Previous studies have identified cardiac troponin I (cTnI) as an important marker in pulmonary hypertension (PH) prognosis. However, traditional assays are limited by poor sensitivity, even among patients at high risk. cTnI was measured in 255 PH patients using a new highly sensitive (hs) assay. Other measures included demographics, creatinine, 6-minute walk distance, hemodynamics, cardiac magnetic resonance imaging, and B-type natriuretic peptide level. The association between cTnI and survival was assessed using Kaplan-Meier analysis and Cox regression. cTnI was detectable with the hs assay in 95% of the patients with a median level of 6.9 pg/ml (IQR 2.7–12.6 pg/ml). Higher cTnI levels associated with higher levels of B-type natriuretic peptide, shorter 6-minute walk distance, and more severe hemodynamic and cardiac magnetic resonance imaging abnormalities. During a median follow-up of 3.5 years, 60 individuals died. Unadjusted event rates increased across higher cTnI quartiles (3, 5, 13, 17 events/100 person-years, respectively, p trend = 0.002). cTnI in the fourth (vs first) quartile remained associated with death in a final stepwise multivariable model that included clinical variables and hemodynamics (adjusted hazard ratio 5.3, 95% confidence interval 1.8–15.6). In conclusion, cTnI levels, detectable with a novel hs assay, identify patients with PH who have more severe hemodynamic and cardiac structural abnormalities and provide novel and independent prognostic information. This hs assay has the potential to detect more at-risk patients and improve current risk-stratification algorithms.
Pulmonary hypertension (PH), irrespective of its cause, carries significant risk of morbidity and mortality. Furthermore, the clinical course of patients with PH is variable, highlighting the need for accurate methods to assess risk to guide therapeutic decisions. Several biomarkers have been evaluated in pulmonary arterial hypertension (PAH) as potential tools to improve risk assessment. These include B-type natriuretic peptide (BNP) and cardiac troponin T (cTnT) and I (cTnI). Detectable cTnT has previously been shown to be a marker of increased mortality in patients with chronic PH, supporting a role of progressive myocyte injury in the pathway leading to right ventricular (RV) failure and hemodynamic collapse. However, the sensitivity of conventional assays has been problematic with only approximately 10% of affected patients having detectable cTnT. Novel highly sensitive (hs) assays can detect cTn levels 10-fold lower than current assays. This study evaluates the association between cTnI, measured by a new hs cTnI assay, and (1) hemodynamic measurements, (2) cardiac magnetic resonance imaging (MRI) findings, and (3) all-cause death among patients with various types of PH.
Methods
The study was approved by the University of Texas (UT) Southwestern Institutional Review Board, and informed consent was obtained from all patients. Patients with PH including World Health Organization (WHO) groups I through V were enrolled from either the UT Southwestern PH Clinic during a routine clinic visit or at the time of right-sided cardiac catheterization (RHC) conducted between 2006 and 2011. RHC was performed for routine clinical purposes, including for the initial evaluation of suspected PH and classification of PH type according to the updated clinical classification (Dana Point, 2008 ) and to monitor response to treatment. Patients were considered to have PH if their mean pulmonary arterial pressure (mPAP) was ≥25 mm Hg. Specifically, PH related to left heart disease was defined as a mPAP ≥25 mm Hg and a pulmonary capillary wedge pressure (PCWP) >15 mm Hg, whereas all other forms of PH had a mPAP ≥25 mm Hg and a PCWP ≤15 mm Hg. In the evaluation for PH subtype, patients underwent pulmonary function testing, chest x-ray, 6-minute walk distance (6MWD) evaluation, laboratory testing, echocardiogram, and either ventilation-perfusion scan (preferred) or computed tomographic angiography. PH diagnosis was determined by chart review conducted by 2 physicians (MVM, KMC); disagreements were settled by consultation with a third physician (SB). A cardiac MRI was also performed when possible on a GE 1.5-T scanner (GE Healthcare, Milwaukee, Wisconsin) using Fiesta cine short-axis images. Cardiac volume and mass measurements were performed using MASS software (MEDIS, Leiden, The Netherlands).
