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Aortic wall thinness was one of the most characteristic changes observed in experimental animals under prolonged continuous flow left heart bypass. The goal of this study was to determine the roles of smooth muscle cells in the vascular remodeling process in cases demonstrating aortic wall thinness under prolonged continuous flow left heart bypass. The aortic samples from three goats in which continuous flow left heart bypass was performed were subjected to histological and immunohistochemical analyses. After 4 weeks of observation, the pulse pressure in the goats under the continuous flow left heart bypass was clearly lower than that in the normal healthy goats. The aortic walls of these goats became thinner, an effect caused by the dilation of their internal diameter. These aortic smooth muscle cells maintained contractile formation due to the fact that they contained abundant alpha-smooth muscle actin (SMA) and smooth muscle myosin heavy chain (SMMS). These cells also synthesized redundant matrix metalloproteinase-2 and -9, and the ratio of the SMMS-positive to the SMA-positive area was significantly lower (0.76) than that observed in the control goat (1.00; P < 0.05). The smooth muscle cells demonstrated synthetic-dedifferentiated formation, which is one of the phenotypes of smooth muscle cell function. In conclusion, aortic wall thinness under prolonged continuous flow left heart bypass is caused by over-synthesis of matrix metalloproteinase in smooth muscle cells, and this refers the vascular remodeling process of the extracellular matrix.

We investigated morphological changes of the arterial systems in the kidneys under prolonged continuous flow left heart bypass. Twelve goats were subjected to 2 weeks of pulsatile left heart bypass followed by 4 weeks of continuous flow left heart bypass (group CF). After autopsy, the kidneys underwent pathological evaluation. Six normal healthy goats were used as controls. The media of the afferent arterioles of group CF were frequently thickened by an increase in the number of the mature smooth muscle cells (SMCs). The juxtaglomerular areas (JGA) were expanded because of an increase in the number and size of SMCs and/or SMC-like cells. Furthermore, the percentage of anti-proliferating cell nuclear antigen antibody-positive cells in the JGA of group CF (9.9 +/- 1.9%) was significantly higher (p = 0.025) than that of the control group (4.6 +/- 3.4%), indicating active proliferation in group CF. We concluded that prolonged continuous flow left heart bypass causes proliferation of SMCs and/or SMC-like cells in the afferent arterioles and their perivascular tissue.

We investigated changes in vasoconstrictive function accompanying prolonged nonpulsatile left heart bypass (NLHB). After 2-week pulsatile left heart bypass (PLHB) in 11 goats, NLHB was conducted for another 4 weeks (Group N) in 6 goats. In the other 5 goats, PLHB was continued for another 4 weeks (Group P). Systemic vascular resistance at rest (rSVR) was measured on the last days of the second and sixth postoperative week (W2 and W6, respectively). Subsequently, phenylephrine was injected, and the maximum values (SVRmax) and the maximum increasing change in SVR (DeltaSVR) were measured. No significant difference was observed in rSVR between groups at W2 or W6. The SVRmax and the DeltaSVR at W2 were consistent in both groups. However, at W6, the SVRmax and the DeltaSVR of Group N were significantly lower than those of Group P. In conclusion, prolonged NLHB caused a significant decrease in the SVR response to phenylephrine, indicating a dimunition of vasoconstrictive function.

We investigated endocrine circadian rhythm (CR) during pulsatile and nonpulsatile left heart bypass (PLHB and NLHB). A ventricular assist device (VAD) was installed in five goats. After 2 weeks of PLHB, NLHB was subsequently conducted for 4 weeks. The levels of melatonin, cortisol, and renin activity were measured every 2 hours for 24 hours on the last day of the second PLHB week and the second and fourth NLHB weeks. Acquired data were compared with those of the normal control goats (Cont) to determine the presence or absence of CR, as well as the timing, acrophase, amplitude, and mesor of CR. Variations in melatonin, CR were consistently detected at all sampling points. In contrast, CR of cortisol during PLHB and NLHB was observed in a few cases, although considerable CR was noted in most of the Cont cases. The variations in renin activity indicated CR in most of the Cont cases and in all cases at all sampling points during PLHB and NLHB, whereas their acrophases were diversified. In conclusion, the CR of melatonin, reflecting the fundamental circadian clock, was maintained during both PLHB and NLHB, while it could be modified for stress sensitive cortisol and hemodynamic responsive renin during these bypass modalities.

