Stephen J. Wort

Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland.

RATIONALE Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. OBJECTIVES To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. METHODS All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. MEASUREMENTS AND MAIN RESULTS A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. CONCLUSIONS This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Improved Survival Among Patients With Eisenmenger Syndrome Receiving Advanced Therapy for Pulmonary Arterial Hypertension

Background— Advanced therapy (AT) for pulmonary arterial hypertension in the context of congenital heart disease (Eisenmenger syndrome) improves pulmonary hemodynamics, functional class, and the 6-minute walk test. We examined the potential effect of AT on survival in this population. Methods and Results— Data on all Eisenmenger patients attending our center over the past decade were collected. Survival rates were compared between patients on and off AT with the use of a modified version of the Cox model, which treats AT as a time-varying covariate. Baseline differences were adjusted for the use of propensity scores. A total of 229 patients (aged 34.5±12.6 years; 35.4% male) were included. The majority had complex anatomy, and 53.7% were in New York Heart Association class ≥III at baseline assessment. Mean resting saturations were 84.3%. Sixty-eight patients (29.7%) either were on AT or had AT initiated during follow-up. During a median follow-up of 4.0 years, 52 patients died, only 2 of them while on AT. Patients on AT were at a significantly lower risk of death, both unadjusted and after adjustment for baseline clinical differences by propensity score regression adjustment (C statistic=0.80; hazard ratio, 0.16; 95% confidence interval, 0.04 to 0.71; P=0.015) and propensity score matching (hazard ratio, 0.10; 95% confidence interval, 0.01 to 0.78; P=0.028). Conclusions— AT for pulmonary arterial hypertension in a contemporary cohort of adults with Eisenmenger syndrome was associated with a lower risk of death. Survival benefits should be considered together with improved hemodynamics and functional class when decisions are made about AT in this population.

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

IntroductionPulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.MethodsA systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.ResultsClinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.ConclusionsThis systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34+, CD34+/AC133+, CD34+/KDR+, and CD34+/AC133+/KDR+ progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients

IntroductionRisk stratification of severely ill patients remains problematic, resulting in increased interest in potential circulating markers, such as cytokines, procalcitonin and brain natriuretic peptide. Recent reports have indicated the usefulness of plasma DNA as a prognostic marker in various disease states such as trauma, myocardial infarction and stroke. The present study assesses the significance of raised levels of plasma DNA on admission to the intensive care unit (ICU) in terms of its ability to predict disease severity or prognosis.MethodsFifty-two consecutive patients were studied in a general ICU. Blood samples were taken on admission and were stored for further analysis. Plasma DNA levels were estimated by a PCR method using primers for the human β-haemoglobin gene.ResultsSixteen of the 52 patients investigated died within 3 months of sampling. Nineteen of the 52 patients developed either severe sepsis or septic shock. Plasma DNA was higher in ICU patients than in healthy controls and was also higher in patients who developed sepsis (192 (65–362) ng/ml versus 74 (46–156) ng/ml, P = 0.03) or who subsequently died either in the ICU (321 (185–430) ng/ml versus 71 (46–113) ng/ml, P < 0.001) or in hospital (260 (151–380) ng/ml versus 68 (47–103) ng/ml, P < 0.001). Plasma DNA concentrations were found to be significantly higher in patients who died in the ICU. Multiple logistic regression analysis determined plasma DNA to be an independent predictor of mortality (odds ratio, 1.002 (95% confidence interval, 1.0–1.004), P = 0.05). Plasma DNA had a sensitivity of 92% and a specificity of 80% when a concentration higher than 127 ng/ml was taken as a predictor for death on the ICU.ConclusionPlasma DNA may be a useful prognostic marker of mortality and sepsis in intensive care patients.

Survival Prospects and Circumstances of Death in Contemporary Adult Congenital Heart Disease Patients Under Follow-Up at a Large Tertiary Centre

Background— Adult congenital heart disease (ACHD) patients have ongoing morbidity and reduced long-term survival. Recently, the importance of specialized follow-up at tertiary ACHD centers has been highlighted. We aimed to assess survival prospects and clarify causes of death in a large cohort of patients at a single, tertiary center. Methods and Results— We included 6969 adult patients (age 29.9±15.4 years) under follow-up at our institution between 1991 and 2013. Causes of death were ascertained from official death certificates. Survival was compared with the expected survival in the general age- and sex-matched population, and standardized mortality rates were calculated. Over a median follow-up time of 9.1 years (interquartile range, 5.2–14.5), 524 patients died. Leading causes of death were chronic heart failure (42%), pneumonia (10%), sudden-cardiac death (7%), cancer (6%), and hemorrhage (5%), whereas perioperative mortality was comparatively low. Isolated simple defects exhibited mortality rates similar to those in the general population, whereas patients with Eisenmenger syndrome, complex congenital heart disease, and Fontan physiology had much poorer long-term survival (P<0.0001 for all). The probability of cardiac death decreased with increasing patient’s age, whereas the proportion of patients dying from noncardiac causes, such as cancer, increased. Conclusions— ACHD patients continue to be afflicted by increased mortality in comparision with the general population as they grow older. Highest mortality rates were observed among patients with complex ACHD, Fontan physiology, and Eisenmenger syndrome. Our data provide an overview over causes of mortality and especially the spectrum of noncardiac causes of death in contemporary ACHD patients.

