Idiopathic Pulmonary Hypertension Patients Research Articles

Prevalence and clinical significance of conduction disease in patients with idiopathic pulmonary arterial hypertension.

Anatomical and physiological changes in the right heart as a direct consequence of the upstream pressure overload characteristic of idiopathic pulmonary hypertension (IPAH) are likely to lead to conduction disease in these patients. However, the prevalence and clinical implications of atrioventricular conduction disease in IPAH patients are not well-characterized. In this observational cohort study, we show that conduction disease is far more prevalent in a cohort of 175 IPAH patients than a group of matched comparators (37.1% vs 10.8%), and is associated with older age, male sex and more severe right heart dilatation. However, conduction disease is independently associated with worse functionality and higher mortality in this patient group. Prospective study is required to substantiate this, and whether intervention such as prophylactic pacing could restore prognosis.

J receptor activity in idiopathic pulmonary hypertension and its expected change in the presence of pulmonary bed vasodilators

Juxtapulmonary receptors (J) lying in the lung parenchyma are stimulated naturally by any condition that produces interstitial oedema, transient increases in interstitial volume and pressure or raised pulmonary capillary pressure. There is no information available about the level of their stimulation in patients with idiopathic pulmonary hypertension (IPH) who have high levels of pulmonary artery systolic pressures.The aim of the present study therefore was to find the level of these receptors activity in these patients at their prevailing pulmonary artery systolic pressures. This was done by the established method of determining the dose of i.v. lobeline that gives rise to threshold levels of sensations in the upper chest areas and accelerates respiration. In IPH patients it was found to be as high as 31.6 ± 5.6 μg/kg i.e., twice as much as that known for healthy individuals which is 15 μg/kg. This shows an enhanced stimulation of J receptors in IPH patients.Expectedly when pulmonary artery systolic pressure falls with pulmonary bed vasodilator medication given to IPH patients, a reduction in the natural stimulus of J receptors would also occur leading to a fall in their activity and hence that of the quantum of their reflexes of respiratory acceleration and inhibition of exercise. This finding provides the first insight of a neural mechanism that could be influenced to produce its effects when pulmonary artery systolic pressure falls by pulmonary vasodilator medication.

Systemic Arterial Stiffness in New Diagnosed Idiopathic Pulmonary Arterial Hypertension Patients.

ObjectiveWe suggested: 1) patients with idiopathic pulmonary hypertension (IPAH) have active factors which could damage not only the pulmonary but systemic arteries too as in arterial hypertensive patients; 2) if these changes were present, they might correlate with other parameters influencing on the prognosis. This study is the first attempt to use cardio-ankle vascular index (CAVI) for the evaluation of systemic arterial stiffness in patients with IPAH.MethodsA total of 112 patients were included in the study: group 1 consisted of 45 patients with new diagnosed IPAH, group 2 included 32 patients with arterial hypertension, and in the control group were 35 healthy persons adjusted by age. Right heart catheterization, ECG, a 6-minute walk test (6MWT), echocardiography, blood pressure (BP) measurement and ambulatory BP monitoring, pulse wave elastic artery stiffness (PWVe; segment carotid-femoral arteries) and muscular artery stiffness (PWVm; segment carotid-radial arteries), CAVI, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level were provided. The Spearman correlation, a linear regression and multivariable binary logistic analysis were performed to indicate the predictors associated with PWV and CAVI.ResultsThe groups were adjusted for principal characteristics influenced on arterial stiffness. IPAH patients had significantly (P<0.001 for all) shorter 6MWT distance and higher Borg dyspnea score than the patients with arterial hypertension (systolic/diastolic BP = 146.1±10.7/94.2±9.8 mmHg) and the control group = 330.2±14.6 vs 523.8±35.3 and 560.9±30.2 m respectively and 6.2±1.8 vs 1.2±2.1 and 0.9±2.8 points. The PWVm and PWVe were the highest in hypertensive patients (10.3±1.5 and 11.42±1.70 m/s). The control group and IPAH did not have significant differences in aorta BP, but PWVm/PWVe values were significantly (P<0.003/0.008) higher in IPAH patients than in the control group (8.1±1.9/8.49±1.92 vs 6.63±1.34/7.29±0.87 m/s). The CAVIs on both sides were significantly lower in the healthy subjects (5.91±0.99/5.98±0.87 right/left side). Patients with IPAH did not differ from the arterial hypertension patients by CAVIs in comparison with the control group (7.40±1.32/7.22±1.32 vs 7.19±0.78/7.2±1.1 PWVe) did not correlate with any parameters except uric acid. PWVm correlated with uric acid (r=0.58, P<0.001), NT-proBNP (r=0.33, P=0.03) and male gender (r=0.37, P=0.013) at Spearman analysis, but not at multifactorial linear regression analysis. The CAVI correlated with age and parameters characterized functional capacity (6MWT distance) and right ventricle function (NT-proBNP, TAPSE) at Spearman analysis and with age and TAPSE at multifactorial linear regression analysis. At binary logistic regression analysis CAVI > 8.0 at right and/or left side had a correlation with age, 6MWT distance, TAPSE, but an independent correlation was only with age (β=1.104, P=0.008, CI 1.026–1.189) and TAPSE (β=0.66, P=0.016, CI 0.474–0.925).ConclusionIn spite of equal and at normal range BP level, the age-adjusted patients with IPAH had significantly stiffer arteries than the healthy persons and they were comparable with the arterial hypertensive patients. Arterial stiffness evaluated by CAVI correlated with age and TAPSE in IPAH patients. Based on our results it is impossible to conclude the pathogenesis of arterial stiffening in IPAH patients, but the discovered changes and correlations suggest new directions for further studies, including pathogenesis and prognosis researches.

