矯正後之法洛氏四重症患者長期功能預後之研究

Long-Term Functional Outcomes in Patients with Repaired Tetralogy of Fallot

陳俊安(Chun-An Chen)

指導教授 ： 吳美環

共同指導教授 ： 何奕倫(Yi-Lwun Ho)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2013年)

https://doi.org/10.6342/NTU.2013.00277

摘要

背景
法洛氏四重症是最常見的發紺性先天性心臟病。隨著手術技術以及臨床照護的進步，超過百分之九十的患者在接受手術矯正後可以順利存活，並長大成人。然而，隨著術後追蹤時間的增加，這群患者逐漸出現一些功能性預後上的侷限，包括心臟功能、運動功能、以及心理社會功能方面的種種問題。這些問題對醫療照護者與病患本身而言，往往是充滿了挑戰的難題。過去的研究指出，法洛氏四重症矯正後右心室纖維化是很常見的現象。雖然在左心室纖維化的疾病中，血清膠原蛋白代謝相關的生物標記所扮演的角色已相當明朗，但對於以右心室纖維化為主的法洛氏四重症之相關研究，在本研究開始之初仍付之闕如。因此在本論文第一部分的研究中，我們試圖檢視血清中第一型膠原蛋白代謝相關的生物標記之表現模式，並進一步探討其臨床意義。法洛氏四重症術後的心臟功能一向都是臨床研究的重點之一。在過去臨床的觀察中，我們發現到術後若合併有輕度右心室出口狹窄，似乎反而對心臟功能有幫助。因此，在本論文第二部分的研究中，我們以心臟核磁共振以及心肺運動功能測試的量化數據來驗證這個觀察的真實性，並試圖解釋其背後的原因。這群患者除了需面對與心臟功能及運動功能相關的醫療問題，其實還面臨到心理社會層次的挑戰，而其中有許多是牽涉到生活品質方面的課題。在本論文第三部分的研究中，我們針對法洛氏四重症術後的患者，以及其他成人期先天性心臟病的病患進行生活品質相關問題的評估，試圖探討臨床心臟功能對於生活品質所造成的影響，以及其他可能影響生活品質的重要因素，包括生理、心理、以及社會各方面的可能因素。

