Risk Factors for Coronary Artery Complications After Prosthetic Pulmonary Valve Implantation in Patients With Congenital Heart Disease

Abstract

Background: Coronary artery complications (CACs) in patients who undergoing prosthetic pulmonary valve implantation for congenital heart disease can lead to fetal outcomes. However, the incidence of and risk factors for CACs in these patients remain unknown.

Methods and Results: A retrospective cohort study was conducted on patients who underwent cardiac computed tomography or invasive coronary angiography after prosthetic pulmonary valve implantation at Seoul National University Hospital from June 1986 to May 2021. Among 341 patients, 25 (7.3%) were identified with CACs, and 2 of them died. Among the patients with CACs, congenital coronary anomalies and an interarterial course of the coronary artery were identified in 11 (44%) and 18 (72%) patients, respectively. Interarterial and intramural courses of the coronary artery were associated with a 4.4- and 10.6-fold increased risk of CACs, respectively. Among patients with tetralogy of Fallot and pulmonary atresia, the aortic root was rotated further clockwise in patients with coronary artery compression compared to those without it (mean [±SD] 128.0±19.9° vs. 113.5±23.7°; P=0.024). The cut-off rotation angle of the aorta for predicting the occurrence of coronary artery compression was 133°.

Conclusions: Perioperative coronary artery evaluation and prevention of CACs are required in patients undergoing prosthetic pulmonary valve implantation, particularly in those with coronary artery anomalies or severe clockwise rotation of the aortic root.

Coronary artery complications (CACs) after congenital heart surgery are often fatal because they can manifest as acute postoperative hemodynamic instability.¹ However, most studies on CACs after congenital heart surgery have been conducted in patients who underwent coronary artery transfer along with an arterial switch operation for transposition of the great arteries (TGA), revealing its incidence and risk factors.^2,3 Chronic heart failure due to compression of the coronary artery by the conduit after the Rastelli procedure, which includes closure of the ventricular septal defect (VSD) and extracardiac conduit interposition between the right ventricle (RV) and pulmonary artery, has rarely been reported.^4,5 Recently, we reported a case series of CACs in patients who underwent pulmonary valve replacement (PVR) or the Rastelli procedure.⁶ However, the incidence and risk factors of CACs in these patients are unknown.

Meanwhile, abnormal rotation of the outflow tract has been reported in patients with conotruncal anomalies requiring prosthetic pulmonary valve implantation.^7,8 In addition, the positions of the coronary orifices on the aortic circumference vary according to the degree of rotation of the outflow tract.^7,8 Therefore, patients with conotruncal anomalies are expected to have a high risk of intraoperative coronary artery injury or compression of the coronary artery by prosthetic materials after surgery owing to the abnormal rotation of the outflow tract and variations in coronary artery anatomy. However, the correlation between anatomical variations and the incidence of CACs has not yet been evaluated.

Thus, the aim of the present study was to investigate the incidence and risk factors of CACs among patients who underwent prosthetic pulmonary valve implantation for congenital heart disease (CHD). We hypothesized that the rotation angle of the aorta and abnormal coronary artery pattern are related to CACs in patients with conotruncal anomalies.

Methods

This retrospective cohort study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital on July 26, 2021 (IRB no. H-2107-054-1233). The study was performed in accordance with the Declaration of Helsinki and the ethical standards of the institutional committee on human experimentation. The requirement for informed consent was waived owing to the retrospective nature of the study and the absence of any clinical intervention.

Study Participants

Among the 582 patients who underwent PVR or the Rastelli procedure at Seoul National University Hospital between June 1986 and May 2021 (35 years), 341 who underwent postoperative cardiac computed tomography (CT) angiography or invasive coronary angiography were included in the present study. Patients’ diagnoses and types of surgery for underlying CHDs are presented in Supplementary Table 1. Patients who had undergone a previous arterial switch operation, the Ross procedure, or the Nikaidoh procedure, which included coronary transfer surgery, were excluded. Patients with functional single ventricles were also excluded.

