論文ID: CJ-13-1264
Background: This study tested the hypothesis that aortic stiffness is increased more in patients with single ventricular (SiV) circulation and dilated aorta than in those without aortic dilatation, and that aortic stiffness is an independent determinant of aortic dilatation in this type of patient.
Methods and Results: Pulse wave velocity (PWV) and aortic size were measured during catheterization in 56 consecutive patients with SiV circulation (aortic dilatation, n=31 [observed/expected aortic root diameter >1.5]; without aortic dilatation, n=25). PWV was found to be significantly higher in the dilatation group than in the non-dilatation group (483.6±10.3 vs. 394.0±8.9 cm/s, P<0.001) after controlling for age and aortic pressure, factors known to influence PWV (P<0.001, analysis of covariance). There was a strong positive correlation between aortic root diameter and PWV (P<0.001). Multivariate analysis adding aortic flow (index of aortic volume load) to independent variables in 25 pre-Glenn patients with directly calculated aortic flow volume showed that PWV was an independent determinant of aortic dilatation (P<0.001).
Conclusions: In patients with SiV circulation and dilated aorta, aortic stiffness is increased and is an independent determinant of aortic dilatation. To improve prognosis of Fontan circulation, further studies on whether aortic stiffness modulation reduces the progression of aortic dilatation and resultant aortic regurgitation are warranted.
Progressive aortic dilatation can occur and may lead to aortic regurgitation in patients with tetralogy of Fallot (TOF).1–4 Intrinsic histological abnormalities in the aortic media, best characterized by elastic fiber disruption, are thought to be a major cause of this pathologic phenomenon.5,6 Disruption of elastic fibers in the aortic media in turn suggests a decrease in the elastic nature of the aortic wall. Indeed, several studies demonstrated increased aortic stiffness and its significant association with aortic dilatation in TOF patients.5,7–12 Notably, abnormal medial histopathology can also be present in congenital heart disease (CHD) of single ventricular (SiV) circulation, and aortic dilatation is also known to occur in this disease,5,13–15 indicating possible aortic stiffening and its significant association with aortic dilatation in these patients. In addition to abnormal aortic medial pathology, aortic volume load induced by right-to-left shunt and/or aortopulmonary shunt has been suggested to play a synergistic role in the development of aortic dilatation in TOF.1 It is also of note that aortic volume overload is often accompanied by SiV circulation, and thus may contribute to the development of aortic dilatation in SiV circulation as well as in TOF. The underlying mechanisms of aortic dilatation observed in SiV circulation, however, are unknown. The present study was therefore conducted to test the hypothesis that aortic stiffness is increased more in patients with SiV circulation and a dilated aorta than in those without aortic dilatation, and that aortic stiffness is an independent determinant of aortic dilatation in this patient type regardless of the presence of aortic volume load.
The study was approved by Institutional Review Board of Saitama Medical University (No.12-024, International Medical Center, Saitama Medical University).
PatientsThe study included 56 consecutive pediatric patients with SiV circulation who underwent cardiac catheterization at International Medical Center, Saitama Medical University. These patients were divided into 2 groups according to the presence or absence of aortic dilatation, defined as observed/expected aortic root diameter >1.5, as follows: a dilatation group, n=31; and a non-dilatation group, n=25.
MeasurementsThe ascending aortic diameter (AOD) of the sinotubular junction was obtained at end diastole from 2-dimensional transthoracic echocardiograms obtained at the time of catheterization and was indexed to the normal reference value for Japanese children.16 Aortic pressure was measured using a high-fidelity micromanometer mounted on a 0.014-in guidewire inserted in a 4-Fr pigtail catheter. As an index of aortic stiffness, pulse wave velocity (PWV)5,6 was measured as the catheter was withdrawn from the ascending aorta to the descending aorta at the level of the diaphragm. The distance between the 2 aortic levels was measured directly from the length of the catheter withdrawn outside the patient’s body. PWV was then calculated by dividing the distance between the ascending and descending aorta by the time delay between the rapid upstroke of the feet of recorded pulse waves at each site. During the catheter drawback from the ascending to the descending aorta (within 1 or 2 s), little change in heart rate and blood pressure was confirmed. Therefore, it can be assumed that vessel area and wall thickness were not significantly changed, and that the time for catheter drawback was short enough to maintain the same condition during PWV measurement. Data were digitized at 500 Hz on a personal computer and stored for subsequent offline analysis.
In 25 pre-Glenn patients in whom pulmonary flow was predominantly supplied via a Blalock-Taussig (BT) shunt, aortic volume flow was calculated as the sum of the pulmonary and systemic flow measured using the Fick principle and used to quantitatively assess the aortic volume load.
Statistical AnalysisAll continuous data are expressed as mean±SD. Comparison between 2 groups was done using unpaired t-test. Pearson’s correlation analysis was used to assess relationships between PWV and AOD. Analysis of covariance and multivariate regression were also performed to determine the independent effect of PWV on aortic dilatation, with the factors potentially influencing aortic dilatation included as independent variables. These factors were age, sex, blood pressure, and history of BT shunt. P<0.05 was considered statistically significant. All statistical analysis was done using JMP version 8.0 and GraphPad PRISM version 5.
