Hyaluronan as a Promising Biomarker for Myocardial Damage.

Hyaluronan is a glycosaminoglycan, one of the chief components of the extracellular matrix. The aim of the present study is to investigate plasma hyaluronan levels among patients with acute myocardial infarction (AMI). This prospective study enrolled 56 consecutive patients with AMI who underwent percutaneous coronary intervention within 2 hours after admission. Plasma levels of hyaluronan were measured at the time of admission (baseline), and on the 7th and 30th day after AMI. Echocardiographic examinations were performed at baseline and on the 30th day after AMI. The hyaluronan levels were 33.2 ± 3.1 ng/ml (mean ± SD) at baseline, increased on the 7th day (46.2 ± 5.9 ng/ml), and continued to remain high on the 30th day after AMI (50.1 ± 5.1 ng/ml). There were significant correlations of the hyaluronan levels between baseline and on the 7th day (r = 0.535, p < 0.001) and between baseline and on the 30th day (r = 0.263, p = 0.05). Significant correlations were also found between hyaluronan levels on the 30th day, and the peak levels of CK-MB (r = 0.429, p = 0.001) or highly sensitive troponin levels (r = 0.360, p = 0.006). The hyaluronan levels were significantly higher on the 30th day after AMI in patients with anterior infarction, but not in patients with non-anterior infarction (p = 0.01 vs. p = 0.653). In conclusion, this is the first report that demonstrates the increase of plasma hyaluronan levels among patients with AMI.

Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase.

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension.

Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phospho-Smad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

The relationship between plasma hyaluronan levels and anthracycline-related cardiotoxicity in breast cancer patients.

AIM: Anthracycline-derived antineoplastic agents are used as the main form of treatment in many malignant diseases, including breast cancer and childhood cancers. Cardiotoxicity is one of the most feared life-threatening complications of cancer therapy. In the present study, we aimed to investigate the relationship between plasma hyaluronan (HA) levels and anthracycline-induced cardiotoxicity. MATERIALS AND METHODS: Fifty eight of 73 female patients who were diagnosed with breast cancer and treated with a chemotherapy regimen including anthracycline were enrolled in this study. Anamneses were taken from each patient before and after chemotherapy. Further, physical examinations, electrocardiography, and transthoracic echocardiography were performed, and plasma hyaluronan levels were determined by using ELISA assay for each patient before and after treatment. RESULTS: Following anthracycline-based chemotherapy, the average left ventricular ejection fraction decreased (62.6±3.7% vs. 58.6±4.4%, p<0.001), and diastolic functions significantly deteriorated (p<0.001). However, troponin and hyaluronan levels significantly increased following chemotherapy [Troponin (ng/ml, mean±SD): before 0.01±0.002, after 0.037±0.02, p<0.001], [Plasma HA (ng/ml, mean±SD): before 41.3±5.4, after 70±8.5, p<0.001]. The increase in troponin values correlated with systolic dysfunction (p=0.002), but did not correlate with diastolic dysfunction (p=0.661). Significant correlations were found between systolic/diastolic dysfunction and plasma HA levels (r=0.417, p=0.001; r=0.339, p=0.009, respectively). CONCLUSIONS: Both systolic and diastolic functions were significantly deteriorated after chemotherapy. In addition, plasma levels of HA and troponin increased after treatment. Further, both systolic and diastolic dysfunctions were found to correlate with serum HA levels. All these data suggest that HA might have a function on anthracycline-induced cardiotoxicity.

Leptin deficiency recapitulates the histological features of pulmonary arterial hypertension in mice.

