Impact of right ventricular stiffness on discordance between hemodynamic parameter and regurgitant volume in patients with pulmonary regurgitation

Background: Accurate detection of significant pulmonary regurgitation (PR) is critical in management of patients after right ventricular (RV) outflow reconstruction in Tetralogy of Fallot (TOF) patients, because of its influence on adverse outcomes. Although pressure half time (PHT) of PR velocity is one of the widely used echocardiographic markers of the severity, shortened PHT is suggested to be seen in conditions with increased RV stiffness with mild PR. However, little has been reported about the exact characteristics of patients showing discrepancy between PHT and PR volume in this population. Methods: Echocardiography and cardiac magnetic resonance imaging (MRI) were performed in 74 TOF patients after right ventricular outflow tract (RVOT) reconstruction [32 ± 10 years old]. PHT was measured from the continuous Doppler PR flow velocity profile and PHT < 100 ms was used as a sign of significant PR. Presence of end-diastolic RVOT forward flow was defined as RV restrictive physiology. By using phase-contrast MRI, forward and regurgitant volumes through the RVOT were measured and regurgitation fraction was calculated. Significant PR was defined as regurgitant fraction ≥ 25%. Results: Significant PR was observed in 54 of 74 patients. While PHT < 100 ms well predicted significant PR with sensitivity of 96%, specificity of 52%, and c-index of 0.72, 10 patients showed shortened PHT despite regurgitant fraction < 25% (discordant group). Tricuspid annular plane systolic excursion and left ventricular (LV) ejection fraction were comparable between discordant group and patients showing PHT < 100 ms and regurgitant fraction ≥ 25% (concordant group). However, discordant group showed significantly smaller mid RV diameter (30.7 ± 4.5 vs. 39.2 ± 7.3 mm, P < 0.001) and higher prevalence of restrictive physiology (100% vs. 42%, P < 0.01) than concordant group. When mid RV diameter ≥ 32 mm and presence of restrictive physiology were added to PHT, the predictive value was significantly improved (sensitivity: 81%, specificity: 90%, and c-index: 0.89, P < 0.001 vs. PHT alone by multivariable logistic regression model). Conclusion: Patients with increased RV stiffness and non-enlarged right ventricle showed short PHT despite mild PR. Although it has been expected, this was the first study to demonstrate the exact characteristics of patients showing discrepancy between PHT and PR volume in TOF patients after RVOT reconstruction.


RVOT
Right ventricular outflow tract ROC Receiver operating characteristic SV Stroke volume TAPSE Tricuspid annular plane systolic excursion TOF Tetralogy of Fallot

Background
Pulmonary regurgitation (PR) is common valvular disease in patients after surgical repair of Tetralogy of Fallot (TOF) [1]. Because of its negative impact on clinical outcomes, accurate detection of significant PR is a critical issue in management of this population [2,3]. Although phase-contrast cardiac magnetic resonance imaging (MRI) is the current gold standard in defining severity of PR, it has several limitations, such as portability, need for bless holding, relatively high costing, or contraindications for some implanted pacemakers and defibrillators [4], for the use in daily practice. In this way, transthoracic echocardiography is first line tool for the follow-up of TOF owing to its repeatability. Currently, several Doppler echocardiographic parameters are recommended for the evaluation of PR severity [5][6][7][8][9]. Pressure half time (PHT) of PR velocity is one of the recommended parameters, reflecting early equalization of the pulmonary and right ventricular (RV) diastolic pressures [5]. Although short PHT of the PR velocity is reported to well detect significant PR defined by phase-contrast MRI, possible limitation has also been mentioned: it could shorten in conditions with increased RV stiffness even if PR was mild [5]. Furthermore, the regurgitant volume can be restricted in a stiff right ventricle even if the regurgitant orifice area was large, in low pressure circuit of the right heart [10]. However, little has been reported about the exact characteristics of patients showing discrepancy between PHT and PR volume in this population. Accordingly, the purpose of this study was (1) to confirm the characteristics of the TOF patients showing shortened PHT despite mild PR and (2) to improve the accuracy of PHT to detect significant PR by adding parameters reflecting these characteristics.

Patient selection
This investigation was designed as a retrospective observational study in a single tertiary hospital. We enrolled consecutive adult patients with Tetralogy of Fallot after RV outflow tract (RVOT) reconstruction, who underwent echocardiography and cardiac MRI within 1 year in Hokkaido University Hospital between January 2014 and December 2021. If a patient underwent the examination multiple times during the sampling period, the data at the first time was analyzed. Three patients in whom echocardiographic data for assessing the severity of PR were missing and two patients with atrial fibrillation were excluded and 74 patients were included for the final analysis ( Fig. 1). Patients' data on clinical characteristics, surgical history, echocardiogram, and cardiac MRI data were abstracted from a detailed chart review. This study was compliant with the Declaration of Helsinki principles and approved by the institutional review board of Hokkaido University Hospital (No. 021 − 0010). Written informed consent was waived and an opportunity to opt-out was given to each participant through a published