Table 1 summarizes patient characteristics. Age, male/female ratio, body weight, body mass index, arterial oxygen saturation, systolic and diastolic blood pressures, and hemoglobin at the time of catheterization were similar between the 2 groups. Underlying cardiac disease was also similar in the 2 groups. No significant difference was observed between the 2 groups in the use of medications that might potentially affect aortic dilation (angiotensin-converting enzyme inhibitor or β-blockers). Angiotensin type I receptor blocker was not used in any of these patients. Of note, the dilatation group had a greater prevalence of history of BT shunt than the non-dilatation group (P=0.0024), suggesting a potential importance of aortic volume load in causing aortic dilatation. Three patients in the dilatation group and 1 patient in the non-dilatation group had mild aortic regurgitation. No patient had moderate or severe regurgitation or aortic stenosis.
| Dilatation group (n=31) |
Non-dilatation group (n=25) |
P-value | |
|---|---|---|---|
| Age (years) | 3.5±0.7 | 4.5±0.7 | 0.340 |
| Male (%) | 58 | 56 | 0.877 |
| Body weight (kg) | 13.6±1.7 | 16.2±1.7 | 0.290 |
| BMI | 15.6±0.4 | 15.5±0.3 | 0.998 |
| SaO2 (%) | 85.1±1.3 | 88.7±1.5 | 0.072 |
| SBP (mmHg) | 92.6±2.7 | 87.2±2.7 | 0.170 |
| DBP (mmHg) | 56.7±2.7 | 58.0±3.4 | 0.769 |
| Hemoglobin (mg/dl) | 13.2±0.3 | 12.8±0.4 | 0.535 |
| Diagnosis (n) | |||
| SV | 21 | 15 | 0.548 |
| PAIVS | 6 | 5 | 0.952 |
| DORV | 3 | 3 | 0.877 |
| TA | 1 | 2 | 0.430 |
| Post-BT shunt (n) | 11 | 14 | 0.125 |
| Post-Glenn (n) | 14 | 5 | 0.048 |
| Post-Fontan (n) | 6 | 6 | 0.674 |
| History of BT shunt (n) | 29 | 15 | 0.0024 |
| Medications | |||
| ACEI | 10 (32) | 7 (33) | 0.93 |
| β-blocker | 9 (31) | 5 (25) | 0.68 |
| Aortic root dimension (mm) | 19.9±0.8 | 16.1±0.8 | 0.001 |
| Aortic root dimension (% of normal) | 170.9±2.9 | 125.5±3.2 | <0.0001 |
Data given as mean±SD or n (%).
ACEI, angiotensin-converting enzyme inhibitor; BMI, body mass index; BT, Blalock-Taussig; DBP, diastolic blood pressure; DORV, double outlet right ventricle; PAIVS, pulmonary atresia with intact ventricular septum; SaO2, arterial oxygen saturation; SBP, systolic blood pressure; SV, single ventricle; TA, tricuspid atresia.
As shown in Figure A, PWV was significantly higher in the dilatation group than in the non-dilatation group (483.6±10.3 vs. 394.0±8.9 cm/s, P<0.001) after controlling for age and aortic pressure, factors known to influence PWV (P<0.001; analysis of covariance). Importantly, a strong positive correlation was noted between AOD and PWV, suggesting that increased arterial stiffness correlates with aortic root dilatation (r=0.76, P<0.001; Figure B). Multivariate analysis using age, sex, history of BT shunt and blood pressure, as well as PWV, as independent variables showed that only PWV correlated significantly with aortic root dilatation (P<0.001).
(A) Comparison of pulse wave velocity (PWV) between patients with dilated aorta (>150% of normal) and non-dilated aorta (<150% of normal). (B) Correlation between PWV and aortic diameter (AOD) normalized to the reference value.
To further assess whether aortic stiffness is a determinant of aortic dilatation, independent of aortic volume load, we carried out multivariate analysis with aortic flow volume added to the independent variables as an index of aortic volume load (25 pre-Glenn patients whose aortic volume flow was directly calculated). On univariate analysis, aortic flow volume had a positive correlation with AOD (r=0.62, P=0.003). In contrast, on multivariate analysis, only PWV had a significant positive correlation with AOD (P<0.001; Table 2).
| Independent variable | Coefficient | SE | P-value |
|---|---|---|---|
| PWV (cm/s) | 0.64 | 0.1 | 0.002 |
| Aortic flow (L·min–1·m–2) | 0.74 | 2.4 | 0.214 |
| Age (years) | 0.74 | 1.5 | 0.813 |
| BP (mmHg) | 0.69 | 0.4 | 0.176 |
BP, blood pressure; PWV, pulse wave velocity.
In clinical practice, aortic dilatation is often observed in patients with SiV circulation and causes significant aortic regurgitation that could adversely affect outcome of patients with Fontan circulation, a surgical goal in SiV patients.17 The present study has shown for the first time that an altered aortic wall property, which is consistent with a previous report of abnormal aortic medial histopathology,5 might contribute to aortic root dilatation independent of aortic volume load in patients with SiV circulation.
