plays a crucial role as a bridge to transplant. Our case and this review highlights the characteristics of PH resulting from heart failure with reduced ejection fraction and discusses the important clinical issues related to the treatment of these patients. We have shown that left ventricular assist device therapy with Impella 5.5 can effectively reduce left-sided filling pressures and lead to PH improvement. We demonstrate the potential benefits of Impella 5.5 in the management of patients with WHO 2 PH and cardiogenic shock with impaired hemodynamics. [ABSTRACT FROM AUTHOR]

Thoracic radiation therapy (RT) may lead to pulmonary vascular remodeling. In this study we investigated vascular pruning (i.e. regression) of proximal-to-distal pulmonary blood vessels (PBV) after thoracic RT for non-small cell lung cancer (NSCLC). In addition, we investigated the association of PBV dose with outcomes. We retrospectively deployed an open-source pulmonary blood vessel (vein and arteries) auto-segmentation algorithm on RT planning CT scans from a clinical dataset of 878 patients with NSCLC. We divided PBVs into small, medium, and large vessels based on diameter cutoffs of <2.5mm2, 2.5mm2 to 10mm2, and >10mm2, respectively. We split the dataset to measure PBV pruning (Cohort 1, n=179) and PBV dose-outcomes (Cohort 2, n=699). Cohort 1 had paired planning and post-RT CT scans. Pre- and post-RT CT scans were registered to measure changes in PBV total density (PBV-TD) and volume changes for small (PBV-S), medium (PBV-M), and large (PBV-L) vessels, based on regions of dose received and RT modality (3D-conformal RT [3D-CRT], volumetric modulated arc therapy [VMAT], stereotactic body RT [SBRT]). In Cohort 2, patients with locally advanced NSCLC were analyzed for association of PBV dose variables all-cause mortality and major adverse cardiovascular events (MACE), using area under the receiver operating curve (AUC) and Cox and Fine and Gray regressions. The baseline median PBV volumes for cohort 1 vs 2 were: PBVTV 183.3cc (IQR: 67.0cc) vs 165.0cc (IQR:44.7cc), PBV-S 30.0cc vs 32.0cc, PBV-M 121.9vs 125.0cc, and PBV-L 36.0cc vs 37.5. The PBV-S (-2.3%) and PBV-M (-6.8%) significantly decreased after RT, while PBV-L increased (+9.5%), but the total vessel volume (PBV-TD <1.1% change) remained almost constant. There was a dose-dependent effect on PBV-S and PBV-M pruning (p<0.01 for trend) and PBV-L increase (p<0.05), and significantly more pruning with SBRT vs 3DCRT and VMAT technique (p< 0.02). The greatest effect was observed in SBRT with 11.7% change. In Cohort 2, dose to the PBV-S and PBV-M were predictive of all-cause mortality on AUC analysis and the strongest predictors were V20 to PBV-S (AUC 0.58) and PBV-M (AUC 0.58). On multivariable analysis adjusting for age, sex, history of cardiac disease, use of surgery, and LAD V15 (but excluding lung V20Gy due to collinearity), PBV-S V20 was associated with mortality (aHR 6.5, 95% CI 1.99-21.20; p=0.002). Though there was no collinearity with planning target volume (PTV), a similar model that included PTV with the above variables resulted in a loss of significance for PBV-S V20 (p>0.05). No PBV DVH parameters were associated with MACE (p>0.05). Radiation dose to the PBVs leads to pruning of small- to medium-sized vessels in a dose dependent manner and is most pronounced with SBRT. Dose to the PBVs may be associated with survival, but not cardiac endpoints. Further analysis of PBV dose and relationship to PTV is warranted to understand the pathophysiological impact of lung vessel pruning. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by substantial morbidity and mortality rates. It is a chronic condition characterized by intricate pathogenesis and uncontrollable factors. We summarized the pathological effects of estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification on PH. PH is not only a pulmonary vascular disease, but also a systemic disease. The findings emphasize that the onset of PH is not exclusively confined to the pulmonary vasculature, consequently necessitating treatment approaches that extend beyond targeting pulmonary blood vessels. Hence, the research on the pathological mechanism of PH is not limited to target organs such as pulmonary vessels, but also focuses on exploring other fields (such as estrogen, genetics, neuroinflammation, intestinal microbiota, metabolic reorganization, and histone modification). [Display omitted] [ABSTRACT FROM AUTHOR]

Metastasis is a major cause of death in cancer patients. The extracellular matrix molecule tenascin-C is a known promoter of metastasis, however the underlying mechanisms are not well understood. To further analyze the impact of tenascin-C on cancer progression we generated MMTV-NeuNT mice that develop spontaneous mammary tumors, on a tenascin-C knockout background. We also developed a syngeneic orthotopic model in which tumor cells derived from a MMTV-NeuNT tumor. Tumor cells were transfected with control shRNA or with shRNA to knockdown tenascin-C expression and, were grafted into the mammary gland of immune competent, wildtype or tenascin-C knockout mice. We show that stromal-derived tenascin-C increases metastasis by reducing apoptosis and inducing the cellular plasticity of cancer cells located in pulmonary blood vessels invasions (BVI), before extravasation. We characterized BVI as organized structures of tightly packed aggregates of proliferating tumor cells with epithelial characteristics, surrounded by Fsp1+ cells, internally located platelets and, a luminal monolayer of endothelial cells. We found extracellular matrix, in particular, tenascin-C, between the stromal cells and the tumor cell cluster. In mice lacking stromal-derived tenascin-C, the organization of pulmonary BVI was significantly affected, revealing novel functions of host-derived tenascin-C in supporting the integrity of the endothelial cell coat, increasing platelet abundance, tumor cell survival, epithelial plasticity, thereby promoting overall lung metastasis. Many effects of tenascin-C observed in BVI including enhancement of cellular plasticity, survival and migration, could be explained by activation of TGF-β signaling. Finally, in several human cancers, we also observed BVI to be surrounded by an endothelial monolayer and to express tenascin-C. Expression of tenascin-C is specific to BVI and is not observed in lymphatic vascular invasions frequent in breast cancer, which lack an endothelial lining. Given that BVI have prognostic significance for many tumor types, such as shorter cancer patient survival, increased metastasis, vessel occlusion, and organ failure, our data revealing a novel mechanism by which stromal tenascin-C promotes metastasis in human cancer, may have potential for diagnosis and therapy. • Host tenascin-C (TNC) encapsulates blood vessel invasions, BVI, promoting metastasis. • TNC increases endothelialization, tumor cell survival, platelet attraction and plasticity. • Through TGFbeta signaling TNC induces EMT and enhances cell migration and survival. • Unlike lymphatic invasions BVI in human cancer are endothelialized and express TNC. [ABSTRACT FROM AUTHOR]

Introduction: Reduced left ventricular (LV) diastolic function can exert significant load to the right ventricle (RV) that can affect RV-pulmonary vasculature (PV) coupling. RV-PV can be assessed with the RV length-force relationship (tricuspid annular plane systolic excursion [TAPSE] to pulmonary artery acceleration time [PAAT] ratio). We aimed to determine the association between LV diastolic function measured using tissue Doppler imaging (TDI) and TAPSE/PAAT.Methods: A study of premature infants <29 weeks gestation. TAPSE/PAAT, LV e' and a' waves were measured on Day 1 following birth. Correlation between diastolic indices and TAPSE/PAAT was performed. The independent effect of LV diastolic function and TAPSE/PAAT was assessed using linear regression.Results: One hundred and sixty-two infants with a mean ± SD gestation & birthweight of 26.6 ± 1.5 weeks & 938 ± 241 g. There was a significant positive correlation between LV e' (r = 0.44, p < 0.01)/LV a' (r = 0.44, p < 0.01) and TAPSE/PAAT. This relationship remained significant when adjusting for important confounders (all p < 0.01). Infants with LV a' values in the lowest quartile had lower TAPSE values (4.2 ± 1.2 vs. 5.1 ± 1.1 mm, p < 0.01) without a difference in PAAT (41 ± 8 vs. 41 ± 10 ms, p = 0.97).Conclusions: We observed a direct correlation between LV diastolic function and RV-PV coupling in the first day of age, highlighting the importance ventricular interdependence in premature infants. TAPSE/PAAT, as the index of the RV-PV interaction may be further explored for its potential to assess RV reserve under stress with preterm infants in health and disease. [ABSTRACT FROM AUTHOR]

