Pulmonary Hypertension and Pulmonary Artery Acceleration Time: A Systematic Review and Meta-Analysis




Background


Measuring mean pulmonary artery pressure by right-heart catheterization is the gold standard for pulmonary hypertension (PH) diagnosis. However, its invasiveness and complication leads to its limited use. The aim of this study was to determine whether echocardiography-derived pulmonary artery acceleration time (PAAT) possesses adequate diagnostic performance for PH, using right-heart catheterization as a reference standard.


Methods


MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched through July 2016 for studies evaluating PAAT for the diagnosis of PH. Methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. For each study, the sensitivity, specificity, and diagnostic odds ratio, along with 95% CIs, were calculated to determine the diagnostic accuracy of PAAT. Meta-regression was conducted to evaluate the impact of potential confounding factors.


Results


Of 430 articles, 21 studies (1,280 patients) were identified, including three studies that used transesophageal echocardiography and 18 studies that used transthoracic echocardiography. The pooled sensitivity across studies was 0.84 (95% CI, 0.75–0.90), the pooled specificity was 0.84 (95% CI, 0.78–0.89), and the pooled diagnostic odds ratio was 28 (95% CI, 16–49). The arrhythmia ratio in the population did not affect the specificity of PAAT’s diagnostic performance and increased the sensitivity of PH detection.


Conclusions


The results of this study suggest that PAAT is useful for PH detection.


Highlights





  • PAAT measured by echocardiography has high pooled sensitivity and specificity across studies in PH prediction, regardless of etiology.



  • The location of PAAT measurement did not affect its diagnostic performance.



  • The arrhythmia ratio in the population did not affect the specificity of PAAT’s diagnostic performance.



Pulmonary hypertension (PH) is a clinically significant disease, and its severity reflects different prognosis. Patients with PH carry a high risk for cardiovascular morbidity and mortality. Early diagnosis and treatment for PH is important, because it can slow disease progression. PH is defined by a mean pulmonary artery pressure (PAP) > 25 mm Hg at rest. Measuring PAP usually requires right-heart catheterization, and right-heart catheterization carries a certain risk for complications. Echocardiography is less invasive and is an alternative choice for PAP estimation. The most commonly used echocardiographic technique for PAP estimation is measurement of the pressure gradient between the right ventricle and right atrium from tricuspid regurgitation (TR). However, in about 40% of patients, an adequate Doppler signal cannot be obtained, and in half of patients, estimation error is >15%. The pulmonary artery acceleration time (PAAT) is the time interval from the beginning of right ventricular (RV) ejection to peak flow velocity across the pulmonary valve. The concept that flow accelerates more rapidly in the RV outflow tract (RVOT) in patients with PH than in those with normal PAP was first reported in 1983 by Kitabatake et al. Measuring PAAT is technically easy, and many studies have shown that mean PAP and PAAT have a negative curvilinear relationship, across a range of pulmonary pressures.


Previous studies measured PAAT in patients with different etiologies of, and the measurement locations differed among these studies. Many studies derived regression equations from their analyses, but none of the pulmonary pressure estimation equations was the same. Therefore, the aim of this study was to evaluate the diagnostic performance of PAAT in PH, using right-heart catheterization or pulmonary artery catheterization as the reference standard, in adult patients.


Methods


We performed a systematic literature search without language restrictions of the electronic databases MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials, for human studies up to and including July 2016. Our searches used the term “pulmonary artery hypertension” or “pulmonary hypertension” in combination with “acceleration time” or “pulmonary artery acceleration time.” The articles identified during the literature search process were first screened by examining their titles and abstracts. The screening process was undertaken independently by two authors (Y.-C.W. and C.-H.H.). Disagreement was resolved by discussion and consensus. Article titles and abstracts were reviewed for eligibility. Moreover, the reference lists of retrieved articles and reviews were screened for relevant studies. Authors were contacted through e-mail in cases of queries or missing information regarding their published studies. A study was included if it met the following criteria: it assessed PAAT as a diagnostic tool to evaluate patients for the presence of PH; PH was defined by pulmonary artery catheterization as the reference test; the inclusion subjects were >18 years of age; and the absolute numbers of true-positive, false-positive, true-negative, and false-negative findings were available, or these data were derivable from the results presented. A study was excluded if it was a conference article, was a review, or was not conducted in humans. Studies published only as abstracts or letters were also excluded.


