The Effects Of Nonpulsatile Flow After Fontan Operation On Pulmonary Microvascular Circulation

The Fontan operation has been shown to benefit patients with a single functioning ventricle and low pulmonary resistance. It is proposed to separate the systemic venous and arterial circulation by means of direct anastomosis between the vena cava and the pulmonary arteries. Its outcome is highly dependent on several risk factors, chief of which is pulmonary vascular resistance. Some patients have a poor outcome even when clinical and hemodynamic parameters indicate that conditions for the Fontan procedure are ideal. The Fontan operation leads to loss or severe attenuation of pulsatile pulmonary blood flow. Pulsatile flow is important for shear stress-mediated release of endothelium-derived nitric oxide and lowering of pulmonary vascular resistance by passive recruitment of capillaries. Even though exogenous NO has been used therapeutically to reduce pulmonary vascular resistance and improve cardiac output in early postoperative states after Fontan operation, Several disadvantages regarding nonpulsatile or decreased pulsatile pulmonary flow after the BCPS have been reported, as well as the importance of flow pulsatile in both globe and microvascular pulmonary circulation. Previous experiment studies have shown pulmonary vascular resistance to be significantly elevated and lung water content to be increased with nonpulsatile pulmonary flow. Few reports, however, confirm sequelae caused by nonpulsatile pulmonary flow in the clinical setting, that is, in patients after TCPC.Part Ⅰ The clinical follow up study of extracardiac total cavopulmonary connectionObject: Follow-up the patients after TCPC, to study the relationship between some complications and bioactive peptidesMethod: Since 1990, 34 patients have undergone extracardiac TCPC. Male 17cases, female 17cases. The average age is 10.9 ± 6.2 years. Of them, TA 11 cases, MA 1 case, DIRV 10 cases, DORV 9 cases, TGA 3 cases. 10 cases had hydrothorax. 4 early deaths because of low cardiac output (2), cardiac arrest (1) and can not break away from bypass unit. 2 late deaths because of refractoriness hydrothorax and hypoproteinemia.Results:a. Plasma level of ET-1 is significantly higher in the early period in patients undergoing extracardiac TCPC than the control, and return normal in followed-up period. ET-1 has a positive correlation with PVR (r= 0.90, P<0.05), and a negative correlation with CI (r= -0.91, P<0.05).b. ANP in experimental group were significantly lower on first day after the operation (t=2.623 P<0.01) ; in study group, 7 patients had complications of hydrothorax, and its ANP levels were significantly lower than other 11 patients in the early post-operative period (P<0.05 ) .c. At the early stage of the postoperative period plasma level of TXA2, PGI2 are significantly higher in two groups, then the TXA2 in both groups and PGI2 in control group all decreased continuously, at the sixth month after the operation, they are all lower than the preoperative period. But PGI2 in study group increased continuously after the operation, and the ratio of TXA2/ PGI2 decreased continuously, till 6 months they were remarkbly lower than the control group (r=3.06; p<0.01).d. select the dosage of hydrothorax drainage as the dependent variable; and select the age, Nakata index, ejection fraction, artificial blood vessel's diameters, mean pulmonary artery pressure and central venous pressure as the independent variables; Create the multi-linear regression. Measure endothelin-1 (ET-1) and calcitonin-gene-related peptide (CGRP) in 1st, 3rd, 5th, 7th day after the operation. The drainage increased progressively with the increase of CVP. (Hypothesis testing of regression equation f=685.600, p<0.01. Regression equation F=0.598x-3.430, r=0.985, r2=0.970). CVP has a positive correlation with ET-1 r=0.982, P<0.05; and has a negative correlation with CGRP, r = -0.986, P<0.05.e. After inhaled NO, PaO2/FiO2 increased from 161 ± 17 to 193 ±23, t=2.75, P<0.01; CI from 2.86±0.24 to 3.13 ± 0.22, t=2.25, P<0.05;PVR decreased from 4.22 ±0.53 to 3.75 ±1.43, r=2.29, P<0.05; CVP from 17±1.8 to 15±1.1, decreased 11.7%. Compare with the control group, respirator time decreased from 86±27h to 54± 18h, t= 2.29, P<0.05; ICU time from 6 ± 2d to 4±2d, r=2.32, P<0.05; But hydrothorax drainage and length of stay has no significant difference.f. The blood perfusion in both lungs is