UNLABELLED: Leptin is a neuroendocrine peptide released by adipose tissue that enhances metabolism and acts on the hypothalamus to suppress appetite. Leptin also regulates aspects of cardiovascular function and low serum leptin has been associated with increased mortality in humans. We hypothesized that leptin deficiency alters the structure and function of the pulmonary vasculature. METHODS: We examined two groups of C57BL/6 male mice aged 12 weeks: five ob/ob (B6.VLepob/ob) leptin-deficient and five wild type (WT) (C57BL/6) control mice. As expected, weight was significantly greater in ob/ob mice relative to WT mice [weight (g), Mean±SD): ob/ob 52±2.5 g, wild type 30±2.5 g; p<0.001]. The pulmonary vasculature of ob/ob mice and WT control animals was examined by histology, immunohistochemistry and immunofluorescence staining. RESULTS: Pulmonary arterial wall thickness was significantly increased in ob/ob mice relative to WT littermates [median (interquartile range) distance in pixels: ob/ob 0.13 (0.05-0.18), wild type 0.03 (0.02-0.04); p=0.001]. The ob/ob mice also exhibited significant right ventricular hypertrophy in comparison to control animals [RV thickness (Mean±SD): ob/ob 0.75±0.19, wild type; 0.58±0.13 p<0.001]. We observed substantial macrophage infiltration and abundant proliferation of myofibroblasts and fibroblasts in histological sections of pulmonary arterioles of ob/ob mice. In addition, we noted increased hyaluronan deposition, colocalizing with SMC-actin in the pulmonary vasculature of ob/ob mice relative to WT controls. CONCLUSIONS: The pulmonary pathology of leptin deficiency in ob/ob mice recapitulates many of the histological features of pulmonary vascular diseases, including pulmonary hypertension, suggesting that leptin deficiency is associated to the pathogenesis of pulmonary vascular disease.

Elevated hyaluronan levels in patients with rheumatic mitral stenosis and pulmonary arterial thromboembolism.

INTRODUCTION: The role of hyaluronan (HA) was previously demonstrated in patients with idiopathic pulmonary arterial hypertension (PAH). Mitral stenosis (MS) and pulmonary arterial thromboembolism (PTE) are important health problems that can cause pulmonovascular pathology. Pulmonary arterial hypertension develops especially in untreated patients with severe MS and most of patients with PTE. However, there is no data about HA levels in patients with MS and PTE. In this study, we investigated HA levels in patients with rheumatic MS and PTE. METHOD: Study population was divided into three groups. MS group consisted of 18 patients with moderate or severe MS. PTE group consisted of 16 patients with PTE. Control group consisted of 15 subjects without cardiac and pulmonary disease. Percutaneous mitral balloon valvuloplasty (PMV) was performed on all patients in MS group. Mitral gradients and systolic pulmonary arterial pressure (sPAP) were measured in all patients. HA levels were measured at baseline and first month after PMV. RESULTS: Mean sPAP±SD (mmHg) was 23±3 in the control group, 44±9 in the MS group and 66±11 in the PTE group (p<0.001). Baseline serum HA levels were significantly correlated with sPAP(echo) (r=0.332 p=0.03) and sPAP(cath) (r=0.559, p=0.007). Serum HA levels (ng/ml) in MS were significantly higher compared to controls [39±14 vs 24±11; p=0.01]. Patients in PTE group had the highest HA levels (61±21; p<0.001). Serum HA levels were significantly decreased at the first month after PMV in patients with MS [MS group: 39±14 (ng/ml), after PMV: 31±8; p=0.03]. CONCLUSION: This is the first article showing that both MS and PTE can cause increased serum HA levels. HA levels were decreased with PMV procedure in patients with MS.

Modification of hyaluronan by heavy chains of inter-α-inhibitor in idiopathic pulmonary arterial hypertension.

We previously reported an altered hyaluronan (HA) metabolism in idiopathic pulmonary arterial hypertension (IPAH) lung tissue and cultured smooth muscle cells. Hyaluronan was present in the smooth muscle cell layer surrounding the pulmonary vasculature and in plexigenic lesions. Additionally, cultured pulmonary artery smooth muscle cells produced spontaneous HA "cable" structures, without additional stimuli, that were leukocyte-adhesive. We now present evidence that the HA that accumulates in IPAH plexigenic lesions is a pathological form of HA in which heavy chains (HCs) from the serum-derived proteoglycan inter-α-inhibitor are covalently attached to the HA backbone to form a pathological HC-HA complex. CD45-positive leukocytes were identified within these HC-HA matrices. Elevated mRNA levels of the enzyme that transfers HCs to HA, known as tumor necrosis factor-stimulated gene 6, were detected in IPAH lung tissue.

