Pulmonary Vascular Sequelae of Palliated Single Ventricle Circulation: Arteriovenous Malformations and Aortopulmonary Collaterals
Abstract
:1. Introduction
2. Pulmonary Blood Flow in Single Ventricle Circulation: Basics
3. Pulmonary Arteriovenous Malformations
3.1. Basics
3.2. Clinical Assessment
3.3. Previous Research: Hepatic Factor Candidates
3.4. Previous Research: PAVM Pathophysiology
3.5. Emerging Data
4. Aortopulmonary Collaterals
4.1. Basics
4.2. Clinical Assessment
4.3. Previous Research: Clinical Significance of APCs
4.4. Previous Research: APC Pathophysiology
5. Future Directions
6. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study | Animal Model | Methods and Time Points | Results | Conclusions |
---|---|---|---|---|
Malhotra, Riemer, Thelitz, et al., 2001 [33] | Lamb Glenn and sham control, n = 12 each | Bubble echo at 8 weeks RNA and protein quantification (1, 2, 5, 15 weeks) | Reduced ACE activity and angiotensin II protein levels at 1, 2, and 5 weeks; no difference at 15 weeks | Early decrease in ACE and angiotensin II post-Glenn, potentially indicating decreased endothelial vasoconstriction after Glenn |
Malhotra, Reddy, Thelitz, et al., 2002 [34] | Lamb Glenn and sham control, n = 12 each | RNA and protein quantification (1, 2, 5, 15 weeks) | Increased angiotensin II receptor type 1 (AT1) and type 2 (AT2) RNA and protein (at 1, 2, and 5 weeks) | AT1 and AT2 are likely involved early in pathologic vascular remodeling after Glenn |
Malhotra, Reddy, Thelitz, et al., 2002 [35] | Lamb Glenn, PA band, and Sham control, n = 6 each | Bubble echo at 8 weeks Protein quantification (2 and 5 weeks) | Glenn and PA band increases angiogenic gene expression (VEGF-A, VEGFR1) Glenn (but not PA band or sham) increases stress-related genes (heme-oxygenase 1, GLUT1, HIF-1α, CD62) | Glenn circulation uniquely induces oxidative stress and may predispose to PAVMs |
Starnes, Duncan, Fraga, et al., 2002 [36] | Rat * n = 8 | Pulmonary angiography (2–13 months) Histology (13 months) | Increased microvessel density starting at 4–8 months Angiographic evidence of PAVMs starting at 11 months | Rat model recapitulates clinical PAVMs after Glenn |
Mumtaz, Fraga, Nicholls, et al., 2005 [37] | Rat * n = 3 | RT-PCR at 2, 8, and 12 months | Progressively increased VEGF-A gene expression over time | Possible role for VEGF in PAVMs |
Tipps, Mumtaz, Leahy, Duncan, 2008 [38] | Rat * n = 6 | RNA microarray at 8 months | Multiple affected pathways: - angiogenesis (angiopoietin-2, placental growth factor, tip cell markers) - matrix remodeling (matrix metalloproteinases, collagen subtypes) - vascular tone (endothelin 1, endothelin receptor B) | Diverse signaling pathways are altered at the 8-month time-point |
McMullan, Reddy, Gottliebson, et al., 2008 [39] | Lamb * n = 40 | Bubble echo (0–27 weeks) Morphologic inspection and vascular casting (2–27 weeks) | Positive bubble studies starting at 5 weeks Dilated and tortuous subpleural vessels arising from bronchial arteries (i.e., APCs) Multiple direct arteriovenous connections (minimal diameter 15–20 µm) visualized with casting | All animals develop intrapulmonary shunting on echo by 6 weeks Central PAVMs bypass alveolar capillaries and have diameter ≥ 15 µm Surface APCs develop separately from PAVMs |
Kavarana, Mukherjee, Eckhouse, et al., 2013 [40] | Pig * n = 5 | Bubble echo Isolated PAEC at 6–8 weeks | Positive bubble studies Comparing right PAECs vs left PAECs: Increased proliferation, tube formation, and gene expression of angiopoietin-1 and TIE2 | Pig model PAVMs detectable by bubble echo Multiple changes in PAEC phenotype and gene expression |
Study | Method for APC Quantification | Study Size | Results | Conclusions |
---|---|---|---|---|
