Abstract
Background
We aim to develop a four-tier severity classification system of main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans.
Methods
In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n=114), we determined the four-tier cutpoints to maximize sensitivity and specificity, and validated it in a separate cohort (n=114). Cutpoints for mPA were defined with the Framingham sex-specific normative values of ≤27mm(F) and ≤29mm(M) as the normal reference range; mild as >27 to <31mm(F) and >29 to <31mm(M); moderate≥31 to 34mm; and severe>34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1.
Results
Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p<0.001). Moderate-severe mPA values of ≥31mm and ratio PA>1.1 had worse survival than normal values (all p≤0.01).
Conclusion
Four-tier severity classification of mPA and ratio PA on CT has high accuracy for PH diagnosis with increase mortality in patients with moderate-severe mPA and ratio PA values supporting its use clinically on chest and cardiac CT reports.
Keywords: Pulmonary Hypertension, Computed Tomography, main pulmonary artery, ratio pulmonary artery
INTRODUCTION
Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis and an estimated mortality of 15% within 1 year 1. Worse prognosis is associated with more advanced disease and worsened functional class, demonstrating the importance of early diagnosis and treatment 2. PH is defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg, irrespective of pulmonary capillary wedge pressure (PCWP) or pulmonary vascular resistance (PVR). Pulmonary arterial hypertension is further defined by elevated PVR >3 Wood units and normal PCWP, while pulmonary venous hypertension by elevated PCWP ≥15 mm Hg and normal PVR, and mixed pulmonary hypertension as elevation of both PCWP and PVR 1. The current gold standard for diagnosis, right heart catheterization (RHC) 1, is invasive and resource-intensive. Imaging may play a role in the early diagnosis of PH in a lower cost and non-invasive manner.
Computed tomography (CT) metrics have been studied as a method for the screening and diagnosis of PH. Enlarged main pulmonary artery (mPA) diameter on CT 3–14 and increased ratio (ratio PA) of mPA to ascending aorta (Ao) diameter 3, 6, 7, 9, 12, 15–17 have been associated with the presence of PH. The Framingham Heart Study (FHS) established sex-specific normative values by CT for mPA diameter in men of ≤29 mm and in women of ≤27 mm as well as the normative value for ratio PA of ≤0.9 18. However, no severity classification for mPA and ratio PA has been established for the diagnosis of PH. Thus, we aimed to derive and validate a four-tier classification of mPA and ratio PA (stratified as normal, mild, moderate and severe) for the diagnosis of PH. Additionally, we assessed the prognostic implication of this severity classification and compared it to RHC and echocardiography (Echo).
METHODS
Study Population
We screened 278 consecutive adult (age≥18 years) patients with suspected PH who underwent RHC and at least one chest or cardiac CT for the evaluation of dyspnea from a single tertiary medical center between March 2000 and February 2013. We excluded patients who did not have a CT during the peri-catheterization period, defined as 6 months prior to RHC through 6 weeks after RHC (n=10), and those whose CT was deemed uninterpretable (n=22) (i.e. due to incomplete visualization or motion of the mPA on chest or cardiac CT). In addition, 13 patients were excluded due to history of lung transplantation, and 5 were excluded due to missing mPAP value. Our final cohort included 228 patients who had both RHC and at least one chest or cardiac CT, of which 195 (86%) had a transthoracic Echo within 2 years of RHC. Median follow-up was 6.4 years [5.0 years, 8.2 years]. The primary endpoint was all-cause mortality.
We used the World Health Organization (WHO) classification of PH 19 by RHC as our gold standard, and defined patients with PH as those with mPAP ≥25 mmHg or PVR >3 Wood units. We measured the diameters of the mPA and Ao at the level of the bifurcation of the right pulmonary artery in 489 transaxial CT scans and calculated the ratio PA, which was previously described as the mPA diameter divided by the Ao diameter 18.