Pronounced transcriptional regulation of apoptotic and TNF-NF-kappa-B signaling genes during the course of thymoquinone mediated apoptosis in HeLa cells.

Thymoquinone (TQ) is the active ingredient extracted from the essential oil of Nigella sativa. A number of studies implicated TQ as an antitumor agent. In this study, cytotoxic effects of the oil of N. sativa and TQ were evaluated on human cervical cancer cell line, HeLa cells. IC50 value was ~0.125 µl/ml for N. sativa oil preparations and 12.5 µM for TQ. TQ strongly inhibited wound healing at all concentrations ranging from 12.5 to 100 µM in a scratch wound healing assay. Additionally, induction of apoptosis by TQ was assessed by Giemsa staining and TQ was found to induce apoptosis in cancer cells especially at concentrations of 50 and 100 µM. TQ-mediated transcriptional regulation of 84 genes involved in apoptosis was studied using a PCR array. At low dose (12.5 µM), TQ was found to induce expression of four pro-apoptotic genes: BIK (~22.7-fold), FASL (~2.9-fold), BCL2L10 (~2.1-fold), and CASP1 (~2-fold). TQ was also found to reduce the expression of an anti-apoptotic gene implicated in NF-kappa-B signaling and cancer: RELA (~8-fold). At high dose (100 µM), TQ mediated the expression of 21 genes implicated directly in apoptosis (6 genes), TNF signaling (10 genes), and NF-kappa-B signaling (3 genes) such as BIK, BID, TNFRSF10A, TNFRSF10B, TNF, TRAF3, RELA, and RELB. In conclusion, this study implicates the role of TQ in the inhibition of cancer cell proliferation and migration. At the same time, our results strongly suggest that TQ intervenes with TNF and NF-kappa-B signaling during TQ-mediated induction of apoptosis in cancer cells.

Elevated plasma hyaluronan levels in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease, with a poor prognosis. The pathophysiologic mechanism of PAH is unknown, but may involve both tissue remodeling and inflammatory processes. Hyaluronan (HA) is a large glycosaminoglycan polymer and a major component of the extracellular matrix. In the present study, we measured plasma HA levels in PAH associated with systolic congestive heart failure (CHF, n = 16) or chronic obstructive pulmonary disease (COPD, n = 18). The control group was consisted of 14 healthy individuals without pulmonary or cardiovascular disease. Plasma HA levels (ng/mL) were determined in all patients by an enzyme linked HA binding assay. Pulmonary arterial pressure (PAP) was calculated in echocardiography (mmHg). Pulmonary arterial pressures were significantly higher in CHF and COPD (CHF: 55.0 ± 11 mmHg and COPD: 62.5 ± 21 mmHg, p < 0.001 for each), compared to the control group (25.4 ± 5.9 mmHg). Plasma HA levels were significantly higher in CHF (73.0 ± 37.5 ng/ml, p = 0.007) and COPD (87.3 ± 53.2 ng/ml, p = 0.001) compared to control patients (26.2 ± 8.4 ng/ml). There was no significant difference in plasma HA levels between the CFH and COPD groups (p = 0.690). In COPD, plasma HA levels were significantly correlated with PAP, left atrium diameter. There was no significant correlation between plasma HA levels and age or with echocardiography parameters in CHF. Both CHF and COPD are associated with increased plasma HA levels. Elevated plasma HA may contribute to the development of PAH.

Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy.

Nitric oxide (NO) is a diffusible gas with diverse roles in human physiology and disease. Significant progress in the understanding of its biological effects has taken place in recent years. This has led to a better understanding of the pathobiology of pulmonary hypertension (PH) and the development of new therapies. This article provides an overview of the NO physiology and its role in the pathobiology of lung diseases, particularly PH. We also discuss current and emerging specific treatments that target NO signaling pathways in PH.

