Thenappan

A USA-based registry for pulmonary arterial hypertension: 1982-2006

The aim of this study was to define the epidemiology of World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) in a large referral centre in the USA. The Pulmonary Hypertension Connection registry, initiated in 2004, evaluated all patients in a single USA practice from 1982–2006. For comparison, the authors divided the group by incident versus prevalent cohorts, aetiology and by treatment era. In total, 578 patients (77% female) aged 48±14 yrs were entered. Of these, 80% had class III or IV symptoms. Over time, connective tissue disease-associated PAH increased, while referrals for HIV remained low. One-third of patients were referred on calcium channel blocker therapy even though only 4.6% had an acute response to vasodilator challenge. When compared by treatment era, there were no differences in the severity of PAH. However, survival had improved over time, with a 1-yr survival of 85% in the incident cohort. In the USA, pulmonary arterial hypertension patients are still referred to tertiary centres too late. Referral of connective tissue disease is increasing, while referral of HIV remains low. Inappropriate calcium channel blocker treatment is common. Survival rates have increased but remain low suggesting that prognosis is improving but PAH is still a progressive, fatal disease.

Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation

The aim of the present study was to determine contemporary survival in pulmonary arterial hypertension (PAH), and to investigate whether or not the National Institutes of Health (NIH) equation remains an accurate predictor of survival. In 576 patients with PAH referred during 1991–2007, observed survival was described using the Kaplan–Meier method. In patients with idiopathic, familial and anorexigen-associated PAH (n = 247), observed versus NIH equation predicted survival was compared. A new survival prediction equation was developed using exponential regression analysis. The observed 1-, 3- and 5-yr survival in the total cohort were 86, 69 and 61%, respectively. In patients with idiopathic, familial and anorexigen-associated PAH, the observed 1-, 3- and 5-yr survival (92, 75 and 66%, respectively) were significantly higher than the predicted survival (65, 43 and 32%, respectively). The new equation (P(t) = e-A(x,y,z)t, where P(t) is probability of survival, t the time interval in years, A(x,y,z) = e(−1.270–0.0148x+0.0402y–0.361z), x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index) performed well when applied to published contemporary studies of survival in PAH. Contemporary survival in the PAH cohort was better than that predicted by the NIH registry equation. The NIH equation underestimated survival in idiopathic, familial and anorexigen-associated PAH. Once prospectively validated, the new equation may be used to determine prognosis.

A united states-based registry for pulmonary arterial hypertension: 1982–2006

The aim of this study was to define the epidemiology of World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) in a large referral centre in the USA. The Pulmonary Hypertension Connection registry, initiated in 2004, evaluated all patients in a single USA practice from 1982–2006. For comparison, the authors divided the group by incident versus prevalent cohorts, aetiology and by treatment era. In total, 578 patients (77% female) aged 48±14 yrs were entered. Of these, 80% had class III or IV symptoms. Over time, connective tissue disease-associated PAH increased, while referrals for HIV remained low. One-third of patients were referred on calcium channel blocker therapy even though only 4.6% had an acute response to vasodilator challenge. When compared by treatment era, there were no differences in the severity of PAH. However, survival had improved over time, with a 1-yr survival of 85% in the incident cohort. In the USA, pulmonary arterial hypertension patients are still referred to tertiary centres too late. Referral of connective tissue disease is increasing, while referral of HIV remains low. Inappropriate calcium channel blocker treatment is common. Survival rates have increased but remain low suggesting that prognosis is improving but PAH is still a progressive, fatal disease.

Dynamin-Related Protein 1–Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1&agr; (HIF-1&agr;) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation. Objective: We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential. Methods and Results: Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1&agr; activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1&agr; activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1–dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1&agr; activation by CoCl2 or desferrioxamine causes DRP1-mediated fission. HIF-1&agr; inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH. Conclusions: DRP-1–mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.

Clinical Characteristics of Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction

Background— Pulmonary vascular disease associated with left-side heart failure and preserved ejection fraction (PH-HFpEF) is an increasingly common cause of pulmonary hypertension. The distinction between PH-HFpEF and pulmonary arterial hypertension (PAH) is important because therapies indicated for PAH can be detrimental in HFpEF. The characteristic features of PH-HFpEF are understudied. Methods and Results— In a cross-sectional study, we compared the clinical, echocardiographic, and hemodynamic features of PH-HFpEF (n=100), with PAH (n=522), and HFpEF without pulmonary vascular disease (n=45). We determined the clinical characteristics that best differentiated PH-HFpEF from PAH. Compared with patients with PAH, patients with PH-HFpEF were older; had a higher prevalence of cardiovascular comorbidities; had worse exercise capacity and renal function; more frequently had left atrial enlargement; and less frequently had right atrial enlargement. PH was less severe in PH-HFpEF patients than in PAH patients (pulmonary vascular resistance 4.8 [interquartile range 3 to 8.4] versus 10.9 [interquartile range 7.4 to 15.7] Wood units; P<0.001). Old age, the presence of hypertension and coronary artery disease, the absence of right atrial enlargement, higher aortic systolic pressure, higher mean right atrial pressure, and higher cardiac output best differentiated PH-HFpEF from PAH (area under the receiver operating characteristics curve; curve 0.97). Compared with HFpEF patients without pulmonary hypertension, PH-HFpEF patients were often female and more symptomatic, more often had right ventricular hypertrophy and right atrial enlargement, and had higher right atrial pressure. Conclusions— These data should help better identify PH-HFpEF, an entity that has become increasingly recognized and difficult to treat.