研究方法與結果
第一部分：血清膠原蛋白代謝相關的生物標記的臨床意義
我們納入了70位法洛氏四重症術後的患者，以及91位性別與年齡匹配的健康對照組，測定血清中第一型膠原蛋白之生成指標(carboxy-terminal propeptide of procollagen type I, PICP)，分解指標(carboxy-terminal telopeptide of collagen type I, CITP)，以及調控膠原蛋白分解之酵素(matrix metalloproteinases, and type I tissue inhibitor, TIMP-1)濃度。所有患者皆接受了心臟核磁共振合併晚期釓強化顯影(late gadolinium enhancement)。相較於對照組，患者的PICP濃度(P < 0.001)、PICP:CITP的比例(P < 0.001)、以及TIMP-1的濃度(P < 0.001)明顯較高。 PICP的濃度越高，右心室晚期釓強化顯影越廣泛(r = 0.427，P < 0.001)，最大攝氧量越低(r = -0.428，P = 0.002)，而且右心室擴大的現象越明顯。進一步使用多變數線性迴歸分析發現，與血清中PICP濃度有關聯的獨立因子包括右心室舒張末期容積指數 > 150 mL/m2 (β = 40.52，P = 0.016)、右心室晚期釓強化顯影計分(β = 3.94，P = 0.008),、以及年齡(β = −1.77，P = 0.011)。若以病情符合肺動脈瓣植入作為依變項進行多變數分析，血清中PICP濃度越高，在收案當下出現臨床病況符合肺動脈瓣植入條件的機會也越高(odds ratio 1.80 per 10 ng/mL，P = 0.003)。而Kaplan-Meier存活分析結果更顯示，在平均追蹤了3.7年後，血清中PICP濃度異常升高的患者(以對照組血清中PICP濃度的第九十百分位數值作為切點，102.7 ng/mL)在未來需要接受肺動脈瓣植入手術的風險的確明顯升高 (log-rank test P = 0.005)。
第二部分：顯著肺動脈瓣逆流合併右心室出口狹窄對於心室重塑與運動功能的影響
在本院資料庫中，共有155位法洛氏四重症術後的患者曾在間隔六個月以內，同時接受過心臟核磁共振造影以及心肺運動功能測試。排除殘存有顯著的血循異常(除了肺動脈瓣逆流及右心室出口狹窄)、全矯正至研究期間曾接受過介入性心血管治療、或運動測試中未盡全力的患者後，共有85位患者符合本研究的收案標準(肺動脈瓣逆流分率 ≥ 20%且右心室出口狹窄最大壓力差以心臟超音波測量 ≤ 50 mmHg)。這85位患者中有29位同時合併輕度的右心室出口狹窄(右心室出口狹窄最大壓力差 ≥ 20 mmHg)，其餘56位則僅有肺動脈瓣逆流(右心室出口狹窄最大壓力差 < 20 mmHg)。在這兩組患者的肺動脈瓣逆流分率並無差異的前提下，同時有肺動脈瓣逆流與右心室出口狹窄者的右心室明顯比僅有肺動脈瓣逆流者來的小，右心室射出分率也比較高(42.3±6.7 vs 38.8±5.9%，P = 0.016)。即使兩組患者中皆有約一半的病患出現右心室出口的瘤狀膨出(aneurysm)，合併右心室出口狹窄者的右心室出口擴大程度明顯較小(右心室出口直徑Z分數−0.57±1.35 vs 0.46±1.10，P < 0.001)。雖然在單變數線性迴歸分析中，存有輕度右心室出口狹窄與右心室舒張末期容積指數以及右心室射出分率有關，但在多變數分析後，輕度右心室出口狹窄似乎是透過較小的右心室出口直徑而影響右心室的重塑。在運動功能方面，肺動脈瓣逆流合併右心室出口狹窄者表現出較高的最大攝氧量預期值的百分比(75.5±12.5 vs 66.7±12.7%，P = 0.003)以及較佳的攝氧效率斜率預期值的百分比(90.9±27.1 vs 73.4±16.3%，P < 0.001)。在多變數分析中，右心室出口狹窄對於最大攝氧量預期值之百分比(β = 7.29，P = 0.007)以及攝氧效率斜率預期值之百分比(β = 12.62，P = 0.003)皆有顯著且獨立的正向影響。
第三部分：法洛式四重症矯正後患者的生活品質
我們在本院門診針對連續138位法洛氏四重症矯正後的成人患者收案(年齡31.4±10.1歲；46%是男性)，進行生活品質的評估。使用的問卷是世界衛生組織簡化之台灣版生活品質問卷(評估生理、精神、社會、與環境等四個範疇)。研究結果發現，女性患者在生理範疇(P < 0.001)以及精神範疇(P = 0.003)的生活品質明顯較一般女性來的低落，而此現象在男性患者身上並未發現。這其中有92位患者在完成生活品質評估後接著馬上進行心肺運動功能測試。我們發現患者在測試前的自我預測體能表現與其整體生活品質滿意度幾乎無法預測患者實際接受心肺運動功能測試的結果。而任何一個範疇的生活品質也都與影像學上的心臟功能指標沒有相關性(n = 78)。我們進一步將研究對象擴展到所有的成人期先天性心臟病，除了探討可能的性別差異外，並透過更詳細的資料收集試圖找出影響生活品質的重要生理、心理、以及社會因素。在289位收案患者中(其中105位是男性)，我們發現在生理與心理範疇的生活品質之性別差異一樣可以在此族群中發現，顯示此現象不是法洛氏四重症患者所特有。性別因素(女性)在多變數迴歸分析中與生理範疇生活品質低落有顯著相關，而性別在精神範疇生活品質中所引致的差異應是透過性別在精神症狀壓力上的不同。交互作用分析進一步發現家庭支持對於精神範疇生活品質的影響也具有性別差異。雖然個別生活品質範疇的決定因素不一，但個人的人格特質、精神症狀嚴重度、以及家庭支持對大部分的範疇而言都扮演著重要的角色。