Abstract Background Ventricular septal defects (VSDs) generally have benign long-term prognoses, but recent studies have indicated increased pulmonary vascular resistance. A potential tool for monitoring pulmonary artery pressure is heart rate variability, and therefore, the aim of this study was to assess heart rate variability in adults with a surgically repaired or unrepaired VSD. Methods In a long-term, follow-up study, three groups were included; VSD-patients operated in early childhood, patients with an open VSD, and controls. For each patient, 24-hour Holter monitoring was performed and heart rate variability was assessed. Results In total, 30 participants with a surgically closed VSD, 30 participants with an unrepaired VSD, and 36 controls were included. In the closed VSD group, there was a higher proportion of participants, who had low sNN50 (p = 0.005) and low sNN6% (p = 0.017) than in the other two groups. Similar differences were found when sNN50 was divided into increases and decreases (p = 0.007 and p = 0.005, respectively) as well as sNN6% (p = 0.014 and p = 0.014, respectively). Lastly, there was a higher proportion of patients in the closed VSD group with low rMSSD than in the other two groups (p = 0.005). For the closed VSD group, the proportion of participants with low total sNN50 (p = 0.046) and low total sNN6% (p = 0.046) were higher among participants with a complete right bundle branch block (RBBB) than among participants with no or an incomplete RBBB. Conclusions Adults who had surgical VSD closure in early childhood had impaired heart rate variability and, particularly, participants with complete RBBB had lower heart rate variability. Highlights • Recent studies have indicated increased pulmonary vascular resistance in patients operated for a ventricular septal defect • Even relatively minor abnormalities of right ventricular function have been associated with abnormalities of HRV • This study shows that adults who had surgical VSD closure in early childhood have impaired heart rate variability • Particularly, patients with complete RBBB have lower heart rate variability [ABSTRACT FROM AUTHOR]

Highlights • We investigate the effect of aging on extravascular lung water at high altitude. • Older adults may be more likely to develop extravascular lung water at altitude. • Our slow acclimatization profile resulted in subclinical and sporadic comet tails. • Future studies should use a faster ascent and image immediately following exercise. Abstract Extravascular lung water (EVLW) increases in healthy adults upon exposure to high altitude, likely due to increased pulmonary vascular resistance (PVR). Older individuals experience increased PVR during exercise, which may be exacerbated by trekking at high altitude. This study aimed to determine whether EVLW development is greater in older versus younger adults during graded altitude exposure. Fourteen younger (32 ± 6y) and 12 older (58 ± 5y) healthy adults completed an 11-day trek of Mount Kilimanjaro. EVLW was assessed at rest via comet tails prior to the trek in Moshi (950 m), at Shira Camp (3505 m), at Barafu Camp (4837 m), and post-descent. An increase in altitude from Baseline to Barafu tended to increase the proportion of participants with mild EVLW (p = 0.06). A higher proportion of older versus younger individuals tended to show mild EVLW at Barafu (56 vs. 14%, p = 0.06). In conclusion, EVLW formation may be more common in older adults trekking at high altitude. However, the presence of EVLW in older adults was subclinical. [ABSTRACT FROM AUTHOR]

Abstract Background Elevation in central venous pressure (CVP) plays a fundamental pathophysiologic role in Fontan circulation. Because there is no sub-pulmonary ventricle in this system, CVP also provides the driving force for pulmonary blood flow. We hypothesized that this would make Fontan patients more susceptible to even low-level elevation in pulmonary vascular resistance index (PVRI), resulting in greater systemic venous congestion and adverse outcomes. Methods Adult Fontan patients and controls without congenital heart disease undergoing clinical evaluation that included cardiac catheterization and echocardiography were examined retrospectively. Outcomes including all-cause mortality and the development of Fontan associated diseases (FAD, defined as protein losing enteropathy, cirrhosis, heart failure hospitalization, arrhythmia, or thromboembolism) were assessed from longitudinal assessment. Results As compared to controls (n = 82), Fontan patients (n = 164) were younger (36 vs 45 years, p < 0.001), more likely to be on anticoagulation or antiplatelet therapy, and more likely to have atrial arrhythmia or cirrhosis. There was a strong correlation between CVP and PVRI in the Fontan group (r = 0.79, p < 0.001), but there was no such relationship in controls. Elevated PVRI identified patients at increased risk for FAD (HR 1.92, 95% CI 1.39–2.41, p = 0.01), and composite endpoint of FAD and/or death (HR 1.89, 95% CI 1.32–2.53, p = 0.01) per 1 WU∗m2 increment. Conclusions Systemic venous congestion, which is the primary factor in the pathogenesis of FAD and death, is related to even low-level abnormalities in pulmonary vascular function. Multicenter studies are needed to determine whether interventions targeting pulmonary vascular structure and function can improve outcomes in the Fontan population. Highlights • Pulmonary vascular resistance is the primary determinant of systemic venous congestion. • Systemic venous congestion is the primary factor in the pathogenesis of Fontan associated diseases (FAD) and death. • Therapy targeted a pulmonary vascular resistance may modify risk of FAD and death. [ABSTRACT FROM AUTHOR]

Purpose: Despite the high prevalence of pulmonary vascular alterations and their substantial impact on chronic obstructive pulmonary disease (COPD), tools for the direct in vivo assessment of pulmonary vascular alterations remain limited. Thus, the purpose of this study was to automatically extract pulmonary vessels from volumetric chest CT and evaluate the associations between the derived quantitative pulmonary vessel features and clinical parameters, including survival, in COPD patients.Methods: This study included 344 adult COPD patients. Pulmonary vessels were automatically extracted from volumetric chest CT data. Quantitative pulmonary vessel features were obtained from various lung surface areas (LSAs), which are theoretical surface areas drawn at different depths from the pleural borders. The total number of vessels (Ntotal) and number of vessels with vessel area (VA) less than 5 mm2 (N<5mm) were counted as both robust values and as values per 10 cm2 of LSA (Ntotal/LSA; N<5mm/LSA). The average VA (VAmean) and percentage of measured VA in the corresponding LSA (%VA) were measured. Associations between quantitative pulmonary vessel features and clinical parameters, including survival and the pulmonary function test (PFT), were evaluated.Results: The pulmonary vessels were automatically extracted with 100% technical success. Cox regression analysis showed Ntotal/LSA, N<5mm/LSA, VAmean, and %VA to be significant predictors of survival (hazard ratio (HR), 0.80, 0.75, 0.70, 0.49, respectively). Patients classified into high-risk groups by %VA18mm (cut-off = 3.258), chosen because it demonstrated the strongest statistical influence on survival in a univariate Cox analysis, were associated with worse overall survival before (HR, 4.83; p < 0.001) and after adjustment for patient age and BMI (HR, 2.18; p = 0.014). Of the quantitative pulmonary vessel features, Ntotal/LSA, N<5mm/LSA, and %VA were correlated with FEV1, FEV1/FVC, and DLCO in all LSAs. The strongest correlation with PFTs was noted at LSA9mm for both Ntotal (FEV1, r = 0.33; FEV1/FVC, r = 0.51) and N<5mm (FEV1, r = 0.35; FEV1/FVC, r = 0.52). For %VA, the association was most evident at LSA18mm (FEV1, r = 0.27; FEV1/FVC, r = 0.47). Significant moderate to strong correlations were consistently observed between the extent of emphysema and quantitative pulmonary vessel features (r = 0.44-0.66; all p < 0.001).Conclusions: The automated extraction of pulmonary vessels and their quantitative assessment are technically feasible. Various quantitative pulmonary vessel features demonstrated significant relationships with survival and PFT in COPD patients. Of the various quantitative features, the percentage of total VA measured at 18 mm depth from the pleural surface (%VA18mm) and the number of small vessels counted per 10 cm2 of LSA at 9 mm depth from the pleural surface (N<5mm/LSA9mm) had the strongest predictability for the clinical parameters. [ABSTRACT FROM AUTHOR]