Progressive aortic dilatation has been well recognized in Marfan syndrome, and is an important clinical problem in the affected patients.18,19 This has also been observed in specific types of CHD such as bicuspid aortic valve5 and TOF,1 and the pathophysiology of these cardiac abnormalities has been investigated extensively.1,5–12 Importantly, these 3 diseases have the common feature of aortic medial pathology characterized by medial degradation that could weaken and stiffen the aortic wall.5,6,19 Indeed, a number of studies have reported increased aortic stiffness and its significant effect on aortic dilatation in these diseases.7–12 In agreement with these previous observations, the present study adds new data showing that aortic medial pathology may also be implicated in the mechanism of aortic dilatation observed in patients with SiV physiology. The increased aortic stiffness observed in the present SiV patients is consistent with data from an important study by Niwa et al, who showed that abnormal aortic medial histopathology, characterized by elastic fiber disruption, was observed in patients with SiV physiology analogous to that of the present patients, including double-outlet right ventricle, single ventricle, or tricuspid atresia.5 The importance of medial elastic fibers in preserving aortic elasticity has been clearly demonstrated in both animal and human studies.19,20 Thus, aortic wall stiffness measured by PWV may be useful as a surrogate marker of aortic medial pathology in patients with SiV.
Increased aortic stiffness, possibly reflecting aortic medial degradation, suggests an abnormal load-bearing capacity of the aorta. Consistent with this notion, increased aortic stiffness was an independent determinant of aortic dilatation in the present cohort of SiV patients. Importantly, according to the Moens-Korteweg equation, PWV increases as vessel diameter decreases and as the vessel elastic modulus (wall stiffness) increases.21 Therefore, the observed association between PWV and AOD, which is the inverse of that described by the Moens-Korteweg equation, strongly suggests a close link between aortic medial pathology (wall stiffening) and increased PWV, as well as an important role of aortic stiffening (increased PWV) in aortic dilatation in patients with SiV circulation.
In addition to aortic medial pathology, volume load on the aortic wall has been suggested as another important cause of the aortic dilatation observed in TOF.1 The present study also supports this possibility because a history of BT shunt, which could cause aortic volume load, was observed more frequently in patients with a dilated aorta, and because there was a significant correlation between aortic flow volume and AOD in subgroup analysis. On multivariate analysis, however, only aortic stiffness correlated with aortic dilatation in the present SiV circulation patients (Table 2). While the results further support the importance of aortic medial pathology in aortic dilatation, because of the limited number of patients studied, the pathophysiologic importance of aortic volume load needs to be elucidated in further studies (on the basis that volume load on the weakened aortic wall could help accelerate aortic dilatation).
The present study has several limitations. First, although the study hypothesis relied on the assumption that increased PWV reflects abnormal medial histopathology, there is no evidence that the present SiV circulation patients had any histological abnormalities. Second, studies of aortic medial histology and mechanical properties in TOF indicated that those abnormities are intrinsic because aortic medial degradation and increased stiffness were observed as early as a few days after birth.6,11 Whether changes in aortic mechanical properties in SiV patients are also intrinsic is worth investigation. In addition, aortic stiffness was increased in some but not all of the present SiV patients. Therefore, factors that cause aortic medial changes, including genetic background or disease specificity, need to be elucidated in future studies. In this regard, the blood lipid profile, which was not measured in this study, may also be an important determinant of aortic stiffness. The time course of aortic dilation and the critical time point, if it exists, when the dilation becomes a clinical problem remain to be elucidated. In addition, although the present study suggests a causative role of increased aortic stiffness in aortic root dilatation, this possibility should be confirmed by prospective studies investigating whether aortic stiffness precedes aortic dilatation and whether medical interventions that potentially ameliorate medial degradation, such as angiotensin type 1 receptor blockade,1,22 affect aortic stiffness and the associated clinical course of aortic dilatation. Finally, because most studies on aortic dilatation in TOF measured aortic root diameter at the sinotubular junction,1,6–11 we used the same methodology to ensure consistency and ease of comparison. The size of the aorta at the sinuses of Valsalva, however, may be more clinically relevant because the most important clinical problem associated with aortic root dilatation may be aortic regurgitation rather than aortic dissection/rupture. In this regard, 1 study that measured aortic size at both the sinuses of Valsalva and the sinotubular junction identified a very similar trend in changes between the 2 measurements,7 suggesting that the results would have been similar if aortic size had been measured at the sinuses of Valsalva instead of at the sinotubular junction.
In agreement with a finding of abnormal aortic medial histopathology in CHD patients with SiV circulation, aortic stiffness was increased and significantly associated with aortic dilatation. Because preservation of ventricular function is a key issue in establishing and maintaining good Fontan circulation,23,24 further studies to define the causative role of aortic stiffening and other potential factors in the development of aortic dilatation may provide important clinical information that could help reduce the progression of aortic dilatation and resultant aortic regurgitation.
We thank our colleagues at Saitama Medical University who performed catheterization and surgery.