Extracted information included author, journal, year of publication, and country; details of study design; patient demographic features (such as number of patients, mean age, percentage of male patients, and percentage of patients with arrhythmia), diagnostic tool (transthoracic echocardiography [TTE] or transesophageal echocardiography [TEE]), location of PAAT measurement (RVOT, main pulmonary trunk, or branched pulmonary arteries), etiology of PH, and numbers of true-positive, false-positive, true-negative, and false-negative findings.


PAAT was measured from the onset of systolic pulmonary artery flow to peak velocity using pulsed-wave Doppler. PAAT could be measured using either TTE or TEE. For TTE, patients were placed in the left lateral decubitus position, and the pulmonary artery could be obtained in the upper esophageal transverse pulmonary artery view.


For TEE, PAAT could be measured in the main pulmonary trunk in the upper esophageal view or midesophageal short-axis view. The other choice for measurement is to use the transgastric RV inflow outflow view to align the cursor with the RVOT. Examples of PAAT measurements are shown in Figure 1 . PH was defined as a mean PAP > 25 mm Hg by right-heart catheterization in our analysis according to 5th World Symposium on PH. Some studies used mean PAP > 20 mm Hg as the cutoff point for the diagnosis of PH. We retained the trials that enabled us to retrieve the original data and recalculated the cutoff point as mean PAP > 25 mm Hg.




Figure 1


PAAT measurement. PAAT measured in (A) upper esophageal aortic arch short-axis view and (B) midesophageal ascending aortic short-axis view in a patient with atrial fibrillation. PAAT was measured from onset of systolic pulmonary artery flow to peak velocity using pulsed-wave Doppler. The patient’s average heart rate was 58 beats/min, PAP was 37/24 mm Hg, and mean PAP was 27 mm Hg. PV , Pulmonary artery valve; PW , pulsed-wave Doppler.


Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool (scale, 0–14). In brief, the assessment was based on 14 items, including covered patient spectrum, reference standard, disease progression bias, verification bias, review bias, clinical review bias, incorporation bias, test execution, study withdrawals, and indeterminate results. A score of 7 of 14 indicates high quality, and scores < 7 indicate low quality. The QUADAS tool is an evidence-based quality assessment tool to be used in systematic reviews of diagnostic accuracy studies.


For extracted data, categorical variables were expressed as percentages, and continuous variables were expressed as mean values. On the basis of the extracted 2 × 2 contingency tables, pooled measures for diagnostic performance, including sensitivity, specificity, diagnostic odds ratio, summary receiver operating characteristic (ROC) curve, and area under the curve (AUC) with 95% CIs, were calculated. Between-study statistical heterogeneity was assessed using I 2 and the Cochrane Q test on the basis of the mixed-effects analysis. Publication bias was examined using the associated regression test of asymmetry described by Deeks et al., with a P value < .10 for the slope coefficient indicating significant asymmetry.


We used bivariate multilevel logistic regression for random-effect meta-analysis. The parameters of the bivariate model were estimated in a single model, so the potential correlations between sensitivity and specificity could be taken into account. The summary ROC curves were also created using this model to estimate the AUC. We also conducted meta-regression regarding sex, percentage of PH, percentage of pulmonary arterial hypertension, cutoff value for PAAT, arrhythmia, use of TTE or TEE, and PAAT measurement site. We wanted to evaluate the influence of these factors on the diagnostic power of PAAT. Statistical analysis was performed using STATA version (StataCorp, College Station, TX).




