Masayuki Miyagishima

Soluble Tumor Necrosis Factor Receptor Abrogates Myocardial Inflammation but Not Hypertrophy in Cytokine-Induced Cardiomyopathy

BACKGROUND Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-alpha develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-alpha on this model. METHODS AND RESULTS An adenovirus encoding the 55-kDa TNF receptor-IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1beta and monocyte chemotactic protein-1. Downregulation of alpha-myosin heavy chain was restored by the treatment, whereas upregulation of beta-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed. CONCLUSIONS These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.

Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure

BACKGROUND Plasma levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, are elevated in patients with congestive heart failure (CHF). Recent studies suggest that the failing human heart is a source of proinflammatory cytokines in the end-stage failing heart. However, the relevance of plasma levels to those of the myocardium remains undefined. We sought to compare cytokine expression in early and end-stage CHF, and to evaluate the correlation of tissue expression to plasma levels. METHODS Two patient populations were studied: patients with recent-onset CHF, all with symptoms less than 6 months (n = 17, duration of symptoms 2.1 +/- 1.6 months, range of New York Heart Association (NYHA) 1 to 3), and end-stage heart-failure patients (n = 7) who underwent left-ventricular assist-device (LVAD) implantation (Duration of symptoms 47.1 +/- 28.0 months, all NYHA class 4). Plasma levels of TNF-alpha and IL-6 proteins were evaluated by an Enzyme-Linked Immuno-Sorbent Assay (ELISA), while myocardial levels of cytokine transcripts were assessed by ribonuclease (Rnase) protection assay. RESULTS In patients with end-stage heart failure, TNF-alpha and IL-6 were increased in the plasma as well as in the myocardium (plasma: TNF-alpha = 7.7 +/- 2.3 pg/ml, IL-6 = 45.0 +/- 47.1 pg/ml; myocardium: TNF-alpha = 0.31 +/- 0.15% of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, IL-6 = 1.56 +/- 1.54% ). In contrast, despite elevated plasma levels of TNF-alpha and IL-6, the myocardium of patients with the recent onset of symptoms demonstrated minimal expression of TNF-alpha and IL-6 messenger ribonucleic acid (mRNA) (plasma: TNF-alpha = 4.3 +/- 1.7 pg/ml, IL-6 = 3.3 +/- 1.8 pg/ml; myocardium: TNF-alpha = 0.13 +/- 0. 04%, IL-6 = 0.02 +/- 0.04%). Plasma levels of TNF-alpha were significantly correlated with those in the myocardium when both populations were combined. (r = 0.69, p < 0.001). CONCLUSIONS Cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent-onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF. Furthermore, plasma levels of TNF-alpha correlates with mRNA expression in the myocardium and thus may serve as an appropriate marker of myocardial cytokine activation. Whether the production of cytokines in the failing human heart precedes the elevation of cytokines in the plasma remains undefined. Therefore, we studied expression of TNF-alpha and IL-6 in the myocardium as well as in the plasma in patients with early and end-stage CHF. The results have demonstrated that cytokines are expressed in the myocardium in end-stage heart failure to a much greater degree than in patients with the recent onset of symptoms. This suggests that induction of cytokines in the myocardium is a relatively late event in the pathogenesis of CHF.

Less Blood Damage in the Impeller Centrifugal Pump: A Comparative Study with the Roller Pump in Open Heart Surgery

A centrifugal pump with an impeller (Nikkiso Centrifugal Pump, Model HPM15; Nikkiso Co. Ltd.) was applied to cardiopulmonary bypass (CPB) in 14 patients who underwent elective coronary artery bypass grafting. Serum hemoglobin level, platelet count, and serum p-thromboglobulin (pTG) level were measured during CPB. The results were compared with those obtained in a comparative roller pump (RP) group (n = 10). There was no difference in the time on CPB between the NP (109 min) and RP (121 min) groups. The serum pTG level (ng/ ml) was lower in the NP group than in the RP group (obtained 90 min after the initiation of CPB). The plasma-free hemoglobin level also was lower in the NP group than in the RP group (obtained 90 min after the initiation of CPB, 120 min after the initiation of CPB, immediately after the termination of CPB, 3 h after termination of CPB; p < 0.01). There was no significant difference in platelet depletion. The HPM15 pump showed excellent hemodynamic performance with less blood trauma compared with the roller pump in its clinical application to open heart surgery.

