Norihide Fukushima

The Registry Report of Heart Transplantation in Japan (1999–2014)

Postoperative cardiac patients frequently are mildly hypothermic, yet the influence of hypothermia on left ventricular (LV) contractility has received little attention. To study the possible effects of mild hypothermia on LV function, six pigs were placed on partial right ventricular bypass, the hearts were electrically paced to control heart rate, and myocardial temperature was varied between 34 degrees and 38 degrees C. Using two pairs of orthogonally oriented sonomicrometer crystals in the left anterior descending (LAD) and left circumflex (LCX) distributions, we estimated regional work (the area within LV pressure-area loops) over a range of LV preloads. Diastolic function was assessed by measurement of the time constant of LV pressure decay during isovolumic relaxation. Regional work data were expressed as percentages of baseline (38 degrees C and end-diastolic pressure of 10 mm Hg). To control for preload variations, regional work and time constants were calculated from beats with end-diastolic areas within 0.1% of baseline. Regional work (mean +/- SEM) declined from 85.1 +/- 6.7% at 38 degrees C to 31.9 +/- 4.4% at 34 degrees C. Time constants were prolonged from 44.8 +/- 2.5 msec at 38 degrees C to 61.6 +/- 2.7 msec at 34 degrees C. These data demonstrate a marked depression of LV contractility, even at mild levels of hypothermia that may be encountered clinically after cardiac operations.

Hepatic dysfunction after left ventricular mechanical assist in patients with end-stage heart failure: role of inflammatory response and hepatic microcirculation

BACKGROUND In the condition of preexisting vital organ failure induced by heart failure, hepatic failure often progresses despite establishment of adequate hemodynamic support through a left ventricular assist device (LVAD) and results in a high mortality rate. We hypothesized that inflammatory responses, including those induced by infection and their influence on organ perfusion, may contribute to the pathogenesis of this progressive hepatic failure and subsequent multiple organ failure as reported in the current investigation on multiple organ failure after major surgery or trauma. METHODS Hepatic function and its relation to inflammatory response and hepatic microcirculation were evaluated in 16 consecutive patients who received an implantation of LVAD for end-stage cardiomyopathy, between 1992 and 2000. Patients were divided into two groups: 5 patients who died from multiple organ failure after severe hepatic failure (group 1) and 11 patients who did not develop severe hepatic failure (group 2). Serum levels of CRP, interleukin (IL)-6, IL-8, and serum hyaluronan, a known indicator of hepatic sinusoidal function, were measured pre- and postoperatively in both groups. RESULTS Serum ALT and AST levels during LVAD support were similar in the two groups. Serum total bilirubin (T-Bil), CRP, IL-6, and IL-8 levels before and during the first 20 days of LVAD support were significantly higher in group 1 than those in group 2 (p < 0.01 to 0.05). Serum hyaluronan levels in both groups were significantly correlated with T-Bil levels (r = 0.60, p < 0.05 in group 1; r = 0.68, p < 0.0001 in group 2). Histopathological examination by transvenous liver biopsy in a group 1 patient showed hepatic sinusoidal damage as well as cholestasis and fibrosis. CONCLUSIONS Patients with hyperbilirubinemia and inflammatory reactions before LVAD support showed increased hyperbilirubinemia and inflammatory cytokine and hyarulonan levels despite adequate hemodynamics achieved under LVAD support. These results suggest that inflammatory response contributes to subsequent aggravation of hepatic dysfunction, probably with underlying and continuing derangement in hepatic sinusoidal microcirculation even under systemic circulatory support.

Prolonging discordant xenograft survival with anticomplement reagents K76COOH and FUT175.

The guinea pig heart, when transplanted into the rat heterotopically, is rejected within 30 min via activation of the alternative complement pathway. Natural antibody does not contribute to rejection. This xenotransplantation model was used to assess the effect of anti-complement reagents on discordant xenograft survival. In vivo administration of K76COOH (K76) to rats induced only slight suppression of factors B and D and a marked decrease of C3, leading to the depression of ACH50 (reflecting the potency of the alternative pathway). On the other hand, FUT175 (FUT) reduced C3 activity by about 80% and inhibited factor B activity nearly 100% < 1 hr after the administration, but inhibited factor D activity only marginally. FUT abrogated ACH50 for > 6 hr. Of note, the xenograft beating time was prolonged approximately 3 times by FUT but not by K76, suggesting that direct inhibition of plasma serine protease factor B results in the complete suppression of ACH50 and graft survival. The administration of both K76 and FUT resulted in the longest graft survival, but the effects of these reagents were abolished by additional antigraft antibody. Anticomplement reagents that block factor B and C3 are therefore effective for prolongation of discordant xenograft survival when the graft rejection is associated with the complement alternative pathway.