Statistical analysis
Descriptive statistics were expressed as mean ± standard deviation (SD) or median with interquartile range [IQR] for continuous variables and as frequency and percentages for categorical variables. We used Student t test or Wilcoxon rank-sum tests for continuous variables and Fisher’s exact test for categorical variables to compare differences between groups, as appropriate. We evaluated the effect of continuous mPA and ratio PA on long-term survival by using Cox proportional hazards models and adjusted for risk factors that were different (p<0.05) between PH and non-PH patients, including (log-transformed) age, coronary artery disease (CAD), diabetes mellitus (DM), New York Heart Association (NYHA) Functional Class and (log-transformed) serum creatinine. To determine the mPA and ratio PA cutpoints for predicting PH, we used a derivation cohort of 114 patients and examined various cutpoints to (1) maximize the sensitivity for “ruling out” PH, (2) maximize the specificity for “ruling in” PH, and (3) define an intermediate gray-zone. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and c-statistic of each cutpoint. We performed similar analyses using the remaining 114 patients as the validation cohort.
We further subdivided the intermediate gray-zone in order to obtain the four-tier severity classification (Figure 1) of mPA size using sex-specific thresholds of: (1) normal from the FHS normative values 18 as ≤27 mm for women and ≤29 mm for men; (2) mild as >27 to <31 mm for women and >29 to <31 mm for men; (3) moderate as ≥31 to 34 mm for both sexes; (4) severe as >34 mm for both sexes. Similarly, for ratio PA, we defined thresholds of: (1) normal as ≤ 0.9; (2) mild as >0.9 to 1.0; (3) moderate as >1.0 to 1.1; and (4) severe as >1.1. Logistic regression was used to determine the c-statistic, or area under the receiver operating characteristic curve (AUC), for the four-tier severity classification of the pulmonary artery metrics in the derivation and validation cohorts for diagnosing PH. Survival probabilities stratified by four-tier severity classification were estimated using the product limit (Kaplan-Meier) method and comparisons were made using the stratified log-rank test. We used Spearman correlation to determine the relationship between continuous mPA and ratio PA and hemodynamic and Echo parameters. A 2-tailed p-value of <0.05 was considered statistically significant. All analyses were performed using SAS (Version 9.4, North Carolina).
Figure 1. Examples of mPA and ratio PA CT Measurements in Each of the Groups in the Four-Tier Severity Classification.
Measures of mPA and ratio PA at the bifurcation of the right pulmonary artery on transaxial CTs are depicted in representative individuals classified as Normal, Mild, Moderate, and Severe.
RESULTS
Study Population
Of the 228 patients with suspected PH who underwent RHC, 136 (60%) were diagnosed with PH, and 92 (40%) did not have PH. Table 1 and Supplemental Table 1 summarize the baseline patient characteristics of these patients and as stratified by WHO Classification. Patients with PH were older and had more comorbidities such as DM, CAD, worse NYHA Functional Class and six-minute walk distances. In the entire cohort, 135 (59%) patients had a CT scan performed with contrast, and 93 (41%) had non-contrast scans, with no significant difference among the overall cohort, PH, and non-PH patients (p=0.10).
Table 1.
Baseline Patient Characteristics of the Entire Cohort and Stratified by Presence or Absence of Pulmonary Hypertension (PH)
| Entire Cohort (n=228) | PH (WHO 1–5)(n=136) | Non-PH(n=92) | p-value | |
|---|---|---|---|---|