Exercise energy expenditure in patients with idiopathic pulmonary arterial hypertension: Impact on clinical severity and survival

Patient with idiopathic pulmonary hypertension (IPAH) develop peripheral inefficiency which could lead to an increase total energy expenditure and that could have a significant prognostic impact.To test the hypothesis, fifty-five consecutive stable IPAH patients (mean age 51±17 years) and 24 matched controls underwent an incremental exercise test and followed for a 5 years’ period. Total energy expenditure was assessed as the ratio between total VO2 uptake (during both effort and recovery) and total external work (VO2 TOT/WTOT).Patients with IPAH had a lower exercise capacity and a significantly higher VO2 TOT/WTOT than controls (VO2 TOT/WTOT 0.33 ± 0.09 ml/j vs 0.22 ± 0.04 ml/j, p < 0.0001). Among patients, VO2 TOT/WTOT was higher in whom died during follow up compared to survivors (0.41 ± 0.11 ml/j vs 0.30 ± 0.06 ml/j, p < 0.0001).In multivariate Cox regression analysis VO2 TOT/WTOT, gender, PETCO2 peak, V˙O2 peak were independent risk factors for death.Patients with IPAH have shown a less efficient muscular oxygen utilization than controls. Notably the high energy expenditure has a relevant independent prognostic impact.

Risk Analysis of Perioperative Death in Lung Transplant Patients With Severe Idiopathic Pulmonary Hypertension

