Kelly M. Chin

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.

Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis

RATIONALE Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. OBJECTIVES To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. METHODS Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. CONCLUSIONS A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.

Selexipag for the treatment of pulmonary arterial hypertension

BACKGROUND In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. METHODS In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). RESULTS A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain. CONCLUSIONS Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

Left atrial structure and function and clinical outcomes in the general population

AIMS Left atrial (LA) structural and functional abnormalities may be subclinical phenotypes, which identify individuals at increased risk of adverse outcomes. METHODS AND RESULTS Maximum LA volume (LAmax) and LA emptying fraction (LAEF) were measured via cardiac magnetic resonance imaging in 1802 participants in the Dallas Heart Study. The associations of LAEF and LAmax indexed to body surface area (LAmax/BSA) with traditional risk factors, natriuretic peptide levels, and left ventricular (LV) structure [end-diastolic volume (EDV) and concentricity(0.67) (mass/EDV(0.67))] and function (ejection fraction) were assessed using linear regression analysis. The incremental prognostic value of LAmax/BSA and LAEF beyond traditional risk factors, LV ejection fraction, and LV mass was assessed using the Cox proportional-hazards model. Both increasing LAmax/BSA and decreasing LAEF were associated with hypertension and natriuretic peptide levels (P < 0.05 for all). In multivariable analysis, LAmax/BSA was most strongly associated with LV end-diastolic volume/BSA, while LAEF was strongly associated with LV ejection fraction and concentricity(0.67). During a median follow-up period of 8.1 years, there were 81 total deaths. Decreasing LAEF [hazard ratio (HR) per 1 standard deviation (SD) (8.0%): 1.56 (1.32-1.87)] but not increasing LAmax/BSA [HR per 1 SD (8.6 mL/m(2)): 1.14 (0.97-1.34)] was independently associated with mortality. Furthermore, the addition of LAEF to a model adjusting Framingham risk score, diabetes, race, LV mass, and ejection fraction improved the c-statistic (c-statistics: 0.78 vs. 0.77; P < 0.05, respectively), whereas the addition of LAmax/BSA did not (c-statistics: 0.76, P = 0.20). CONCLUSION In the general population, both LAmax/BSA and LAEF are important subclinical phenotypes but LAEF is superior and incremental to LAmax/BSA.

Changes in Right Ventricular Structure and Function Assessed Using Cardiac Magnetic Resonance Imaging in Bosentan-Treated Patients With Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension (PAH) usually show improvements in symptoms, exercise capacity, and hemodynamics after treatment with approved medical therapies. This study sought to determine whether improvement in right-sided cardiac function measured using cardiac magnetic resonance imaging would also be seen and whether these changes would correlate with improvement in exercise capacity. Sixteen patients with PAH underwent evaluation at baseline and after 12 months of treatment with bosentan. After treatment, cardiac index, pulmonary vascular resistance, and 6-minute walk distance improved, and there was a trend toward improvement in right ventricular (RV) stroke volume (70 +/- 27 to 81 +/- 30 ml; p = 0.08), but no change in RV ejection fraction (RVEF) or RV end-diastolic volume. Six-minute walk distance improved by 59 m (p <0.05) in the overall cohort and improved more in patients in whom RVEF increased compared with those with stable or decreased RVEF (+98 vs -37 m, respectively; p = 0.01). Three patients died during follow-up, and these patients had significantly lower RVEF and left ventricular end-diastolic volume indexes than surviving patients. In conclusion, these results suggest that cardiac magnetic resonance imaging may have value in determining response to therapy and prognosis in patients with PAH.

Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension

BACKGROUND Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Hemodynamics and Epoprostenol Use Are Associated With Thrombocytopenia in Pulmonary Arterial Hypertension

BACKGROUND Thrombocytopenia develops in some patients with advanced pulmonary arterial hypertension (PAH) while receiving IV epoprostenol therapy. In this study, we evaluate whether epoprostenol use, other PAH medication use, hemodynamics, or PAH etiology are associated with thrombocytopenia in PAH. METHODS Platelet counts were evaluated in 47 PAH patients receiving IV epoprostenol, and in 44 patients with an inadequate response to initial therapy with oral agents in a cross-sectional study. Associations between thrombocytopenia (platelet count < 150,000/mL) and epoprostenol use, hemodynamics, PAH etiology, and use of other PAH medications were evaluated in univariable and multivariable analyses. RESULTS PAH subtypes included idiopathic (69%), fenfluramine (18%), connective tissue disease (10%), and congenital heart disease (2%)-associated PAH. Thrombocytopenia was observed in 34% of patients treated with epoprostenol, compared with 15% of patients receiving oral therapy (odds ratio [OR], 2.9; p < 0.05), and the association between epoprostenol and thrombocytopenia remained significant after adjustment for differences in hemodynamics (OR, 5.0; p < 0.05). Right atrial pressure (OR, 1.12 per mm Hg; p < 0.05) and mixed venous oxygen saturation (Svo(2)) [OR, 0.92 per percentage; p < 0.05] were also associated with thrombocytopenia in univariable analyses; after logistic regression analysis, both the use of epoprostenol and Svo(2) were independently associated with thrombocytopenia. In a separate analysis including only patients with current or prior epoprostenol use, epoprostenol dose and right atrial pressure were inversely associated with platelet count. CONCLUSION Epoprostenol use and severity of hemodynamic abnormalities are associated with thrombocytopenia in PAH, and these effects appear to be independent and additive.