結論
我們發現法洛氏四重症術後患者心肌纖維化之現象，一方面是因為第一型膠原蛋白的生成過度，另一方面是則是因為相關酵素特異的表現造成分解調控異常。血清中PICP濃度的升高不但反映出右心室纖維化的嚴重度，更與臨床上的不良預後有密切關聯。此外，透過心臟核磁共振造影以及心肺運動功能測試的量化數據，本論文研究證實了一個長期以來所觀察到的現象：在肺動脈瓣逆流嚴重的患者中，同時合併有輕度的右心室出口狹窄對於右心室重塑以及運動功能皆有正面的影響。而在心理社會功能方面，我們發現法洛氏四重症術後的女性患者，乃至於整個成人期先天性心臟病族群的女性患者，在生理以及精神範疇的生活品質明顯較一般女性來的差，而男性患者卻沒有此現象。主觀的生活品質以及自我預測之運動能力無法有效反映實際上的心臟功能及運動功能。疾病相關因素對生活品質的影響遠不及患者自身的人格特質、精神症狀、以及家庭支持。總之，法洛氏四重症術後的長期功能性預後有很大的個別差異。在追蹤這群患者時，必須運用多面向的量化性評估工具，方能發現若干功能初期減退的現象，並應透過各種預後因子進行患者之風險分級，進而提供適切的醫療與非醫療之介入。

關鍵字

生物標記 ； 心臟纖維化 ； 心肺運動功能測試 ； 心臟核磁共振 ； 生活品質 ； 矯正後之法洛氏四重症

並列摘要

Background
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. With the advances in surgical techniques and medical care, over 90% of the patients could survive to adulthood, resulting in progressive increase in the prevalence of TOF in adults. However, patients with repaired tetralogy of Fallot (rTOF) pose unique challenges for medical professionals since these patients are at increased risk for long-term functional deficits regarding to cardiac function, exercise function, and psychosocial function. Previous studies have demonstrated that right ventricular (RV) fibrosis is common in rTOF patients. Although accumulating evidence indicates the role of circulating biomarkers of collagen metabolism in left ventricular fibrosis, such data in rTOF are lacking. In the first part of this thesis, we examined the expression profile and clinical relevance of circulating biomarkers of collagen type I metabolism in rTOF patients. As to exercise function, we have little evidence regarding to the relationships between types of ventricular remodeling and exercise performance. In the second part of this thesis, we sought to use quantitative data from cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPX) to examine the relationship between types of ventricular remodeling and exercise performance. We also examined our longstanding observation: rTOF patients with mild RV outflow tract (RVOT) obstruction tend to have better cardiac function. Aside from medical problems related to cardiac dysfunction and exercise intolerance, these patients also faced a new set of psychosocial challenges, including issues pertaining to quality of life (QoL). Therefore, in the third part of this thesis, we assessed the QoL in adults with rTOF, as well as in a cohort of adults with congenital heart disease (ACHD), and to explore the relationships between objective measurements of cardiac function and QoL, as well as potential biopsychosocial determinants of QoL.