ObjectiveTo investigate the risk factors for perioperative mortality in patients with severe idiopathic pulmonary hypertension (IPAH) undergoing lung transplantation (LTx). MethodsTwenty-two IPAH patients were included in the study and were divided 2 groups: a case group with early death post LTx (n = 5, 22.7%) and the remaining 17 recipients (87.3%), who did not die at perioperative time (the control group). All the preoperative clinical data and surgical procedures were analyzed using an independent t-test and Fisher's exact probability test. ResultsAll the patients had over class III heart function rated by World Health Organization classification. Both groups had significantly reduced capacity of 6-min walking distance (6 MWD), decreased oxygen saturation, increased N-terminal probrain natriuretic peptide (NT-proBNP), certain frequent syncope, hemoptysis, and lower extremity edema. In addition, cardiac catheterization examination demonstrated that all patients had elevated pulmonary artery systolic pressure, mean pulmonary artery systolic pressure, and right atrial pressure. Furthermore, reduced mixed venous oxygen saturation and partial pressure of oxygen were seen in oxygen inhalation in a dose of 5 L/min in both groups. Cardiovascular morphological changes in both groups by cardiac ultrasonography included dilated diameter of the right ventricle and the main pulmonary artery. However, the right ventricular ejection fraction and stroke volume were notedly dropped. Distended inferior vena cava and enhanced frequency of hypertensive tricuspid regurgitation velocity response to stress were seen, and pericardial effusion was developed in both groups of patients. Nevertheless, a paired t-test (n = 5 vs n = 17) showed no significance between groups (P > .05), while there was a significant difference in frequencies of brief loss of consciousness (P < .01). Serum sodium concentration, cardiac index (CI), inner diameter of the left ventricle at end diastolic phase, and inner diameter ratio of RV/LV were 116.80 ± 5.76 mmol/L vs 29.88 ± 7.28 mmol/L (P = .002), 1.30 ± 0.07 L/min/m2 vs 1.58 ± 0.26 L/min/m2 (P = .030), 28.80 ± 3.70 mm vs 34.76 ± 5.43 mm (P = .033) and 1.81 ± 0.28 mmol/L vs 1.43 ± 0.26 (P = .011) between case and control group, respectively. ConclusionsAll patients with IPAH waiting for lung transplantation were in critical condition. The highest death risks at perioperative time in IPAH patients were high frequencies of syncope, hyponatremia, lower CI, inner diameter of the left ventricle, and upward RV/LV ratio.

Genetic variants in a Polish population of patients with pulmonary arterial hypertension: sequencing of BMPR2, ALK1, and ENG genes.

Pulmonary arterial hypertension (PAH) is a rare disease with a very serious prognosis. It seems that mutations in genes related to transforming growth factor-b signalling pathway are often related to the development of the disease. No study covers this problem in a Polish population. To screen for genetic mutations in a Polish cohort of patients with pulmonary hypertension, especially with idiopathic PAH, treated in a single hospital in Poland. DNA sequencing method was used. Samples from 50 patients with pulmonary hypertension were screened for mutations in type 2 bone morphogenetic protein receptor of the transforming growth factor-b superfamily gene (BMPR2). Samples from 20 patients with idiopathic PAH (11 men, mean age 55 years) were also screened for mutations in activin A receptor-like type 1 gene (ALK1) and endoglin gene (ENG). No genetic variations were found for the BMPR2 gene. In all 20 samples from idiopathic pulmonary hypertension patients we found heterozygosity of single nucleotide polymorphism (SNP) rs 372023206 in ALK1 gene. Three samples from these patients showed variations of ENG gene: we found one sample with heterozygosity of SNP rs 200525684, one with heterozygosity of SNP rs 3739817, and one with both. We detected benign polymorphisms or genetic variants of unknown importance. It is possible that the Polish population of PAH patients differs from the previously described populations of other countries in terms of the frequency and importance of mutations in BMPR2, ALK1 and ENG genes.

Activation of the nicotinamide N-methyltransferase (NNMT)-1-methylnicotinamide (MNA) pathway in pulmonary hypertension.

BackgroundPulmonary arterial hypertension (PAH) is associated with inflammatory response but it is unknown whether it is associated with alterations in NNMT activity and MNA plasma concentration. Here we examined changes in NNMT-MNA pathway in PAH in rats and humans.MethodsPAH in rats was induced by a single subcutaneous injection of MCT (60 mg/kg). Changes in NNMT activity in the lungs and liver (assessed as the rate of conversion of nicotinamide (NA) to MNA), changes in plasma concentration of MNA and its metabolites (analyzed by LC/MS) were analyzed in relation to PAH progression. PAH was characterized by right ventricular hypertrophy (gross morphology), cardiac dysfunction (by MRI), lung histopathology, lung ultrastructure, and ET-1 concentration in plasma. NO-dependent and PGI2-dependent function in isolated lungs was analyzed. In naive patients with idiopathic pulmonary hypertension (IPAH) characterized by hemodynamic and biochemical parameters MNA and its metabolites in plasma were also measured.ResultsMCT-injected rats developed hypertrophy and functional impairment of the right ventricle, hypertrophy of the pulmonary arteries, endothelial ultrastructural defects and a progressive increase in ET-1 plasma concentration—findings all consistent with PAH development. In isolated lung, NO-dependent regulation of hypoxic pulmonary vasoconstriction was impaired, while PGI2 production (6-keto-PGF1α) was increased. NNMT activity increased progressively in the liver and in the lungs following MCT injection, and NNMT response was associated with an increase in MNA and 6-keto-PGF1α concentration in plasma. In IPAH patients plasma concentration of MNA was elevated as compared with healthy controls.ConclusionsProgression of pulmonary hypertension is associated with the activation of the NNMT-MNA pathway in rats and humans. Given the vasoprotective activity of exogenous MNA, which was previously ascribed to PGI2 release, the activation of the endogenous NNMT-MNA pathway may play a compensatory role in PAH.