Results


The primary literature research yielded 430 publications. After excluding duplicates from different electronic databases and conference articles, we identified 126 articles. By screening the titles and abstracts, an additional 96 articles were excluded. After review of the full text, 10 articles were excluded. The flowchart of the screening process is presented in Figure 2 .




Figure 2


Study design. The flowchart illustrates the selection process of published reports.


Eventually, 21 articles published between 1983 and 2016, representing a total of 1,280 patients, were included in our systematic review. The main characteristics of the trials included in the systematic review and retained for meta-analysis are summarized in Table 1 and Supplemental Table 1 (available at www.onlinejase.com ). One fourth of the studies did not report the etiology of PH. Reported etiologies included left-heart disease, chronic hypoxia, and pulmonary arterial hypertension. Seven studies included patients in sinus rhythm. In the rest of the included studies, the arrhythmia ratio ranged from 28% to 45.7%. Three studies used TEE for PAAT measurements, and the others used TTE.



Table 1

List of the included trials for PAAT assessment






















































































































































































































































































































































































Study Year Country Sample size PH (%) PAH (%) TTE/TEE Arrhythmia ratio (%) Cutoff value (sec) PAAT Sensitivity (95% CI) Specificity (95% CI)
TP FP FN TN
Cowie et al. 2016 Belgium 98 40.4 0 TEE 0 107 30 3 10 55 0.75 (0.59–0.87) 0.95 (0.86–0.99)
Sohrabi et al. 2016 Iran 300 80.7 0 TTE 38 104 231 21 11 37 0.95 (0.92–0.98) 0.64 (0.50–0.76)
Tousignant et al. 2015 Canada 74 19.4 0 TEE 0 90 8 13 6 47 0.57 (0.29–0.82) 0.78 (0.66–0.88)
Tossavainen et al. 2013 Sweden 56 62.5 57.1 TTE 0 90 21 4 5 26 0.81 (0.61–0.93) 0.87 (0.69–0.96)
Granstam et al. 2013 Sweden 29 66 38 TTE 0 100 17 2 3 7 0.85 (0.62–0.97) 0.78 (0.40–0.97)
Serra et al. 2010 Italy 19 52.6 52.6 TTE 0 100 4 0 6 9 0.40 (0.12–0.74) 1.00 (0.66–1.00)
Lanzarini et al. 2005 Italy 86 57.0 5 TTE 0 93 34 13 15 24 0.69 (0.55–0.82) 0.65 (0.47–0.80)
Yamasa et al. 1993 Japan 32 18.8 0 TEE 0 95 1 0 5 26 0.17 (0.00–0.64) 1.00 (0.87–1.00)
Campos Filho et al. 1993 Brazil 61 70.5 6.6 TTE 31.3 100 38 1 5 17 0.88 (0.75–0.96) 0.94 (0.73–1.00)
Mirrakhimov et al. 1992 Kyrgyzstan 36 30.6 0 TTE 31.8 101 10 3 1 22 0.91 (0.59–1.00) 0.88 (0.69–0.97)
Tramarin et al. 1991 Italy 98 38.1 0 TTE 0 80 28 11 9 50 0.76 (0.59–0.88) 0.82 (0.70–0.91)
Liu et al. 1991 China 18 88.9 0 TTE 0 100 13 0 3 2 0.81 (0.54–0.96) 1.00 (0.16–1.00)
Corinaldesi et al. 1991 Italy 19 73.7 0 TTE 0 100 14 2 0 3 1.00 (0.77–1.00) 0.60 (0.15–0.95)
Hu et al. 1990 China 17 100 11.8 TTE 29 100 13 0 4 0 NA NA
Niederle et al. 1989 Czechoslovakia 50 56 4 TTE 0 115 14 5 1 30 0.93 (0.68–1.00) 0.86 (0.70–0.95)
Eysmann et al. 1989 United States 26 100 100 TTE 0 90 24 0 2 0 NA NA
Torbicki et al. 1989 Poland 74 44.3 <9 TTE 0 79.5 24 6 9 35 0.73 (0.54–0.87) 0.85 (0.71–0.94)
von Bibra et al. 1987 Germany 70 44.3 5.7 TTE 45.7 90 29 8 2 31 0.94 (0.79–0.99) 0.79 (0.64–0.91)
Dabestani et al. 1987 United States 39 41 6.7 TTE 28 104 15 4 1 19 0.94 (0.70–1.00) 0.83 (0.61–0.95)
Isobe et al. 1986 Japan 45 53.5 8.9 TTE 44.4 109 25 5 0 15 1.00 (0.86–1.00) 0.75 (0.51–0.91)
Kitabatake et al. 1983 Japan 33 39.4 6.1 TTE 39.4 103 12 3 1 17 0.92 (0.64–1.00) 0.85 (0.62–0.97)
Summary estimates 0.84 (0.75–0.90) 0.84 (0.78–0.89)