| Age at RHC (years) | 61±14 | 63±13 | 59±15 | 0.03 |
| Female, n (%) | 140 (61) | 79 (58) | 61 (66) | 0.27 |
| Race | 0.51 | |||
| Caucasian, n (%) | 191 (87) | 111 (86) | 80 (88) | |
| Black, n (%) | 24 (11) | 16 (12) | 8 (9) | |
| Asian, n (%) | 5 (2) | 2 (2) | 3 (3) | |
| Ethnicity: Hispanic, n (%) | 11(5) | 9 (7) | 2 (2) | 0.13 |
| Co-morbidities | ||||
| Hypertension, n (%) | 93 (41) | 59 (43) | 34 (37) | 0.34 |
| Diabetes, n (%) | 53 (23) | 41 (30) | 12 (13) | 0.004 |
| Coronary artery disease, n (%) | 55 (24) | 43 (32) | 12 (13) | 0.001 |
| Hyperlipidemia, n (%) | 62 (27) | 38 (28) | 24 (26) | 0.88 |
| Tobacco use (past or current), n (%) | 130 (57) | 78 (57) | 52 (57) | 1.00 |
| ESRD, n (%) | 4 (2) | 4 (3) | 0 (0) | 0.15 |
| Functional Parameters | ||||
| NYHA Functional Class, n (%) | 0.002 | |||
| I | 15 (8) | 10 (9) | 5 (7) | |
| II | 81 (43) | 37 (32) | 44 (59) | |
| III | 81 (43) | 57 (50) | 24 (32) | |
| IV | 13 (7) | 11 (10) | 2 (3) | |
| 6-Minute Walk Distance (m) | 298±134 | 270±127 | 356±132 | 0.003 |
| Hemodynamic Parameters (RHC) | ||||
| RA Pressure (mmHg) | 8±6 | 11±6 | 5±3 | <0.001 |
| PVR (Wood units) | 6±5 | 8±5 | 2±1 | <0.001 |
| Mean PAP (mmHg) | 34±17 | 45±13 | 18±4 | <0.001 |
| Systolic PAP (mmHg) | 54±27 | 72±21 | 29±7 | <0.001 |
| Diastolic PAP (mmHg) | 21±12 | 28±10 | 10±4 | <0.001 |
| Cardiac Index (L/min/m2) | 2.7±1.0 | 2.5±1.0 | 3.3±1.0 | <0.001 |
| PCWP (mmHg) | 12±7 | 15±7 | 9±4 | <0.001 |
| Echocardiographic Parameters | ||||
| LVEF (%) | 64±11 | 64±13 | 66±7 | 0.11 |
| RV dysfunction, n (%) | 78 (41) | 73 (62) | 5/72 (7) | <0.001 |
| RV dilation, n (%) | 10 (54) | 90 (75) | 13/71 (18) | <0.001 |
| RVSP (mm Hg)* | 65±27 | 76±25 | 41±11 | <0.001 |
| RVSP number reported (%)* | 136 (60) | 92 (68) | 44 (48) | 0.004 |
| Laboratory Values | ||||
| Hemoglobin (g/dL) | 13.1±2.2 | 13.0±2.4 | 13.2±1.8 | 0.35 |
| Creatinine (mg/dL) | 1.19±0.78 | 1.30±0.97 | 1.02±0.28 | 0.001 |
| CT Parameters | ||||
| Main PA (mPA, mm) | 31.1 [26.8, 36.5] | 35.3 [30.9, 39.0] | 26.3 [23.6, 29.1] | <0.001 |
| Aorta (Ao, mm) | 31.7 [29.2, 34.8] | 31.7 [29.4, 35.0] | 31.7 [28.6, 34.2] | 0.32 |
| mPA/Ao ratio (ratio PA) | 0.99 [0.85, 1.13] | 1.07 [0.99, 1.20] | 0.84 [0.76, 0.93] | <0.001 |
WHO=World Health Organization, ESRD=End-stage Renal Disease, NYHA=New York Heart Association, RA=Right Atrium, PVR=Peripheral Vascular Resistance, PAP=Pulmonary Artery Pressure, PCWP=Pulmonary Capillary Wedge Pressure, LVEF=Left Ventricle Ejection Fraction, RV=Right Ventricle, RVSP=Right Ventricle Systolic Pressure, PA=Pulmonary Artery.
Relationship of Continuous mPA and Ratio PA to PH Diagnosis and Outcomes
Compared to non-PH patients (Table 1), PH patients had larger mPA diameter (26.3 vs 35.3 mm) and higher ratio PA (0.84 vs 1.07; both p<0.001). The c-statistics for both continuous mPA and ratio PA for the diagnosis of PH were 0.89 (Figure 2A).
Figure 2. Receiver Operating Characteristic (ROC) Curves for the Diagnosis of Pulmonary Hypertension using (A) Continuous mPA and ratio PA, and Four-Tier Severity Classification of mPA and ratio PA with the (B) Derivation and (C) Validation Cohorts.
AUC = Area Under the Curve.
Over a median period of 6.5 years, there were a total of 85 (37%) deaths, of which 65 (48%) deaths were PH patients and 20 (22%) deaths were non-PH patients. Per log unit increase in mPA and ratio PA (Supplemental Table 2), there was a 4-fold increased risk of death for mPA (adjusted HR 4.1, p=0.01; and 20% increased risk of death for ratio PA (adjusted HR 1.2, p=0.004). When stratified by PH and non-PH groups, there was no difference in survival by mPA and ratio PA size (all p=NS).