Assessment of Thyroid Function in Idiopathic Pulmonary Hypertension.

Background:Idiopathic pulmonary hypertension (IPAH) is a rare, debilitating, and fatal disease. Late-onset treatment can lead to right heart failure, multiple organ damage, and death. Since the thyroid plays a major role in the metabolism and hemodynamics in humans, the screening of thyroid function is crucial. Thyroid dysfunction has been reported to cause pulmonary hypertension, but the thyroid is also involved in IPAH.Objectives:The aim of this study was to evaluate thyroid function in IPAH patients.Patients and Methods:Fifty-three IPAH patients aged 16 - 75 years-old were enrolled in this cross sectional study, and their right ventricular functions, hemodynamics, and six minute walk tests (SMWTs) were evaluated. Thyroid function tests were conducted, and their associations with the patients’ pulmonary arterial pressures (PAPs) and functional capacities were assessed. The data were analyzed using the SPSS 15 statistical software.Results:In this research, 84.8% of the participants were women. The mean PAP was 51.6 mmHg (31-87) and mean thyroid stimulating hormone (TSH) level was 4.2 mIU/ml (0.7 - 10). Subclinical hypothyroidism was detected in 26 patients (49.1%). There were significant correlations of the TSH level with the right ventricular (RV) end diastolic dimension (P value = 0.05) and triiodothyronine (T3) with the tricuspid annular plane systolic excursion (TAPSE) (P value = 0.04), an inverse relationship between the SMWT and the TSH level (P value = 0.004), but no significant relationship between these parameters and the thyroxine (T4) level.Conclusions:IPAH is associated with subclinical hypothyroidism and low patient functional capacity, and is more common in RV failure.

Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a.

Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression.

Role of asymmetric methylarginine and connexin 43 in the regulation of pulmonary endothelial function.

Abstract Circulating levels of asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, are increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication, required for the coordinated regulation of endothelial barrier function and angiogenesis, and so contributes to pulmonary endothelial dysfunction. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells; pulmonary endothelial microvascular cells from mice deficient in an enzyme metabolizing ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI); and blood-derived endothelial-like cells from patients with IPAH. Exogenous and endogenous ADMA inhibited protein expression and membrane localization of connexin 43 (Cx43) in a nitric oxide/soluble guanosine monophosphate/c-jun-dependent manner in pulmonary endothelial cells, resulting in the inhibition of gap junctional communication, increased permeability, and decreased angiogenesis. The effects of ADMA were prevented by overexpression of DDAHI or Cx43 and by treatment with rotigaptide. Blood-derived endothelial-like cells from IPAH patients displayed a distinct disease-related phenotype compared to cells from healthy controls, characterized by reduced DDAHI expression, increased ADMA production, and abnormal angiogenesis. In summary, we show that ADMA induces pulmonary endothelial dysfunction via changes in expression and activity of Cx43. Cells from IPAH patients exhibit abnormal DDAHI/Cx43 signaling as well as differences in gap junctional communication, barrier function, and angiogenesis. Strategies that promote DDAHI/Cx43 signaling may have an endothelium-protective effect and be beneficial in pulmonary vascular disease.

Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary hypertension (IPAH) share a similar clinical presentation, and a differential diagnosis requires a thorough workup. Once CTEPH is confirmed, patients who can be safely operated have to be identified. We investigated risk factors associated with CTEPH and IPAH, and the criteria for the selection of operable CTEPH patients. This case-control study included 436 consecutive patients with CTEPH and 158 with IPAH in eight European centres, between 2006 and 2010. Conditions identified as risk factors for CTEPH included history of acute venous thromboembolism (p < 0.0001), large size of previous pulmonary embolism (p = 0.0040 in univariate analysis), blood groups non-O (p<0.0001 in univariate analysis), and older age (p=0.0198), whereas diabetes mellitus (p=0.0006), female gender (p=0.0197) and higher mean pulmonary artery pressure (p = 0.0103) were associated with increased likelihood for an IPAH diagnosis. Operability of CTEPH patients was associated with younger age (p=0.0108), proximal lesions (p ≤ 0.0001), and pulmonary vascular resistance below 1200 dyn.s.cm⁻⁵ (p=0.0080). Non-operable CTEPH patients tended to be less differentiable from IPAH patients by risk factor analysis than operable patients. This study confirmed the association of CTEPH with history of acute venous thromboembolism and blood groups non-O, and identified diabetes mellitus and higher mean pulmonary artery pressure as factors suggesting an IPAH diagnosis. Non-operable CTEPH is more similar to IPAH than operable CTEPH regarding risk factors.

Abstract 18601: The Role of ADMA Metabolism in the Regulation of Human Pulmonary Endothelial Cell Function

Objective: Asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication required for the coordinated regulation of pulmonary endothelial permeability and angiogenesis, contributing to the disease. Methods and Results. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells (HPAECs). ADMA inhibited protein expression and cell surface localization of connexin 43 (Cx43) in HPAECs (2-fold decrease, P&lt;0.01), resulting in impaired gap junctional communication, as shown by Fluorescence Recovery After Photobleaching (FRAP). ADMA regulated Cx43 expression and function via the nitric oxide signalling pathway, as effects could be reversed by the nitric oxide donor SNAP, and nitric oxide secondary messengers, cAMP and cGMP. Defective gap junction communication in HPAECs led to endothelial dysfunction, including increased trans-endothelial permeability (1.7-fold increase, P&lt;0.001), and impaired angiogenesis(1.7-fold decrease, P&lt;0.001). The effects of ADMA were prevented by over expressing dimethylarginine dimethylaminohydrolase I (DDAHI), an enzyme that metabolised ADMA, or treatment with the Cx43-gap junction activating drug, rotigaptide.Reduced Cx43 expression was also found in lungs of mice deficient in DDAHI. In vivo lung permeability was increased in DDAHI homozygous knockout mice (1.2-fold increase, P&lt;0.05), and was alleviated by application of rotigaptide. Endothelial colony forming cells from IPAH patients showed reduced expression of DDAHI and Cx43 (2-fold decrease, P&lt;0.05), resulting in impaired endothelial barrier function and abnormal angiogenesis. Conclusions. ADMA is critical in the regulation of gap junctional communication in pulmonary endothelium. Endothelial cells from IPAH patients show reduced ADMA metabolism resulting in defective gap junctional communication and abnormal angiogenic responses. Enhancing Cx43 function may have endothelium-protective effects in conditions associated with reduced nitric oxide signalling, such as pulmonary hypertension.

Alterations of Orai, STIM, and TRPC Expression and Store‐ Operated Calcium Entry in Pulmonary Arteries of Monocrotaline‐Induced Pulmonary Hypertensive Rats