Objective This study investigated the impact of SO 2 on rats with hypoxic pulmonary vascular structural remodeling and its possible mechanisms. Materials and methods Pulmonary vascular morphological change was examined by HE staining. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in Normal and Hypoxia–induced Pulmonary hypertension (HPH) rats. The Real-time quantitative RT-PCR (q RT-PCR) was used for validation of wnt7b, sfrp2, cacna1f, DKK1, CaSR and vimentin mRNA expression levels. Protein levels of CaSR, Vimentin, Caspase3, E-cadherin and P-Akt1/2/3 were detected by Western blot and immunohistochemistry. Results This study showed that SO 2 significantly attenuated the interstitial thickening and prominent media hypertrophy of pulmonary arteries. SO 2 downregulated p-Akt1/2/3 protein level and upregulated E-cadherin protein level in lung tissues, which inhibited the proliferation and epithelial-to-mesenchymal transition (EMT) in HPH rats. RNA-seq and PCR validation results showed that levels of Wnt7b, Sfrp2 and Cacna1f mRNAs decreased and Dkk1 mRNA level increased obviously in HPH rats. Moreover, SO 2 attenuated the mRNA and protein level of CaSR, which was activated in HPH rats and resulted in the proliferation of PASMCs. Besides, the mRNA and protein expression of vimentin in PASMCs significantly reduced after SO 2 treatment. Conclusion Together, these findings indicate that SO 2 could attenuate hypoxia-induced pulmonary arteriolar remodeling and may suppress the proliferation and migration of PASMCs at least in part through the Dkk1/Wnt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Effective pulmonary blood flow (COEPBF) has recently been validated as a technique for determining cardiac output (CO) in animals of varying sizes. The primary aim of our study was to investigate this new technique in paediatric surgical patients, compared with suprasternal two-dimensional Doppler (COSSD).Methods: A total of 15 children undergoing cleft lip/palate surgery were investigated. Before the start of surgery, manoeuvres that were anticipated to reduce (increase in PEEP from 3 to 10 cm H2O) and increase (atropine) CO were undertaken. A study in mechanically ventilated piglets was also undertaken under general anaesthesia, measuring COEPBF and pulmonary artery (COTS) flow by ultrasonic probe as the comparator. Bias (Bland-Altman plots) and limits of agreement were assessed for effective pulmonary blood flow and COSSD or COTS.Results: In paediatric patients (median age 8.5 months), overall bias was -8.1 (limits of agreement -82 to +66) ml kg-1 min-1, with a mean percentage error of 48% and a concordance rate of 64%. In the piglet model, overall bias was -1 (-36 to +38) ml kg-1 min-1, with a mean percentage error of 31% and a concordance rate of 95%.Conclusions: Under controlled experimental conditions, COEPBF is associated with excellent agreement and good trending ability when compared with the gold standard COTS. In the paediatric clinical setting, COEPBF performs well; by contrast, COSSD, an operator- and anatomy-dependent technology, appears less reliable than COEPBF. [ABSTRACT FROM AUTHOR]

Immune cell death caused by neutrophil extracellular traps (NETs), referred to as NETosis, can contribute to the pathogenesis of endotoxemia and organ damage. Although the mechanisms by which infection induces NETosis and how that leads to organ dysfunction remain largely unknown, NET formation is often found following citrullination of histone H3 (CitH3) by peptidylarginine deiminase (PAD). We hypothesized that lipopolysaccharide (LPS)-induced activation of PAD and subsequent CitH3-mediated NET formation increases endothelial permeability and pulmonary dysfunction and, therefore, that inhibition of PAD can mitigate damage and improve survival in lethal endotoxemia. Here, we showed that treatment with YW3–56, a PAD2/PAD4 inhibitor, significantly diminished PAD activation, blocked LPS-induced pulmonary vascular leakage, alleviated acute lung injury, and improved survival in a mouse model of lethal LPS-induced endotoxemia. We found CitH3 in the bloodstream 30 min after intraperitoneal injection of LPS (35 mg/kg) into mice. Additionally, CitH3 production was induced in cultured neutrophils exposed to LPS, and NETs derived from these LPS-treated neutrophils increased the permeability of endothelial cells. However, YW3–56 reduced CitH3 production and NET formation by neutrophils following LPS exposure. Moreover, treatment with YW3–56 decreased the levels of circulating CitH3 and abolished neutrophil activation and NET formation in the lungs of mice with endotoxemia. These data suggest a novel mechanism by which PAD-NET-CitH3 can play a pivotal role in pulmonary vascular dysfunction and the pathogenesis of lethal endotoxemia. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT 2A/2B/7 . In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single-agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO 2 , and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO 2 measurements, as compared with MCT+Veh ( P  < 0.05), and diastolic pulmonary artery pressure ( P  < 0.05), as compared with single-agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single-agent RP in PAH. RP, as mono and adjunctive therapy compared with induced-control, mitigated the functional and structural effects of MCT-induced PAH. [ABSTRACT FROM AUTHOR]

Background Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4 ) gene, leading to a loss of general control nonderepressible 2 ( GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Methods Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [ BMPR2 ] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. Results PVOD patients showed a significant decrease of pulmonary arterial patency ( p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis ( p = 0.001), less severe medial hypertrophy ( p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins ( p = 0.002). GCN2 expression was abolished in heritable PVOD ( p < 0.0001), but also importantly decreased in sporadic PVOD ( p = 0.03) as well as in heritable ( p = 0.002) and idiopathic PAH ( p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model ( p < 0.0001 for all models). Conclusions Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities. [ABSTRACT FROM AUTHOR]

Introduction A wide variety of pulmonary conditions are found in cirrhotic patients and may compromise the pleura, diaphragm, parenchyma, and pulmonary vasculature, influencing the results of liver transplantation. Objective To evaluate the pulmonary function (lung capacities, volumes, and gasometric study) of patients with liver cirrhosis awaiting liver transplantation. Patients and Methods Cirrhotic patients, subdivided into 3 groups stratified by liver disease severity using the Child-Pugh-Turcotte score, were compared with a control group of healthy volunteers. In spirometry, the parameters evaluated were total lung capacity, forced volume in the first second, and the relationship between forced volume in the first minute and forced vital capacity. Blood gas analysis was performed. In the control group, arterial oxygenation was evaluated by peripheral oxygen saturation by pulse oximetry. Results Of the 55 patients (75% men, 51 ± 12.77 years), 11 were Child A (73% men, 52 ± 14.01 years), 23 were Child B (75% men, 51 ± 12.77 years), and 21 were Child C (95% men, 50 ± 12.09 years). The control group had 20 individuals (50% men, 47 ± 8.15 years). Pulmonary capacities and volumes by the parameters evaluated were within the normal range. Arterial blood gas analysis detected no hypoxemia, but a tendency to low partial gas pressure was noted. Conclusion In this population of cirrhotic patients the parameters of spirometry were normal in relation to the lung capacities and volumes in the different groups. No hypoxemia was detected, but a tendency to hypocapnia in the blood gas was noted. [ABSTRACT FROM AUTHOR]

Background: The clinical impact of pulmonary capillary wedge pressure (PCWP) on long-term mortality among patients with pulmonary arterial hypertension (PAH) has been incompletely reported, particularly in relation to concomitant treprostinil administration. The goal of this study was to assess the impact of PCWP on long-term mortality in PAH patients treated with parenteral treprostinil.Methods: We studied a cohort of 743 patients with PAH treated with parenteral treprostinil therapy. The long-term all-cause mortality was compared in patients with baseline mean PCWP≤8mmHg, 811mmHg over 4-year follow-up.Results: Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP ≤ 8mmHg, 233 patients (31.4%) had a mean PCWP of >8mmHg and ≤11mmHg, and 230 patients (31.0%) had a mean PCWP >11mmHg. While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between patients with PCWP≤8mmHg, 811mmHg at 1 year (10.4% vs 9.9% vs 10.0%, p=0.980) and 4 years (16.8% vs 21.9% vs 19.2%, p=0.353) respectively. In multivariate analysis, PCWP was not independently predictive of 4-year all-cause mortality [HR 1.00, 95%CI 0.95-1.05, p=0.98 (permmHg)]. Predictors of 4-year mortality included older age [HR 1.02, 95%CI 1.00-1.03, p=0.0091 (per year)], non-​Caucasian race, and higher PVR [HR 1.06, 95% CI 1.04-1.08, p<0.0001 (per Woods Unit)].Conclusions: In this study of patients with PAH receiving parenteral treprostinil, PCWP was not associated with long-term all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted. [ABSTRACT FROM AUTHOR]