Four-Tier Severity Classification of mPA and ratio PA for Diagnosis of PH
Table 2 shows the diagnostic accuracy of the mPA and ratio PA cutpoints for the diagnosis of PH using the derivation cohort. To “rule-out” PH, we selected the FHS sex-specific cutpoints, which maximized sensitivity at 99% and served as the upper limit of normal of mPA for excluding PH 18. For ratio PA, the upper limit of normal of 0.9 18 was selected with a sensitivity at 93% to rule out PH. To “rule-in” PH, we selected the mPA cutpoint of >34 mm as severe, which maximized specificity at 98%. For ratio PA, the severe category was established at the cutpoint of >1.1, with a specificity of 100%. We confirmed these findings in our validation cohort of 114 patients (Supplemental Table 3).
Table 2.
Diagnostic Accuracy of the mPA and ratio PA Cutpoints for the Diagnosis of PH using the Derivation Cohort (n=114)
| mPA cutpoint | Sensitivity | Specificity | PPV | NPV |
| mPA > 27 (F), 29 (M) | 67/68, 99% (92% – 100%) | 26/46, 57% (41% – 71%) | 67/87, 77% (67% – 85%) | 26/27, 96% (81% – 100%) |
| mPA > 31 | 53/68, 78% (66% – 87%) | 37/46, 80% (66% – 91%) | 53/62, 85% (74% – 93%) | 37/52, 71% (57% – 83%) |
| mPA > 34 | 44/68, 65% (52% – 76%) | 45/46, 98% (88% – 100%) | 44/45, 98% (88% – 100%) | 45/69, 65% (53% – 76%) |
| Ratio PA cutpoint (mPA/Ao) | Sensitivity | Specificity | PPV | NPV |
| ratio PA > 0.9 | 63/68, 93% (84% – 98%) | 30/46, 65% (50% – 79%) | 63/79, 80% (69% – 88%) | 30/35, 86% (70% – 95%) |
| ratio PA > 1 | 53/68, 78% (66% – 87%) | 40/46, 87% (74% – 95%) | 53/59, 90% (79% – 96%) | 40/55, 73% (59% – 84%) |
| ratio PA > 1.1 | 34/68, 50% (38% – 62%) | 46/46, 100% (92% – 100%) | 34/34, 100% (90% – 100%) | 46/80, 58% (46% – 68%) |
PPV=Positive Predictive Value, NPV=Negative Predictive Value
We further subdivided the intermediate gray zone for mPA and ratio PA to establish mild and moderate cutpoints to develop the four-tier severity classification (Table 3). Using this four-tier severity classification of mPA and ratio PA, the c-statistics for both mPA and ratio PA severity were 0.90 for the derivation cohort, and 0.85 for the validation cohort (Table 3, Figure 2B and 2C).
Table 3.
Four-Tier Severity Classification of mPA and ratio PA Based on Derivation and Validation Cohorts
| Derivation cohort | Validation cohort | ||||
|---|---|---|---|---|---|
| n (%) | c-statistic | n (%) | c-statistic | ||
| mPA, sex-specific, mm | 0.90 | 0.85 | |||
| Normal | ≤27(F) / 29(M) | 27 (24) | 42 (37) | ||
| Mild | >27(F) / 29 (M) - <31 | 22 (19) | 20 (18) | ||
| Moderate | ≥31–34 | 20 (18) | 18 (16) | ||
| Severe | >34 | 45 (39) | 34 (30) | ||
| Ratio PA | 0.90 | 0.85 | |||
| Normal | ≤ 0.9 | 35 (31) | 39 (34) | ||
| Mild | >0.9 – 1 | 20 (18) | 24 (21) | ||
| Moderate | >1 – 1.1 | 25 (22) | 17 (15) | ||
| Severe | >1.1 | 34 (30) | 34 (30) | ||
Derivation cohort n=114, Validation cohort n=114.