Angiopoietin 2 levels in serum and bronchial lavage fluids and their relationship with cancer stages in lung cancer patients.

BACKGROUND: Angiopoietin 2 (Ang-2) has an important role in tumor angiogenesis. In this study, Ang-2 levels of serum and bronchioloalveolar lavage fluids (BALF) in patients with lung cancer were measured and correlated with clinical and biochemical parameters. METHODS: Thirty-five cases newly diagnosed with lung cancer and 18 controls with non-cancerous lung diseases were included in the study. Tumor histology, staging, metastasis, tumor markers, biochemical and clinical parameters were all recorded. RESULTS: Serum Ang-2 levels were significantly higher in the lung cancer group compared to the control (lung cancer median: 2.42 ng/mL [2.19-2.98], control 0.67 [0.31-1.10]; P < 0.001), whereas Ang-2 levels in BALF were lower in the lung cancer group compared to the control (lung cancer median 0.41 ng/mL [0.22-0.79], control 0.67 [0.46-1.03]; P = 0.02). In the cancer group, higher serum Ang-2 levels (r = 0.52, P < 0.001) were associated with the stage of cancer. No significant correlation was observed between BALF Ang-2 levels and non-small cell lung cancer stages and small-cell lung cancer advanced stage (P = 0.793, r = 0.07). Serum Ang-2 levels were significantly higher in distant metastasis (M1) versus no distant metastasis (M0) (M1: 2.57 ng/mL [2.38-2.87], M0: 2.22 [1.49-2.40], P = 0.01). No significant correlation was observed between BALF Ang-2 levels and M1 (r = 0.11, P = 0.53). CONCLUSIONS: Serum Ang-2 levels were significantly higher in lung cancer patients and positive correlations were observed between serum Ang-2, tumor stage, and metastasis.

Leptin levels predict survival in pulmonary arterial hypertension.

Evidence suggests that leptin is involved in relevant processes in the cardiovascular system. Low serum leptin levels have been associated with increased cardiovascular events and mortality in patients with coronary artery, diabetes, or chronic kidney disease. We hypothesized that leptin is increased in pulmonary arterial hypertension (PAH) and provides prognostic information. We correlated leptin levels with clinical data and assessed its association with survival. Sixty-seven patients with PAH and 29 healthy controls were studied. Plasma leptin levels were nonlinearly associated with BMI. Leptin level <15 µg/l was associated with higher mortality in PAH patients, with an adjusted (age, gender, BMI, and smoking status) hazard ratio of 3.8 (95% CI: 1.3-11.2), P=0.016. Similarly, PAH patients with leptin/BMI ratio <0.5 µg * m(2)/kg * l had worse survival than those with a level >0.5 µg * m(2)/ kg * l (P=0.046 by log-rank test). Two-year mortality in PAH patients was 24%. A receiver operating characteristic curve using leptin/BMI ratio as the test variable and 2-year mortality as the state variable showed an area under the curve of 0.74 (95% CI: 0.62-0.86). A leptin/BMI ratio cut-off of 0.6 had a high sensitivity (94%) and negative predictive value (96%) for predicting death of any cause at 2 years. In PAH, plasma leptin levels are directly associated with BMI. Lower leptin levels, when adjusted by BMI, are associated with an increased overall mortality and leptin/BMI ratio has high negative predictive value for mortality at 2 years.

Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease. Several processes are believed to lead to the fatal progressive pulmonary arterial narrowing seen in IPAH including vasoconstriction, cellular proliferation inflammation, vascular remodeling, abnormalities in the lung matrix, and in situ thrombosis. Nitric oxide (NO) produced by NO synthases (NOS) is a potent vasodilator and plays important roles in many other processes including platelet function. Reduced NO levels in patients with IPAH are known to contribute to the development of pulmonary hypertension and its complications. Platelet defects have been implied in IPAH, but original research supporting this hypothesis has been limited. Normal platelets are known to have NOS activity, but little is known about NOS expression and NO production by platelets in patients with IPAH. Here we characterized the phenotype of the platelets in IPAH and show a defect in their ability to be activated in vitro by thrombin receptor activating protein but not adenosine diphosphate. We also show that endothelial NOS (eNOS) levels in these platelets are reduced and demonstrate that NO is an important regulator of platelet function. Thus reduced levels of eNOS in platelets could impact their ability to regulate their own function appropriately.