Blood was collected in ethylenediamine tetra-acetic acid tubes and refrigerated at 4°C immediately after blood draws. Plasma was subsequently stored in a −80°C freezer. Blood samples were obtained during a routine, scheduled visit and were not collected in response to the clinical status of the patient. Samples were shipped on dry ice to Abbott Diagnostics (Abbott Park, Illinois) for testing. cTnI was measured using a precommercial prototype of the ARCHITECT STAT hsc TnI assay with a lower detection limit of 1.2 pg/ml and a reported 99th percentile value in apparently healthy individuals of 24 pg/ml. In comparison, the lower detection limit of the contemporary ARCHITECT cTnI in clinical use is 9 pg/ml. Lab personnel were blinded to all clinical information. Subsequent data analysis was performed at UT Southwestern. Median time from blood sampling for cTnI measurement to performance of RHC was 89 (interquartile ranges [IQR] 17–189) days.
The Social Security Death Index was queried to confirm participant mortality through January 2012. Continuous variables are reported as medians (IQR) and categorical variables as proportions. All volumes and masses were indexed to body surface area. For all analyses, the RHC, 6MWD, and cardiac MRI closest to the date of cTnI sampling were used. Only BNP results within 3 months were included. Demographic, clinical, hemodynamic, and cardiac MRI variables were compared across cTnI quartiles using the Jonckheere-Terpstra trend test. Continuous hemodynamic and cardiac MRI variables were also compared with cTnI levels by Spearman correlation. Stepwise multiple linear regression was used to identify associations of age, hemodynamic, and imaging variables with log-transformed cTnI (with a p value of 0.1 for entry and exit into the model). Survival analyses assessed cTnI level as an ordered, categorical variable (in quartiles), as well as a continuous variable, log-transformed cTnI. Similar analyses were performed using BNP. All-cause mortality was estimated using the Kaplan Meier product-limit estimator, and cumulative survival curves were compared across cTnI quartiles using the log-rank test.
Multivariable analyses were also performed using Cox proportional hazard regression adjusting for the following prespecified covariates within both the overall cohort and PAH subgroup: age, race, gender, cTnI quartiles, BNP quartiles, 6MWD, creatinine, and WHO group or PAH etiology (clinical model). A second model incorporated the foregoing clinical model plus hemodynamic variables including right atrial pressure (RAP), cardiac index, pulmonary artery saturation (PAO 2 saturation), mPAP, and pulmonary vascular resistance. Cox hazards assumptions were met by noting that there were no trends with time for Schoenfeld residuals. Time-dependent C statistics were calculated for models with and without cTnI or BNP and compared using bootstrap resampling, with model fit assessed by the likelihood ratio test and calibration by the modified Hosmer-Lemeshow statistic. A p value of <0.05 was considered statistically significant. Statistical analysis was performed using NCSS 2007 (NCSS LLC, Kaysville, Utah) and SAS version 9.2 (SAS Institute, Cary, North Carolina).
Results
Two hundred fifty-five patients with PH were enrolled. Most were women, and the median age was 56 years (IQR 44–66) ( Table 1 ). Median follow-up time was 3.5 years. Patients in the PAH subgroup were slightly younger (median age 50, IQR 58–64). At the time of study enrollment, 26 PAH patients were treatment naive, and 141 were receiving PAH-specific therapies ( Supplemental Table ).