The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension.

The term pulmonary arterial hypertension (PAH) describes a rare group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles (< 100 mm). Left untreated, patients die from right heart failure, with a mortality approaching most serious cancers. Endothelin-1(ET-1) is not only a potent vasoconstrictor, but causes proliferation of many of the vascular cells involved in vascular remodelling. Although produced mainly by the vascular endothelium, other cells such as smooth muscle, fibroblasts and macrophages are known sources of ET-1 when these cells are challenged by relevant stimuli. Plasma ET-1 levels are raised in patients with PAH and correlate with important clinical outcomes. Furthermore, ET-1 receptor antagonism has been demonstrated to improve both morbidity and mortality in conditions associated with PAH. We review the literature supporting the role for ET-1 in the pathogenesis of PAH.

Detection of Pulmonary Hypertension with Multidetector CT and Echocardiography Alone and in Combination

PURPOSE To test the reliability of potentially new computed tomographic (CT) indicators of pulmonary hypertension (PH) and to establish whether a combination of CT and echocardiographic measurements was more predictive of PH than either test alone. MATERIALS AND METHODS The institutional review board approved this retrospective study; patient consent was not required. Seventy-seven patients undergoing right-sided heart catheterization were examined. CT diameters of the main pulmonary artery, ascending aorta, and thoracic vertebra and cross-sectional area of the main pulmonary artery were measured. Segmental and subsegmental arterial diameters were recorded, and segmental artery size was compared with adjacent bronchus size by using a semiquantitative scoring system. The relationship between CT measurements and mean pulmonary arterial pressure (mPAP) was tested with linear regression. Multivariate regression was used to establish a composite index of mPAP by using CT markers of PH with echocardiography-derived right ventricular systolic pressure (RVSP). Post hoc logistic regression and receiver operating characteristic curve analysis were performed to test the diagnostic ability of the CT-echocardiography composite. RESULTS The ratios of the diameter of the main pulmonary artery to the diameter of the ascending aorta (R(2) = 0.45; P < .001) and of the cross-sectional area of the pulmonary artery to the diameter of the ascending aorta (R(2) = 0.45; P < .001) correlated equally with mPAP. The ratio of the diameter of the main pulmonary artery to the diameter of the thoracic vertebra, the segmental arterial diameter, and the segmental artery-to-bronchus ratio were related to mPAP but did not strengthen correlations compared with the ratio of the diameter of the main pulmonary artery to the diameter of the ascending aorta alone. A composite index of the ratio of the diameter of the main pulmonary artery to the diameter of the ascending aorta and echocardiography-derived RVSP was more strongly related (R(2) = 0.55) to mPAP and was more significantly predictive of PH than either measure alone. CONCLUSION A combination of CT and echocardiographic markers of PH is more closely related to mPAP than either test in isolation.

Pulmonary Vascular Resistance Predicts Early Mortality in Patients with Diffuse Fibrotic Lung Disease and Suspected Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is associated with a poor prognosis in diffuse lung disease (DLD). A study was undertaken to compare the prognostic significance of invasive and non-invasive parameters in patients with DLD and suspected PH. Methods: Hospital records of consecutive patients with DLD undergoing right heart catheterisation (RHC) were reviewed (n = 66). Mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and non-invasive variables were examined against early (within 12 months) and overall mortality. A priori thresholds were examined against early mortality. Relationships between mPAP, PVR and non-invasive markers were assessed. Results: Fifty patients had PH on RHC (mean (SD) mPAP 33.5 (11.8) mm Hg, PVR 5.9 (4.3) Wood units (WU)). Raised PVR was strongly associated with early mortality (odds ratio (OR) 1.30; 95% confidence interval (CI) 1.11 to 1.52; p = 0.001), with PVR ⩾6.23 WU being the optimal threshold after adjustment for age, gender, composite physiological index (CPI) and diagnosis of idiopathic pulmonary fibrosis (OR 11.09; 95% CI 2.54 to 48.36; p = 0.001). Early mortality was linked, albeit less strongly, to right ventricular dilation at echocardiography, but not to other non-invasive variables or mPAP. Overall mortality was most strongly associated with increasing CPI levels. Correlations between PVR and non-invasive variables were moderate (R2 <0.32), improving little following construction of a multivariate index which did not itself predict mortality. Conclusion: In severe DLD, early mortality is strongly linked to increased PVR but not to other RHC or non-invasive variables. These findings suggest that the threshold for RHC in severe DLD should be low, enabling prioritisation of aggressive treatment including lung transplantation.

Pulmonary hypertension related to congenital heart disease: a call for action

Pulmonary arterial hypertension related to congenital heart disease (PAH-CHD) is a common type of pulmonary arterial hypertension (PAH). Despite this, little emphasis has been given to this group of patients until recently, when compared with idiopathic PAH. This is largely because of the complexity and the wide range of underlying cardiac anatomy and physiology, with a multitude of adaptive mechanisms not fully understood. Pulmonary arterial hypertension related to congenital heart disease is, therefore, best diagnosed and managed in centres specializing in both CHD and PAH, to avoid common pitfalls and old practices and to provide state-of-the-art care. We discuss the optimal management of PAH-CHD patients in a series of actions to be taken in order to optimize short- and long-term outcome, based on current knowledge of the condition and the advent of targeted advanced therapies.