Selective chemokine and receptor gene expressions in allografts that develop transplant vasculopathy

BACKGROUND Chemokine systems probably play a role in transplant vasculopathy; however, a comprehensive study of the expression of chemokines and their receptors in this disease has not been performed. METHODS The expression of all the rat chemokines and chemokine receptor genes for which the nucleotide sequences are known were quantitatively monitored using the fluorescence-based real-time reverse-transcriptase polymerase chain reaction technique, and selected cytokine-receptor pairs were determined using immunohistochemical staining. The analysis covered the whole time course of transplant vasculopathy in 2 different graft models (cardiac and aortic grafts) with 4 different strain combinations of rats. RESULTS Among the 13 receptor genes examined, the CXCR3, CCR5, and CCR2 genes and those of their corresponding ligands were selectively and strongly induced in grafts that develop transplant vasculopathy. The expression patterns of the receptors were similar in both cardiac and aortic allografts, although their induction and their absolute levels of expression were amplified several fold in the grafted aorta compared with heart grafts. The genes were induced before morphologic changes became apparent and expression was sustained during the whole period of neointimal formation. Interestingly, immunohistochemical staining for CXCR3 showed a unique pattern of expression: we found weak expression on cells in the outer layer of the neointima and adventitia and found the strongest staining in the innermost layer of the neointima. CONCLUSIONS This study suggested diagnostic as well as potential functional roles of the chemokine-receptor pairs IP10-CXCR3, RANTES-CCR5, and MCP1-CCR2 in rat models of transplant vasculopathy.

Prevalence of Arrhythmias and Their Risk Factors Mid- and Long-Term After the Arterial Switch Operation

Early results of the arterial switch operation (ASO) for transposition of the great arteries (TGA) are good, but there are few mid- and long-term data on postoperative arrhythmias, especially in Japan. In this study, clinical data on 624 1-year survivors who had an ASO between 1976 and 1995 were collected from six institutes in Japan up to October 2002. Sixty (9.6%) 1-year survivors had significant arrhythmias. Bradycardia occurred in 22 patients, including complete atrioventricular block (CAVB) in 12, sick sinus syndrome (SSS) in 6, and second-degree atrioventricular block in 4. Syncope developed in 2 with CAVB and 2 with SSS. Ten patients with bradycardia underwent permanent pacemaker implantation. Supraveutricular tachycardia (SVT) was seen in 25 patients, including paroxysmal supraventricular tachycardia in 16, atrial flutter in 7, and atrial fibrillation in 2. Six patients with SVT received antiarrhythmic medication. SVT was transient in 20 and persistent in 5. Ventricular arrhythmias occurred in 13 patients, including nonsustained ventricular tachycardia in 5, paroxysmal ventricular contractions with couplets in 5, ventricular flutter in 2, and sustained ventricular tachycardia in 1. Four patients with ventricular arrhythmias received antiarrhythmic medication. Of the study patients, 8 died 1 year or more after ASO. Death was directly related to arrhythmia in 1 patient and was due to nonsustained ventricular tachycardia with severe congestive heart failure. The presence of a ventricular septal defect (VSD) was a risk factor for postoperative arrhythmia. Patients with TGA and VSD had more arrhythmias than those with TGA and an intact ventricular septum (13.7 vs 8.7%, p < 0.05), and this was especially true for CAVB (3.9% vs 1.0%, p < 0.05). In 36 patients clearly documented time onset of postoperative arrhythmia arrhythmia developed in 18 (50%) after less than 1 year and in 15 (42%) after more than 5 years. In summary serious arrhythmias after ASO were uncommon, but postoperative arrhythmias, such as unpaced CAVB, SSS, and VT, were related to morbidity and mortality. VSD was a risk factor for postoperative arrhythmia, especially CAVB. Approximately half of the arrhythmias developed late. Lifelong monitoring with respect to arrhythmia is needed for patients after ASO.

A novel strategy of decoy transfection against nuclear factor-κB in myocardial preservation

BACKGROUND Nuclear factor-kappaB (NFkappaB) is critical for the transcription of multiple genes involved in myocardial ischemia-reperfusion injury. Therefore, we hypothesized that blocking NFkappaB would attenuate ischemia-reperfusion injury after prolonged myocardial preservation, resulting in an improvement in cardiac function. METHODS Double-stranded oligodeoxynucleotides with a specific affinity for NFkappaB (NFkappaB decoy group) or a scrambled decoy group were transfected into rat hearts using a hemagglutinating virus of Japan-liposome method. After 16 hours of preservation in Euro-Collins solution at 4 degrees C, the cardiac grafts were heterotopically transplanted into recipient rats of the same strain. RESULTS Fluorescein isothiocyanate staining showed introduction of double-stranded oligonucleotides into the nuclei of endothelial cells and cardiomyocytes. After 1 hour of reperfusion the NFkappaB decoy group showed significantly higher degrees of recovery of left ventricular function as well as significantly lower levels of serum creatine phosphokinase, myocardial water content, tissue IL-8, and neutrophil infiltration than did the scrambled decoy group (p < 0.05). CONCLUSIONS Gene transfection of the NFkappaB decoy attenuates ischemia-reperfusion injury after prolonged heart preservation. As a result, this method appears to be a novel strategy for enhanced myocardial preservation.

First brain dead donor heart transplantation under new legislation in Japan.