The effect of adenotonsillectomy on right ventricle function and pulmonary artery pressure in children with adenotonsillar hypertrophy.

OBJECTIVES: Adenotonsillar hypertrophy (ATH) is the most common cause of upper airway obstruction in children. Severe upper airway obstruction may have an effect on chronic alveolar hypoventilation, which consequently may lead to right ventricle (RV) dysfunction induced by hypoxemic pulmonary vasoconstriction. The investigators aimed to study RV function and mean pulmonary artery pressure (mPAP) in patients with ATH who were undergoing adenotonsillectomy by using tissue Doppler echocardiography (TDE). METHODS: The study examined 27 children with ATH who had a mean age of 8 ± 2 years. The subjects were comprised 17 (63%) males and 10 (37%) females. Hypertrophy of the tonsils was graded according to the Brodsky scale. Children having either grade 3 or 4 hypertrophied adenotonsils were recruited for the study. Adenotonsillectomy was performed on all subjects in the study group and echocardiographic examination was repeated 3 months postoperatively. RESULTS: Tricuspid Em significantly increased after adenotonsillectomy (17.7 ± 3.6 vs. 19.1 ± 5.5, p=0.04). The RV myocardial performance index (MPI) and mPAP significantly decreased after adenotonsillectomy (RV MPI: 0.57 ± 0.13 vs. 0.40 ± 0.12, p<0.001 and mPAP (mmHg): 31 ± 9 vs. 25 ± 7, p=0.001). CONCLUSION: The results of this study, evaluated with the results of previous studies, demonstrated that adenotonsillectomy improved RV performance and reduced mPAP in children with ATH.

The relationship between inflammation and slow coronary flow: increased red cell distribution width and serum uric acid levels.

OBJECTIVES: The underlying mechanism of slow coronary flow (SCF) has yet to be elucidated. Increased red cell distribution width (RDW) and uric acid level may be indicative of an underlying inflammatory state. We aimed to investigate RDW and serum uric acid levels in patients with normal coronary arteries and SCF without stenosis. STUDY DESIGN: The study included 46 consecutive patients (25 males, 21 females; mean age 54 ± 11 years) with angiographically normal coronary arteries but having SCF in all three coronary arteries. The control group consisted of 40 patients (18 males, 22 females; mean age 54 ± 9 years) with angiographically normal coronary arteries without SCF. In both groups, RDW and serum uric acid levels were measured and compared. RESULTS: In the SCF group, TIMI frame counts measured in the left anterior descending coronary artery, left circumflex coronary artery, and right coronary artery were significantly higher compared to the control group (p<0.05). Patients with SCF exhibited significantly higher RDW (13.4 ± 1.6% vs. 12.6 ± 1.2%, p=0.01) and serum uric acid levels (5.3 ± 1.6 mg/dl vs. 4.7 ± 1.3 mg/dl, p=0.01) compared to controls. In logistic regression analysis, uric acid [Exp(B)=1.612, 95% CI 0.206-5.35, p=0.021] and RDW [Exp(B)=1.496, 95% CI 0.403-4.72, p=0.030] were found as independent predictors of SCF. CONCLUSION: Our findings show that patients with SCF have significantly increased RDW and serum uric acid levels. This may help throw more light on the pathophysiological basis of SCF.

A comparison of the sensitivity, specificity, and molecular weight accuracy of three different commercially available Hyaluronan ELISA-like assays.