FN , False negative; FP , false positive; NA , not available; PAH , pulmonary arterial hypertension; TN , true negative; TP , true positive.


The methodologic quality of the 21 studies was assessed using the QUADAS tool. Review of the QUADAS checklist for all studies showed that all studies (21 of 21) were scored >7, which is considered good quality. During QUADAS assessment, most studies were found to have problems with the representativeness of included patients, questionable time gaps between index test and reference test, unclear masking during interpretation of the reference test, masked reading of the index test, and a lack of reporting for uninterpretable results, which may have resulted in bias ( Supplemental Table 2 , available at www.onlinejase.com ).


The I 2 index showed substantial heterogeneity with regard to sensitivity and moderate heterogeneity with regard to specificity for all index tests. The PAAT cutoff point for PH prediction is listed in Table 1 . Most studies (30.4%) used 100 msec as their cutoff point, followed by 90 msec (17.4%) and 104 msec (13.0%). Of the total 21 studies, sensitivity was >90% in nine studies and <50% in three studies. The specificity for all the index tests was >60%. The funnel plot and regression tests showed a statistically nonsignificant P value of .78 for the slope coefficient, indicating symmetry in the data and a low likelihood of publication bias ( Figure 3 ).




Figure 3


Deeks funnel plot asymmetry test. The vertical axis displays the inverse of the square root of the effective sample size (ESS). The symmetry in the data indicates a low likelihood of publication bias for the included studies.


The pooled sensitivity across studies for PAAT was 0.84 (95% CI, 0.75–0.90), and the pooled specificity across studies was 0.84 (95% CI, 0.78–0.89; Table 1 , Figure 4 ). The pooled positive diagnostic likelihood ratio across studies was 5.26 (95% CI, 3.86–7.17), and the pooled negative diagnostic likelihood ratio was 0.19 (95% CI, 0.12–0.30). The diagnostic odds ratio was 28 (95% CI, 16–49). The summary ROC curves are shown in Figure 5 A. The global AUC across all included studies was 0.90 (95% CI, 0.83–0.95).




Figure 4


Forest plot for PAAT and PH prediction. The forest plot depicts the pooled sensitivity and specificity for PAAT as a diagnostic tool for PH.



Figure 5


Summary ROC (SROC) curve. The summary ROC curves show the results for (A) PAAT in PH prediction and (B) TVPG in PH detection by prediction and confidence contours. The confidence contour shows the CI or region for the summary point. The prediction contour outlines the prediction region for the true sensitivity (SENS) and specificity (SPEC) in a future study.


Eight studies compared both PAAT and tricuspid valve regurgitation pressure gradient (TVPG) with right-heart catheterization ( Table 2 ). PAAT measurement was successful for >90% of the patients in all studies. The successful rate for TVPG measurement varied across studies. The feasibility of TVPG measurement ranged from 24% to 86.2%, and the reasons for failure included insufficient TR, eccentric jet, and inadequate regurgitation flow contour. The pooled sensitivity across studies for TVPG in PH diagnosis was 0.93 (95% CI, 0.90–0.95), and the pooled specificity across studies was 0.75 (95% CI, 0.63–0.83). The summary ROC curves are shown in Figure 5 B. The global AUC across studies with TVPG was 0.93 (95% CI, 0.89–0.95).