Data Collection

Patients’ medical records were retrospectively reviewed to identify the diagnosis of CHD, number of previous open cardiac surgeries, the type and size of the prosthetic valve or conduit, as well as symptoms or signs of coronary insufficiency. Electrocardiography (ECG), echocardiography, cardiac magnetic resonance imaging (MRI), and myocardial single photon emission CT were reviewed to assess the potential presence of CACs. Results of cardiac CT angiography and invasive coronary angiography were retrospectively analyzed to evaluate the cardiac anatomy, coronary artery pattern, and to identify the occurrence of CACs. The following values were measured in contrast-enhanced CT images taken at the end-systolic phase using a picture archiving and communication system by a pediatric cardiologist, employing 3-dimensional reconstruction software Xelis 3D (INFINITT Healthcare, Co., Ltd., Seoul, Republic of Korea): the rotation angle of the aorta, angles of both coronary artery orifices, and the interarterial distance between the aorta and prosthetic pulmonary valve (Figure 1). The cardiac axis was adjusted to be parallel with the interventricular septum and to pass through the center of the aorta in the sagittal and coronal planes (Figure 1A,B). In the axial plane, corrected according to the sagittal and coronal planes, we drew a line passing through the center of the sternum and the center of the spine (Figure 1C,E,F, green dotted line), as well as a line parallel to the green dotted line and passing through the center of the aorta (Figure 1C,E,F, green line). We measured the angle between the green and red lines, which connect the center of the aorta and the commissure of the right- and left-facing sinuses, to determine the rotation angle of the aorta (Figure 1C). We also measured the angles between the green line and each coronary artery orifice in the axial plane (Figure 1E,F). The distance between the aorta and the prosthetic pulmonary valve/conduit was measured with a line passing through the center of the aortic valve and the pulmonary valve or conduit in the axial and coronal planes (Figure 1G,H). The shorter distance between these 2 values was used as the shortest interarterial distance between the aorta and the prosthetic pulmonary valve/conduit.

Figure 1.

Example of the measurement of values using 3-dimensional cardiac computed tomography angiography. (A,B) The cardiac axis was adjusted in sagittal and coronal planes to be parallel with the interventricular septum and pass through the center of the aorta (blue lines). (C) In the axial plane, corrected according to the sagittal and coronal planes, lines were drawn: one passing through the center of the sternum and the center of the spine (green dotted line), and another parallel line through the center of the aorta (green line). The angle between the green and red lines connecting the center of the aorta and the commissure of the right- and left-facing sinuses was measured as the aortic rotation angle. (D) The blue cross indicates the position of the corrected cardiac axis in the 3-dimensional image. (E,F) Angles between the green line and each coronary artery orifice were measured as the right and left coronary angles in the axial plane. (G,H) The distance between the aorta and the prosthetic pulmonary valve or conduit was measured in the axial and coronal planes. The shorter of the two values was adopted as the interarterial distance between the aorta and the prosthetic pulmonary valve/conduit. A, anterior; F, foot; H, head; L, left; LCA, left coronary artery; P, posterior; R, right; RCA, right coronary artery.

Definitions

Obstructive coronary artery disease (CAD) and clinically significant CAD were defined as >50% stenosis of the luminal diameter of the coronary artery according to the guidelines for the management of acute myocardial infarction in adults and stable ischemic heart disease, respectively.^9,10 Therefore, CACs after prosthetic pulmonary valve implantation were defined as a proximal coronary artery diameter >50% smaller than that of the distal coronary artery on postoperative cardiac CT angiography or invasive coronary angiography. Distal coronary artery injury detected on invasive coronary angiography was also categorized as a CAC.

Coronary artery anomalies included the anomalous aortic origin of the coronary artery, a single coronary artery, high take-off of the coronary artery, and an intramural course of the coronary artery, according to the embryological–anatomical classification by the Development, Anatomy, and Pathology Working Group of the European Society of Cardiology.¹¹ An interarterial course of the coronary artery was defined as the coronary artery running between the pulmonary artery and aorta.¹¹

Left ventricular systolic dysfunction was defined as an ejection fraction <50% on echocardiography or <55% on cardiac MRI.^12,13 RV systolic dysfunction was defined as a tricuspid annular plane systolic excursion <16 mm and/or an RV fractional area change <35% on echocardiography or an RV ejection fraction <47% on cardiac MRI.^12,14

Statistical Analysis

Data were analyzed using SAS statistical software (SAS system for Windows, version 9.4; SAS Institute, Cary, NC, USA) with assistance from the Medical Research Collaborating Center of Seoul National University Hospital. Categorical variables are presented as frequencies and percentages. Continuous variables are presented as the mean±SD or the median with interquartile ranges (IQR). Student’s t-test or the Mann-Whitney U test was used to compare the means of 2 independent groups. The Kruskal-Wallis test was used to compare the means of more than 2 independent groups. Pearson’s Chi-squared test or Fisher’s exact test was used to compare proportions between 2 independent groups.

Cox regression analysis was used to identify variables predicting the occurrence of CACs. Risk factors with P<0.20 during univariate analysis were entered into a multivariable model. We controlled for multicollinearity between risk factors by using stepwise selection (entry condition: P<0.05; removal condition: P>0.10), and a final model was constructed using only variables with a P<0.05. For independent variables that could not be estimated using general Cox regression analysis, odds ratios were derived using penalized maximum likelihood estimation, and the confidence interval (CI) was derived as the penalized profile likelihood. The significance of each factor was assessed using a penalized likelihood ratio test. Survival rates were assessed using Kaplan-Meier analysis, and the log-rank test was performed to compare the survival distributions of the 2 groups. P<0.05 was considered statistically significant.