Methods and Results
Part I: Circulating biomarkers of collagen type I metabolism in adults with rTOF
Serum biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I, PICP), degradation (carboxy-terminal telopeptide of collagen type I, CITP), and enzymes regulating collagen degradation (matrix metalloproteinases, MMP, and type I tissue inhibitor, TIMP-1) were measured in 70 rTOF patients (≥ 18 years) and 91 age- and sex-matched healthy adults. All patients had complete clinical data and received CMR with late gadolinium enhancement (LGE). Compared to the controls, rTOF patients had higher PICP levels (P < 0.001), PICP:CITP ratios (P < 0.001), and TIMP-1 concentrations (P < 0.001). MMP-9 level was lower in rTOF patients (P = 0.001). Increasing PICP levels correlated with higher RV LGE scores (r = 0.427, P < 0.001), lower peak oxygen consumption (the percentage of predicted peak VO2) (r = -0.428, P = 0.002), and significant RV dilatation. Furthermore, stepwise multivariate linear regression analysis identified RV end-diastolic volume index (RVEDVi) > 150 mL/m2 (β = 40.52, P = 0.016), RV LGE score (β = 3.94, P = 0.008), and age (β = -1.77, P = 0.011) as independent correlates of circulating PICP levels. Using multivariate logistic regression with fulfilling the indication for pulmonary valve replacement (PVR) as the outcome variable, higher serum PICP level significantly linked to the presence of PVR indication (odds ratio 1.80 per 10 ng/mL, P = 0.003) after B-type natriuretic peptide and right ventricular mass index were adjusted for. Furthermore, Kaplan-Meier survival analysis revealed that patients with high PICP level (higher than the 90th percentile value of the PICP concentrations in control subjects, 102.7 ng/mL) had significantly greater risk for receiving PVR (log-rank test P = 0.005) after a mean follow-up duration of 3.7 years.
Part II: Effect of mild RVOT obstruction on ventricular remodeling and exercise function in rTOF patients with significant PR
In our institutional database, 155 rTOF patients have ever received both CMR and CPX within 6 months. Patients with significant additional hemodynamic residuals other than pulmonary regurgitation/stenosis, having received cardiovascular intervention between total correction and study enrollment, and those with inadequate exercise effort were excluded. A total of 85 cases with a PR fraction ≥ 20% and a peak RVOT pressure gradient ≤ 50 mmHg (assessed by echocardiography) were enrolled in the following analysis. Although PR fraction was similar, patients with combined PR and mild RVOT obstruction (peak pressure gradient ≥ 20 mmHg but ≤ 50 mmHg, n = 29) had significantly better RV function than those with isolated PR (peak pressure gradient < 20 mmHg, n = 56): RVEDVi (median 115.5 vs 123.4 mL/m2, P = 0.029), RV end-systolic volume index (RVESVi) (median 66.7 vs 75.8 mL/m2, P = 0.011), and RV ejection fraction (42.3±6.7 vs 38.8±5.9%, P = 0.016). Patients with combined PR and RVOT obstruction also had smaller RVOT diameter Z score (−0.57±1.35 vs 0.46±1.10, P < 0.001) even though the prevalence of RVOT aneurysm was similar between these two patient groups. In multivariate analysis, the beneficial effect of RVOT obstruction on RV remodeling seemed to be mediated by smaller RVOT diameter rather than differences in RV hypertrophy or PR severity. Furthermore, patients with combined PR and mild RVOT obstruction exhibited better exercise performance as evaluated by the percentage of predicted peak VO2 (a maximal exercise parameter) (75.5±12.5 vs 66.7±12.7%, P = 0.003) and the percentage of predicted oxygen uptake efficiency slope (a submaximal exercise parameter) (90.9±27.1 vs 73.4±16.3%, P < 0.001). In multivariate analysis, we demonstrated positive and independent effect of mild RVOT obstruction on both the percentage of predicted peak VO2 (β = 7.29, P = 0.007) and the percentage of predicted oxygen uptake efficiency slope (β = 12.62, P = 0.003).
Part III: Quality of life in adults with rTOF
The QoL of 138 adults with rTOF (age: 31.4 ± 10.1 years; 46% men) was investigated using the Taiwanese version of the QoL questionnaire designed by the World Health Organization, which assesses 4 domains of QoL (physical, psychological, social, and environmental domains). Women with rTOF had significantly lower QoL scores in the physical and psychological domains compared to the age-matched general population, whereas such differences were not observed between rTOF men and the general population. A subset of patients (n = 92) received CPX immediately after the assessment of QoL and self-estimated exercise capacity. We found that self-estimated exercise capacity and QoL could hardly predict actual exercise capacity. Similarly, CMR-derived data of ventricular function (n = 78) and other disease-related variables had no relationships with QoL. We further evaluated 289 consecutive ACHD in our clinics. Personality, psychological distress, and family support were also assessed. We found that sex-related differences in QoL were also observed in this ACHD cohort, suggesting that sex discrepancy in QoL was not unique for rTOF. Multivariate analysis showed that female gender was associated with poorer physical QoL, and the sex difference in the psychological QoL was mediated by psychological distress. Interaction analysis revealed that the effect of family support on the psychological domain of QoL may be different by sex. The determinants of QoL varied between different domains. Extroversion personality trait, psychological distress, and family support were common determinants of most domains of QoL.

Conclusions
We demonstrated that patients with rTOF exhibited a profibrotic state with excessive collagen type I synthesis and dysregulated degradation. Elevated circulating PICP levels might reflect RV fibrosis, and link to adverse markers of clinical outcome. Utilizing quantitative data of CMR and CPX, our study results confirmed that mild RVOT obstruction was beneficial for RV function and exercise function in rTOF patients with significant PR. As to the psychosocial function, we found that female gender was associated with poor physical and psychological QoL, both in rTOF and overall ACHD population. Objective measurements of ventricular function and exercise function had little relationship with patients’ QoL and self-estimated exercise capacity. The common denominators for QoL were primarily personality trait, psychological distress, and family support but not disease-related factors. In summary, patients with rTOF exhibited a wide variety of functional outcomes. Multidisciplinary approaches using quantitative tools are mandatory to detect subtle changes in each functional aspect, and to stratify risks for unfavorable functional outcomes.

並列關鍵字

Biomarkers ； Cardiac fibrosis ； Cardiopulmonary exercise testing ； Cardiac magnetic resonance ； Quality of life ； Repaired tetralogy of Fallot

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