Long-term Outcomes with Ambrisentan Monotherapy in Pulmonary Arterial Hypertension

BACKGROUND This study evaluated long-term outcomes in patients with pulmonary arterial hypertension (PAH) undergoing treatment with ambrisentan monotherapy, a selective oral endothelin-1 receptor antagonist. METHODS AND RESULTS Patients who participated in the Ambrisentan in Pulmonary Arterial Hypertension: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy Study (ARIES-1) clinical trial and extension phase at our institution were included. Cardiac catheterization, 6-minute walk distance (6MWD), and cardiac magnetic resonance (MRI) data were retrospectively reviewed. Twelve patients with PAH (11 idiopathic, 1 fenfluramine) had follow-up from 3 to 5.5 years from the initiation of ARIES-1. Patients received ambrisentan therapy throughout the study period and were on ambrisentan monotherapy for the first 2 years. At year 1, improvements in median mean pulmonary arterial pressure (PA), cardiac output, and pulmonary vascular resistance (PVR) were seen (P = .02, P = .03, P < .01), and the improvement in PVR persisted at 2 years. 6MWD also improved significantly between baseline (350 m) and 1 and 2 years (397 m, P < .01 and 393 m, P = .01). Cardiac MRI results were more varied, with an increase in RV ejection fraction from 29% at baseline to 46% at 2 years (P = .02), but other MRI variables did not improve. CONCLUSIONS Ambrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension.

International Classification of Diseases Coding Changes Lead to Profound Declines in Reported Idiopathic Pulmonary Arterial Hypertension Mortality and Hospitalizations: Implications for Database Studies

BACKGROUND Database studies have reported several associations between the diagnosis of idiopathic pulmonary arterial hypertension (IPAH) and mortality attributable to IPAH, including older age, black race, and diabetes. METHODS We investigated reported deaths and hospital discharges coded as IPAH and compared these with other forms of pulmonary hypertension. Three databases were used: the US National Center for Health Statistics database (1979-2006), queried for mortality data; the Nationwide Inpatient Sample database (1993-2007), queried for hospital discharge data; and the University of Texas Southwestern Hospital-Zale Lipshy discharge database (1999, 2002). RESULTS Marked increases in mortality attributable to IPAH and to pulmonary hypertension (all codes combined) generally were reported from 1979 until 2002 in the National Center for Health Statistics database. In 2003, reported IPAH mortality fell sharply while total pulmonary hypertension deaths increased. The Nationwide Inpatient Sample database showed a similar pattern of changes beginning approximately 2 years earlier. In both cases, the timing of these observations corresponded with changes made to the International Classification of Diseases (ICD) coding system in use for pulmonary hypertension in that particular database. Review of pulmonary hypertension discharge data from the University of Texas Southwestern Hospital-Zale Lipshy showed similar changes in diagnosis code use. CONCLUSIONS Sudden shifts in reported IPAH mortality and hospital discharges were seen in all databases, likely related to coding changes. These findings raise questions about the accuracy of pulmonary hypertension diagnosis codes. Studies based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, 10th Revision codes may have inadvertently included patients with other forms of pulmonary hypertension and should be reevaluated in this context. Validation studies of the IPAH diagnosis code are needed, and changes to the ICD coding system should be considered.

Efficacy and Safety of Exercise Training in Chronic Pulmonary Hypertension Systematic Review and Meta-Analysis

Background—Exercise training has been shown to improve cardiorespiratory fitness, physical capacity, and quality of life in patients with cardiopulmonary conditions, such as heart failure and chronic obstructive pulmonary disease. However, its role in management of pulmonary hypertension is not well defined. In this study, we aim to evaluate the efficacy and safety of exercise training in patients with pulmonary hypertension. Methods and Results—We included all prospective intervention studies that evaluated the efficacy and safety of exercise training in patients with pulmonary hypertension. Primary outcome of this meta-analysis was a change in 6-minute walk distance. We also assessed the effect of exercise on peak oxygen uptake, resting pulmonary arterial systolic pressure, peak exercise heart rate, and quality of life. A total of 469 exercise-training participants enrolled in 16 separate training studies were included. In the pooled analysis, exercise training was associated with significant improvement in 6-minute walk distance (weighted mean difference, 53.3 m; 95% confidence interval, 39.5–67.2), peak oxygen uptake (weighted mean difference, 1.8 mL/kg per minute; 95% confidence interval, 1.4–2.3), pulmonary arterial systolic pressure (weighted mean difference, −3.7 mm Hg; 95% confidence interval, −5.4 to −1.9), peak exercise heart rate (weighted mean difference, 10 beats per min; 95% confidence interval, 6–15), and quality of life as measured on SF-36 questionnaire subscale scores. Furthermore, exercise training was well tolerated with a low dropout rate, and no major adverse events were related to exercise training. Conclusions—Exercise training in patients with pulmonary hypertension appears safe and is associated with a significant improvement in exercise capacity, pulmonary arterial pressure, and quality of life.