Results

Characteristics of Study Participants

Among the 341 patients included in the study, coronary artery anomalies were identified in 44 (12.9%), and an interarterial course of the coronary artery was observed in 67 (19.6%). The incidence of coronary artery anomalies in specific CHDs differed, and the interarterial course of a coronary artery after prosthetic pulmonary valve implantation differed among CHDs (Table 1). Coronary artery anomalies were most frequently observed in patients with truncus arteriosus (41%), and the interarterial course of the coronary artery was most common in patients with congenitally corrected TGA (50%). The mean rotation angle of the aortic root and the mean angle of each coronary artery significantly differed depending on the type of CHD (all values, P<0.0001; Figure 2). Patients with pulmonary atresia (PA) with an intact ventricular septum, critical pulmonary stenosis, aortic atresia, aortic stenosis, isolated VSD, and atrioventricular septal defect exhibited normal rotation of the aortic root and had no coronary artery anomalies; therefore, they were classified as the ‘others’ group.

Table 1.

Incidence of CA Anomalies and an Interarterial Course of the CA

	All patients (n=341)	PA VSD (n=125)	TOF (n=112)	TA (n=29)	DORV (n=25)	TGA (n=19)	ccTGA (n=16)	Others (n=15)	P value
CA anomalies	44 (12.9)	17 (13.6)	0	12 (41.4)	8 (32.0)	2 (10.5)	4 (25.0)	1 (14.0)	<0.0001
AAOCA	30 (8.8)	13 (10.4)	0	7 (24.1)	5 (20.0)	2 (10.5)	2 (12.5)	1 (6.7)	0.001
Single CA	9 (2.6)	1 (0.8)	0	5 (17.2)	1 (4.0)	0	2 (12.5)	0	<0.0001
High take-off of CA	7 (2.1)	2 (1.6)	0	2 (6.9)	3 (12.0)	0	0	0	0.004
Intramural course of CA	6 (1.8)	1 (0.8)	0	2 (6.9)	2 (8.0)	0	1 (6.3)	0	0.019
Interarterial course of CA	67 (19.6)	37 (29.6)	6 (5.4)	6 (20.7)	8 (32.0)	2 (10.5)	8 (50.0)	0	<0.0001

Unless indicated otherwise, data are given as n (%). AAOCA, anomalous aortic origin of coronary artery; CA, coronary artery; ccTGA, congenitally corrected transposition of great arteries; DORV, double-outlet right ventricle; PA, pulmonary atresia; TA, truncus arteriosus; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Figure 2.

Schematic diagrams of (A) the rotation angle of the aorta and the angles of the right (B) and left (C) coronary arteries. Angles are presented as the mean±SD. ccTGA, congenitally corrected transposition of great arteries; DORV, double-outlet right ventricle; LCA, left coronary artery; PA, pulmonary atresia; RCA, right coronary artery; TA, truncus arteriosus; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Patients With CACs

Of the 341 patients in the study, 25 (7.3%) were diagnosed with CACs, of whom 2 (8%) died. The median age at diagnosis of a CAC was 20 years (IQR 12.5–25 years). The patterns of CAC are shown in the Supplementary Figure. The mechanisms of CACs included compression by an adjacent RV outflow tract patch or prosthetic valve/conduit (n=19) and intraoperative injury (n=6). The right coronary artery (RCA) was involved in 13 patients, the left anterior descending coronary artery (LAD) in 10, and the left main coronary artery in 2. Patients were divided into 2 categories depending on the timing of the onset of CAC (Supplementary Table 2). Seven patients developed early postoperative hypotension, ventricular arrhythmia, or cardiac arrest secondary to CACs. One of the patients who experienced postoperative cardiac arrest due to LAD injury died from brain injury on extracorporeal membrane oxygenation support even after coronary artery bypass surgery was performed. CACs were diagnosed in 18 patients with late-onset symptoms or signs of coronary insufficiency at a median follow-up of 9.5 years (IQR 6.5–12.3 years) after the PVR or Rastelli procedure. In 5 out of the 18 patients (Patients 21–25, Supplementary Table 2), prior coronary insufficiency were recently validated through imaging studies conducted during assessments for heart failure, syncope, or ventricular arrhythmia. Upon reviewing immediate postoperative functional studies, such as echocardiography and ECG, it was revealed that coronary artery injuries, which occurred during the procedure were not initially recognized and were confirmed later. Only 5 of 18 patients (28%) experienced non specific chest pain at the time of diagnosis; 6 patients had palpitations, 3 had dyspnea, and 1 had syncope. Four patients had ventricular arrhythmias. Nine of the 18 patients (50%) were asymptomatic despite the presence of ECG abnormalities or ventricular dysfunction on echocardiography or cardiac MRI. One of the asymptomatic patients (Patient 25) who had distal LAD injury during the surgery and interarterial course of RCA experienced sudden death at the age of 26 years.