| Quartile 1 (n = 64) | Quartile 2 (n = 63) | Quartile 3 (n = 64) | Quartile 4 (n = 64) | p Trend | |
|---|---|---|---|---|---|
| Age (yrs) | 52 (38–63) | 56 (38–65) | 59 (50–70) | 56 (43–67) | 0.01 |
| Men | 8 (13%) | 13 (21%) | 17 (27%) | 20 (31%) | 0.01 |
| African-American | 9 (14%) | 8 (14%) | 13 (20%) | 12 (19%) | 0.34 |
| White | 43 (67%) | 40 (64%) | 37 (58%) | 45 (70%) | 0.89 |
| Hispanic | 9 (14%) | 13 (21%) | 11 (17%) | 5 (8%) | 0.27 |
| Asian | 3 (5%) | 1 (2%) | 3 (5%) | 2 (3%) | 0.88 |
| WHO Group 1 | 42 (66%) | 41 (66%) | 39 (61%) | 45 (70%) | 0.75 |
| WHO Group 2 | 9 (14%) | 11 (18%) | 9 (14%) | 9 (14%) | 0.87 |
| WHO Group 3 | 7 (11%) | 3 (6%) | 11 (17%) | 3 (5%) | 0.63 |
| WHO Group 4 | 3 (5%) | 5 (8%) | 3 (5%) | 3 (5%) | 0.80 |
| WHO Group 5 | 3 (5%) | 1 (2%) | 2 (3%) | 4 (6%) | 0.57 |
| Creatinine (mg/dL) | 0.9 (0.7–1.0) | 0.9 (0.67–1.1) | 0.9 (0.8–1.3) | 1.0 (0.8–1.4) | <0.001 |
| Body mass index (kg/m 2 ) | 29 (25–35) | 28 (24–33) | 28 (24–35) | 28 (23–35) | 0.26 |
| BNP | n = 55 | n = 51 | n = 54 | n = 50 | |
| BNP (pg/ml) | 35 (15–111) | 49 (19–168) | 178 (71–299) | 238 (74–523) | <0.001 |
| 6MWD | n = 55 | n = 55 | n = 54 | n = 54 | |
| 6MWD (m) | 402 (353–451) | 361 (290–424) | 329 (240–400) | 315 (235–379) | <0.001 |
| Cardiac MRI | n = 45 | n = 42 | n = 48 | n = 38 | |
| LV end-diastolic volume (ml/m 2 ) | 100 (87–114) | 95 (85–113) | 108 (84–126) | 93 (75–119) | 0.63 |
| LV ejection fraction (%) | 69 (65–72) | 69 (62–75) | 65 (61–72) | 67 (58–75) | 0.13 |
| RV end-diastolic volume (ml/m 2 ) | 141 (111–161) | 149 (116–178) | 166 (132–230) | 181 (144–261) | <0.001 |
| RV ejection fraction (%) | 55 (47–60) | 50 (38–58) | 45 (37–55) | 44 (31–52) | <0.001 |
| LV mass (g/m 2 ) | 97 (84–118) | 104 (85–119) | 110 (90–137) | 115 (92–146) | 0.003 |
| Hemodynamics | n = 59 | n = 62 | n = 63 | n = 59 | |
| Right atrial pressure (mm Hg) | 7 (3–9) | 7 (3–11) | 8.5 (4–13) | 11 (6–15) | <0.001 |
| mPAP (mmHg) | 34 (27–42) | 43 (31–50) | 48 (39–55) | 46 (38–55) | <0.001 |
| PAO 2 saturation (%) | 68 (64–71) | 67 (61–70) | 64 (56–68) | 60 (56–65) | <0.001 |
| PCWP (mm Hg) | 10 (7–14) | 10 (7–14) | 10 (7–15) | 11 (8–14) | 0.36 |
| Cardiac index thermodilution (L/min/m 2 ) | 3 (2.7–3.5) | 2.8 (2.5–3.3) | 2.8 (2.1–3.2) | 2.5 (2.1–3.0) | <0.001 |
| Pulmonary vascular resistance (Woods units) | 4.5 (2.7–6.5) | 5.7 (3.8–8.6) | 6.1 (3.8–10) | 7.7 (5.3–10.3) | <0.001 |
| Outcome: death (events/100 person-yrs) | 3 | 5 | 13 | 17 | 0.002 |
cTnI was detectable (≥1.2 pg/ml) in 95% of the patients (n = 241) in the overall cohort as well as 95% of those within the PAH subcohort with a median level of 6.9 pg/ml in both cohorts (IQR 2.7–12.6 pg/ml and IQR 2.7–14.1 pg/ml, respectively). However, only 37% of values were >9 pg/mL, the limit of detection of the contemporary ARCHITECT assay in commercial use. Clinical variables, hemodynamics, 6MWD, BNP, and cardiac MRI results by cTnI quartiles are shown in Table 1 . Increasing quartiles of cTnI were associated with RV dysfunction and dilation, more severe hemodynamic abnormalities, and higher creatinine and BNP ( Table 1 ).