We investigated changes in the cerebral metabolism with long-term reduced pulse pressure. Nine goats underwent pulsatile left heart bypass (LHB) for 2 weeks while awake, and nonpulsatile LHB was subsequently conducted for 4 weeks. The average pulse pressure during nonpulsatile LHB (13, 10, 11, and 11 mm Hg at the 1st, 2nd, 3rd, and 4th nonpulsatile LHB week, respectively) was significantly lower than that during pulsatile LHB (36 mm Hg). There were no significant differences in either arterio-jugular venous oxygen differences (AJDO2) and cerebral oxygen extraction ratio between the 2nd pulsatile LHB week and the 1st, 2nd, 3rd, and 4th nonpulsatile LHB weeks. The arterio-jugular venous glucose differences, jugular venous-arterial lactate differences (JAD Lactate), and lactate oxygen indexes (JAD Lactate/AJDO2) also remained unchanged during the entire course of the experiments. In conclusion, the cerebral metabolism during nonpulsatile LHB did not change compared to that during pulsatile LHB.

We investigated the mechanical properties of the descending aortic wall relative to its structural change caused by reduced pulse pressure in long-term nonpulsatile left heart bypass (LHB). Fifteen adult goats (53-68 kg) were divided into three groups: five goats underwent LHB with a nonpulsatile pump for 31 to 381 days (Group N), five goats underwent LHB with a pulsatile pump for 24 to 130 days (Group P), and the other five goats were used as normal control animals (Group C). The aortic pulse wave pressure was 17+/-7 mm Hg in Group N, 43+/-1 mm Hg in Group P, and 39+/-2 mm Hg in Group C. Structural changes were evaluated using wall thickness and the volume ratio of elastin and collagen. The mechanical properties were evaluated using "beta," which was calculated according to the equation: = (In P/Ps)/(Do/Ds-1), where Ps was the standard pressure, Ds was the wall diameter at pressure Ps, and Do was the wall diameter at pressure P. The wall thickness of the aortic wall in Group N (1.6+/-0.3 mm) was significantly thinner than that in either Group P (2.2+/-0.3 mm) or Group C (2.1+/-0.2 mm). The volume ratio of elastin in Group N (51 +/- 3%) was higher than that in Group P (44+/-1%) or Group C (40+/-1%), whereas no significant difference was found in the volume ratio of collagen between those in Group N (10+/-1%), Group P (9+/-2%), and Group C (10+/-1%). The stiffness parameter, beta, in Group N (3.1+/-0.7) was slightly higher than that seen in Group P (2.9+/-0.4) or Group C (2.9+/-0.2), but there was no significant difference between the three groups. These results indicate that long-term nonpulsatile LHB caused marked structural changes in the aortic wall, whereas the change in mechanical properties were not significant with regard to stiffness.

We investigated the functional changes of the systemic vascular system due to prolonged nonpulsatile left heart bypass (NPLHB). Three adult goats underwent pulsatile left heart bypass (PLHB). Two weeks later the PLHB was changed to the NPLHB, which was conducted for 4 weeks. The aortic pulse pressure was 39 and 16 mm Hg during the PLHB and NPLHB, respectively. Systemic vascular resistance (SVR) and the plasma norepinephrine level were measured at the end of PLHB (PUL), and in the 1st, 2nd, 3rd, and 4th weeks of NPLHB (NP1w, NP2w, NP3w, and NP4w). At each point, 1 microg/kg norepinephrine was injected, and the elevation of the SVR (deltaSVR) was calculated. The SVR and the plasma norepinephrine level did not change significantly during the entire course. However, deltaSVR decreased during NPLHB and became significantly lower at NP3w and NP4w than that at PUL (NP3w: 839 +/- 164, NP4w: 746 +/- 268, and PUL: 1,239 +/- 324 dyne x s x cm(-5)). These results strongly indicated that prolonged NPLHB significantly diminished the constrictive function of the vascular system.