The first heart transplantation was carried out in Japan successfully, after the brain death and organ transplantation law was settled in 1997. The recipient patient was a 47-year-old man with the dilated phase of hypertrophic cardiomyopathy who had been on a Novacor implantable left ventricular assist system for the previous 4 months. Since the donor hospital was about 200 km from the recipient hospital which took approximately 2 hours for transportation, the total ischemic time was 3 hours and 24 minutes. The post-transplant course was smooth, and the patient was discharged on postoperative day 75.

The role of anti-pig antibody in pig-to-baboon cardiac xenotransplant rejection.

The role of naturally produced antibody in discordant xenograft rejection is still uncertain. Twelve or-thotopic pig-to-baboon heart transplants (HTx) were performed. In 2 baboons, no antibody adsorption (AbA) was performed. In 5 baboons, AbA with a pig lung was performed during circulatory arrest. In 5 baboons, AbA and blood exsanguination at the beginning of cardiopulmonary bypass (CPB) were performed. Baboons were divided into 2 groups; group 1 (n=4) died within 24 hr of HTx and group 2 (n=8) survived more than 24 hr. Mean survival period was 9.8±3.0 hr in group 1 and 151±33 hr in group 2. Baboon anti-pig antibody (Ab) was measured before CPB, before circulatory arrest, during AbA, at the end of CPB, and daily after HTx. Anti-RBC Ab was measured by the titration method at temperatures of 4°C and 37°C (RAb-4 and RAb-37). Anti-endothelial cell Ab (EAb) and anti-white blood cell Ab (WAb) titers were measured with ELISA. RAb titration ≥l/4 and EAB and WAb ≥ 1/256 were determined to be seropositive (S(+)). S(+) rate of RAb-37 at the end of CPB (endCPB) in group 2 was significantly higher than that in group 1 (8/8 vs. 1/4; P<0.05). The seronegative (S(-)) rates of RBC-4 and EAb (endCPB) in group 2 were higher than those in group 1 (7/8 vs. 1/4 and 6/8 vs. 1/4, respectively), but not significantly. There was no difference in S(-) rate of WAb (endCPB) between group 1 and group 2. More than 4-fold decrease in RAb-4 and RAb-37 by AbA with a pig lung was observed in 5 and 7 of 8 baboons, while EAb and WAb did not change by AbA. In all of group 2, RAb-4 reverted to S(+) within 3 days after HTx. One baboon had no rejection episode and died of infection 16 days after HTx (baboon 16); however, it also became S(+) for RAb-4 a day after HTx until death. In 4 of group 2, RAb-37 became S(+) 1 or 2 days before death by rejection. Baboon 16, however, became S(+) for RAb-37 7 days after HTx and S(-) again 9 days after HTx until death. EAb became S(+) in all of group 2, but 5 of them survived more than 5 days after seroconver-sion. It was concluded that a pig lung absorbed RAb-4 and RAb-37 but not EAb or WAb, and that RAb, especially RAb-37, may play a role in discordant xenograft rejection.

Analysis of sympathetic nerve activity in end-stage cardiomyopathy patients receiving left ventricular support

BACKGROUND The left ventricular assist system (LVAS) has been used increasingly for patients with end-stage heart failure who are awaiting transplantation. Sympathetic nerve activity is known to correlate with cardiac function in chronic heart failure patients, but little is known about sympathetic nerve activity during LVAS support. In this study, we examined the status of sympathetic nerve activity in relation to mechanical support. METHODS In this study, we included 10 consecutive patients with end-stage cardiomyopathy who were on LVAS support for at least 2 months (duration, 222 +/- 59 days). None of these patients achieved enough functional recovery to be taken off LVAS. In these patients, we used iodine-125-metaiodobenzylguanidine (125I-MIBG) scintigraphy to examine the change of sympathetic nerve activity after LVAS implantation, and compared the results with the change of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels as well as with histologic optional findings. Samples for ANP and BNP measurement were obtained before and 30 days after LVAS implantation. Specimens for histologic analysis were obtained at the time of LVAS implantation and at the time of cardiac transplantation or autopsy. RESULTS We observed marked decrease in serum levels of ANP and BNP 1 month after LVAS implantation. But myocardial sympathetic nerve function, which was evaluated with 125I-MIBG scintigraphy and expressed as the heart-to-mediastinum activity ratio, remained below normal even 2 months after the LVAS implantation (1.57 +/- 0.19; normal, 2.34 +/- 0.36). Serial histologic analysis in these 10 patients showed continuous increase in percentage of fibrosis and cell diameter despite ventricular unloading by the LVAS. CONCLUSIONS Sympathetic nerve function, which was evaluated on 125I-MIBG scintigraphy, did not improve during left ventricular support. Because none of the patients included in our study showed improvement in cardiac function or histologic findings, the recovery of myocardial sympathetic nerve function may be an important factor in myocardial recovery for cardiomyopathy patients on LVAS support.

Late true aneurysm after bypass grafting for long aortic coarctation

Two adolescent patients who underwent a repair of long aortic coarctation using bypass grafting with subsequent late true aneurysm formation are reported. To our knowledge, only 1 case of late true aneurysm formation after bypass grafting has been reported in the English-language literature.