Among the patients who experienced late-onset symptoms or signs of coronary insufficiency, 4 had undergone CT angiography twice before the diagnosis of CAC. Two of them (Patients 10 and 15) exhibited an increase in aortic root size by 1 and 5.7 cm, respectively, over an 8-year period. The interarterial distance between the aorta and the prosthetic valve/conduit decreased by 0.7 and 3.4 mm in Patients 10 and 15, respectively, and ultimately resulted in the compression of the RCA in the narrow space.

Comparison of Clinical Data Between Patients With and Without CAC

At the time of the last PVR or Rastelli procedure, patients in the CAC group were significantly younger, and their weight and body surface area (BSA) were significantly less than those of the non-CAC group (Table 2). The follow-up duration was longer in the CAC than non-CAC group. In the CAC group, the Rastelli procedure was performed more frequently than PVR. Although there was no difference in the mean size of the prosthetic pulmonary valve/conduit between the groups, the mean sizes indexed to body weight and BSA were larger in the group with CACs compared to the group without it. The groups did not differ in terms of the diagnosis of CHD; however, the angles of both coronary arteries differed significantly between the 2 groups. Coronary artery anomalies and an interarterial course of the coronary artery were more frequently observed in patients with than without CACs (44% vs. 10.4% and 72% vs. 15.5%, respectively).

Table 2.

Clinical Data for All Patients and Those With and Without CACs Separately

	Total (n=341)	CACs (n=25)	No CACs (n=316)	P value
Male sex	212 (62.2)	16 (64.0)	196 (62.0)	0.845
Age at first surgery (years)	8.4±10.7	4.2±5.4	8.8±11.0	0.130
Age at last surgery (years)	13.7±10.6	9.3±6.9	14.1±10.8	0.040*
Weight at last surgery (kg)	39.0±22.7	31.1±22.0	39.7±22.7	0.029*
BSA at last surgery (m2)	1.19±0.50	0.99±0.51	1.21±0.50	0.031*
Age at last visit (years)	22.1±12.0	23.8±9.8	22.0±12.2	0.490
Follow-up duration (years)	8.2±6.8	13.4±7.7	7.8±6.6	<0.001*
Cardiac death	12 (3.5)	2 (8.3)	10 (3.2)	0.217
Diagnosis				0.403
PA VSD	125 (36.7)	11 (44.0)	114 (36.1)
TOF	112 (32.8)	3 (12.0)	109 (34.5)
TA	29 (8.5)	3 (12.0)	26 (8.2)
DORV	25 (7.3)	4 (16.7)	21 (6.6)
TGA	19 (5.6)	1 (4.0)	18 (5.7)
ccTGA	16 (4.7)	3 (12.0)	13 (4.1)
Others	15 (4.4)	0	12 (3.8)
CA anomalies	44 (12.9)	11 (44.0)	33 (10.4)	<0.001*
AAOCA	30 (8.8)	7 (28.0)	23 (7.3)	0.003*
Single CA	9 (2.6)	2 (8.0)	7 (2.2)	0.135
High take-off of CA	7 (2.1)	1 (4.0)	6 (1.9)	0.416
Intramural course of CA	6 (1.8)	4 (16.0)	2 (0.6)	<0.001*
Interarterial course of CA	67 (19.6)	18 (72.0)	49 (15.5)	<0.001*
Type of surgery				0.043*
PVR	133 (39.0)	5 (20.8)	128 (40.4)
Rastelli procedure	208 (61.0)	19 (79.2)	189 (59.6)
Prosthetic valve or conduit				0.015*
Porcine valve	146 (42.8)	12 (48.0)	134 (42.4)
PTFE valved conduit	111 (32.6)	2 (8.0)	109 (34.5)
Bovine pericardial valve	61 (17.9)	8 (32.0)	53 (16.8)
Other	23 (6.7)	3 (12.0)	20 (6.3)
Size of valve or conduit (mm)	22.2±4.6	21.0±5.1	22.3±4.6	0.233
Size/weight (mm/kg)	0.82±0.55	1.09±0.76	0.80±0.52	0.013*
Size/BSA (mm/m2)	21.53±7.67	25.46±9.80	21.22±7.41	0.011*
No. previous surgeries	3.1±1.1	3.0±1.2	3.1±1.1	0.915

Unless indicated otherwise, data are given as the mean±SD or n (%). *The data with a P value less than 0.05 is indicated with an asterisk in the table. BSA, body surface area; CAC, coronary artery complication; PTFE, polytetrafluoroethylene; PVR, pulmonary valve replacement. Other abbreviations as in Table 1.

To investigate the clear effect of aortic rotation on the incidence of CACs, a subgroup analysis was performed in 237 patients with tetralogy of Fallot (TOF) and PA VSD, as the remaining patients were heterogeneous in their underlying CHDs. In this subgroup, the aorta was rotated further in a clockwise direction in patients with coronary artery compression than in those without CACs (Table 3). The incidence of coronary artery compression was significantly higher in the group with a rotation angle >133° than in the group with a rotation angle ≤133° (P<0.001; Figure 3A). Upon Cox regression analysis, the risk of coronary artery compression was 7.6-fold higher in the group with a rotation angle >133° than in the group with a rotation angle ≤133° (P=0.002; 95% CI 2.146–27.113). Even in patients without coronary anomalies, the frequency of interarterial course was higher and the interarterial distance was shorter in the patients with CACs compared to the patients without it (Table 3C, 1.81±0.96 vs. 3.13±2.01 mm; P=0.032).