higher in postoperation than the preoperation. The ratio of right to left lung perfusion has no statistic difference after the operation, but it can obstain the righ lung dominant perfusion in right group, R(right/left)=1.15 ± 0.19. An abnormal increased upper to lower lobe perfusion ratio in follow-up period was found than in the early stage after the operation, in right group R(upper/lower)=0.94 ± 0.17 t=1.92 P<0.05; in left group R(upper/lower) = 0.92 t=1.97 p<0.05. Analyze the bivariate correlations between half lung radionuclide counts and PAI, Pearson correlation r=0.748, p<0.01.Conclusion:a. The Anoxia amelioration and the non-pulsatile blood flow in pulmonary circulation may increase the section of ET-1, an decrease the secretion ratio of TXA2/PGI2; this may have some effects on pulmonary vascular resistance (PVR), and may affect the patients' early postoperative recovery. The release of ANP can be suppressed in patients undergoing total cavopulmonary connection. The impairment of this response in the early postoperative period may have some correlations with hydrothorax complications.b. On the premise of strictly grasps of the accommodation, high pressure of CVP is the independent risk factor leading to hydrothorax. And the excretion derangement of ET-1 and TXA2 on the early period of post operation may be causes of high pressure of CVP and will result in hydrothorax.c. Though Inhaled nitric oxide has no significant long-term effects on patients after TCPC, but it may play an important role in the management of low cardiac output syndrome and high cava pressure caused by reactive elevated pulmonary vascular resistance in the early postoperative period after TCPC.d. Both lungs can have more blood perfusion after the ETCPC. The right lung dominant perfusion can be obtained with IVC deviating to theright side. But the blood distribution may mainly be determined by the development of pulmonary vascular tone and the resistance. The abnormal distribution of pulmonary blood flow to the upper lung segment develops in patients after the Fontan procedure, and the hypostasis pulmonary congestion may be responsible for this perfusion abnormality.Part Ⅱ Experimental study of nonpulsatile flow on pulmonary vascular endothelial cellThe vascular endothelium is known to play a crucial role in the local regulation of pulmonary vascular tone and in smooth muscle cell function. The vascular endothelium produces and releases a variety of substance. Among them, nitric oxide is a potent endothelium-derived vasorelaxant that prevents the proliferation of smooth muscle cells. Endothelin- 1 is also a potent endothelium-derived peptide with vasoconstrictive and mitogenic properties. We postulate that the pulmonary microcirculation was involved in the Fontan circulation. To support this hypothesis, we attempted to determine whether the structure of the pulmonary arteries or endothelial expression of vasoactive substances were altered under the long term of nonpulsatile blood flow.Objection: To study the long effects of Fontan circulation on pulmonary microvascular.Methods: Adult mongrel dogs weighing 25-30 kg (n=20) were anesthetized. Ligated the azygous vein. After systemic heparinization (1mg/kg), venous cannulation was performed with 28F venous cannulas between SVC and right atrial appendage. Transected the proximal SVC, closed the proximal part of right atrial appendage, placed two cross-clamps on the proximal and distal part of the right pulmonary artery. Anastomosed the SVC end to side to the right pulmonary artery. Released the clamp and ligated the proximal part of the right pulmonary artery. Then the right thoracotomy was closed with a drainage tube. This new chronic animal model is to anastomosis superior vena cava with right pulmonary artery directly, and ligated proximal right pulmonary artery without the aid of the cardiopulmonary bypass technique. The blood from superior vena cava can perfuse right lung with nonpulsatile flow; and the blood from inferior vena cava perfuse left lung with pulsatile flow. 3 month after the operation, aftermedian sternotomy, blood samples were obtained from SVC, IVC, right and left pulmonary vein, and the biopsy specimen were taken from the left and right lung, and study the pulmonary microvascular with immunohistrochemistry and histomorphometric. Results:a. Histomorphometric study: In each biopsy specimen the pulmonary vascular structure was analyzed by using