Echocardiographic measurements
Comprehensive transthoracic echocardiography was performed in the left decubitus position using commercially available ultrasound equipment systems. Measurements performed for clinical purpose according to the guideline [11] and available in the laboratory database included left ventricular (LV) mass, volumes, ejection fraction, RV fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE). Particularly, RV diameter was measured at the mid level of the inflow in the RV focused apical four chamber view (Fig. 2). RV wall thickness was measured at end diastole in the subcostal view. From the continuous-wave Doppler images of the PR, PHT was measured by drawing a line along with the PR velocity envelope (Fig. 3). PR index was calculated as the ratio of the Mid-cavity right ventricular dimension was measured at halfway between the maximal basal diameter and the apex cardiac cycle with both 1.5T and 3.0T). Cine MRI images were analyzed using commercially available analysis software (Extended MR Work Space, Philips Medical Systems, Amsterdam, The Netherlands). Using cine MRI, the endocardial contours of the right ventricle were manually traced from the most apical slice to the uppermost slice, and RV end-diastolic volume (EDV), end-systolic volumes (ESV), stroke volume (SV), and ejection fraction were calculated. Using two-dimensional cine phase-contrast sequence, the contours of the main pulmonary artery were manually traced, and forward flow volume, backward flow volume, net flow volume, and regurgitant fraction were computed. Significant PR was defined as regurgitant fraction ≥ 25%.

Estimation of regurgitant effective orifice area
Effective regurgitant orifice (ERO) area of the pulmonary valve was calculated as following: ERO area = phase-contrast-derived regurgitant volume / Doppler-derived PR velocity time integral [cm 2 ].

Statical Analysis
Continuous variables were expressed as mean ± standard deviation or medians (interquartile range: IQR) as appropriate. Comparisons of continuous variables among different groups were analyzed by analysis of covariance followed by Tukey-Kramer post hoc test or Kruskal-Walls test followed by Steel-Dwass test, as appropriate. Categorical variables time occupied by the regurgitation signal divided by the total diastolic time interval (Fig. 4). As well, peak pressure gradient at RVOT was estimated from the continuous-wave Doppler image and significant RV outflow stenosis was defined as ≥36 mmHg [12]. Pulsed-wave Doppler image of the RVOT flow was obtained by placing a sample volume at just below the pulmonary valve. Restrictive physiology was then defined as the presence of end-diastolic forward RVOT flow. [13][14][15]

Fig. 4 Measurement of pulmonary regurgitation index
Continuous-wave Doppler image of the pulmonary regurgitation is indicated. Pulmonary regurgitation index was calculated as: 100 x pulmonary regurgitation duration (solid arrow) / diastolic duration (dashed arrow) [%] group showed RV restrictive physiology whereas it was found in 42% of concordant group. Furthermore, substantial patients showed wide jet width (jet width / RVOT width > 0.7) and large ERO area (≥0.30 cm 2 ) enough to be judged as significant PR in discordant group ( Table 1).
On the other hand, there were 2 patients showing long PHT despite large regurgitant fraction (Fig. 5). Each of these "negatively discordant" patients showed severely enlarged RV EDV whereas lacked restrictive physiology (Supplemental Table).
Incremental value of RV restrictive physiology and diameter to predict significant PR Figure 6 A indicates an ROC curve to predict significant PR by PHT. PHT < 100 ms well predicted significant PR with sensitivity of 96%, specificity of 52%, and c-statistics of 0.72, which was consistent with the previous findings. When dilation of mid RV diameter larger than median value (> 32 mm) and the presence of restrictive physiology were used in addition to PHT, the predictive value of the multivariable was significantly improved, especially for the specificity (sensitivity: 81%, specificity: 90%, and c-statistics: 0.89, P < 0.001) (Fig. 6B).

Discussion
This study aimed to evaluate the characteristics of TOF patients after RVOT reconstruction showing discrepancy of the findings between PHT of the PR flow and regurgitant fraction assessed by phase-contrast MRI. The results of the present study can be summarized as following. First, shortened PHT well predicted significant PR with a high sensitivity, whereas substantial patients showed shortened PHT despite non-significant regurgitant fraction on MRI. Second, the patients showing shortened PHT despite non-significant PR were characterized by non-enlarged right ventricle and RV restrictive physiology. Third, the predictive value of PHT for significant PR was significantly improved when mid RV diameter ≥ 32 mm and presence of restrictive physiology were incorporated. Importantly, ERO area was large in substantial patients showing non-significant regurgitant fraction despite shortened PHT, highlighting that regurgitant volume can be gentle even in the presence of large ERO in the right heart system.
were expressed as number and percentage and compared among the groups using Chi-square test or Fisher exact tests as appropriate. The Pearson correlation coefficient was used to determine the correlation between the two continuous variables for the relationship between RF and PHT by CMR. Accuracy of each test was determined by calculating the c-statistic with receiver operating characteristic (ROC) analysis. All statistical analyses were performed using JMP software version 16.2 (SAS Institute Inc., Cary, NC, USA). For all statistical tests, we considered a two-sided P value of < 0.05 to be significant.