Table 3.

Subgroup Analysis in Patients With TOF and PA With VSD

(A) All TOF and PA VSD patients (n=237)	No CACs (n=223)	All CACs (n=14; 5.9%)	P value	Compression (n=11)	P value	Injury (n=3)	P value
Rotation angle of the aorta (°)	113.5±23.7	122.2±23.0	0.197	128.0±19.9	0.024*	90.7±0.9	0.093
LCA angle (°)	173.8±24.0	170.5±46.2	0.402	184.6±18.5	0.079	92.5±88.4	0.044*
RCA angle (°)	36.5±27.3	54.7±33.6	0.032*	60.7±33.2	0.006*	21.9±3.0	0.335
CA anomaly	11 (4.9)	6 (42.8)	<0.0001*	5 (45.5)	<0.0001*	1 (33.3)	0.452
Interarterial course of CA	32 (14.3)	11 (78.6)	<0.0001*	10 (90.9)	<0.0001*	1 (33.3)	0.200
Interarterial distanceA (mm)	3.20±2.01	1.59±1.18	0.002*	1.50±1.20	0.001*	2.60 (n=1)	0.764
(B) TOF and PA VSD patients with CA anomalies (n=17)	No CACs (n=11)	All CACs (n=6; 35.3%)	P value	Compression (n=5)	P value	Injury (n=1)	P value
Rotation angle (°)	134.6±26.6	121.8±25.2	0.687	128.1±22.2	0.820	90.0	0.167
LCA angle (°)	183.4±45.2	158.8±65.1	0.365	170.6±61.8	0.938	30.0	0.111
RCA angle (°)	67.7±25.3	60.4±47.1	0.588	63.3±28.0	0.913	19.8	0.118
Interarterial course of CA	8 (72.7)	6 (100)	0.171	5 (100)	0.065	1 (100)	1.000
Interarterial distanceA (mm)	4.59±1.28	1.28±1.51	0.003*	1.28±1.51	0.001*	–	–
(C) TOF and PA VSD patients without CA anomalies (n=220)	No CACs (n=212)	All CACs (n=8; 3.6 %)	P value	Compression (n=6)	P value	Injury (n=2)	P value
Rotation angle (°)	112.4±23.1	122.6±22.9	0.207	127.8±20.0	0.067	91.3	0.363
LCA angle (°)	173.3±22.5	180.4±21.9	0.410	184.7±20.7	0.181	155.0	0.371
RCA angle (°)	35.0±26.6	49.9±18.8	0.056	54.2±16.4	0.021*	24.0	0.714
Interarterial course of CA	24 (11.4)	5 (62.5)	0.001*	5 (83.3)	<0.0001*	0	1.000
Interarterial distanceA (mm)	3.13±2.01	1.81±0.96	0.032*	1.68±0.98	0.025*	2.6	0.895

Unless indicated otherwise, data are given as the mean±SD or n (%). *The data with a P value less than 0.05 is indicated with an asterisk in the table. ^AThe narrowest diameter between the aorta and the prosthetic pulmonary valve/conduit. LCA, left coronary artery; RCA, right coronary artery. Other abbreviations as in Tables 1,2.

Figure 3.

Kaplan-Meier estimates of (A) coronary artery compression-free survival and (B) overall survival after the surgery. (A) Coronary artery compression-free survival after surgery in patients with tetralogy of Fallot and pulmonary atresia with ventricular septal defect. The predicted coronary artery compression-free survival rate was 92.1% at 5 years, 73.5% at 10 years, and 73.5% at 20 years in the group with an aortic rotation angle >133°, compared with 99.5% at 5 years, 98.1% at 10 years, and 94.7% at 20 years in the group with an aortic rotation angle ≤133° (log-rank test, P<0.001). (B) Overall survival after prosthetic pulmonary valve implantation. No significant differences in the survival rate were detected according to the occurrence of CACs (log-rank test, P=0.418). CAC, coronary artery complication; PVR, pulmonary valve replacement.