quantitative morphometric techniques.11 12 13. Pulmonary arterial muscularity was assessed by determining the mean percentage arterial medial thickness of at least 40 arteries in different size ranges. Right lung exhibited abnormal distal intra-acinar pulmonary arteries (external diameter < 50 μm), the mean percentage wall thickness of the distal pulmonary arteries was markedly decreased (13.64±12.8%, P<0.05).b. Immunohistochemical Study: In the right lung, eNOS reactivity was higher in the pulmonary arteries(13136.1 ± 189.6, P<0.05) and mainly observed in endothelial cells of the distal muscular pulmonary arteries and capillaries. There was a good correlation between the histomorphometric and immunohistocheniial result (r=0.87, P<0.05).c. ET-1 Immunostaining: In right lung, ET-1 reactivity was weaker (11011.1 ± 197.1, P<0.05). There was a good correlation between the histomorphometric and immunohistochemial result (r=0.89, P<0.05 ) .d. In right lung, VEGF reactivity was weaker (13121.1 ± 192.6, P< 0.05) . fas reactivity was weaker (14254.1 ±217.1, P<0.05) . fas-L reactivity was weaker (14396.1±223.3, P<0.05) .Conclusion: The Fontan operation has been applied for the correction of complex cardiac lesions for which biventricular repair is impossible. In the absence of a pulmonary ventricle, even a slight increase in pulmonary vascular resistance can result in failure of the procedure. Its outcome is highly dependent on several risk factors, chief of which is pulmonary vascular resistance. Some patients have a poor outcome even when clinical and hemodynamic parameters indicate that conditions for the Fontan procedure are ideal. In the absence of driving force from a ventricle, a low pulmonary vascular resistance is essential for the optimum functioning of the Fontan circulation. Several disadvantages regarding nonpulsatile or decreased pulsatile pulmonary flow after the BCPS have been reported, as well as the importance of flow pulsatile in both globe and microvascularpulmonary circulation. We postulate that endothelial dysfunction might be at least partly responsible for this situation.To find out whether markers of such dysfunction could be evidenced in Fontan circulation, we estsblished a chronic canine model with nonpulsatile blood flow in the right lung, and evaluated the pulmonary vascular structure and the expression of endothelial vasoactive factors in lung biopsy speciments after 3 months of operation. For this purpose, we used both histomorphometric criteria and immunohistochemical markers of eNOS and ET-1 and VEGF on endothelium; furthermore, we use fas and fas-L to study the apoptosis of the smooth muscle cell in pulmonary arteriole.Our results showed abnormal muscle extension into the distal pulmonary arteries of the right lung which underwent the nonpulsatile flow. These arteries contribute greatly to pulmoany vascular resistance and to failure of the Fontan circulation. We also found that the expression of endothelial vasoactive factors altered in lung in which the pulmonary pulsatile flow attenuated, contrast to the pulmonary hypertension '" . Immunoreactivity was indeed weak for ET-1, VEGF and high for eNOS in right lung.We have known that the pulsatile flow play an important role in pulmonary microcirculation. Presson RG 15 provide the first direct account of how the pulmonary capillaries respond to pulsatile flow contrast to nonpulsatile flow by showing that capillaries are recruited during the systolic pulse and that, once open, the capillaries remain open throughout the pulsatile cycle. Raj JU16 showed that vascular resistance is higher with nonpulsatile flow, particularly in the microvascular segment, and that pulsatile flow can decrease the microvascular resistance. In our experiment model, the pressure gradient from SVC to right pulmonary vein is higher than the left lung, it also can show that the nonpulsatile flow can increase the microvascular resistance.Endothelial dysfunction seems to play an integral role in mediating the structural changes in the pulmonary vasculature. Disordered endothelial cell proliferation along with concurrent neoangiogenesis, when exuberant, results in the formation of glomeruloid structures known as the plexiform lesions, which are common pathological features of the pulmonary vessels of patients with pulmonary arterial hypertension (PAH). In addition, an altered production of various endothelial vasoactive mediators, such as NO,...