Background The optimal duration of oral anticoagulant therapy after a first, unprovoked venous thromboembolism is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. Risk stratification tools may assist in decision making. Objectives We sought to determine the relationship between residual pulmonary embolism assessed by baseline ventilation-perfusion scan after completion of 5–7 months of oral anticoagulant therapy and the risk of recurrent venous thromboembolism in patients with the first episode of unprovoked pulmonary embolism. Methods We conducted a multicentre prospective cohort study of participants with a first, unprovoked venous thromboembolism enrolled after the completion of 5–7 months of oral anticoagulation therapy. The participants completed a mean 18-month follow-up. Participants with pulmonary embolism had baseline ventilation-perfusion scan before discontinuation of oral anticoagulant therapy and the percentage of vascular obstruction on baseline ventilation-perfusion scan was determined. During follow-up after discontinuation of oral anticoagulant therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated with reference to baseline imaging. Measurements and main results During follow-up, 24 of 239 (10.0%) participants with an index event of isolated pulmonary embolism or pulmonary embolism associated with deep vein thrombosis and central assessment of percentage of vascular obstruction on baseline ventilation-perfusion scan had confirmed recurrent venous thromboembolism. As compared to participants with no residual pulmonary embolism on baseline ventilation-perfusion scan, the hazard ratio for recurrent venous thromboembolism was 2.0 (95% CI 0.5–7.3) for participants with percentage of vascular obstruction of 0.1%–4.9%, 2.1 (95% CI 0.5–7.8) for participants with percentage vascular obstruction of 5.0%–9.9% and 5.3 (95% CI 1.8–15.4) for participants with percentage vascular obstruction greater than or equal to 10%. Conclusions Residual pulmonary embolism assessed by pulmonary vascular obstruction on baseline ventilation-perfusion performed after 5–7 months of oral anticoagulant therapy for the first episode of unprovoked pulmonary embolism was associated with a statistically significant higher risk of subsequent recurrent venous thromboembolism. Percentage of pulmonary vascular obstruction assessment by ventilation-perfusion scans maybe a useful tool to help guide the duration of oral anticoagulant therapy after a first unprovoked pulmonary embolism. Trial registration Registered at www.clinicaltrials.gov identifier: NCT00261014 . [ABSTRACT FROM AUTHOR]

The effect of gene silencing by survivin siRNA (siSurvivin) on the proliferation and apoptosis of lung tumor has been attracted more interest. GABA B receptor ligand-directed nanoparticles consisting of baclofen functionalized trimethyl chitosan (Bac-TMC) as polymeric carriers, tripolyphosphate (TPP) as ionic crosslinker, and siSurvivin as therapeutic genes, were designed to enhance the survivin gene silencing. GABA B receptor agonist baclofen (Bac) was initially introduced into TMC as a novel ligand. This Bac-TMC/TPP nanoparticles increased the uptake of survivin siRNA through the interaction with GABA B receptor, further resulted in efficient cell apoptosis and gene silencing. For siRNA-loaded nanoparticles pulmonary delivery, mannitol was utilized for it delivery into pressurized metered dose inhalers (pMDI). The fine particle fractions of this formulation was (45.39 ± 2.99)% indicating the appropriate deep lung deposition. These results revealed that this pMDI formulation containing Bac-TMC/TPP nanoparticles would be a promising siRNA delivery system for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Endothelial injury is considered as a trigger of pulmonary vascular lesions in the pathogenesis of hypoxic pulmonary hypertension (HPH). Although endothelial colony-forming cells (ECFCs) have vascular regeneration potential to maintain endothelial integrity, hypoxia-induced precise alteration in ECFCs function remains controversial. This study investigated the impact of hypoxia on human ECFCs function in vitro and the underlying mechanism. We found that hypoxia inhibited ECFCs proliferation, migration and angiogenesis. Compared with no treatment, the expression of hypoxia inducible factor-1α (HIF-1α) in hypoxia-treated ECFCs was increased, with an up-regulation of p27 and a down-regulation of cyclin D1. The over-secreted vascular endothelial growth factor (VEGF) was detected, with the imbalanced expression of fetal liver kinase 1 (flk-1) and fms related tyrosine kinase 1 (flt-1). Hypoxia-induced changes in ECFCs could be reversed by HIF-1α inhibitor KC7F2. These data suggest that HIF-1α holds the key in regulating ECFCs function which may open a new perspective of ECFCs in HPH management. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) is the main etiological cause of chronic obstructive pulmonary disease, the prevalence of which has continuously increased in recent years. 4-Hydroxycinnamic acid (HA) is a plant phenolic acid that has anti-inflammatory activities. In this study, we explored the therapeutic effects of HA on airway inflammation caused by CS and lipopolysaccharide (LPS) in mice. The animals received 1 h of CS exposure for 7 days and intranasal instillation of LPS on day 4. HA (10 and 20 mg/kg) was administered to animals via oral gavage 1 h before CS exposure. HA treatment significantly decreased the accumulation of inflammatory cells and production of cytokines, including tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, caused by CS and LPS exposure. After histological examination, we observed that HA treatment significantly reduced the infiltration of inflammatory cells into lung tissue caused by CS and LPS exposure. Furthermore, HA-treated groups showed significantly decreased phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor-κB, and activity of cytochrome c oxidase subunit-2 caused by CS and LPS. In conclusion, HA effectively suppresses the airway inflammatory response induced by CS and LPS exposure, and is closely associated with the downregulation of mitogen-activated protein kinases signaling. [ABSTRACT FROM AUTHOR]

Sodium silicate (Na2SiO 3) is an inorganic silica salt used in many products. Few studies reported autoimmune diseases (AIDs) due to Na2SiO 3 exposure. This study investigates the role of Na2SiO 3 exposure by different routes and doses in AID development in rats. We assigned 40 female rats to four groups: G1 control group, G2 rats were subcutaneously injected with 5 mg Na2SiO 3 suspension, and G3 and G4 rats were orally administered 5 mg and 7 mg Na2SiO 3 suspension, respectively. Na2SiO 3 was administered weekly for 20 weeks. Serum anti-nuclear antibodies (ANA) detection, histopathology of kidney, brain, lung, liver, and heart, oxidative stress biomarkers (MDA and GSH) in tissues, Matrix metalloproteinase activity in serum, TNF-α, and Bcl-2 expression in tissues were performed. ANA was significantly increased in silicate groups, especially G2. Creatinine was significantly increased in silicate groups. Histopathology revealed vasculitis and fibrinoid degeneration of blood vessels, a picture of immune-mediated glomerulonephritis in the kidneys, and chronic interstitial pneumonia with medial hypertrophy of pulmonary blood vessels. The activity of gelatinases (MMP-2 and MMP-9) and collagenase (MMP-13), which play role in inflammation, remodeling, and immune complex degradation, were significantly increased in the silicate-exposed groups. Bcl-2 was significantly decreased, indicating apoptosis. Therefore, oral administration and subcutaneous injection of Na2SiO 3 induced immune-mediated glomerulonephritis with elevated ANA levels and overexpression of TNF-α in rats. • Development of autoimmune disease model by administration of sodium silicate. • Elevation of anti-nuclear antibodies by sodium silicate. • Development of immune-mediated glomerulonephritis. • Sodium silicate induced apototosis and elevated serum matrix metalloproteinases. • Sodium silicate resulted in inflammation and increased TNF-alpha expression. [ABSTRACT FROM AUTHOR]