cTnI levels correlated with continuous measures of both right heart function and PH severity assessed by hemodynamics, BNP level, 6MWD, and cardiac MRI results ( Table 2 ) within the overall cohort and PAH subgroup. cTnI also correlated significantly with increasing left ventricular (LV) mass (r = 0.26, p <0.05) but not with other measures of LV structure/function, such as LV volume, ejection fraction, or PCWP. Despite the significant correlations between cTnI levels and markers of prognosis in PH, there was considerable variability within each cTnI quartile including some patients with otherwise low-risk profiles who had significantly elevated cTnI levels ( Figure 1 ). In a multivariable linear regression model, we identified 6 variables that were independently associated with log-transformed cTnI levels: age, mPAP, LV mass, and creatinine were positively correlated, and PAO 2 saturation and RV ejection fraction were inversely correlated ( Table 3 ). Similar results were found in the PAH subgroup.
| Overall Cohort | PAH Subgroup | |||
|---|---|---|---|---|
| Correlation Coefficient | p Value | Correlation Coefficient | p Value | |
| Hemodynamics | ||||
| Right atrial pressure | 0.28 | <0.001 | 0.35 | <0.001 |
| mPAP | 0.32 | <0.001 | 0.29 | <0.001 |
| PAO 2 saturation | −0.38 | <0.001 | −0.42 | <0.001 |
| PCWP | 0.04 | 0.55 | 0.05 | 0.52 |
| Cardiac output | −0.23 | <0.001 | −0.25 | <0.001 |
| Cardiac index | −0.25 | <0.001 | −0.24 | <0.001 |
| Transpulmomary gradient | 0.27 | <0.001 | 0.26 | <0.001 |
| Pulmonary vascular resistance | 0.31 | <0.001 | 0.31 | <0.001 |
| Cardiac MRI parameters | ||||
| LV end-diastolic volume | −0.08 | 0.29 | −0.12 | 0.17 |
| LV ejection fraction | −0.13 | 0.08 | −0.14 | 0.13 |
| RV end-diastolic volume | 0.35 | <0.001 | 0.35 | <0.001 |
| RV ejection fraction | −0.33 | <0.001 | −0.35 | <0.001 |
| LV mass | 0.26 | <0.001 | 0.32 | <0.001 |
| 6MWD | −0.31 | <0.001 | −0.35 | <0.001 |
| BNP | 0.52 | <0.001 | 0.52 | <0.001 |
| Stepwise Selection Model | Standardized β | p Value |
|---|---|---|
| Overall cohort | ||
| Age | 0.29 | <0.001 |
| mPAP | 0.23 | <0.05 |
| PAO 2 saturation | −0.17 | <0.05 |
| LV Mass | 0.19 | <0.05 |
| RV ejection fraction | −0.24 | <0.001 |
| Creatinine | 0.14 | 0.05 |
| PAH subgroup | ||
| Age | 0.22 | <0.05 |
| Mean Pulmonary Arterial Pressure | 0.32 | <0.001 |
| PAO 2 saturation | −0.23 | <0.05 |
| LV Mass | 0.28 | <0.001 |
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