Pulmonary hypertension (PH) is associated with alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Previous studies show that store‐operated Ca2+ entry (SOCE) is enhanced in PASMCs of chronic hypoxia‐ and monocrotaline (MCT)‐induced PH rats, and idiopathic PH patients. Since the SOCE pathway is composed of many different proteins and channels, including the sarcoplasmic Ca2+ sensor stromal interaction molecules (STIM), Orai channels, and transient receptor potential channels, we sought to examine the alterations in the expression of these molecular constituents of SOCE in the PASM of MCT‐induced PH rats. Rats developed severe PH and right ventricular hypertrophy within three weeks after a single injection of MCT. Quantitative RT‐PCR found that there was significant increase in the expression of STIM2, Orai1, Orai2, TRPC1, and TRPC4, whereas the expression of STIM1, Orai3, and TRPC6 was unchanged. Unregulation of Orai1, TRPC1, and TRPC4 proteins were also verified by Western blot. Moreover, the time‐course of increase in the expression of STIM2, Orai1, and TRPC1 were similar to that of the increase in SOCE induced PA contraction. These results suggest that multiple components of the SOCE pathways are altered during PH and contribute synergistically to the enhanced SOCE in PASMCs. (This work is supported by NSFC 30670772 and 31171104, FJMU09ZD010, NSF‐Fujian 2010J01173, and R01‐HL075134)

INHALED NITRIC OXIDE: CLINICAL EFFECTS AND INFLUENCE ON THE PROFILE OF INFLAMMATORY MARKERS IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

Aim. To study the effect of treatment with inhaled nitric oxide (iNO) on the clinical status of patients with idiopathic pulmonary hypertension (IPH), and the profile of proinflammatory cytokines in peripheral blood. Material and methods. Patients with IPH (n=48) were included into the study. Evaluation of the IPH functional class (FC), the 6-minute walk test (6MWT) with the assessment of the Borg index, echocardiography , laboratory tests [blood count, evaluation of high-sensitivity C-reactive protein (hsCRP), interleukins (IL), interferon-γ (INFγ), tumor necrosis factor a (TNFa), macrophage inflammatory protein a (MIP1 a), soluble adhesion molecules (sICAM-1, sVCAM-1) in peripheral blood] were performed at baseline and on day 21 of iNO therapy course. The iNO course 40 ppm during 5 hours a day for 21 days was carried out additionally to the standard IPH therapy under the toxicity control by the PrinterNOx (England). Results. Increase in exercise tolerance, improvement of IPH FC (from 3.35±0.52 to 2.71±0.56; p=0.008), reduction in systolic pulmonary artery pressure (SPAP) by Doppler echocardiography (from 96.23±23.65 to 82.36±20.92 mmHg; p&lt;0.05) were found in IPH patients as a result of iNo therapy. The significance of inflammation in IPH pathogenesis was confirmed due to assessment of the initial levels of proinflammatory cytokines. iNO therapy resulted in significant decrease in proinflammatory cytokines-IL-1β, IL-6, IL-8, TNFa levels. iNO induced significant dynamics of IL-1β and sVCAM in patients with IPH FC II. It reduced IL-8 and TNFa and increase INFγ (p&lt;0.05) in patients with IPH FC III-IV. Changes in IL-1β and sVCAM levels (ΔIL-1β and ΔsVCAM) by the 21 day of iNO therapy in comparison with these at baseline correlated with ΔSPAP , and ΔIL-6 correlated with ΔFC and Δ6MWT distance (30.5 [21.0; 53.0] m; p&lt;0.001). This allows considering these indicators as markers of iNO treatment efficacy. Conclusions. 21-day iNO therapy in IPH patients resulted in significant improvement of functional status, reduce SPAP and caused the positive dynamics of proinflammatory cytokines blood levels.

Strain and strain rate echocardiography for evaluation of right ventricular dysfunction in patients with idiopathic pulmonary arterial hypertension