Incremental Value of ratio PA beyond mPA for Diagnosis of PH
In the 228 patients, 130 (57%) patients had concordant categories of mPA and ratio PA, with good agreement and weighted kappa of 0.62 (95% CI 0.55 – 0.69). Supplemental Table 4 depicts the agreement between mPA and ratio PA as stratified by the four-tier severity classification system. Notably, there were no patients with severe ratio PA and normal mPA. There were, however, 2 PH patients with severe mPA enlargement and normal ratio PA due to thoracic aortic aneurysms with ascending aortas greater than 40 mm which made their ratio PA<1.0. Using the entire cohort of 228 patients, there was an increase in the c-statistics for the diagnosis of PH from 0.87 for mPA alone to 0.91 for mPA with ratio PA (p=0.02).
Prognosis Based on the Four-Tier Severity Classification of mPA and ratio PA
Figure 3 depicts the survival curves of patients based on the four-tier severity classification of mPA and ratio PA. For both mPA and ratio PA, being classified as either moderate or severe tiers was associated with increased mortality as compared to those classified as normal. Specifically, patients with moderate or severe mPA enlargement had 2–3 fold increased risk of mortality than those with normal mPA size (HR 1.8 and HR 2.9, both p≤0.01). Similarly, patients with moderately or severely increase ratio PA had over 2-fold increased risk of mortality than those with normal ratio PA (HR 2.4 and HR 2.6, both p≤0.009). Of note, patients within the mild tier for both mPA and ratio PA values did not have worse prognosis when compared to patients with normal values (both p=0.12).
Figure 3. Kaplan-Meier Curves for Survival by Four-Tier Severity Classification of (A) mPA and (B) ratio PA by CT.
CI denotes confidence interval; RHC, right heart catheterization.
Relationship to Right Heart Catheterization and Echocardiography
With increasing mPA and ratio PA tier severity, the proportion of patients with PH defined by RHC increased (both p<0.001, Figure 4A). Similarly, the proportion of patients with PH defined by RVSP >40 mmHg on Echo increased with increasing mPA and ratio PA tier severity (both p<0.001, Figure 4B).
Figure 4.
Proportion of Patients with PH Defined by (A) Right Heart Catheterization (RHC) and (B) Echo Right Ventricular Systolic Pressure (RVSP) >40 mmHg as Stratified by Four-Tier Severity Classification of mPA and ratio PA by CT.
Table 4 shows that the four-tier severity classification of mPA and ratio PA were associated appropriately with PA pressure, RA pressure, PCWP, and cardiac index measured on RHC and Echo (all p≤0.03). Additionally, continuous mPA and ratio PA correlated with these hemodynamic parameters (all p≤0.005).
Table 4.
Hemodynamic Parameters by RHC and RVSP on Echo are Associated with Severity in the Four-Tier Classification of mPA and Ratio PA and with Continuous mPA and Ratio PA
| mPA by Severity Tier | Continuous mPA | |||||
| Normal (n=70) | Mild (n=44) | Moderate (n=40) | Severe (n=74) | p-value | Spearman Correlation* | |
| Hemodynamic Parameters | ||||||
| RA Pressure (mmHg) | 5 [3, 7] | 7 [4, 12] | 7 [4, 10] | 10 [6, 16] | <0.001 | ρ=0.34 |
| PVR (Wood units) | 2 [1, 3] | 4 [2, 7] | 5 [2, 11] | 7 [4, 12] | <0.001 | ρ=0.47 |
| Mean PAP (mmHg) | 19 [15, 22] | 30 [21, 43] | 34 [24, 49] | 46 [38, 56] | <0.001 | ρ=0.66 |
| Systolic PAP (mmHg) | 30 [24, 36] | 45 [32, 71] | 60 [37, 81] | 73 [60, 89] | <0.001 | ρ=0.65 |
| Diastolic PAP (mmHg) | 10 [8, 13] | 20 [12, 27] | 21 [16, 30] | 27 [23, 36] | <0.001 | ρ=0.63 |
| Cardiac Index (L/min/m2) | 3.1 [2.5, 3.9] | 2.9 [2.2, 3.4] | 2.5 [1.9, 3.1] | 2.2 [1.8, 2.7] | <0.001 | ρ=−0.40 |
| PCWP (mmHg) | 10 [7, 13] | 11 [7, 16] | 11 [7, 17] | 14 [9, 18] | 0.007 | ρ=0.22 |