Background: Few studies have addressed the value of combining computed tomography-derived pulmonary vasculature metrics for the diagnosis and haemodynamic evaluation of pulmonary arterial hypertension (PAH).Materials and Methods: We measured three computed tomography parameters for the pulmonary artery, peripheral vessels, and pulmonary veins: the ratio of the diameter of the pulmonary artery to the aorta (PA/Ao), the cross-sectional area of small pulmonary vessels <5mm2 as a percentage of total lung area (%CSA<5), and the diameter of the right inferior pulmonary vein (PVD). The measured quantities were compared between patients with PAH (n=45) and control subjects (n=56), and their diagnostic performance and associations with PAH-related clinical indices, including right heart catheterization measurements, were examined.Results: PA/Ao and %CSA<5 were significantly higher in patients with PAH than in controls. Receiver-operating characteristic curve analysis for ability to diagnose PAH showed a high area under the curve (AUC) for PA/Ao (0.95) and modest AUCs for %CSA<5 (0.75) and PVD (0.56). PA/Ao correlated positively with mean pulmonary arterial pressure and PVD correlated negatively with pulmonary vascular resistance. The %CSA<5 correlated negatively with mean pulmonary arterial pressure and pulmonary vascular resistance and positively with cardiac index. Notably, the PA/Ao and PVD values divided by %CSA<5 correlated better with right heart catheterization indices than the non-divided values.Conclusion: PA/Ao, %CSA<5, and PVD are useful non-invasive pulmonary vasculature metrics, both alone and in combination, for diagnosis and haemodynamic assessment of PAH. [ABSTRACT FROM AUTHOR]

Background There is a lack of procedural and follow-up data on pulmonary vein isolation (PVI) with the second-generation pulmonary vein ablation catheter® (PVAC Gold) in patients with atrial fibrillation (AF). This study provides data on PVI procedures and 1-year follow-up results with PVAC Gold in patients with AF treated in clinical practice. Methods and results Three hundred and eighty four patients with documented symptomatic paroxysmal (n = 198) or persistent (n = 186) AF were included in a non-randomized prospectively designed database. Patients were enrolled consecutively at 2 high-volume centers. Procedural as well as 1 year follow-up data were systematically analyzed. Average procedure times ± standard deviations were 94 ± 23 min and 97 ± 23 min, respectively, in patients with paroxysmal and persistent AF. Average fluoroscopy times were 14.7 ± 5.4 min and 15.2 ± 5.6 min and total application times 18.1 ± 5.0 min and 18.8 ± 5.2 min, respectively, in the 2 patient cohorts. At 12 months, 70.7% (70/99) and 61.9% (70/113) of patients with paroxysmal and persistent AF, respectively, were free from AF. Four early complications occurred. In the group with persistent AF, 1 posterior cerebral infarction occurred 2 days after the procedure during initiation of anticoagulation. There was no phrenic nerve palsy or esophageal injury associated with the procedures. No thromboembolic events were recorded during follow-up. Conclusions In patients with paroxysmal or persistent AF, second generation multi-electrode-phased radiofrequency ablation delivers favorable mid-term PVI success rates with few procedure-related or follow-up complications. [ABSTRACT FROM AUTHOR]

Background There are limited literatures regarding the non-pulmonary vein (NPV) triggers in long-standing persistent atrial fibrillation (LSPAF). The goal of the present study was to investigate the characteristics and long-term outcome of catheter ablation among these patients. Methods The study included 776 patients (age 53.59 ± 11.38 years-old, 556 males) who received catheter ablation for drug-refractory atrial fibrillation (AF). We divided these patients into 3 groups. Group 1 consisted of 579 patients with paroxysmal AF (PAF), group 2 consisted of 103 patients with persistent AF (PerAF) and group 3 consisted of 94 patients with long-standing persistent AF (LSPAF). The average follow-up duration was 28.53 ± 23.21 months. Results The clinical endpoint was the recurrence of atrial tachyarrhythmia. Among these 3 groups, higher percentages of male (93.6%, P < 0.001), NPV triggers (44.7%, P < 0.001), longer AF duration (6.65 ± 6.72 years, P = 0.029), larger left atrium diameter (44.44 ± 6.79 mm, P < 0.001), and longer procedure time (181.94 ± 70.02 min, P < 0.001) were noted in LSPAF. After the first catheter ablation, the recurrence rate of AF was highest in LSPAF (Log Rank, P < 0.001). Larger left atrium diameters (LAD) ( P = 0.006; HR: 1.063; CI: 1.018–1.111) and NPV triggers ( P = 0.035; HR: 1.707; 1.037–2.809) independently predicted AF recurrence in LSPAF. Conclusions Compared with PAF and PerAF, LSPAF had a higher incidence of NPV triggers and worse long-term outcome after catheter ablation. NPV triggers and LAD independently predicted AF recurrence after catheter ablation in LSPAF. [ABSTRACT FROM AUTHOR]

Background and aims One central factor in hepatopulmonary syndrome (HPS) pathogenesis is intravascular accumulation of activated macrophages in small pulmonary arteries. However, molecular mechanism underlying the macrophage accumulation in HPS is unknown. In this study, we aimed to explore whether elevated COX-2 induces the Bone morphogenic protein-2 (BMP-2)/Crossveinless-2 (CV-2) imbalance and then activation of BMP signaling pathway promotes the macrophage accumulation in Common Bile Duct Ligation (CBDL) rat lung. Methods The COX-2/PGE2 signaling activation, the BMP-2/CV-2 imbalance and the activation of Smad1 were evaluated in CBDL rat lung and in cultured pulmonary microvascular endothelial cells (PMVECs) under the HPS serum stimulation. The effects of Parecoxib (COX-2 inhibitor), BMP-2 and CV-2 recombinant proteins on 4-week CBDL rat lung were determined, respectively. Results The COX-2/PGE2 signaling pathway was activated in CBDL rat lung in vivo and PMVECs in vitro , which was due to the activation of NF-κB P65. The inhibition of COX-2 by Parecoxib reduced macrophage accumulation, decreased lung angiogenesis and improved HPS. Meanwhile, the CBDL rat lung secreted more BMP-2 but less CV-2, and the imbalance between BMP-2 and CV-2 exacerbated the BMP signaling activation thus promoting the macrophage accumulation and lung angiogenesis. The BMP-2/CV-2 imbalance is dependent on the COX-2/PGE2 signaling pathway, and thus the effects of this imbalance can be reversed by adminstration of Parecoxib. Conclusion Our findings indicate that inhibition of COX-2 by parecoxib can improve the HPS through the repression of BMP signaling and macrophage accumulation. [ABSTRACT FROM AUTHOR]

Background Excessive exercise-induced hyperventilation and high prevalence of exercise oscillatory breathing (EOB) are present in patients with post-capillary pulmonary hypertension (PH) complicating left heart disease (LHD). Patients with pre-capillary PH have even higher hyperventilation but no EOB. We sought to determine the impact of a pre-capillary component of PH on ventilatory response to exercise in patients with PH and left heart disease. Methods We retrospectively compared patients with idiopathic or heritable pulmonary arterial hypertension (PAH, n = 29), isolated post-capillary PH (IpcPH, n = 29), and combined post- and pre-capillary PH (CpcPH, n = 12). Diastolic pressure gradient (DPG = diastolic pulmonary artery pressure − pulmonary wedge pressure) was used to distinguish IpcPH (DPG <7 mm Hg) from CpcPH (DPG ≥7 mm Hg). Results Pulmonary vascular resistance (PVR) was higher in PAH, intermediate in CpcPH, and low in IpcPH. All patients with CpcPH but 1 had PVR >3 Wood unit. Exercise-induced hyperventilation (high minute ventilation over carbon dioxide production, low end-tidal carbon dioxide) was marked in PAH, intermediate in CpcPH, and low in IpcPH ( p < 0.001) and correlated with DPG and PVR. Prevalence of EOB decreased from IpcPH to CpcPH to PAH ( p < 0.001). Conclusions Patients with CpcPH may have worse hemodynamics than patients with IpcPH and distinct alterations of ventilatory control, consistent with more exercise-induced hyperventilation and less EOB. This might be explained at least in part by the presence and extent of pulmonary vascular disease. [ABSTRACT FROM AUTHOR]