Patients characteristics
Clinical characteristics of the 74 patients are summarized in Table 1. The mean age was 31.6 ± 10.3 years with a mean time difference from the intracardiac repair of 24 (IQR 20-32) years. 69 patients (93%) denied heart failure symptoms. The median interval between the echocardiographic assessment and the phase-contrast MRI was 89 (IQR 5-193) days.
Significant PR was observed in 54 patients (73%). Overall, right ventricle was enlarged and hypertrophied, and RV ejection fraction was slightly reduced, whereas LV ejection fraction was preserved with a normal early-diastolic mitral annular velocity. RV outflow stenosis was observed in 8 patients and restrictive physiology was found to be frequent in our population (45%).

Characteristics of patients showing nonsignificant PR despite short PHT
In consistent with the previous reports [5,16,17], there was a negative correlation between PHT and regurgitant fraction of the PR (Fig. 5). However, significant PR was not observed in 10 of the 62 patients showing PHT < 100 ms (discordant group) in contrast to the remaining 52 patients who showed PHT < 100 ms and regurgitant fraction ≥25% (concordant group) (Fig. 1). When clinical, echocardiographic, and cardiac MRI findings were compared between concordant and discordant groups by serving the 10 patients showing mild PR and long PHT (lower right group in Fig. 5) as a control, patients in discordant group were characterized as non-enlarged right ventricle with relatively thickened wall and preserved RV ejection fraction ( Table 1). In association, prevalence of RV outflow stenosis was more frequent in discordant group than in concordant group. Notably, the most apparent difference was that all the patients in discordant   dysfunction, fatal ventricular arrhythmias, and ultimately left heart dysfunction. Therefore, accurate evaluation of the PR severity is required in TOF clinics [1]. Although regurgitant volume assessed by cardiac MRI is currently the gold standard for the severity of PR, echocardiography is used most frequently because of its feasibility and repeatability. As in other valvular regurgitations, the guideline recommends the integration of multiple semi-quantitative

Non-invasive assessment of the PR severity
Owing to the development of management strategies for congenital heart diseases, TOF patients after surgical treatment are substantially increasing [18,19]. Among the TOF patients after intracardiac repair, significant PR remains one of the frequent and important functional problems because it leads to worse clinical outcomes through the right heart   Second, since the interval between the MRI and echocardiographic assessment was large (median of 89 days), the severity of PR may vary within patients at different time points related to hemodynamic states. Third, our data lacked invasive data to confirm the RV stiffness. Finally, the results may not be applied to the pediatric population, as the study primarily focused on TOF obtained from adult patients. Finally, our study did not provide outcome data and thus further study is needed to address whether the present findings could be applied for prediction of adverse outcomes.

Conclusion
Patients with increased RV stiffness and non-enlarged right ventricle showed short PHT despite mild PR. Although it has been expected, this was the first study to demonstrate the exact characteristics of patients showing discrepancy between PHT and PR volume in patients after RVOT reconstruction. parameters is recommended to be used for the assessment of PR severity; such as jet width / pulmonary valve annulus diameter ≥ 70%, dense jet Doppler signal, PHT < 100 ms, PR index < 0.77, diastolic reversal flow in a branch of the pulmonary artery, and RV enlargement [20]. Amongst the single parameters, PHT of the PR flow, which reflects the early equalization of pulmonary artery and RV diastolic pressures due to the regurgitation, is widely used to detect significant PR owing to its feasibility. At the same time, it is mentioned that PHT can shorten in conditions with augmented RV stiffness without large regurgitant orifice area [11]. In fact, we found that patients showing short PHT despite small regurgitant fraction had normal RV size and RV restrictive physiology. Notably, this is the first study to confirm the characteristics of this population. Further, backward flow in the blanch of pulmonary artery is an indirect finding reflecting severe PR [7]. Renella and coworkers reported that branch pulmonary artery diastolic flow reversal was a highly specific finding to detect severe PR in TOF patients [6], suggesting that this finding can overcome the overestimation of PHT when the parameters were combined. However, clear visualization of the Doppler signal in the pulmonary artery branches is sometimes difficult in patients after RVOT reconstruction because of the ultrasound reflection at RVOT. Indeed, the feasibility of the assessment of the flow reversal was quite low in our study cohort (37.8%), which might reduce the diagnostic value of this finding.

Clinical implication
We demonstrated that the RV diameter and the presence of restrictive physiology improved the specificity and diagnostic performance of significant PR of short PHT. Although multiple parameters are needed to judge the severity of PR, assessment of the severity by using the combination of PHT of PR, RV diameter, and restrictive physiology could be a reasonable way in daily clinical practice. In addition, our data suggest that regurgitant volume can be small even if regurgitant orifice area was large, which underlines the importance of regurgitant volume rather than ERO to express the severity of the valve regurgitation in the right heart.

Limitation
Several limitations of this study should be acknowledged. First, this is a retrospective study from a tertiary referral center, and as such, has inherent flaws related to selection and referral bias.