| Echocardiography Parameters | ||||||
| RVSP | 40 [35, 48] | 63 [48, 80] | 62 [46, 94] | 72 [58, 95] | <0.001 | ρ=0.51 |
| Ratio PA by Severity Tier | Continuous ratio PA | |||||
| Normal (n=74) | Mild (n=44) | Moderate (n=42) | Severe (n=68) | p-value | Spearman Correlation* | |
| Hemodynamic Parameters | ||||||
| RA Pressure (mmHg) | 5 [3, 8] | 7 [4, 9] | 9 [5, 12] | 9 [5, 15] | <0.001 | ρ=0.32 |
| PVR (Wood units) | 2 [1, 4] | 3 [2, 5] | 6 [3, 10] | 9 [4, 12] | <0.001 | ρ=0.51 |
| Mean PAP (mmHg) | 19 [15, 23] | 29 [21, 38] | 41 [25, 47] | 49 [40, 58] | <0.001 | ρ=0.68 |
| Systolic PAP (mmHg) | 30 [24, 36] | 45 [35, 64] | 65 [37, 82] | 81 [62, 93] | <0.001 | ρ=0.67 |
| Diastolic PAP (mmHg) | 11 [8, 15] | 17 [12, 25] | 24 [14, 29] | 30 [23, 37] | <0.001 | ρ=0.63 |
| Cardiac Index (L/min/m2) | 3.1 [2.4, 4.3] | 2.8 [2.1, 3.4] | 2.4 [2.0, 3.0] | 2.2 [1.8, 3.0] | 0.002 | ρ=−0.29 |
| PCWP (mmHg) | 10 [7, 13] | 12 [7, 19] | 12 [7, 15] | 12 [9, 19] | 0.03 | ρ=0.19 |
| Echocardiography Parameters | ||||||
| RVSP | 40 [35, 46] | 64 [45, 70] | 68 [54, 80] | 79 [58, 106] | <0.001 | ρ=0.60 |
RA=Right Atrium, PVR=Peripheral Vascular Resistance, PAP=Pulmonary Artery Pressure, PCWP=Pulmonary Capillary Wedge Pressure, RVSP=Right Ventricular Systolic Pressure.
All p≤0.005.
DISCUSSION
CT metrics of mPA diameter and ratio PA have been shown to be associated with PH, and reference values for normal patients have been previously established 18. The main value of these metrics is its simplicity, where the methods are those that can be applied rapidly by a CT reader without the need for advanced visualization software. We found that mPA and ratio PA values are both increased in PH patients when compared with non-PH patients. For the diagnosis of PH, we established a four-tier severity classification for both mPA and ratio PA that has high diagnostic accuracy for the diagnosis of PH in both a derivation and independent validation cohort. There was incremental value of ratio PA beyond mPA for the diagnosis of PH, with minimal discordancy (n=2) between severe and normal tiers for the two metrics. Using the four-tier severity classification, increasing tier severity for mPA and ratio PA was associated with hemodynamic parameters by RHC and Echo RVSP. Moreover, the four-tier severity classification has prognostic implications, with increased mortality for patients with moderate or severe mPA and/or ratio PA values as compared to patients with normal values.
Chest and cardiac CT have become readily available worldwide and frequently routinely ordered for pulmonary, cardiac, vascular, and a myriad of other clinical indications. Transaxial mPA and Ao diameters are easily measured by CT. A wide range of values, from 29 to 38 mm for mPA 3, 5–7, 9, 11, 12, 14, and from 0.84 to 1.4 for ratio PA 3, 6, 7, 9, 12, 15 have been reported in prior studies to be suggestive of PH, with variable diagnostic accuracy for the binary cutpoints. However, a four-tier severity classification of mPA size and ratio PA has not been defined for diagnosis of PH. Our study establishes a four-tier severity classification of normal, mild, moderate, and severe for the diagnosis of PH that is both sensitive and specific. For both mPA and ratio PA, the normal tier was based on the normative values which were established in a large population-based study 18. For mPA, the normal tier sex-specific values of ≤27 mm for women and ≤29 mm for men to “rule out” PH has a sensitivity of 99%, whilst the severe tier of >34 mm for either sexes to “rule in” PH has a specificity of 98%. For ratio PA, the normal tier of ≤0.9 has a sensitivity of 93%, and the severe tier of >1.1 has a specificity of 100% irrespective of sex.