We investigated possible functional changes in the vascular system accompanying the morphological change in prolonged nonpulsatile left heart bypass (LHB). Three adult goats underwent pulsatile LHB. Two weeks postoperatively, the pulsatile ventricular assist device was replaced with a centrifugal pump and nonpulsatile LHB was subsequently conducted for 4 weeks. The mean aortic pulse pressure was 39 and 16 mmHg during the pulsatile and nonpulsatile LHB, respectively Systemic vascular resistance (SVR) and plasma norepinephrine levels were measured at the end of pulsatile LHB (PUL), and at the end of 1st, 2nd, 3rd, and 4th week of nonpulsatile LHB (NP1w, NP2w, NP3w, NP4w, respectively). At each point, 50 microg/kg nitroglycerin and 1 microg/kg norepinephrine were injected and the minimal and maximal values of SVR after injection were calculated as parameters reflecting the vascular tonus and contractility. The SVR and plasma nor epinephrine level did not significantly change during the entire course (SVR: 1106, 895, 982, 920, and 938 dyne x sec x cm(-5); norepinephrine level: 0.3, 0.2, 0.1, 0.2, and 0.1 ng/ml; at PUL, NP1w, NP2w, NP3w, and NP4w, respectively). The minimal value of SVR after nitroglycerin injection remained unchanged, indicating that vascular tonus was stable during the entire course (618, 687, 623, 560, 653 dyne x sec x cm(-5), respectively). In contrast, the maximal value of SVR after norepinephrine injection at NP3w and NP4w (1695 and 1759 dyne x sec x cm(-5)) became significantly reduced compared to that at PUL (2346 dyne x sec x cm(-5)). These results indicated that prolonged nonpulsatile left heart bypass did not affect the vascular tonus, but significantly diminished the vascular contractility.

We investigated the changes in cardiac autonomic nervous activities during long-term nonpulsatile left heart bypass (NLHB) by analyzing heart rate variability. A pulsatile ventricular assist device was installed in 3 goats, and pulsatile left heart bypass (PLHB) was conducted for 2 weeks. Then, NLHB was maintained for the following 4 weeks. The segmental data of the R-R intervals (R-Rs) was analyzed by maximum entropy spectral analysis. Changes in evaluated parameters from the last week of PLHB to the 4th week of NLHB were as follows: the mean R-Rs increased from 511 ms to 692 ms; the coefficient of variation of R-R increased from 10.2 to 14.1%; the power of the low frequency band (LF) increased from 747 ms2 to 2,855 ms2; the power of the high frequency band (HF) increased from 512 ms2 to 1,270 ms2; and the ratio of LF to HF increased from 2.6 to 6.5. These results indicated that the cardiac autonomic nervous activity, both sympathetic and parasympathetic, increased during long-term NLHB.

We investigated the morphological changes in the aorta due to reduced systemic pulse pressure in prolonged nonpulsatile left heart bypass (LHB). Nineteen adult goats were divided into 3 groups, the nonpulsatile group in which nonpulsatile LHB was conducted, the pulsatile group in which pulsatile LHB was conducted, and the control group used as the normal control. The average aortic pulse pressures were 12, 47, and 37 mm Hg, respectively. The descending aorta was subjected to morphological examination. In the nonpulsatile group, the wall was significantly thinner, and the volume ratio of smooth muscle cells (SMCs) was much lower. In terms of the SMC type classification, the proportion of SMCs with low activity and low contractility was higher, and the cell density of the SMCs was increased compared to those in the other groups. These results indicate that prolonged nonpulsatile LHB causes morphological atrophic changes in the aorta.

A centrifugal pump with a unique structure has been developed for chronic support. The pump is driven by a magnetic coupling and has no rotating shaft, no seal around the rotating part, and a balancing hole at the center of the impeller and the thrust bearing. The pump was improved in stepwise fashion to realize good antithrombogenicity and low hemolysis. The first pump, the National Cardiovascular Center (NCVC)-0, had an impeller with 4 rectangular and curved vanes; 6 triangularly shaped curved vanes were employed in the second model, the NCVC-1, to reduce trauma to the blood. In the third design, the NCVC-2, the central hole was enlarged, and the thrust bearing shoulder was rounded so that blood washing was enhanced around the impeller; stream lines also were smoothed for improved antithrombogenicity. The hemolytic property of the device was evaluated in vitro with heparinized fresh goat blood; hemolysis indexes of the NCVC-0, -1, and -2 were 0.05, 0.01, and 0.006 g per 100 L, respectively. Antithrombogenicity of the pumps was examined in animal experiments as a left heart bypass device in goals weighing 52-75 kg. Six NCVC-0 pumps were driven for 14 to 33 (22.0 +/- 7.6) days in goats receiving the antiplatelet drug cilostazol orally. Four NCVC-1 pumps ran for 1 to 80 (28.5 +/- 30.6) days with the same drug regimen in 2 cases and with no anticoagulation therapy in 2 cases. After 3 preliminary 1-week tests of NCVC-2 pumps in animals, the pump was installed in 3 goats; 2 pumps were still running on the 182nd and 58th pumping day. Intracorporeal implantation also was attempted successfully. The results indicate that this pump has promising features for chronic support although longer term and additional evaluations are necessary.