Optimizing the non-invasive imaging of right ventricular (RV) function is of increasing interest for therapy monitoring and risk stratification in patients with idiopathic pulmonary hypertension (IPAH). Therefore, this study evaluated strain and strain rate echocardiography as a tool for comprehensive assessment of RV function and disease severity in IPAH patients. In 30 IPAH patients [WHO functional classes II-IV; mean pulmonary artery pressure (mPAP) 48.8 +/- 12.5 mmHg; pulmonary vascular resistance (PVR) 7.9 +/- 5.3 Wood units] and in 10 matched healthy control subjects' two-dimensional echocardiography, 6-MWD and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were obtained. In IPAH patients when compared with controls, RV systolic strain (-18.8 +/- 4.3 vs. -34.5 +/- 3.8%, p = 0.0016) and strain rate (-1.6 +/- 0.6 vs. -2.7 +/- 0.5 s(-1), p = 0.018) were significantly altered and correlated significantly with elevated NT-proBNP levels (r = 0.73 and r = 0.62; p < 0.001, respectively) and reduced 6-MWD (r = -0.76 and r = -0.81; p < 0.001). In IPAH patients, reduced strain correlated with both mPAP (r = 0.61, p = 0.01 for strain; and r = 0.55, p = 0.04 for strain rate, respectively), and PVR (r = 0.84, p < 0.001 for strain; and r = 0.67, p < 0.001 for strain rate, respectively). This study gives first comprehensive evidence that strain echocardiography allows accurate non-invasive assessment of RV function and disease severity in patients with IPAH.

Apelin: A new plasma marker of cardiopulmonary disease

Objectives Dyspnea is a major symptom of both parenchymal lung disease and chronic heart failure. Underlying cardiac dysfunction can be assessed by measurement of cardiac-derived B-type natriuretic peptide or its precursor in plasma. However, no specific endocrine marker of the lung parenchyma has so far been identified. We therefore examined whether plasma concentrations of apelin, a novel inotropic hormone, is affected in patients with chronic parenchymal lung disease without cardiac dysfunction. Methods and results Patients with severe chronic parenchymal lung disease and normal cardiac function ( n = 53), idiopathic pulmonary hypertension with increased right ventricular pressure ( n = 10), and patients with severe left ventricular systolic dysfunction ( n = 22) were enrolled. Plasma apelin-36 and proBNP concentrations were measured with radioimmunoassays. While proBNP plasma concentrations were unaffected in chronic parenchymal lung disease patients compared to normal subjects, the apelin-36 concentration was reduced 3.3-fold (median 35 pmol/l (0–162 pmol/l) vs. 117 pmol/l (55–232 pmol/l), P < 0.001). Moreover, the apelin-36 concentration was decreased in chronic heart failure patients (2.1-fold, P < 0.01) and in patients with idiopathic pulmonary hypertension (4.0-fold, P < 0.001). In contrast, the proBNP concentration was highly increased in both chronic heart failure and idiopathic pulmonary hypertension patients. Conclusion Plasma concentrations of apelin-36, a novel inotropic peptide, are decreased in patients with chronic parenchymal lung disease and preserved cardiac function. Combined measurement of apelin-36 and proBNP may be a new diagnostic approach in distinguishing pulmonary from cardiovascular causes of dyspnea.

106 Contribution of the angiopoietin/Tie2 pathway to pulmonary artery smooth muscle hyperplasia in idiopathic pulmonary hypertension

Introduction Angiopoietins are involved in blood-vessel maturation and stabilization through activation of the selective endo-thelial-specific receptor Tie2, which leads to inhibition of endothelial cell (EC) proliferation and induces release of endothe-lial-derived growth factors. Recent studies suggest that alterations in the Ang 1/Tie2 pathway may contribute to pulmonary artery smooth muscle cell (PA-SMC) hyperplasia in idiopathic pulmonary hypertension (IPH). Methods In the present study, we used lung homogenates and cultured cells (PA-EC and PA-SMC) from patients with IPH and controls to examine expression of angiopoietins (Angl and Ang 2) and Tie2 receptors, as well as the consequences of Tie2 receptor activation on release of serotonin, endothelin-1, EGF, and PDGF-BB from PA-EC. Results We found that expression of Angl and Ang2 (quantitative RT/PCR and Western blot for determination of mRNA and protein, respectively) in lungs and PA-SMCs did not differ between IPH patients and controls. Tie2 receptor expression (mRNA and protein) was 3-4 fold higher in lungs and cultured PA-EC from patients with IPH than from controls (p Conclusion The results show that an increase in Angl-induced activation of Tie2 receptors in IPH is responsible for increased production of growth factors acting on PA-SMC.