Transatrial Repair of Submitral Left Ventricular Pseudoaneurysm

In a 57-year-old man with Wolff-Parkinson-White syndrome, a left ventricular pseudoaneurysm developed, induced by the pop phenomenon, after radiofrequency catheter ablation of the posterolateral accessory pathway. The pseudoaneurysm was positioned at the atrioventricular groove with moderate pericardial adhesions, and the rupture site was located just below the P3 annulus of the posterior mitral leaflet. With this anatomy and in the presence of adhesions, we repaired the rupture site from within the heart through an incision made in the posterior mitral leaflet. This transmitral approach might be a reasonable surgical option for treating this type of submitral left ventricular pseudoaneurysm.

Aortic root replacements in reoperations

We evaluated 4 patients who had undergone previous cardiac surgery underwent reoperation involving aortic root replacement. Subjects were a 55-year-old man who had undergone separate valve graft replacement for a dissecting aneurysm (DeBakey type I) 3.25 years earlier; a 51-year-old woman who had undergone separate valve graft replacement for a dissecting aneurysm (DeBakey type I) 6 years earlier; a 66-year-old woman who had undergone aortic valve replacement and single coronary artery bypass grafting for severe aortic regurgitation, angina pectoris, and aortitis syndrome 11 years earlier; a 47-year-old man who had undergone mitral valve replacement and 3-coronary artery bypass grafting for severe mitral regurgitation and angina pectoris 4 years earlier. Development of a surgical technique, coupled with myocardial protection, and pharmacological treatment at reoperation yielded excellent early surgical results. To reduce the incidence of reoperation and ensure satisfactory long-term results, we recommend radical management for the individual case be selected at initial operation and entire resections be conducted for aneurysmal degeneration or dissected segments.

What Will Happen to Permanent Left Ventricular Assist Device Recipients? Clues from Long-Term Outcomes of Heterotopic Heart Transplants

Donor organ shortage and successful experience with left ventricular assist devices as a bridge to transplantation have prompted us to consider a permanent alternative to transplantation. However, we have little information on the long-term follow-up, because the left ventricular assist device has been used as a bridge to transplantation for a period of just over one year. In recipients of a left ventricular assist device, the potential heart-related complications expected include arrhythmia, thromboembolism, valvular heart disease, and progression of ischemic heart disease. Heterotopic heart transplantation (in which the native heart is retained) may be a good model to study long-term pathophysiological processes in the native heart. We analyzed the prevalence of native-heart-related complications in heterotopic heart transplantation to help in predicting the performance of the native heart in patients with a permanent left ventricular assist device. Between December 1984 and December 1994, 16 patients (13 men, 3 women, 37–60 years old) underwent heterotopic heart transplantation at the University of Pittsburgh. The indication for heterotopic heart transplantation in all recipients was pulmonary hypertension unresponsive to vasodilators. The one- and five-year survival rates after transplantation were 81% and 44%. Pulmonary hemodynamics improved significantly after the operation. The actuarial percentages of patients free of complications related to the native heart after one and four years were, respectively: ventricular arrhythmia: 85%, 75%; ischemic heart disease: 85%, 64%; and valvular heart disease: 100%, 88%. The actuarial freedom from all these complications was 70% after one year and 50% after four years. These results will give us an indication of the native heart performance to expect in the patient with a permanent left ventricular assist device.