Risk Factors for the Occurrence of CACs

The analysis of the risk factors associated with the occurrence of CACs after prosthetic pulmonary valve implantation included 326 patients with conotruncal anomalies, excluding the ‘others’ group. The results of the univariable analysis are presented in Table 4. In multivariable analysis, younger age at the last surgery, more clockwise rotation of the RCA, an interarterial course of the coronary artery, and an intramural course of the coronary artery were significant independent risk factors (Table 5). An interarterial course of the coronary artery and an intramural course of the coronary artery were associated 4.4- and 10.6-fold higher risks of CAC, respectively. A subgroup analysis of the risk of CACs was performed according to the type of CAC and the coronary artery involved. In patients with coronary artery compression and RCA complications, a shorter patient’s height at the last surgery was associated with a higher risk of the CAC. An interarterial course of the coronary artery was associated with an 11.4-fold higher risk of coronary artery compression and a 12.3-fold higher risk of RCA complications. When the RCA angle increased by 10°, the risk of RCA complications increased by 15%. Situs inversus and an intramural course of the coronary artery were associated with 15.3- and 16.6-fold higher risks of intraoperative coronary injuries, respectively. In addition, as the distance between the aorta and the prosthetic pulmonary valve/conduit increased by 1 mm, the risk of RCA complications was reduced by 37.9%. For each increase in the number of previous operations, the risk of left coronary artery (LCA) complications increased 1.8-fold. Coronary artery anomalies yielded a 13.9-fold increased risk of LCA complications.

Table 4.

Univariable Analysis of Risk Factors for CACs in Patients With Conotruncal Anomalies

	Total (n=326)	CAC (n=25)	No CAC (n=301)	Unadjusted HR	95% CI		P value
					Lower	Upper
Age at first surgery (years)	8.4±10.5	4.2±5.4	8.7±10.8	0.992	0.985	0.998	0.014*
Age at last surgery (years)	13.7±10.4	9.3±6.9	14.1±10.6	0.994	0.988	0.999	0.029*
Height at last surgery (cm)	135.5±34.4	122.5±38.2	136.6±33.9	0.983	0.971	0.995	0.007*
Weight at last surgery (kg)	39.3±22.9	30.2±22.0	40.0±22.8	0.976	0.955	0.998	0.032*
BSA at last surgery (m2)	1.19±0.50	0.99±0.51	1.21±0.50	0.323	0.127	0.820	0.017*
No. previous surgeries	1.9±1.0	2.0±0.8	1.9±1.0	1.193	0.821	1.734	0.354
Diagnosis
TOF (reference)	112 (34.36)	3 (12)	109 (36.21)
PA VSD	125 (38.34)	11 (44)	114 (37.87)	4.543	1.478	18.029	0.021*
TA	29 (8.9)	3 (12)	26 (8.64)	4.817	1.009	22.939	0.052
DORV	25 (7.67)	4 (16)	21 (6.98)	5.398	1.314	24.150	0.026*
TGA	19 (5.83)	1 (4)	18 (5.98)	0.798	0.006	8.299	0.888
ccTGA	16 (4.91)	3 (12)	13 (4.32)	5.330	1.072	26.098	0.043*
Anatomy
Dextrocardia	14 (4.3)	2 (8.0)	12 (4.0)	1.258	0.292	5.414	0.758
Situs inversus	13 (4.0)	3 (12.0)	10 (3.3)	2.355	0.693	8.009	0.170
Right aortic arch	88 (27.0)	9 (36.0)	79 (26.3)	1.203	0.512	2.828	0.671
LSVC	53 (16.3)	6 (24.0)	47 (15.6)	1.702	0.673	4.301	0.261
Rotation angle (°)	123.4±41.2	127.2±51.9	123.1±40.2	0.999	0.990	1.008	0.802
LCA angle (°)	176.8±41.3	196.0±68.2	175.2±38.1	1.007	1.000	1.015	0.064
RCA angle (°)	24.0±62.5	62.3±59.2	20.9±61.8	1.014	1.007	1.022	<0.001*
Distance between aorta and prosthetic pulmonary valve (mm)	3.38±2.24	1.81±1.47	3.51±2.24	0.593	0.433	0.813	0.001*
CA anomaly
AAOCA	29 (8.9)	7 (28.0)	22 (7.3)	4.265	1.756	10.360	0.001*
Single CA	9 (2.8)	2 (8.0)	7 (2.3)	1.761	0.403	7.691	0.452
High take-off of CA	7 (2.2)	1 (4.0)	6 (2.0)	6.239	0.782	49.784	0.084
Intramural course of CA	6 (1.8)	4 (16.0)	2 (0.7)	11.334	3.823	33.604	<0.001*
Interarterial course of CA	67 (20.6)	18 (72.0)	49 (16.3)	8.396	3.468	20.326	<0.001*
Type of surgery
PVR (reference)	126 (38.65)	5 (20)	121 (40.2)	–	–	–
Rastelli procedure	200 (61.35)	20 (80)	180 (59.8)	3.270	1.197	8.930	0.021*
Material of prosthetic valve/conduit
Porcine valve (reference)	139 (42.64)	12 (48)	127 (42.19)	–	–	–
PTFE valved conduit	106 (32.52)	2 (8)	104 (34.55)	0.586	0.110	2.149	0.494
Bovine pericardial valve	59 (18.1)	8 (32)	51 (16.94)	0.786	0.299	1.930	0.626
Bovine jugular vein	8 (2.45)	0 (0)	8 (2.66)	1.378	0.011	11.113	0.839
Homograft	7 (2.15)	2 (8)	5 (1.66)	1.168	0.162	5.204	0.862
Mechanical valve	7 (2.15)	1 (4)	6 (1.99)	0.877	0.088	4.026	0.892
Size of valve or conduit (mm)	22.2±4.6	20.96±5.14	22.31±4.55	0.914	0.816	1.025	0.123
Size/weight (mm/kg)	0.81±0.5	1.09±0.76	0.79±0.47	2.327	1.263	4.285	0.007*
Size/BSA (mm/m2)	21.48±7.59	25.46±9.8	21.15±7.3	1.044	1.003	1.087	0.036*
Operation time (min)	438.7±118.7	432.0±141.2	439.3±117.0	1.001	0.998	1.005	0.397
CPB time (min)	190.5±74.3	208.5±97.1	189.0±72.0	1.005	1.001	1.009	0.017*
Intraoperative event	22 (6.75)	9 (36)	13 (4.32)	8.228	3.493	19.384	<0.001*
Postoperative event	14 (4.29)	6 (24)	8 (2.66)	10.768	4.068	28.504	<0.001*
ECMO use	6 (1.84)	3 (12)	3 (1)	102.821	16.927	624.573	<0.001*

