Published online Apr 29, 2024.
https://doi.org/10.22468/cvia.2023.00108
Time-to-Notch Doppler Right Ventricular Outflow Tract: Non-Invasive Parameter for Predicting Pulmonary Vascular Disease in Adults With Ostium Secundum Atrial Septal Defect
,
Muhamad Adrin AP,
Radityo Prakoso,
Arwin Saleh Mangkuanom,
Aditya Agita Sembiring,
Nurnajmia Curie Proklamartina
and Amiliana M Soesanto
Abstract
Objective
Uncorrected atrial septal defect (ASD) leads to pulmonary vascular disease (PVD) later in adulthood. Attempts to close the defect have proven to be detrimental in the presence of PVD. Although right heart catheterization (RHC) is the gold standard for PVD, it remains an invasive approach with complications. Notch characteristics on the right ventricular outflow tract (RVOT) Doppler correlate well with parameters of pulmonary hypertension. Therefore, this study evaluated whether time-to-notch RVOT Doppler could detect PVD in adults with ASD.
Materials and Methods
Between March 2019 and June 2020, we consecutively sampled adult patients with ostium secundum ASD. Time-to-notch was examined by transthoracic echocardiogram within 24 hours of RHC. A vasoreactivity test was performed when the ratio of resistance arterial pulmonary to systemic (PVR:SVR) was ≥0.33. PVD was diagnosed if the final resistance ratio was ≥0.33.
Results
We analysed 89 subjects with ASD. A vasoreactivity test was performed in 54 patients with pure oxygen, and 37% (n=24) had PVD. The majority of subjects in this study were women (85%) with a median age of 38 years. The time-to-notch RVOT Doppler was significantly shorter in subjects with PVD compared to those without (132±17 ms vs. 177±29 ms, p<0.001). The area under the curve was 0.923 for time-to-notch to predict PVR:SVR≥0.33. A cutoff point of <147.5 ms was able to detect PVD (sensitivity 88%, specificity 87%, positive predictive value 72%, negative predictive value 95%, positive likelihood ratio [LR] 7.11, and negative LR 0.14).
Conclusion
Time-to-notch RVOT Doppler has substantial predictive value in detecting PVD in secundum ASD-pulmonary arterial hypertension populations.
INTRODUCTION
Atrial septal defect (ASD) is the most common uncorrected congenital heart disease (CHD) in adults and around 80% of ASD patients have the ostium secundum ASD type [1, 2, 3]. If ASD remains uncorrected, it can lead to pulmonary hypertension and eventually pulmonary vascular disease (PVD). Right heart catheterization (RHC) is used as the gold standard to determine the presence of PVD and the risk of defect closure [4, 5, 6]. However, RHC is an invasive procedure with potential risks, including pneumothorax, arrhythmia, hematoma, and hypotension, although the incidence of these complications is rare [7, 8]. Echocardiography is a cost-effective, widely available, and non-invasive diagnostic tool. It is currently used as an alternative to assess cardiovascular anatomy as well as haemodynamics in patients with structural heart disorders [9]. Various studies have reported a strong correlation between notch characteristics of the right ventricular outflow tract (RVOT) Doppler and mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and compliance of the pulmonary artery across different pulmonary hypertension (PH) groups [10, 11, 12, 13]. Furthermore, RVOT acceleration time (AT) and/or midsystolic notch have been recommended by the British Society of Echocardiography (BSE) to reinforce the probability of PH [14]. Although notch RVOT has been evaluated in PH cases, the possible use of notch RVOT in ASD-pulmonary arterial hypertension (PAH) populations, particularly in detecting PVD, has not yet been determined. Consequently, we aimed to evaluate notch RVOT Doppler as an alternative to invasive RHC in determining the presence of PVD adult ostium secundum ASD.