The high sensitivities of the normal tiers validate the values previously established in the FHS study 18 and could be simple metrics used by cardiac imagers and radiologists to indicate that PH is unlikely present, while the high specificity of the severe tier of mPA (>34 mm) and ratio PA (>1.1) should alert caregivers that patient likely has PH and warrants further diagnostic confirmation testing, such as Echo and/RHC. One caveat to consider is that the ratio PA is not reliable in patients with thoracic aortic aneurysm and the mPA should be used solo in those patients.
In addition to classifying patients into normal and severe categories, this four-tier severity classification also divides patients into the mild and moderate groups. With the four-tier classification, there is a gradual increase in the proportion of patients with PH by RHC and those with PH by RVSP on Echo with escalating severity tiers. Importantly, the distinction between mild and moderate holds important prognostic implications, as the higher tiers of moderate and severe mPA (≥31 mm) and ratio PA (>1.0) enlargement were associated with increased mortality compared to patients with normal values, while those with mildly enlarged values had no statistical difference in prognosis when compared to those with normal values. Thus, patients with enlarged mPA and ratio PA particularly in the moderate-severe range (mPA≥31 mm and ratio PA>1.0) may also warrant further diagnostic work-up for PH, as early diagnosis of PH is important for initiating treatment and altering prognosis.
Our study had several notable limitations. We acknowledge that 3D structures may not be accurately assessed with the 2D measurements made in a standard axial view and that they do not account for specific patient differences in shape and orientation. However, these two transaxial measurements of mPA and ratio PA are highly reproducible,18 and the ease and simplicity of the measurements requires no sophisticated software is a major strength of the study. The study was located at a single tertiary center, and the population studied was predominantly Caucasian. As such, it may be useful to study a more diverse group of patients. The study design was cross-sectional, and did not take into account chronicity of disease. Furthermore, we assessed PH as a cumulative disease entity of pre-and post-capillary pulmonary hypertension and the severity tiers are not able to differentiate between pre-capillary, post-capillary, or mixed disease processes.
CONCLUSIONS
Four-tier classification of mPA and ratio PA by CT has high accuracy for the diagnosis of PH and can be used clinically on chest and cardiac CT exams. Normal values (mPA: ≤27 mm for women and ≤29 mm for men; ratio PA: ≤ 0.9) have excellent sensitivity for excluding PH, while the severe tier of mPA (>34 mm) and ratio PA (>1.1) have excellent specificity for PH diagnosis. Moderate-severe mPA (≥31 mm) and ratio PA (>1.0) enlargement are associated with worse prognosis compared to normal values. These findings support the routine use of the four-tier severity classification of mPA and ratio PA when reporting findings on chest and cardiac CT scans and can be directly transferable to clinical practice.
Supplementary Material
Acknowledgments
Funding Sources: Dr. Malhotra was supported by the K08HL111210 grant from the National Heart, Lung, and Blood Institute, the Wild Family Foundation, and the Hassenfeld Scholar Award.
Disclosures: Dr. Truong received grant support from Ziosoft, USA (formerly Qi Imaging, LLC) and consulting fees from HeartFlow. Dr. Semigran is employed full-time as Chief Medical Officer at Myokardia Inc. Dr. Malhotra has received consultant fees from MyoKardia Inc. and Third Pole. All other authors have no disclosures.
ABBREVIATIONS LIST
- CT
Computed Tomography
- Echo
Echocardiogram
- FHS
Framingham Heart Study
- mPA
Main pulmonary artery
- mPAP
Mean Pulmonary Artery Pressure
- PAH
Pulmonary Arterial Hypertension
- PCWP
Pulmonary Capillary Wedge Pressure
- PH
Pulmonary Hypertension
- PVR
Pulmonary Vascular Resistance
- Ratio PA
Ratio of main pulmonary artery to ascending aorta diameter
- RHC
Right heart catheterization
- WHO
World Health Organization
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