Table 2

Trials using PAAT and TR for PH estimation

























































































































Study n PH (%) TTE/TEE PAAT feasibility (%) TVPG feasibility (%) Echocardiographic cutoff point Catheterization criteria TR TP TR FP TR FN TR TN
Sohrabi et al. (2016) 300 80.7 TTE 98.6 72.9 TRVTI mPAP > 25 mm Hg 234 14 15 37
Granstam et al. (2013) 29 69.0 TTE 100 86.2 TVPG > 30 mm Hg sPAP > 38 mm Hg 16 1 1 7
Lanzarini et al. (2005) 86 57.0 TTE 91 69.8 NA
Tramarin et al. (1991) 98 38.1 TTE 98 30 TVPG sPAP > 35 mm Hg 20 2 3 5
Liu et al. (1991) 18 88.9 TTE 100 83.3 TVPG > 30 mm Hg mPAP > 25 mm Hg 14 0 1 0
Eysmann et al. (1989) 26 100 TTE 100 42.3 NA
Torbicki et al. (1989) 74 44.3 TTE 97 24 TVPG > 32 mm Hg sPAP > 35 mm Hg 10 1 2 4
von Bibra et al. (1987) 70 44.3 TTE 100 41.4 NA

FN , False negative; FP , false positive; mPAP , mean PAP; NA , not available; sPAP , systolic PAP; TN , true negative; TP , true positive; TRVTI , TR jet velocity-time integral.


Results from meta-regression are shown in Table 3 . Higher PH prevalence increased the sensitivity for PAAT ( P = .019), but pulmonary arterial hypertension percentage did not. A larger cutoff value increased the sensitivity of PAAT ( P = .044). There were five studies using 100 msec as a cutoff value for PH detection, and the adjusted sensitivity and specificity were 0.84 and 0.90, respectively. Arrhythmia in the population did not affect the specificity of PAAT’s diagnostic performance but increased the sensitivity of PH detection (adjusted sensitivity, 0.94; P < .001). In comparison with TEE, analyzing PAAT using TTE had higher sensitivity for PH detection (adjusted sensitivity, 0.88; P = .011). The RVOT was the most commonly chosen site for PAAT measurement, but measuring PAAT in the RVOT, main pulmonary artery, or right pulmonary artery did not result in statistically different sensitivity or specificity.



Table 3

Univariate meta-regression for potential factors affecting diagnostic performance















































































































































































Variable No. of studies Sensitivity Specificity
Adjusted P Adjusted P
Male, % 16 .706 .217
≤60 11 0.87 .770 0.86 .215
>60 5 0.84 0.76
PH, % 19 .019 .099
≤60 13 0.80 .112 0.85 .404
>60 6 0.91 0.81
PAH, % 19 .358 .375
≤30 16 0.86 .289 0.83 .406
>30 3 0.73 0.89
Cutoff value 19 .044 .809
<100 7 0.71 0.83
100 5 0.84 .183 0.90 .423
>100 7 0.92 .004 0.83 .990
Arrhythmia, % 19 <.001 .351
0 7 0.74 <.001 0.85 .489
≥1 12 0.94 0.81
TEE/TTE
TEE 3 0.55 .011 0.91 .072
TTE 12 0.88 0.82
PAAT measurement site
MPA 2 0.56 1.00
RPA 1 0.57 .954 0.79 .984
RVOT 16 0.87 .056 0.83 .984

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Apr 15, 2018 | Posted by in CARDIOLOGY | Comments Off on Pulmonary Hypertension and Pulmonary Artery Acceleration Time: A Systematic Review and Meta-Analysis

Full access? Get Clinical Tree

Get Clinical Tree app for offline access