It has been shown that the sympathetic nervous system is activated in pulmonary arterial hypertension (PAH). Norepinephrine (NE) levels are increased by chemoreflex-dependent sympathetic overactivation and involved in pulmonary vascular remodeling. However, the underlying mechanisms of the remodeling induced by NE are poorly understood. In this study, we found that, in vivo , the expression of tyrosine hydroxylase and the concentration of plasma NE were increased in PAH rats compared with normal rats. Increases in ventricular hypertrophy and medial width of the pulmonary arteries were reversed by prazosin, α 1 -adrenoceptor (α 1 -AR) antagonists, in PAH rats. Elevated expression of α 1D -AR was detected in PAH rats. In addition, prazosin reduced the increasing expression of PCNA, CyclinA and CyclinE induced by hypoxia. In vitro , MTT assay, flow cytometry, Western blotting and immunofluorescence were performed to investigate the effects of NE on proliferation of pulmonary artery smooth muscle cells (PASMCs). We revealed that NE promoted PASMCs viability, increased the expression of PCNA, CyclinA and CyclinE, made more cells from G 0 /G 1 phase to G 2 /M + S phase and enhanced the microtubule formation. Above NE-induced changes could be suppressed by BMY 7378, an inhibitor of α 1D -AR. Furthermore, ERK-1/2 pathway was activated by NE. U0126, a specific inhibitor for ERK-1/2, attenuated the NE-induced proliferation of PASMCs under normoxia and hypoxia. Taken together, our results suggest that NE which stimulates α 1D -AR promotes proliferation of PASMCs and the effect is, at least in part, mediated via the ERK-1/2 pathway. [ABSTRACT FROM AUTHOR]

Pulmonary Hypertension (PHT) is relatively common, dangerous and under-recognised. Pulmonary hypertension is not a diagnosis in itself; it is caused by a number of differing diseases each with different treatments and prognoses. Therefore, timely and accurate recognition of the underlying cause for PHT is essential for appropriate management. This is especially true for patients with Pulmonary Arterial Hypertension (PAH) in the current era of disease-specific drug therapy. Measurement of Pulmonary Vascular Resistance (PVR) helps separate pre-capillary from post-capillary PHT, and is measured with right heart catheterisation (RHC). Echocardiography has been used to derive a number of non-invasive surrogates for PVR, with varying accuracy. Ultimately, the goal of non-invasive assessment of PVR is to separate PHT due to left heart disease from PHT due to increased PVR, to help streamline investigation and subsequent treatment. In this review, we summarise the physiology and pathophysiology of pulmonary blood flow, the various causes of pulmonary hypertension, and non-invasive surrogates for PVR. [ABSTRACT FROM AUTHOR]

Background The long-term effectiveness of pulmonary arterial hypertension–specific drug therapy (PAH-SDT) in Eisenmenger syndrome is controversial. We investigated short-term and long-term hemodynamic changes under PAH-SDT and their associations with outcomes in a bicentric cohort. Methods Over 20 years, we included 69 patients with congenital heart disease, an indexed pulmonary vascular resistance (PVRi) >8 WU·m 2 , and 292 standardized catheterizations at baseline and after PAH-SDT initiation or intensification. Oxygen consumption was measured and the Fick principle applied to calculate indexed pulmonary output (Qpi) and PVRi. Results After PAH-SDT initiation or intensification, median (interquartile range) PVRi decrease was 5.1 WU·m 2 (−1.4, −12.6) ( p < 0.0001). Median Qpi and 6-minute walk test increases were +0.4 liter/min/m 2 (0.0, +0.9) ( p < 0.0001) and +49 m (+15, +93) ( p = 0.0003), respectively. Hemodynamic response combining increased Qpi with decreases in transpulmonary gradient and PVRi occurred in 68.0% of patients. After a median of 4.9 years, PVRi and Qpi changes were no longer significant. Over a median of 7.2 years, 23 (33.3%) patients met a composite criterion (death, n = 8; heart-lung transplantation or listing for transplantation, n = 15). The 15-year cumulative event rate was 49.2%. By multivariate analysis, independent predictors of events were superior vena cava oxygen saturation and hemodynamic response ( p = 0.048 and p < 0.0001). Conclusions In Eisenmenger syndrome, PAH-SDT induces early hemodynamic improvements, which decline over time. Hemodynamic changes under PAH-SDT vary across patients. Hemodynamic parameters at baseline and under PAH-SDT are associated with events. PAH-SDT may need to be individualized based on hemodynamic changes. [ABSTRACT FROM AUTHOR]

Background RV dyssynchrony has been described in patients with pulmonary hypertension (PH) and is an independent predictor of clinical worsening; however, the optimal method for measuring RV dyssynchrony has not been fully established. This study aimed to investigate whether RV dyssynchrony is correlated with hemodynamics and prognosis in PH patients and to identify the best parameter for evaluating RV dyssynchrony. Methods This study assessed 100 PH patients, measuring mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI) by right heart catheterization (RHC). RV strain curves were obtained using two-dimensional speckle-tracking echocardiography (2DSTE), and time from QRS onset to maximum peak longitudinal strain (T max ) or time to first peak (T first ) was measured. Difference in time between the earliest and the latest segment (TD) and standard deviation (SD) of T in 6 segments with RV apex (− SD6) and 4 segments without RV apex (− SD4) were also assessed. Results Among all RV dyssynchrony parameters, T max -SD6 showed the strongest correlation with RV hemodynamics such as mPAP (R 2 = 0.27, P < 0.0001) and PVR (R 2 = 0.22, P < 0.0001). Univariate and multivariate Cox proportional hazard analyses showed that T max -SD6 significantly correlated with and independently predicted event-free survival in patients with PH. Conclusions RV dyssynchrony is a useful index for RV function and an independent predictor of clinical outcomes in patients with PH. In addition, the inclusion of apical motion is essential for the optimal assessment of RV dyssynchrony. [ABSTRACT FROM AUTHOR]

Quantitative understanding of nanoparticles delivery in a complex vascular networks is very challenging because it involves interplay of transport, hydrodynamic force, and multivalent interactions across different scales. Heterogeneous pulmonary network includes up to 16 generations of vessels in its arterial tree. Modeling the complete pulmonary vascular system in 3D is computationally unrealistic. To save computational cost, a model reconstructed from MRI scanned images is cut into an arbitrary pathway consisting of the upper 4-generations. The remaining generations are represented by an artificially rebuilt pathway. Physiological data such as branch information and connectivity matrix are used for geometry reconstruction. A lumped model is used to model the flow resistance of the branches that are cut off from the truncated pathway. Moreover, since the nanoparticle binding process is stochastic in nature, a binding probability function is used to simplify the carrier attachment and detachment processes. The stitched realistic and artificial geometries coupled with the lumped model at the unresolved outlets are used to resolve the flow field within the truncated arterial tree. Then, the biodistribution of 200 nm, 700 nm and 2 µm particles at different vessel generations is studied. At the end, 0.2–0.5% nanocarrier deposition is predicted during one time passage of drug carriers through pulmonary vascular tree. Our truncated approach enabled us to efficiently model hemodynamics and accordingly particle distribution in a complex 3D vasculature providing a simple, yet efficient predictive tool to study drug delivery at organ level. [ABSTRACT FROM AUTHOR]

Introduction Up to 50% of patients with pulmonary embolism (PE) present lung perfusion defects after six months of anticoagulant treatment, suggesting residual pulmonary vascular obstruction (RPVO). The risk of recurrence in patients with RPVO remains unknown. The present study aims to assess the risk of recurrent venous thromboembolism (VTE) in patients with RPVO after a first symptomatic episode of PE. Methods Consecutive patients who survived a first objectively proven acute PE, treated for at least three months with anticoagulants, were included and followed prospectively. RPVO was defined as a pulmonary vascular obstruction of > 10% on ventilation/perfusion lung scan performed at inclusion. Objectively proven VTE recurrences were registered and confirmed by an investigator unaware of the result of the ventilation/perfusion lung scan . Results Among the 310 patients (median age: 61 years) included in the study, 60 (19%) had RPVO. During a median follow-up of 51.3 months, 66 patients (21.2%, 95% CI [17.5–26.7]) experienced recurrent VTE. In an adjusted cox proportional hazards analysis, we identified RPVO (HR 1.94; 95% CI [1.11–3.39]; p = 0.026) and unprovoked PE (HR 3.56; 95% CI [1.79–7.07]; p = 0.00051) as independent risk factors for recurrent VTE whereas extended anticoagulation therapy (HR 0.19; 95% CI [0.07–0.55]; p = 0.00014) was associated with a low risk of recurrence. Conclusion The results suggest that RPVO is an independent risk factor of recurrent VTE after a first PE. [ABSTRACT FROM AUTHOR]