Ichikawa, Yagihara, Kishimoto, et al., 1995 [47] | Direct flow measurement on cardio-pulmonary bypass during Fontan palliation | n = 33 | APC flow: 6–55% of total pump flow Greater APC flow associated with increased post-Fontan systemic venous pressures (p < 0.01) | High APC flow is a risk factor for Fontan operation |
Spicer, Uzark, Moore, et al., 1996 [60] | Angiography during pre-Fontan catheterization Graded on 4-point scale | n = 71 | 60/71 (84.5%) patients had APCs visualized angiographically Higher APC grade is associated with more prolonged pleural chest tube drainage APC occlusion is associated with shorter duration pleural drainage | APCs increase the risk for prolonged pleural effusions post-Fontan “Significant” APCs should be occluded at pre-Fontan catheterization |
McElhinney, Reddy, Tworetzky, et al., 2000 [61] | Angiography during pre-Fontan catheterization Binary classification (APCs present or absent) based on angiographic criteria | n = 76 with previous Glenn palliation | APCs were identified in 49/76 (59%) of patients after Glenn palliation and 22/43 (51%) after Fontan Duration of chest tubes post-Fontan was shorter in patients with identified APCs (8 ± 6 vs 19 ± 15 days, p = 0.007) Patients with APCs identified were more likely to have pulmonary arterioplasty with Fontan (67% vs 24%, p = 0.04) | APCs were not associated with worse post-Fontan outcomes Paradoxically, APCs identified angiographically were associated with better outcomes |
Bradley, McCall, Sistino, et al., 2001 [48] | Direct flow measurement on cardio-pulmonary bypass during Fontan palliation | n = 32 | APC flow: 9–49% (median 19%) of total pump flow APC flow (3 control patients): 0.5–1.4% of total pump flow Greater APC flow had no effect on post-op Fontan pressure, atrial pressure, transpulmonary gradient, duration of pleural effusions, or resource utilization post-Fontan | APCs are universal but a degree of APC flow varies widely APC flow does not impact Fontan outcomes, but results may not be generalizable to higher-risk Fontan candidates |
Odenwald, Quail, Giardini, et al., 2012 [63] | Pre-Fontan MRI | n = 65 | Greater APC flow associated with increased post-Fontan chest drain volume (p = 0.001), chest drain duration (p = 0.005), ICU LOS (p = 0.04), hospital LOS (p = 0.048) | Increased APC flow is strongly associated with adverse early post-Fontan outcomes independent of conventional risk factors |
Glatz, Rome, Small, et al., 2012 [55] | Pre-Fontan MRI | n = 44 | APC flow: 31 ± 11% (Qs), 44 ± 15% Qp APC flow associated with hospital admission ≥ 7 days (OR = 9.2, p = 0.02) and chest tube duration ≥ 10 days (OR = 22.7, p = 0.009) | Increased APC flow is associated with increased post-Fontan hospitalization and chest tube duration |
Grosse-Wortmann, Drolet, Dragulescu, et al., 2012 [54] | Pre-Fontan MRI | n = 33 | APC flow: 35 ± 12% (Qs), 43 ± 13% Qp Greater APC flow associated with greater duration of hospital stay (p = 0.02) and pleural drainage (p = 0.03) | Increased APC flow is associated with adverse early post-Fontan outcomes |
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Spearman, A.D.; Ginde, S. Pulmonary Vascular Sequelae of Palliated Single Ventricle Circulation: Arteriovenous Malformations and Aortopulmonary Collaterals. J. Cardiovasc. Dev. Dis. 2022, 9, 309. https://doi.org/10.3390/jcdd9090309
Spearman AD, Ginde S. Pulmonary Vascular Sequelae of Palliated Single Ventricle Circulation: Arteriovenous Malformations and Aortopulmonary Collaterals. Journal of Cardiovascular Development and Disease. 2022; 9(9):309. https://doi.org/10.3390/jcdd9090309
Chicago/Turabian StyleSpearman, Andrew D., and Salil Ginde. 2022. "Pulmonary Vascular Sequelae of Palliated Single Ventricle Circulation: Arteriovenous Malformations and Aortopulmonary Collaterals" Journal of Cardiovascular Development and Disease 9, no. 9: 309. https://doi.org/10.3390/jcdd9090309