Unless indicated otherwise, data are given as the mean±SD or n (%). *The data with a P value less than 0.05 is indicated with an asterisk in the table. CI, confidence interval; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio; LSVC, left superior vena cava; LV, left ventricular; m, months; RV, right ventricular. Other abbreviations as in Tables 1–3.

Table 5.

Multivariable Analysis of Risk Factors for CACs

	Adjusted HR	95% CI	P value
All patients with conotruncal anomalies
Age at last surgery	0.990	0.983–0.997	0.005
RCA angle increased by 10	1.103	1.003–1.017	0.008
Interarterial course of CA	4.406	1.628–11.925	0.004
Intramural course of CA	10.578	3.085–36.2725	<0.001
Patients with CA compression
Patient’s height at last surgery	0.976	0.960–0.992	0.004
RCA angle increased by 10	1.109	1.017–1.209	0.019
Interarterial course of CA	11.376	3.232–40.035	<0.001
Patients with intraoperative coronary injury
Situs inversus	15.301	2.997–78.120	0.001
Intramural course of CA	16.607	1.736–158.881	0.015
Patients with RCA complications
Patient’s height at last surgery	0.970	0.949–0.991	0.006
RCA angle increased by 10	1.150	1.034–1.279	0.010
Interarterial course of CA	12.295	2.584–58.492	0.002
Distance between aorta and prosthetic pulmonary valve	0.621	0.419–0.921	0.018
Patients with LCA complications
No. previous surgeries	1.755	1.066–2.889	0.027
CA anomaly	13.866	3.895–49.366	<0.001

CA, coronary artery; CI, confidence interval; HR, hazard ratio; LCA, left coronary artery; RCA, right coronary artery.

CAC-Free Survival and Overall Survival

The predicted CAC-free survival rates were 97.3% at 5 years, 92.5% at 10 years, 85.5% at 20 years, and 61.1% at 30 years. No significant difference in the overall survival rate was observed according to the occurrence of CACs (P=0.418; Figure 3B). Upon Cox regression analysis, the risk of cardiac death seemed higher (1.865-fold; 95% CI 0.403–8.628) in patients with than without CACs; nevertheless, the difference was not statistically significant (P=0.425).

Discussion

CACs following the prosthetic pulmonary valve implantation were not uncommon in the present study (7.3%), and mortality among patients with CACs was high (8%). A calcified conduit or prosthetic valve and an anatomically narrow space between the aorta and RV outflow tract can cause coronary artery stenosis, kinking, or occlusion after PVR or the Rastelli procedure.⁶ Coronary artery compression during balloon angioplasty or conduit stent placement is a well-known life-threatening complication of percutaneous pulmonary valve implantation (PPVI) in patients with CHDs.^15,16 To avoid this complication, aortic root or selective coronary angiography with simultaneous balloon inflation in the RV outflow tract is recommended before PPVI.¹⁷ However, no guidelines have been published for the diagnosis and prevention of CACs after surgical PVR or the Rastelli procedure. Invasive coronary angiography may not be feasible for all patients undergoing prosthetic pulmonary valve implantation. Therefore, we recommend a thorough coronary artery evaluation with echocardiography and cardiac CT angiography to identify coronary anomalies and assess the relationship between the aorta and the prosthetic pulmonary valve/conduit.⁶ Intraoperative fluorescence coronary imaging may be considered to avoid intraoperative coronary artery injury.^18,19 According to the imaging results, careful selection of the valve/conduit position in patients with conotruncal anomalies is important, especially in those at a high risk of CACs.

