Steven M. Kawut

Delayed access and survival in idiopathic pulmonary fibrosis: a cohort study.

RATIONALE Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis. OBJECTIVES To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis. METHODS We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation. MEASUREMENTS AND MAIN RESULTS The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation. CONCLUSIONS Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non‐Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non‐Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait‐listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age‐adjusted mortality rate was higher among non‐Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06–1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06–1.56, p = 0.01) compared to non‐Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non‐Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98–1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99–1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.

Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea

Background— Indirect evidence implicates endothelial dysfunction in the pathogenesis of vascular diseases associated with obstructive sleep apnea (OSA). We investigated directly whether dysfunction and inflammation occur in vivo in the vascular endothelium of patients with OSA. The effects of continuous positive airway pressure (CPAP) therapy on endothelial function and repair capacity were assessed. Methods and Results— Thirty-two patients with newly diagnosed OSA and 15 control subjects were studied. Proteins that regulate basal endothelial nitric oxide (NO) production (endothelial NO synthase [eNOS] and phosphorylated eNOS) and inflammation (cyclooxygenase-2 and inducible NOS) and markers of oxidative stress (nitrotyrosine) were quantified by immunofluorescence in freshly harvested venous endothelial cells before and after 4 weeks of CPAP therapy. Vascular reactivity was measured by flow-mediated dilation. Circulating endothelial progenitor cell levels were quantified to assess endothelial repair capacity. Baseline endothelial expression of eNOS and phosphorylated eNOS was reduced by 59% and 94%, respectively, in patients with OSA compared with control subjects. Expression of both nitrotyrosine and cyclooxygenase-2 was 5-fold greater in patients with OSA than in control subjects, whereas inducible NOS expression was 56% greater. Expression of eNOS and phosphorylated eNOS significantly increased, whereas expression of nitrotyrosine, cyclooxygenase-2, and inducible NOS significantly decreased in patients who adhered to CPAP ≥4 hours daily. Baseline flow-mediated dilation and endothelial progenitor cell levels were lower in patients than in control subjects, and both significantly increased in patients who adhered to CPAP ≥4 hours daily. Conclusions— OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress while decreasing NO availability and repair capacity. Effective CPAP therapy is associated with the reversal of these alterations.

Percent Emphysema, Airflow Obstruction, and Impaired Left Ventricular Filling

BACKGROUND Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease. METHODS We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects. RESULTS Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction. CONCLUSIONS In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.

Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

Treatment of idiopathic pulmonary fibrosis with Ambrisentan: A parallel, randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

BACKGROUND The American Thoracic Society recommends race-specific spirometric reference values from the National Health and Nutrition Survey (NHANES) III for clinical evaluation of pulmonary function in whites, African-Americans, and Mexican-Americans in the United States and a correction factor of 0.94 for Asian-Americans. We aimed to validate the NHANES III reference equations and the correction factor for Asian-Americans in an independent, multiethnic sample of US adults. METHODS The Multi-Ethnic Study of Atherosclerosis (MESA) recruited self-identified non-Hispanic white, African-American, Hispanic, and Asian-American participants aged 45 to 84 years at six US sites. The MESA-Lung Study assessed prebronchodilator spirometry among 3,893 MESA participants who performed acceptable tests, of whom 1,068 were asymptomatic healthy nonsmokers who performed acceptable spirometry. RESULTS The 1,068 participants were mean age 65 +/- 10 years, 60% female, 25% white, 20% African-American, 23% Hispanic, and 32% Asian-American. Observed values of FEV(1), FEV(6), and FVC among whites, African-Americans, and Hispanics of Mexican origin in MESA-Lung were slightly lower than predicted values based on NHANES III. Observed values among Hispanics of non-Mexican origin were consistently lower. Agreement in classification of participants with airflow obstruction based on lower limit of normal criteria was good (overall kappa = 0.88). For Asian-Americans, a correction factor of 0.88 was more accurate than 0.94. CONCLUSIONS The NHANES III reference equations are valid for use among older adults who are white, African-American, or Hispanic of Mexican origin. Comparison of white and Asian-American participants suggests that a correction factor of 0.88, applied to the predicted and lower limits of normal values, is more appropriate than the currently recommended value of 0.94.

Sex and Race Differences in Right Ventricular Structure and Function The Multi-Ethnic Study of Atherosclerosis–Right Ventricle Study

Background— Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease; however, determinants of RV anatomy have not been well studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease. Methods and Results— In the Multi-Ethnic Study of Atherosclerosis (MESA), cardiac magnetic resonance imaging was performed on 5098 participants. Right ventricular volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived with an allometric approach. The study sample (n=4123) was 61.5±10.1 years of age and 47.5% men. Older age was associated with lower RV mass (≈5% lower mass per decade), with larger age-related decrements in men than in women ( P <0.05 for interaction). Older age was also associated with higher RV ejection fraction, an association that differed between races/ethnicities ( P ≤0.01 for interaction). Overall, men had greater RV mass (≈8%) and larger RV volumes than women, but had lower RV ejection fraction (4% in absolute terms; P <0.001). Blacks had lower RV mass than whites ( P ≤0.002), whereas Hispanics had higher RV mass ( P ≤0.02). When the derived normative equations were used, 7.3% (95% confidence interval, 6.5 to 8.1) met the criteria for RV hypertrophy, and 5.9% (95% confidence interval, 5.2 to 6.6) had RV dysfunction. Conclusion— Age, sex, and race are associated with significant differences in RV mass, RV volumes, and RV ejection fraction, potentially explaining distinct responses of the RV to cardiopulmonary disease. # Clinical Perspective {#article-title-48}Background— Right ventricular (RV) morphology is an important predictor of outcomes in heart and lung disease; however, determinants of RV anatomy have not been well studied. We examined the demographic factors associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease. Methods and Results— In the Multi-Ethnic Study of Atherosclerosis (MESA), cardiac magnetic resonance imaging was performed on 5098 participants. Right ventricular volumes and mass were available for 4204 participants. Normative equations for RV parameters were derived with an allometric approach. The study sample (n=4123) was 61.5±10.1 years of age and 47.5% men. Older age was associated with lower RV mass (≈5% lower mass per decade), with larger age-related decrements in men than in women (P<0.05 for interaction). Older age was also associated with higher RV ejection fraction, an association that differed between races/ethnicities (P⩽0.01 for interaction). Overall, men had greater RV mass (≈8%) and larger RV volumes than women, but had lower RV ejection fraction (4% in absolute terms; P<0.001). Blacks had lower RV mass than whites (P⩽0.002), whereas Hispanics had higher RV mass (P⩽0.02). When the derived normative equations were used, 7.3% (95% confidence interval, 6.5 to 8.1) met the criteria for RV hypertrophy, and 5.9% (95% confidence interval, 5.2 to 6.6) had RV dysfunction. Conclusion— Age, sex, and race are associated with significant differences in RV mass, RV volumes, and RV ejection fraction, potentially explaining distinct responses of the RV to cardiopulmonary disease.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Background— Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (&Dgr;6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in &Dgr;6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. Methods and Results— First, to determine whether &Dgr;6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the &Dgr;6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. &Dgr;6MWD accounted for 22.1% (95% confidence interval, 12.1%– 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in &Dgr;6MWD of 22.4 m (95% confidence interval, 17.4–27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33–0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Conclusions— Our results suggest that &Dgr;6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.