MATERIALS AND METHODS
Study population and data collection
From March 2019 to June 2020, 112 adult patients (≥18 years) with ostium secundum ASD and PAH treated at the National Cardiovascular Centre Harapan Kita (NCCHK) Hospital were consecutively included. Patients with uncorrected secundum ASD and symptoms of heart failure, who were scheduled for hemodynamic evaluation through RHC, which is a standard practice preceding the decision-making process for ASD intervention in NCCHK Hospital, were informed and consented before undergoing echocardiography examination one day before the procedure. The data collected from each patient included the demographics (age, gender, and body mass index [BMI]), medical history, comorbidities (hypertension, diabetes, coronary artery disease, and chronic kidney disease), and the presence of arrhythmia. Available data from the two methods (echocardiography and RHC) were compared. We selected patients with suspected PH from echocardiographic examination (defined by the BSE [14]) which was later confirmed with RHC criteria (defined by the World Symposium of Pulmonary Hypertension 2018 [15]). The inclusion criteria include patients diagnosed with secundum ASD who exhibit suspected PH based on echocardiography findings, subsequently confirmed by RHC, along with the presence of a noticeable notch in the RVOT. In contrast, exclusion criteria involve patients with other ASD types (ostium primum or sinus venosus), significant valve diseases (excluding tricuspid valve conditions), the presence of additional congenital heart defects, and the absence of an RVOT tract notch in Doppler echocardiography. From these criteria, we excluded 23 patients and included 89 patients in the study. This study was reviewed and approved by the Ethical Committee of the Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia, NCCHK (LB.02.01/VII/454/KEP 021/2020).
Echocardiogram
Echocardiography ultrasound examination was performed mainly using General Electric Vivid E9 (GE Healthcare, Little Chalfont, UK). The echocardiography examination was conducted by technicians who remained blinded to the ASD/PH condition of the patient throughout the procedure. Measurements of the RVOT were obtained from the parasternal shortaxis view at the level of the aortic valve during systole. The sweep speed was approximately 100 mm/s and the values obtained are the average of three beats on sinus rhythm or five beats on atrial fibrillation. The forward velocity profile obtained by pulsed wave Doppler in the RVOT close to the pulmonary valve was used to obtain time-to-notch (TTN), AT, and RVOT velocity time integral (VTI) (Fig. 1). TTN was estimated by the duration of the first wave to the appearance of the notch from the RVOT Doppler outflow wave. The AT was defined as the time from onset to maximal velocity. The notch ratio was defined as TTN divided by duration from the notch to the endwave RVOT Doppler. The main pulmonary artery (MPA) diameter was obtained from the short-axis view of the outflow tract. The tricuspid regurgitation profile was obtained from the multiple view and the highest value was analyzed. The left ventricular ejection fraction was determined by Teichholz. Tricuspid annulus plane systolic excursion (TAPSE) was measured using the four-chamber view in M-mode. Intra-observer variability was assessed by the same observer in a blinded fashion after the initial measurements. Interobserver variability was assessed by a second observer blind to the results of the first observer.
Fig. 1
Schematic picture of pulsed-wave Doppler RVOT in normal conditions (A) and pulmonary hypertension (B). AT, acceleration time; T2, duration of notch to wave-end; TTN, time-to-notch; RVOT, right ventricular outflow tract.
Hemodynamic measurement
RHC was performed within one day of the echocardiography examination. Catheterization was conducted by experienced invasive cardiologists, who were blinded to the results of previous notch RVOT Doppler. RHC was done using a standardized procedure in our center without general anaesthesia. A catheter was inserted through the right femoral vein. Right atrial pressure (RAP), left atrial pressure (LAP), right ventricle pressure, and mPAP were measured along with oxygen saturation. Cardiac output (CO) was calculated using Fick’s method in which oxygen consumption was determined. PVR was presented in Wood units (WU) from the following equation: (mPAP–mean LAP)/CO. Systemic vascular resistance (SVR) was calculated by using the following equation: (mean arterial pressure–mean RAP)/CO. The pulmonary vascular resistance index (PVRI) was calculated from the PVR multiplied by the body surface area (BSA). The resistance ratio (RR) was calculated from the PVR:SVR. Pulmonary arterial compliance (PAC) was calculated from the following equation: stroke volume pulmonary/pulsatile pressure. Stroke volume pulmonary was measured by CO/heart rate. Pulse pressure was measured by using the following equation: systolic PAP–diastolic PAP. The vasoreactivity test was performed using 100% oxygen with a mask in patients with initial RR>0.33 or PVRI>8 WU.m2 and all data was re-measured after 10 minutes of oxygenation [3]. PVD was defined as PVRI>8 WU.m2 following the vasoreactivity test, while non-PVD was defined as PVRI<8 WU.m2 following vasoreactivity test.