[Display omitted] Calcium-activated chloride channels (CaCC) provide a depolarizing stimulus to a variety of tissues through chloride efflux in response to a rise in internal Ca2+ and voltage. One of these channels, Anoctamin-1 (ANO1 or TMEM16A) is now recognized to play a central role in promoting smooth muscle tone in various types of blood vessels. Its role in hypertension, and thus the therapeutic promise of targeting ANO1, is less straightforward. This review gives an overview of our current knowledge about the potential role ANO1 may play in hypertension within the systemic, portal, and pulmonary vascular systems and the importance of this information when pursuing potential treatment strategies. While the role of ANO1 is well-established in several forms of pulmonary hypertension, its contributions to both the generation of vascular tone and its role in hypertension within the systemic and portal systems are much less clear. This, combined with ANO1′s various roles throughout a multitude of tissues throughout the body, command caution when targeting ANO1 as a therapeutic target and may require tissue-selective strategies. [ABSTRACT FROM AUTHOR]

Background Ex vivo lung perfusion (EVLP) may be an essential process for the pre-transplant evaluation of the donor lungs. Currently, the partial pressure of oxygen/fraction of inspired oxygen (PaO 2 /FiO 2 , or PF) ratio is the standard in the assessment of lung function in cellular EVLP, whereas other parameters, including airway and vascular parameters, have only been partially utilized. The primary purpose of this study is to assess the potential utility of other parameters as a surrogate of lung function in EVLP. Methods Yorkshire swine lungs ( n = 12) and rejected human donor lungs ( n = 12) were perfused in cellular-based EVLP for 2 hours. PF ratio, airway parameters (peak airway pressure, plateau pressure, dynamic compliance and static compliance) and vascular parameters (pulmonary vascular resistance and pulmonary artery pressure) were measured. The correlations between PF ratio and one of these parameters were analyzed. Results Correlations were identified in the following combinations: PF ratio and airway parameters ( p < 0.05, each); PF ratio and vascular parameters ( p < 0.05, each); static compliance and pulmonary vascular resistance in swine lungs ( p = 0.0001); and PF ratio and airway parameters in rejected human lungs ( p < 0.05, each). There were significant differences in all parameters between suitable cases and non-suitable cases in swine lungs ( p < 0.02, each). Conclusions Our results show that airway parameters are complementary quantitative indicators of lung function in cellular EVLP, based on the correlations with PF ratio in both swine lungs and human lungs. [ABSTRACT FROM AUTHOR]

Objectives: Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Its effect on pulmonary perfusion has not been quantified; we examined the clinical significance of pulmonary blood volume (PBV) using dual-energy computed tomography (DECT) in patients with CTEPH undergoing BPA. Methods: In this retrospective study of 16 BPAs in eight female patients with CTEPH, we evaluated both-lung (n=16), right- or left-lung (n=32), and three right- or left-segment (upper, middle, and lower) (n=96) PBVs before and after BPA, using DECT. We evaluated the relationships between improvement in lung PBV and pulmonary artery (PA) pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), and 6-min walking distance. We measured PA enhancement (PAenh) on DECT images and calculated lung PBV/PAenh to adjust timing. Results: Pre- and post-BPA 6-segment lung PBV/PAenh were 0.067±0.021 and 0.077±0.019, respectively, in the treated segment (p<0.0001). There were significant positive correlations between pre- to post-BPA improvements in both-lung PBV/PAenh and PAP (R=0.69, p=0.005), PVR (R=0.56, p=0.03), and 6-min walking distance (R=0.67, p=0.01). Conclusions: Improved PBV after BPA, reflecting increased lung perfusion, was positively correlated with PAP, PVR, and 6-min walking distance. Lung PBV may be an indicator of BPA treatment effect. [ABSTRACT FROM AUTHOR]

Purpose: Lung volume and pulmonary blood flow decrease in patients with interstitial lung disease (ILD). The purpose of this study was to assess the relationship between pulmonary blood flow and lung volume in ILD patients. Methods: This research was approved by the institutional review board. Twenty-seven patients (9 men, 18 women; mean age, 59 years; range, 24-79 years) with ILD were included. Blood flow was assessed in the pulmonary trunk and the left and right pulmonary arteries by phase contrast magnetic resonance imaging (MRI). Lung volume and the computed tomography (CT) visual score that indicates the severity of ILD were assessed on the left and right sides by thin-section CT scanning. Lung volume was automatically measured by lung analysis software (VINCENT Ver. 4). The CT visual score was measured by averaging the proportion of abnormal lung area at five anatomic levels. Pearson's correlation coefficient was used to determine the relationship between pulmonary blood flow and lung volume. Results: Pulmonary blood flow showed a significant correlation with lung volume (both: r=0.52, p=0.006; left: r=0.61, p=0.001; right: r=0.54, p=0.004) and CT visual score (both: r=-0.39, p=0.04; left: r=-0.48, p=0.01; right: r=-0.38, p=0.04). Partial correlation analysis, controlled for age, height and weight, showed a significant correlation between pulmonary blood flow and lung volume (both: r=0.43, p=0.03; left: r=0.55, p=0.005; right: r=0.48, p=0.01) and CT visual score (both: r=-0.58, p=0.003; left: r=-0.51, p=0.01; right: r=-0.64, p=0.001). Conclusion: In ILD, reduced pulmonary blood flow is associated with reduced lung volume and increased abnormal lung area. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether the extent of perfusion defects assessed by examining lung perfused blood volume (PBV) images is a stronger estimator of the clinical severity of chronic thromboembolic pulmonary hypertension (CTEPH) compared with other computed tomography (CT) findings and noninvasive parameters. Materials and Methods: We analyzed 46 consecutive patients (10 men, 36 women) with CTEPH who underwent both dual-energy CT and right-heart catheter (RHC) examinations. Lung PBV images were acquired using a second-generation dual-source CT scanner. Two radiologists independently scored the extent of perfusion defects in each lung segment employing the following criteria: 0, no defect, 1, defect in <50% of a segment, 2, defect in ≥50% of a segment. Each lung PBV score was defined as the sum of the scores of 18 segments. In addition, all of the following were recorded: 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, and RHC hemodynamic parameters including pulmonary artery pressure (PAP), right ventricular pressure (RVP), cardiac output (CO), the cardiac index (CI), and pulmonary vascular resistance (PVR). Bootstrapped weighted kappa values with 95% confidence intervals (CIs) were calculated to evaluate the level of interobserver agreement. Correlations between lung PBV scores and other parameters were evaluated by calculating Spearman's rho correlation coefficients. Multivariable linear regression analyses (using a stepwise method) were employed to identify useful estimators of mean PAP and PVR among CT, BNP, and 6MWD parameters. A p value<0.05 was considered to reflect statistical significance. Results: Interobserver agreement in terms of the scoring of perfusion defects was excellent (κ=0.88, 95% CIs: 0.85, 0.91). The lung PBV score was significantly correlated with the PAP (mean, rho=0.48; systolic, rho=0.47; diastolic, rho=0.39), PVR (rho=0.47), and RVP (rho=0.48) (all p values<0.01). Multivariable linear regression analyses showed that only the lung PBV score was significantly associated with both the mean PAP (coefficient, 0.84, p<0.01) and the PVR (coefficient, 28.83, p<0.01). Conclusion: The lung PBV score is a useful and noninvasive estimator of clinical CTEPH severity, especially in comparison with the mean PAP and PVR, which currently serve as the gold standards for the management of CTEPH . [ABSTRACT FROM AUTHOR]