Hyaluronan (HA) is a glycosaminoglycan found in the extracellular matrix and ranges from several thousand to millions of daltons in size. HA has importance in various pathological conditions and is known to be elevated in several diseases. Three commonly used, commercially available HA enzyme-linked immunosorbent assay (ELISA)-like assays (from Corgenix, Echelon and R&D) were compared on the basis of accuracy, sample variability and ability to measure a range of HA sizes. The Corgenix HA ELISA-like assay displayed the lowest intra-assay variability [coefficient of variation (CV) = 11.7 ± 3.6%], followed by R&D (CV = 12.3 ± 4.6%) and Echelon (CV = 18.9 ± 9.2%). Interassay variability was also lowest for the Corgenix assay (CV = 6.0%), intermediate for the Echelon assay (9.5%) and highest for the R&D assay (CV = 34.1%). The high interassay variability seen for the R&D assay may have been due to the effect of dilution, since the dilution-independent interassay variability was 15.5%. The concentration of the standard HA was overestimated by the Echelon assay by 85% and underestimated by the R&D and Corgenix assays by 34 and 32%, respectively. The Echelon HA ELISA-like assay was the most effective at measuring all sizes of HA tested (2 MDa and 132, 66 and 6.4 kDa), whereas the Corgenix and R&D assays were unable to detect 6.4 kDa HA. These findings suggest that the Echelon HA ELISA-like assay is better suited for size-sensitive HA measurements but has a relatively high variability. The Corgenix and R&D HA ELISA-like assays have low variability and high accuracy but are not suitable for detecting low-molecular-weight HA.

[Pulmonary arterial hypertension: past, present and future]. / Pulmoner arteryel hipertansiyon: dünü, bugünü ve yarini.

Pulmonary arterial hypertension (PAH) is a rare disease with incidence of approximately two to five per million per year and it is characterized by high pulmonary artery pressure. The mechanism of high blood pressure in pulmonary arteries is still unknown and also the pathogenesis of idiopathic PAH is not fully understood. Despite recent advances in therapy, PAH remains a progressive disease with high mortality and morbidity. Traditional hemodynamic markers of disease severity and progression have significant limitations and non-invasive markers are needed to guide follow-up and the effectiveness of therapy in idiopathic PAH patients. Our goal in this review is to give an overview of pulmonary hypertension and to provide researchers with a better understanding of this disease.

Plasma levels of high-density lipoprotein cholesterol and outcomes in pulmonary arterial hypertension.

RATIONALE: High-density lipoprotein cholesterol (HDL-C) promotes healthy vascular function, and it is decreased in insulin resistance. Insulin resistance predisposes to pulmonary vascular disease. OBJECTIVES: We hypothesized that HDL-C is associated with clinical outcomes in pulmonary arterial hypertension (PAH). METHODS: Plasma HDL-C concentrations were measured in 69 patients with PAH (age, 46.7 +/- 12.9 yr; female, 90%) and 229 control subjects (age, 57 +/- 13 yr; female, 48%). Clinical outcomes of interest included hospitalization for PAH, lung transplantation, and all-cause mortality. Survival and time to clinical worsening curves were derived by the Kaplan-Meier method. Cox regression modeling of outcome versus HDL-C with individual covariate adjustments was performed. MEASUREMENT AND MAIN RESULTS: HDL-C was low in subjects with PAH compared with control subjects (median, interquartile range: PAH: 36, 29-40 mg/dl; control subjects: 49, 40-60 mg/dl; P < 0.001). An HDL-C level of 35 mg/dl discriminated survivors from nonsurvivors, with a sensitivity of 100% and specificity of 60%. After a median follow-up of 592 days, high HDL-C was associated with decreased mortality (hazard ratio for every 5-mg/dl increase in HDL-C, 0.643; 95% confidence interval, 0.504-0.822; P = 0.001) and less clinical worsening (hazard ratio for every 5-mg/dl increase in HDL-C, 0.798; 95% confidence interval, 0.663-0.960; P = 0.02). HDL-C remained a significant predictor of survival after adjusting for cardiovascular risk factors, C-reactive protein, indices of insulin resistance, and severity of PAH (all P < 0.05). CONCLUSIONS: Low plasma HDL-C is associated with higher mortality and clinical worsening in PAH. This association does not appear to be explained by underlying cardiovascular risk factors, insulin resistance, or the severity of PAH.