Statistical analysis
The data of patients was divided into two groups: PVD and non-PVD. The data was summarized as means±standard deviation, median (min-max), or presented as counts and percentages. For discrete variables, the differences between the two groups were compared with the chi-square (χ2) or Fisher’s exact tests when appropriate. For numeric variables, the differences between the two groups were assessed with Student’s t-test or Mann–Whitney test. Logistic regression models were used to evaluate the univariate and multivariate influences of the variables in the PVD group. In the multivariate logistic model, useful parameters were selected using the backward selection of p-value <0.50. The area under the receiver operating characteristic (ROC) curve was used to find the best decisive threshold that maximized sensitivity and specificity between the TTN and the PVD group. The intra-observer and interobserver variability of the estimated values were calculated using the intraclass correlation coefficient (ICC). A p-value ≤0.05 was considered statistically significant. All statistical analysis was conducted using SPSS software, version 26 (IBM Corp., Armonk, NY, USA).
RESULTS
Following the echocardiography and RHC, 23 patients were excluded because they were other ASD types, had significant valve diseases other than tricuspid regurgitation, the presence of additional congenital heart defects, or the absence of an RVOT notch in Doppler echocardiography, and a total of 89 patients were available for TTN Doppler RVOT and PVD analysis. Overall, 65 patients underwent the vasoreactivity test during RHC and 24 patients were identified in the PVD group. The mean age between the two groups was similar (40.9±12.4 years vs. 37.7±10.0 years, p=0.255). The PVD group had significantly lower BMI compared to the non-PVD group (18.9 kg/m2 vs. 16.9 kg/m2, p=0.013). Gender, BSA, haemoglobin, and heart rhythm between groups were indistinguishable (Table 1).
Table 1
Demographic findings in adult ostium secundum ASD patients
According to the assessment of echocardiography data, no significant differences were reported in notch ratio, MPA diameter, TAPSE and severity of tricuspid valve regurgitation between groups (Table 2). However, the PVD group had a significantly lower TTN, AT, and RVOT-VTI compared to the non-PVD group (132±17 ms vs. 177±29 ms, p<0.001; 67.3±3.4 ms vs. 86.7±20.4 ms, p<0.001; 10.8±4.8 cm vs. 17.4±7.6 cm, p<0.001, respectively). Baseline tricuspid regurgitation maximal velocity (TR Vmax) and tricuspid valve gradient were significantly higher in the PVD group (4.6±0.7 m/s vs. 3.9±0.8 m/s, p< 0.001; 87.0±24.5 mm Hg vs. 63.0±23.6 mm Hg, p<0.001, respectively) (Table 2).
Table 2
Echocardiographic characteristics of ASD patient groups
Haemodynamic data from RHC were analyzed. Mean RAP and LAP were comparable between the two groups. However, significant differences were observed in mPAP (44.5 mm Hg vs. 61.9 mm Hg, p<0.001), PVR (4.9 WU vs. 20.4 WU, p<0.001), PVRI (6.4 WU.m2 vs. 28.0 WU.m2, p<0.001), PAC (1.46 mL/mm Hg vs. 0.49 mL/mm Hg, p<0.001), RR (0.3 vs. 0.8, p<0.001), and flow ratio (2.0 vs. 0.8, p<0.001) before the vasodilator test. Similar results were discerned after conducting vasodilator tests (Table 3).
Table 3
Right heart catheterization findings in adult ostium secundum ASD patients
In multivariate logistic analysis, TTN was found to be a significant predictor for PVD (odds ratio 0.87, 95% confidence interval [CI] 0.81–0.93, p<0.001). A ROC curve was drawn to assess whether TTN could predict PVD and the sensitivity and specificity of the corresponding values were calculated. The AUC of the TTN was 0.923 and the best cutoff value of TTN with maximum sensitivity and specificity was 147.5 ms (Fig. 2). A cutoff TTN value of 147.5 ms has a sensitivity of 88%, specificity of 87%, positive predictive value of 72%, negative predictive value of 95%, positive likelihood ratio of 7.11, and negative likelihood ratio of 0.14 in predicting PVD in adults with ostium secundum ASD. The relationship between TTN and final RR (PVR:SVR) is depicted in Fig. 3. Acceptable results were obtained when intra-observer and interobserver variations were analysed with the ICC (0.93, 95% CI 0.85–0.97, p=0.96 and 0.96, 95% CI 0.93–0.98, p=0.14, respectively).
