Gustavo A. Heresi

Causes and Circumstances of Death in Pulmonary Arterial Hypertension

RATIONALE The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). OBJECTIVES We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. METHODS All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. MEASUREMENTS AND MAIN RESULTS PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. CONCLUSIONS Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

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.

Interstitial pneumonitis and alveolar hemorrhage complicating use of rituximab: case report and review of the literature.

The use of rituximab has been uncommonly associated with delayed pulmonary toxicity. We present a case of interstitial pneumonitis and diffuse alveolar hemorrhage, which represents the second such case reported in the literature.

Prevalence and Prognostic Value of Left Ventricular Diastolic Dysfunction in Idiopathic and Heritable Pulmonary Arterial Hypertension

BACKGROUND Little is known about the association between left ventricular (LV) diastolic dysfunction and outcomes in patients with idiopathic or heritable pulmonary arterial hypertension (PAH). Our rationale was to investigate the prevalence of LV diastolic dysfunction, and its association with disease severity and outcomes, in patients with idiopathic or heritable PAH. METHODS Using the Cleveland Clinic Pulmonary Hypertension Registry, we identified subjects with heritable or idiopathic PAH who underwent Doppler echocardiography and right-sided heart catheterization. Echocardiographic diastolic parameters were assessed in each patient. RESULTS A total of 61 patients met the inclusion criteria (idiopathic 85%, heritable 15%). The age at the time of echocardiography was 48.3 ± 18 years, 84% of the subjects were women, and 48% were on PAH-targeted therapies. Normal LV diastolic function, impaired relaxation, and pseudonormalization were seen in 10%, 88%, and 2% of the patients, respectively. Peak early diastolic (peak E) velocity was directly associated with LV end-diastolic volume and cardiac index and inversely associated with the degree of right ventricular dilation, right atrial pressure, and pulmonary vascular resistance. Peak E velocity was associated with mortality adjusted for age and sex (hazard ratio [HR], 1.5; 95% CI, 1.1-2 per 10 cm/s decrease; P = .015) and age, sex, 6-min walk distance, and cardiac output (HR, 1.8; 95% CI, 1.2-2.9 per 10 cm/s decrease; P = .01). CONCLUSIONS LV diastolic dysfunction of the impaired relaxation type is observed in the majority of patients with advanced idiopathic or heritable PAH. A decrease in transmitral flow peak E velocity is associated with worse hemodynamics and outcome.

Sensitive cardiac troponin I predicts poor outcomes in pulmonary arterial hypertension

Circulating cardiac troponins are markers of myocardial injury. We sought to determine whether cardiac troponin I (cTnI), measured by a sensitive assay, is associated with disease severity and prognosis in pulmonary arterial hypertension (PAH). cTnI was measured in 68 patients with PAH diagnostic category 1 in a research-based sensitive immunoanalyser with a lower limit of detection of 0.008 ng·mL−1. The associations between cTnI and PAH severity and clinical outcomes were assessed using Chi-squared and Wilcoxon rank sum tests, Kaplan–Meier analysis and Cox regression models. cTnI was detected in 25% of patients. Patients with detectable cTnI had more advanced functional class symptoms, a shorter 6-min walk distance, more pericardial effusions, larger right atrial area, and higher B-type natriuretic peptide and C-reactive protein levels. 36-month transplant-free survival was 44% in patients with detectable cTnI versus 85% in those with undetectable cTnI. cTnI was associated with a 4.7-fold increased risk of death related to right ventricular failure or transplant (hazard ratio 4.74, 95% CI 1.89–11.89; p<0.001), even when adjusted individually for known parameters of PAH severity. Elevated plasma cTnI, even at subclinically detectable levels, is associated with more severe disease and worse outcomes in patients with PAH.

Augmentation therapy in α-1 antitrypsin deficiency

Background: α-1 Antitrypsin deficiency is a genetic disorder that leads to early-onset emphysema. Recently, exogenous supplementation of the enzyme has become a therapeutic alternative. Objective: To review the role of so-called augmentation therapy with pooled human plasma α-1 antitrypsin as a specific treatment for emphysema caused by α-1 antitrypsin deficiency. Methods: The authors performed a Medline (1966 – 2007) search with the keywords ‘α-1 antitrypsin deficiency’ and ‘therapy’. The authors focused on articles regarding biochemical and clinical efficacy. Results/conclusion: Augmentation therapy has been shown to raise antiprotease serum and epithelial lining fluid levels above the ‘protective threshold’ value. Evidence suggests that this approach slows the decline in lung function, could reduce infection rates, might enhance survival, and is well tolerated. Questions about the cost-effectiveness of this therapy remain.

Plasma interleukin-6 adds prognostic information in pulmonary arterial hypertension

To the Editor: Noninvasive biomarkers are needed to aid in making challenging clinical decisions in pulmonary arterial hypertension (PAH). Several biomarkers have been described, but only the natriuretic peptides have gained clinical utility. A key question to answer is whether or not a new biomarker adds independent incremental information [1]. Novel PAH markers may be discovered from new pathobiological pathways, such as inflammation. In particular, interleukin (IL)-6 has been linked with the development of severe pulmonary hypertension in animal models, mimicking the pathology of human disease [2]. IL-6 is a major regulator of the production of C-reactive protein (CRP), a marker of cardiovascular risk [3]. We conducted this study to determine if these inflammatory biomarkers add incremental prognostic information in PAH. This is a cohort study based on a prospective Biobank. We enrolled patients with idiopathic, heritable, connective tissue-associated and congenital heart disease-associated PAH, as defined by current guidelines [4], between March 2005 and June 2011. The study was approved by the Cleveland Clinic Institutional Review Board. We used ELISA (RD Siemens Healthcare Diagnostics, Inc., Tarrytown, NY, USA) Peripheral plasma samples were kept at -80°C until retrieved for the measurement of the biomarkers (September 2011 for hsCRP and BNP, and February 2012 for IL-6). Investigators who performed the biomarker determination were blinded to the study participants’ outcomes. All-cause mortality since the date of study blood sampling was ascertained via manual and automated …