Usefulness of Red Cell Distribution Width as a Prognostic Marker in Pulmonary Hypertension

Red blood cell distribution width (RDW), a widely available biomarker, independently predicts adverse outcomes in left-sided heart failure. The relation between RDW and death in pulmonary hypertension (PH) is unknown. In a prospective study of 162 consecutive patients with PH, RDW was recorded during initial diagnostic right-sided cardiac catheterization, and patients were followed for 2.1 +/- 0.8 years to determine vital status. Demographic, clinical, laboratory, and hemodynamic variables were compared by tertile of RDW. Cox proportional-hazards models were used to determine whether RDW was independently associated with death, and the prognostic utility of RDW was compared to that of other laboratory predictors, including N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP). Of the 162 study patients, 78% were women, and 62% had pulmonary arterial hypertension. The mean age was 53 +/- 15 years, and most patients had severe PH (mean pulmonary artery pressure 48 +/- 13 mm Hg). The highest tertile of RDW predicted death (univariate hazard ratio 4.86, 95% confidence interval 1.37 to 17.29, p = 0.015; multivariate hazard ratio 2.4, 95% confidence interval 1.02 to 5.84, p = 0.045, after adjusting for age, gender, diabetes mellitus, connective tissue disease, diuretic use, phosphodiesterase inhibitor use, hemoglobin, mean corpuscular volume, and blood urea nitrogen [BUN]). Of the laboratory data, only RDW, BUN, and NT-pro-BNP were associated with death on univariate analysis. When RDW, BUN, and NT-pro-BNP were entered into a multivariate model, only RDW was still associated with death (p = 0.037 for RDW, p = 0.18 for BUN, and p = 0.39 for NT-pro-BNP). Adding NT-pro-BNP to RDW did not improve the prediction of mortality. In conclusion, RDW is independently associated with death in patients with PH and performs better as a prognostic indicator than NT-pro-BNP.

Lung 18F-Fluorodeoxyglucose Positron Emission Tomography for Diagnosis and Monitoring of Pulmonary Arterial Hypertension

RATIONALE Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer (18)F-fluorodeoxyglucose (FDG). OBJECTIVES The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. METHODS PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. MEASUREMENTS AND MAIN RESULTS Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1α (HIF-1α), which underlies their glycolytic phenotype. CONCLUSIONS HIF-1α-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.

A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome: Reversal by Macrophage Depletion

RATIONALE The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. OBJECTIVES We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion. METHODS Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group). MEASUREMENTS AND MAIN RESULTS CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+)macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. CONCLUSIONS HPS results from intravascular accumulation of CD68(+)macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.

Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension

Background— Renal dysfunction predicts mortality in patients with cardiovascular disease. How renal dysfunction relates to hemodynamics and mortality in pulmonary arterial hypertension (PAH) remains unclear. Methods and Results— We performed a cohort study of 500 patients with World Health Organization group I PAH from 1982 to 2006 with data on demographics, comorbidities, medications, functional class, laboratory tests, exercise testing results, and hemodynamics. Serum creatinine (SCr) was determined on entry into the study (initial PAH clinic visit). Vital status was determined from hospital records and the Social Security Death Index. We used a Cox proportional hazards analysis to determine whether SCr was an independent predictor of mortality. Mean age on entry into the study was 48±14 years, and 79% of subjects were female. Mean SCr was 1.05±0.35 mg/dL. Elevated SCr was associated with higher right atrial pressure and lower cardiac index. During a median follow-up of 3.5 years, 279 deaths (55.8% of the cohort) occurred. Compared with patients with SCr <1.0 mg/dL, those with SCr 1.0 to 1.4 mg/dL and SCr >1.4 mg/dL had an increased hazard ratio of death (unadjusted hazard ratio 1.65, 95% confidence interval 1.26 to 2.17, P<0.0001 for SCr 1.0 to 1.4 mg/dL; unadjusted hazard ratio 2.54, 95% confidence interval 1.73 to 3.71, P<0.0001 for SCr >1.4 mg/dL). On multivariable analysis, we found a significant interaction between SCr and right atrial pressures (interaction P<0.0001); increased SCr best predicted death in patients with right atrial pressure <10 mm Hg. Conclusions— Renal dysfunction is associated with a worse hemodynamic profile and is an independent predictor of mortality in PAH. Measurement of SCr is practical and offers a simple way to noninvasively predict outcome.

United States Validation of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)

BACKGROUND The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first pulmonary hypertension-specific instrument for assessing patient-reported symptoms, functioning, and quality of life. To enable use in the United States, this study adapted, field-tested, and evaluated its reliability and validity at a single center in Chicago. METHODS A lay panel confirmed appropriate wording of CAMPHOR for United States patients, and 15 patients with pulmonary hypertension field-tested the CAMPHOR for face and content validity. A postal validation study, with the Medical Outcomes Study Short Form 36 (SF-36) Health Survey as a comparator, was sent to patients on 2 occasions, 2 weeks apart. World Health Organization (WHO) functional class and 6-minute walk test data were obtained. RESULTS Field-test interviews found the CAMPHOR relevant and comprehensible. A total of 147 patients (84.0% women) with a mean of 50 +/- 14.6 years participated in the validation study. The new scales had good test-retest reliability (range, 0.80-0.95) and internal consistency (range, 0.78-0.95). The CAMPHOR scales correlated with the SF-36 and 6-minute walk test. Patients in WHO functional class III had worse scores than those in class II (p = 0.02), as did patients who rated their health worse (p < 0.001). CONCLUSIONS The US CAMPHOR is a reliable and valid measure of quality of life and health status in pulmonary hypertension and can be recommended for use in clinical practice and trials in the United States.