Purpose The aim of our study is to investigate if lung carbon monoxide diffusing capacity (DLCO) measured during effort is able to detect early respiratory functional impairment. Methods We enrolled 25 very light smokers and 20 healthy non smokers. Subjects underwent plethysmography, DLCO (single breath technique) and calculated effective pulmonary blood flow (Qc) by rebreathing method. During exercise by cycle ergometer (duration 10 ± 2 min; recovery 11 ± 3 min) DLCO and Qc were calculated at 25% and 50% of theoretical maximum workload. Results At baseline lung function and Qc did not differ between groups. DLCO and DLCO/Qc measured during exercise were significantly greater in non smokers (p < 0.001); Qc was not statistically different. In very light smokers, DLCO, DLCO/Qc measured during exercise significantly correlated with the number of pack years (r = −0.60 p < 0.001; r = −0.58 p < 0.05; r = −0.55 p < 0.05, respectively). Conclusions In very light smokers there is lung function impairment and our data show that DLCO during exercise may reveal this underlying early damage. [ABSTRACT FROM AUTHOR]

Background Patients with a failing Fontan continue to have decreased survival after heart transplant (HT), particularly those with preserved ventricular function (PVF) compared with impaired ventricular function (IVF). In this study we evaluated the effect of institutional changes on post-HT outcomes. Methods Data were retrospectively collected for all Fontan patients who underwent HT. Mode of failure was defined by the last echocardiogram before HT, with mild or no dysfunction considered PVF and moderate or severe considered IVF. Outcomes were compared between early era (EE, 1995 to 2008) and current era (CE, 2009 to 2014). Management changes in the CE included volume load reduction with aortopulmonary collateral (APC) embolization, advanced cardiothoracic imaging, higher goal donor/recipient weight ratio and aggressive monitoring for post-HT vasoplegia. Results A total of 47 patients were included: 27 in the EE (13 PVF, 14 IVF) and 20 in the CE (12 PVF, 8 IVF). Groups were similar pre-HT, except for more PLE in PVF patients. More patients underwent APC embolization in the CE (80% vs 28%, p < 0.01). There was no difference in donor/recipient weight ratio between eras. There was a trend toward higher primary graft failure for PVF in the EE (77% vs 36%, p = 0.05) but not the CE (42% vs 75%, p = 0.20). Overall, 1-year survival improved in the CE (90%) from the EE (63%) ( p = 0.05), mainly due to increased survival for PVF (82 vs 38%, p = 0.04). Conclusions Post-HT survival for failing Fontan patients has improved, particularly for PVF. In the CE, our Fontan patients had a 1-year post-HT survival similar to other indications. [ABSTRACT FROM AUTHOR]

Background: Primary mitral regurgitation (MR) is a growing health problem due to the aging population.Objectives: The purpose of this study was to assess the impact of baseline pulmonary hypertension on long-term outcomes in patients with significant primary MR and preserved left ventricular ejection fraction (LVEF).Methods: We studied 1,318 patients with ≥3+ primary MR and LVEF ≥60% using echocardiography at rest; they were evaluated at our center from 2005 to 2008. Baseline clinical and echocardiography data were recorded, and the Society of Thoracic Surgeons (STS) score was calculated. The primary outcome was death.Results: Mean STS score was 3.98 ± 1%; 54% of patients were in New York Heart Association (NYHA) functional class I and 31% were in NYHA functional class II; and 18% had atrial fibrillation (AF). Mean LVEF, mitral effective regurgitant orifice, indexed LV end-systolic diameter (LVESD), and right ventricular systolic pressure (RVSP) were 62 ± 2%, 0.56 ± 0.30 cm(2), 1.6 ± 0.3 cm/m(2), and 37 ± 14 mm Hg, respectively. At 7.1 ± 2.0 years, 86% had mitral valve (MV) surgery. Death occurred in 130 (10%) patients. On Cox multivariable analysis, baseline RVSP, together with age, baseline NYHA functional class, pre-operative AF, coronary artery disease, and indexed LVESD were associated with a higher rate of longer term mortality (all p < 0.01), whereas MV surgery (as a time-dependent covariate) was associated with improved survival (p < 0.001). Addition of RVSP to the STS score significantly reclassified the risk for longer term mortality (integrated discrimination index: 0.07; p < 0.001); 77% patients who died had RVSP ≥35 mm Hg.Conclusions: In patients with significant primary MR and preserved LVEF, baseline RVSP is independently associated with long-term survival. Impact of RVSP is progressive and not confined to those with the highest baseline values. [ABSTRACT FROM AUTHOR]

Information on ultrasound examination of equine pulmonary veins is scarce due to a lack of in-depth anatomical information. Each pulmonary vein drains a specific lung lobe region, after which those veins merge into a collecting antrum, before opening into the left atrium through their respective ostia. The aim of this study was, by using anatomical dissection and silicone casting of equine cardiopulmonary sets, to study the venous drainage of both lungs and the position of the ostia and to investigate whether the ostia can be identified and differentiated using ultrasound. Three out of the four ostia could be observed echocardiographically in the standing horse. The ostium draining the most caudal aspects of both lungs showed little variability, while the ostium draining the rest of the right lung could be used as an easily recognisable landmark, since it was located adjacent to the interatrial septum. The identification of the equine pulmonary vein ostia using ultrasound might allow for the determination of size and flow patterns in the assessment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background Secondary pulmonary hypertension is common in heart failure (HF) patients. We hypothesized that inhibition of feedback from locomotor muscle group III/IV neurons contributes to reduced pulmonary vascular pressures independent of changes in cardiac function during exercise in HF. Methods 9 HF patients (ages, 60 ± 2; EF, 26.7 ± 1.9%; New York Heart Association classes, I–III) and 9 age/gender matched controls (ages, 63 ± 2) completed five-minutes of constant-load cycling (65% Workload peak ) with intrathecal fentanyl or placebo on randomized separate days. Mean arterial pressure (MAP), heart rate (HR), end-tidal partial pressure of CO 2 (P ET CO 2 ), and oxygen consumption (VO 2 ) were measured at rest and exercise. Non-invasive surrogates for cardiac power (circulatory power, CircP = VO 2 × MAP), stroke volume (oxygen pulse, O 2 pulse = VO 2 /HR), and pulmonary arterial pressure (GX CAP = O 2 pulse × P ET CO 2 ) were calculated. Results At rest and end-exercise, differences between fentanyl versus placebo were not significant for CircP in HF or controls. Differences between fentanyl versus placebo for GX CAP were not significant at rest in HF or controls. At end-exercise, GX CAP was significantly higher with fentanyl versus placebo in HF (691 ± 59 versus 549 ± 38 mL/beat × mm Hg), but not controls (536 ± 59 versus 474 ± 43 mL/beat × mm Hg). Slopes (rest to end-exercise) for GX CAP were significantly higher with fentanyl versus placebo in HF (95.1 ± 9.8 versus 71.6 ± 6.0 mL/beat × mm Hg), but not controls (74.3 ± 9.5 versus 60.8 ± 6.5 mL/beat × mm Hg). CircP slopes did not differ between fentanyl versus placebo in HF or controls (p > 0.05). Conclusion We conclude that feedback from locomotor muscle group III/IV neurons may evoke increases in pulmonary vascular pressures independent of changes in cardiac function during exercise in HF. [ABSTRACT FROM AUTHOR]

Objectives Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations. Methods and results Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC 50 4 × 10 −8 mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro- l - arginine methyl ester (L-NAME) and K + channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro . Conclusions Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery. [ABSTRACT FROM AUTHOR]

Anomalous left coronary artery from pulmonary artery (ALCAPA) is an uncommon congenital heart defect. In most of the cases it presents in early infancy when the pulmonary artery pressure decreases and pulmonary vascular resistance falls. ECG and chest X-ray help in diagnosing this condition, however, transthoracic echocardiography confirms the diagnosis in most of the cases. 2D echo shows origin of left coronary artery from pulmonary artery and on colour Doppler retrograde flow is seen in left main, left anterior descending and left circumflex coronary arteries. Antegrade flow in the left coronary artery has been described in past when ALCAPA was associated with a shunt lesion like a ventricular septal defect (VSD) or a patent ductus arteriosus (PDA). We are reporting a case of ALCAPA with severe left ventricular (LV) dysfunction with normal flow pattern in left coronary artery with no associated cardiac anomaly and demonstration of retrograde flow on oxygen inhalation. [ABSTRACT FROM AUTHOR]