Long-term experience after transition from parenteral prostanoids to oral agents in patients with pulmonary hypertension

BACKGROUND Long-term follow-up after transition to oral agents from parenteral prostanoid therapy has not been well characterized. METHODS We reviewed our long-term experience after oral transitioning in patients with pulmonary hypertension. Patients were weaned off parenteral therapy based on a pre-determined outpatient protocol. Data were collected retrospectively after transition had taken place. RESULTS Twenty-one transitioned patients were identified. Fifteen patients (71.4%) were successfully transitioned (ST): 7 to bosentan, 5 to bosentan and sildenafil, and 3 to sildenafil. Six patients failed transition (FT). None of the patients in the FT group received sildenafil. Prior to transition attempt, patients in the ST group were treated with parenteral agents for a mean of 26 months vs. 16 months in the FT group (p=0.12). Maximal epoprostenol dose was low in both groups (ST 17.8 ng/kg/min vs. FT 14.5 ng/kg/min). Mean duration of oral therapy prior to transition was 11 months. After a mean follow-up of 24 months, most patients on both groups were able to maintain stable 6 min walk distance and hemodynamics. FT was not associated with short- or long-term adverse events. CONCLUSIONS Oral transition from parenteral prostanoid agents can be safely done in a selected group of patients. Most patients are able to maintain stable functional class and hemodynamics at long follow up regardless of success of transition attempt. Combination therapy with sildenafil appears to be associated with higher likelihood of successful transitioning.

Clinical Characterization and Survival of Patients with Borderline Elevation in Pulmonary Artery Pressure

Normal resting mean pulmonary artery pressure (PAP) is 8–20 mmHg. Pulmonary hypertension is defined as mean PAP of ≥25 mmHg. Borderline PAP levels of 21–24 mmHg are of unclear significance. We sought to determine the clinical characteristics and survival of subjects with mean PAP of 21–24 mmHg. We examined 1,491 patients enrolled in the Cleveland Clinic Pulmonary Hypertension Registry between February 1990 and May 2012 with baseline right heart catheterization. The relationship between PAP and all-cause mortality was assessed by Cox models and a tree-based analysis. Sixty-three patients had borderline PAP (underlying conditions: 12 left heart disease, 20 respiratory disease, 17 connective-tissue disease, 4 others, and 10 none). We then compared 3 groups: borderline PAP without heart or lung disease (n = 31), normal PAP without heart or lung disease (n = 51), and category 1 pulmonary arterial hypertension (PAH; n = 387). Borderline-PAP patients had levels of hemodynamic and functional compromise between those for normal-PAP patients and those for patients with PAH. Borderline PAP was associated with increased mortality compared to normal PAP (hazard ratio: 4.03 [95% confidence interval: 0.78–20.80], P = 0.099). A tree-based analysis demonstrated almost identical cut points in mean PAP (≤20, 21–26, and ≥27 mmHg) associated with differential survival (P < 0.001). Connective-tissue disease and an elevated transpulmonary gradient were predictors of worse survival in the borderline-PAP population. Borderline PAP elevation is associated with decreased survival, particularly in the context of connective-tissue disease and an elevated transpulmonary gradient.

Strengths and limitations of the six-minute-walk test: a model biomarker study in idiopathic pulmonary fibrosis.

duction in lung cells. Am J Physiol 1999;277:L667–L683. 4. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54–61. 5. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 6. Hager DN, Krishnan JA, Hayden DL, Brower RG; ARDS Clinical Trials Network. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241–1245. 7. Tsuchida S, Engelberts D, Peltekova V, Hopkins N, Frndova H, Babyn P, McKerlie C, Post M, McLoughlin P, Kavanagh BP. Atelectasis causes alveolar injury in nonatelectatic lung regions. Am J Respir Crit Care Med 2006;174:279–289. 8. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and metaanalysis. JAMA 2010;303:865–873. 9. Puybasset L, Gusman P, Muller JC, Cluzel P, Coriat P, Rouby JJ; CT Scan ARDS Study Group. Regional distribution of gas and tissue in acute respiratory distress syndrome: III. Consequences for the effects of positive end-expiratory pressure. CT Scan ARDS Study Group. Adult Respiratory Distress Syndrome. Intensive Care Med 2000;26: 1215–1227. 10. Caironi P, Cressoni M, Chiumello D, Ranieri M, Quintel M, Russo SG, Cornejo R, Bugedo G, Carlesso E, Russo R, et al. Lung opening and closing during ventilation of acute respiratory distress syndrome. Am J Respir Crit Care Med 2010;181:578–586. 11. Grasso S, Stripoli T, De Michele M, Bruno F, Moschetta M, Angelelli G, Munno I, Ruggiero V, Anaclerio R, Cafarelli A, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med 2007;176:761– 767. 12. Grasso S, Mascia L, Del Turco M, Grasso S, Mascia L, Del Turco M, Malacarne P, Giunta F, Brochard L, Slutsky AS, Ranieri VM. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002;96:795–802. 13. Ospina-Tascon GA, Buchele GL, Vincent JL. Multicenter, randomized, controlled trials evaluating mortality in intensive care: doomed to fail? Crit Care Med 2008;36:1311–1322. 14. Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975; 292:284–289. 15. Marini JJ, Gattinoni L. Ventilatory management of acute respiratory distress syndrome: a consensus of two. Crit Care Med 2004;32:250– 255.