In the multivariable risk factor analysis of all the patients with conotruncal anomalies, interarterial and intramural courses of the coronary artery were significantly correlated with the incidence of CACs. Therefore, both coronary artery anomalies and the abnormal course of the coronary artery should be confirmed before performing PVR or the Rastelli procedure. In addition, in the subgroup analysis of patients with TOF and PA VSD, a more clockwise rotation of the aortic root was associated with the occurrence of coronary artery compression. Therefore, for patients with TOF and PA VSD, the degree of aortic rotation can be assessed using preoperative cardiac CT angiography before surgery.

We also observed that a narrow space between the aorta and the prosthetic pulmonary valve or conduit increased the risk of CACs. This finding is consistent with prior studies indicating that a shorter distance between the RV outflow tract and the coronary artery is associated with a higher risk of coronary artery compression in patients undergoing PPVI.^20,21 Furthermore, as the patient grows, coronary artery compression may develop due to the enlargement of the aorta, while the prosthetic valve/conduit remains fixed.⁵ To mitigate the risk of coronary artery compression, it is advisable to implant the prosthetic valve/conduit as far from the aorta as possible. Following PVR or the Rastelli procedure, regular follow-up imaging studies for the enlargement of the aortic root are recommended, with particular attention to the development of CACs.

For the prevention of CACs, it is essential to carefully consider not only the location but also the size of the valve/conduit. The body weight- and BSA-indexed sizes of prosthetic pulmonary valve/conduits were larger in the CAC than non-CAC group. Inserting a large valve or conduit into a small patient may lead to coronary artery compression due to limited intrathoracic space. Therefore, the practice of inserting an excessively large valve or conduit in a small child should be avoided. Although it is challenging to recommend a specific size for a growing child based on our current data, the size of the prosthetic valve may be selected by referring to the Z-score of the pulmonary valve annulus.²²

In patients with LCA complications, a higher number of previous surgeries was associated with the increased risk of CACs, possibly owing to severe adhesions. Therefore, special attention should be paid to the occurrence of LCA injury in patients with a history of multiple previous open-heart surgeries. In addition, efforts are needed to reduce the number of operations in a lifetime through non-surgical treatments, such as PPVI, or the development of more durable valves.

In the present study, only a few patients experienced chest pain at the time of diagnosis of CACs despite the presence of ECG abnormalities or ventricular dysfunction in imaging studies. Therefore, regular follow-up ECG and echocardiography are recommended after prosthetic pulmonary valve implantation. Current guidelines for managing adults with CHD recommend performing ECG and echocardiography every 6–24 months and cardiac MRI/CT and exercise tests every 12–60 months in patients with TOF and in those with a conduit between the RV and pulmonary artery, according to the patient’s physiological stage.²³ However, given that coronary stenosis or occlusion may progress gradually before symptoms indicative of CACs, it may be necessary to conduct more frequent screenings even in patients with a generally good physiological status. Aaccurate history taking and a high index of suspicion for CAC are necessary when new ECG changes, ventricular dysfunction, or ventricular arrhythmias occur during follow-up.

This study had several limitations. First, due to the retrospective study design, the evaluation for the development of CACs was inconsistent, depending on the patient’s clinical status and physician’s preferences. For instance, cardiac CT angiography and invasive coronary angiography were not performed in all patients who underwent PVR or the Rastelli procedure. Therefore, patients who developed asymptomatic CACs may have been overlooked. In addition, the occurrence of CACs cannot be ruled out in patients who were excluded from this study because they had died without cardiac CT angiography owing to their worsening general condition. Second, because no diagnostic criteria are currently available for CACs after PVR or the Rastelli procedure, the diagnostic criteria in this study were developed based on the institutional experience and imaging criteria for acquired CAD. Clear diagnostic criteria and treatment guidelines for CACs after prosthetic pulmonary valve implantation should be established. Third, the results of stress echocardiography and invasive functional studies were not available in this study. Such functional studies may assist with the determination of the clinical importance of CACs and policymaking in surgical or interventional therapy. Finally, we did not study serial changes in the aortic root diameter in all patients. Aortic root dilatation, frequently observed in repaired TOF, may decrease the distance between the aorta and the prosthetic pulmonary valve/conduit, and could lead to distortion of the coronary artery orifice. Further studies are required to determine the relationship between changes in the aortic root size and the occurrence of CACs.

Conclusions

CACs are not uncommon in patients undergoing prosthetic pulmonary valve implantation and can be fatal. Pre- and postoperative long-term coronary assessments should be performed in patients with conotruncal anomalies, especially in those with severe clockwise rotation of the aortic root and coronary artery anomalies, to prevent ventricular dysfunction, arrhythmias, and death after surgery.

Acknowledgments

None.

Sources of Funding

This study did not receive any specific funding.

Disclosures

The authors declare that there are no conflicts of interest.

IRB Information

This study was approved by the Institutional Review Board (IRB) of Seoul National University Hospital on July 26, 2021 (IRB no. H-2107-054-1233).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0752

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