Fig. 2
Receiver operation characteristics (ROC) curve of time-to-notch in predicting pulmonary vascular disease in an adult with ostium secundum atrial septal defect.
Fig. 3
Scatter plot graph between time-to-notch and final resistance ratio (PVR:SVR). X-axis border shows a time-to-notch of 147.5 ms; Y-axis border shows a PVR:SVR ratio of 0.33 (R2=0.488). PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.
DISCUSSION
PVD remains a critical factor in the decision of defect closure in CHD, even in cases of longstanding ostium secundum ASD. The presence of PVD precluding ASD closure has been associated with significant mortality and a contraindication in corrective surgery. RHC is an invasive method of diagnosis that is used to assess PVD amidst possible complications. Our study demonstrates the predictive value of PVD with non-invasive RVOT Doppler. This study demonstrates that a third of the study population (37%) have more severe PH that might lead to a severe spectrum of PVD. This proportion is similar to a previous study that found 39% of patients had severe PH [16]. In our first analysis, there was no difference in age between the two groups with a mean age of 37.7 years in the PVD group and 40.9 years in the non-PVD group. This is consistent with the natural history of ASD patients who experience significant symptoms in the 3rd to 4th decade of life [3].
Progressive remodelling of the pulmonary vasculature, typically hallmarked by intimal proliferation, medial hypertrophy, neointimal formation, and lesions, would advance into an irreversible state without intervention. Abnormality in pulmonary vasculature is indicated by high pulmonary artery pressure, high PVR, and low pulmonary artery compliance [5, 6]. The relationship of the RVOT Doppler shape was first reported by Kitabake and demonstrated a link between the presence of midsystolic notch to pulmonary artery pressure [10]. The degree and timing of arterial wave reflection, seen as a notch, are influenced by vascular resistance and stiffness. In normal conditions, the pulmonary vascular bed has low resistance thus the reflected wave is small and reaches RVOT at the diastolic phase. However, in the presence of increased PVR and low pulmonary artery compliance, the reflected wave has a greater magnitude and faster flow rate and is identified during systole. This results in a systolic deceleration time and RVOT notching. Another study also found that the presence of a notch (either midsystolic or late-systolic) indicated a PVR value higher than 3 WU (OR 22.3; 95% CI 5.2–96.4) in patients with PH [11]. They also found that the location of the notch is important to the degree of PVD, as a midsystolic notch was associated with a higher PVR (61%) and a lower pulmonary artery compliance (30%) when compared to a late-systolic notch [11]. Our study corresponds to these data as it demonstrates a lower TTN (or earlier onset of notch) in the PVD group compared to the non-PVD group (132±17 ms vs. 177±29 ms, p<0.001). From basic wave reflection theory, the earlier onset of wave reflection (“notch”) represents a narrower and less compliant pulmonary vascular bed [17]. In the PVD group, we also identified a significantly lower RVOT VTI (10.8±4.8 cm vs. 17.4±7.6 cm, p<0.001), reduced AT (67.3±13.4 ms vs. 86.7±20.4 ms, p<0,001), elevated TR Vmax (4.6±0.7 m/s vs. 3.9±0.8 m/s, p<0.001), and decreased TAPSE (18.3±3.6 mm vs. 20.6±6.2 mm, p=0.028) (Table 2). These findings suggest increased pulmonary arterial pressure and increased PVR in the PVD group.
Our study also shows that TTN <147.5 ms can predict PVD in adults with secundum ASD (sensitivity 88%, specificity 87%). We found no significant difference in the baseline heart rate between the PVD group and the non-PVD group. This finding helps eliminate the potential bias stemming from baseline heart rate variations. Thus, the present study confirms that TTN is strongly associated with PVD and RVOT Doppler could enhance the screening of the high-risk population for defect closure. To the best of our knowledge, this study is the first to assess the predictive value of TTN to predict PVD in adult ostium secundum ASD. It can be assumed that TTN can determine the risk of defect closure and operability of ASD. Although the notch ratio is also a potential predictor for PVD, we found that its relationship with PVRI is weak (correlation coefficient -0.149) and the correlation is not significant (p=0.281) (Table 4), thus making it less reliable. However, the notch ratio has a strong relationship with right atrium pressure with a significant correlation (correlation coefficient -0.847, p=0.016). Additionally, we also found that the TTN cutoff of 147.5 ms has a strong relationship with PVRI (correlation coefficient of 0.557) and a very strong relationship with PVD (correlation coefficient of 0.705), both with a significant correlation (p<0.001) (Table 5).
