Experimental Study of Nonpulsatile Flow Perfusion and Structural Remodeling of Pulmonary Microcirculation Vessels

Abstract

Objective: The aim of the study was to investigate whether functional changes and structural remodeling occurs in the microvascular bed of the pulmonary circulation under nonpulsatile flow perfusion. Materials and Methods: An animal model of unilateral nonpulsatile flow in the right lung was established in dogs. Streptavidin-biotin enzyme complex (SP method) was used to detect the expression of endothelial nitric oxide synthase (eNOS) in vascular endothelial cells and the apoptosis-related protein Fas in smooth muscle cells of the pulmonary artery of both lungs, and structural changes of the arterioles in the capillary bed of both lungs were observed under light microscope. Results: eNOS expression in right lung arterioles with nonpulsatile flow perfusion was significantly lower than in the left lung (10 846.7 ± 177.8 vs. 13 136.1 ± 189.6; t = 2.24, p < 0.05). Expression of the apoptosis-related protein Fas in smooth muscle cells of the arteriole of the right lung was significantly higher than in the left lung (14 254.1 ± 217.1 vs. 11 976.7 ± 195.7; t = 2.16, p < 0.05). Image analysis of pulmonary arterioles showed that the ratio of vascular wall thickness and the external vessel diameter (13.64 % ± 12.8 % vs. 14.96 % ± 13.1 %) and the ratio of vascular wall area and the total vessel area (46.4 % ± 11.7 % vs. 47.8 % ± 12.2 %) of the right lung were significantly lower than in the left lung. Conclusions: Long-term nonpulsatile flow perfusion of the Fontan circulation can decrease the synthesis of eNOS in endothelial cells of the pulmonary vessels, increase the apoptosis of smooth muscle cells of the arteriole wall, and lead to arterial venous conversion and pulmonary vessel remodeling.

Key words

cardiovascular surgery - heart disease - cardiomyopathy - congenital heart disease - pulmonary artery - endothelium - Fontan circulation - endothelial nitric oxide synthase (eNOS) - apoptosis

References

• 1 Fujii Y, Sano S, Kotani Y et al. Midterm to long-term outcome of total cavopulmonary connection in high-risk adult candidates.  Ann Thorac Surg. 2009;  87 (2) 562-570
• 2 Kim S J, Kim W H, Lim H G, Lee J Y. Outcome of 200 patients after an extracardiac Fontan procedure.  J Thorac Cardiovasc Surg. 2008;  136 (1) 108-116
• 3 Kirklin J K, Brown R N, Bryant A S et al. Is the “perfect Fontan” operation routinely achievable in the modern era?.  Cardiol Young. 2008;  18 (3) 328-336
• 4 Khairy P, Fernandes S M, Mayer Jr J E et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery.  Circulation. 2008;  117 (1) 85-92
• 5 Vasků J, Wotke J, Dobsák P et al. Acute and chronic consequences of non-pulsatile blood flow pattern in long-term total artificial heart experiment.  Pathophysiology. 2007;  14 (2) 87-95
• 6 Malhotra S P, Reddy V M, Thelitz S et al. The role of oxidative stress in the development of pulmonary arteriovenous malformations after cavopulmonary anastomosis.  J Thorac Cardiovasc Surg. 2002;  124 (3) 479-485
• 7 Ostrow A M, Freeze H, Rychik J. Protein-losing enteropathy after Fontan operation: investigations into possible pathophysiologic mechanisms.  Ann Thorac Surg. 2006;  82 (2) 695-700
• 8 Chiu J J, Chen L J, Lee C I et al. Mechanisms of induction of endothelial cell E-selectin expression by smooth muscle cells and its inhibition by shear stress.  Blood. 2007;  110 (2) 519-528
• 9 Busse R, Fleming I. Vascular endothelium and blood flow.  Handb Exp Pharmacol. 2006;  176 (Pt 2) 43-78
• 10 Presson jr. R G, Baumgartner jr. W A, Peterson A J, Glenny R W, Wagner jr. W W. Pulmonary capillaries are recruited during pulsatile flow.  J Appl Physiol. 2002;  92 (3) 1183-1190
• 11 Lee J J, Tyml K, Menkis A H, Novick R J, Mckenzie F N. Evaluation of pulsatile and nonpulsatile flow in capillaries of goat skeletal muscle using intravital microscopy.  Microvasc Res. 1994;  48 (3) 316-327
• 12 Tuttle J L, Nachreiner R D, Bhuller A S et al. Shear level influences resistance artery remodeling: wall dimensions, cell density, and eNOS expression.  Am J Physiol Heart Circ Physiol. 2001;  281 (3) H1380-H1389
• 13 Dajnowiec D, Sabatini P J, Van Rossum T C et al. Force-induced polarized mitosis of endothelial and smooth muscle cells in arterial remodeling.  Hypertension. 2007;  50 (1) 255-260
• 14 Tuchscherer H A, Vanderpool R R, Chesler N C. Pulmonary vascular remodeling in isolated mouse lungs: effects on pulsatile pressure-flow relationships.  J Biomech. 2007;  40 (5) 993-1001
• 15 Sakamoto N, Ohashi T, Sato M. Effect of fluid shear stress on migration of vascular smooth muscle cells in cocultured model.  Ann Biomed Eng. 2006;  34 (3) 408-415
• 16 Wang H Q, Huang L X, Qu M J et al. Shear stress protects against endothelial regulation of vascular smooth muscle cell migration in a coculture system.  Endothelium. 2006;  13 (3) 171-180
• 17 Nawa S, Irie H, Takata K, Sugawara E, Teramoto S. Development of a new experimental model for total exclusion of the right heart without the aid of cardiopulmonary bypass.  J Thorac Cardiovasc Surg. 1989;  97 (1) 130-134
• 18 Kaku K, Matsuda H, Kaneko M et al. Experimental complete right heart bypass. Proposal of a new model and acute hemodynamic assessment with vasoactive drugs in dogs.  J Thorac Cardiovasc Surg. 1990;  99 (1) 161-166
• 19 Cloutier A, Ash J M, Smallhorn J F et al. Abnormal distribution of pulmonary blood flow after the Glenn shunt or Fontan procedure: risk of development of arteriovenous fistulae.  Circulation. 1985;  72 (3) 471-479
• 20 Premsekar R, Monro J L, Salmon A P. Diagnosis, management, and pathophysiology of post-Fontan hypoxaemia secondary to Glenn shunt related pulmonary arteriovenous malformation.  Heart. 1999;  82 (4) 528-530