Table 4
Correlation of haemodynamics parameters in RHC with RVOT notch ratio in Doppler echocardiography
Table 5
Correlation of time-to-notch <147.5 ms with PVRI and PVD
This study has a few limitations. Echocardiography and invasive RHC exams were not performed simultaneously. However, such a temporal delay in clinical practice is common because it ensures that the difference in notch RVOT relative to PVD is durable over time. These findings may not apply to other populations of ASD with other possible causes of PH. Nevertheless, our results integrate the reflected wave theory, routine echo-Doppler parameters, and hemodynamic data. Good agreement was noted between the two observers and this is considered promising, although consistency in the extensive application remains to be seen. Another limitation of this study is its small sample size, which could limit the applicability of the findings in a broader ASD-PH population.
In conclusion, routine and non-invasive assessment of the RVOT pattern provides a noteworthy insight into the hemodynamic basis of PAH and PVD. The presence of lower TTN (cutoff< 147.5 ms) is highly sensitive and specific for PVD in adults with secundum ASD. Therefore, the clinical utility of the RVOT profile should be integrated into the risk stratification of ASD closure.
Conflicts of Interest:The authors have no potential conflicts of interest to disclose.
Author Contributions:
Conceptualization: Oktavia Lilyasari.
Data curation: Oktavia Lilyasari, Muhamad Adrin AP, Radityo Prakoso, Arwin Saleh Mangkuanom, Aditya Agita Sembiring, Nurnajmia Curie Proklamartina.
Formal analysis: Muhamad Adrin AP.
Investigation: Oktavia Lilyasari, Muhamad Adrin AP.
Methodology: Oktavia Lilyasari, Muhamad Adrin AP.
Project administration: Muhamad Adrin AP, Nurnajmia Curie Proklamartina.
Resources: Oktavia Lilyasari.
Software: Muhamad Adrin AP.
Supervision: Oktavia Lilyasari, Radityo Prakoso, Arwin Saleh Mangkuanom, Aditya Agita Sembiring, Amiliana M Soesanto.
Validation: Oktavia Lilyasari, Muhamad Adrin AP, Amiliana M Soesanto.
Writing—original draft: Oktavia Lilyasari, Muhamad Adrin AP.
Writing—review & editing: Oktavia Lilyasari, Radityo Prakoso, Arwin Saleh Mangkuanom, Aditya Agita Sembiring, Nurnajmia Curie Proklamartina, Amiliana M Soesanto.
Funding Statement:None
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Acknowledgments
The authors would like to thank Shindi Eugene Tiurma Tampubolon and Rifqi Rizkani Eri for their valuable contributions.
References
-
Xuan Tuan H, The Phuoc Long P, Duy Kien V, Manh Cuong L, Van Son N, Dalla-Pozza R. Trends in the prevalence of atrial septal defect and its associated factors among congenital heart disease patients in Vietnam. J Cardiovasc Dev Dis 2019;7:2
-
-
Topyła-Putowska W, Tomaszewski M, Wysokiński A, Tomaszewski A. Echocardiography in pulmonary arterial hypertension: comprehensive evaluation and technical considerations. J Clin Med 2021;10:3229
-
-
Troutman GS, Bhattacharya PT, Birati EY, Zamani PL, Chirinos JA, Prenner SB, et al. Right ventricular outflow tract Doppler notching predicts survival in patients with pulmonary hypertension and heart failure with preserved ejection fraction. J Card Fail 2019;25 8 Suppl:S65
-
-
Cosssío-Aranda J, Zamora KD, Nanda NC, Uzendu A, Keirns C, Verdejo-Paris J, et al. Echocardiographic correlates of severe pulmonary hypertension in adult patients with ostium secundum atrial septal defect. Echocardiography 2016;33:1891–1896.
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