Selective Reconstruction of Preoperatively Identified Adamkiewicz Artery During Descending and Thoracoabdominal Aortic Aneurysm Repair; What we have Learned

Paraparesis and paraplegia after repair of the descending (TAA) or thoracoabdominal (TAAA) repair remains devastating complication. The purpose of this study was to determine the effects of selective reconstruction of Adamkiewicz artery (ARM) preoperatively identified with MDCT upon neurological outcome. Methods: Sixty two consecutive patients who had aneurysms of the descending (n = 15) or thoracoabdominal aorta (n = 47) were studied prospectively with MDCT to identify ARM before and after surgery. Median age was 62 years (29 to 77) and 37 patients had non-dissecting aneurysm and 23 had aortic dissections. The repair was performed and the segmental intercostals arteries (ICA) connected with ARM were reconstructed selectively according to the identification of ARM with MDCT. Results: MDCT demonstrated the ARM in 57 (91.9%) of the 62 patients. The hospital deaths occurred in 3 patients (4.8%). No paraplegia but 1 paraparesis (1.6 %) occurred in a patients. Major different source of blood supply was identified in 18 (34.6%), and 12/58 (20.6%) reconstructed arteries were occluded with other collateral development. Conclusion: Selective reconstruction of ARM during repair of thoracoabdominal aortic aneurysm is safe and effective reducing the incidence of neurological deficit. Collateral blood supply for spinal cord develops postoperatively and the considerations of collateral source is crucially important.

Mid-term follow up results of Japanese heart transplant patients operated in UCLA Medical Center

UNLABELLED Japanese candidates have been accepted for heart transplantation by the UCLA Medical Center in the US since 1993 due to the lack of donors available from brain-dead patients. OBJECTIVES AND METHODS We monitored to patients who underwent such heart transplantation and have been seen at the out-patient clinic at Tokyo Womens Medical University following transplantation. Pre-operative diagnosis was dilated cardiomyopathy in all patients. One patient underwent Novacor implantation as a bridge to heart transplant. All patients underwent cardiac echocardiography and cardiac catheterization including intraluminal echography. RESULTS All patients survived with an actuarial survival curve of 100% at 1 year, 100% at 3 years and 87% at 5 years in 4.15 years of average follow-up. Two patients died due to liver dysfunction and cerebral emboli. The postoperative functional status of patients was New York Heart Association classification I in 8 (100%). Immunosuppressive therapies included triple drug therapy using either cyclosporin or tacrolimus. The incidence of acute rejection (/pt) exceeding grade 3 was 4% within three months, 3.5% in 3-6 months, and no significant rejection episode more than 6 months after transplantation. Posttransplantation coronary artery disease was seen in 2 patients, but no progression was seen after diltiazem therapy. CONCLUSION Our postoperative follow-up after cardiac transplantation appears to be satisfactory.

Overexpression of tumor necrosis factor-α activates both anti- and pro-apoptotic pathways in the myocardium

We have previously reported that mice with cardiac-specific overexpression of tumor necrosis factor (TNF)- alpha develop myocardial inflammation, cardiac hypertrophy, and dilated cardiomyopathy. TNF- alpha is reported to induce apoptosis in cultured cardiac myocytes. To investigate the role of apoptosis in this transgenic model, wild-type controls (WT) and transgenic mice (TG) at the age of 1, 8, and 40 weeks were analyzed. Increased incidence of apoptosis in TG was indicated by DNA laddering. TUNEL assays revealed that the frequencies of apoptotic cells were increased in the TG myocardium at all ages. However, as revealed by histochemical and immunofluorescent methods, most of the apoptotic cells appeared to be non-myocytes even in the mice with overt congestive heart failure. To elucidate the signaling pathways responsible for TNF- alpha induced apoptosis, expression of apoptosis-related genes were evaluated by multi-probe RNase protection assays. Transcripts for death-domain-related proteins, including TNFR1, Fas, FADD, TRADD, and RIP, were constitutively expressed in WT and upregulated in the TG myocardium. Expression of caspase-1 through -8 was also enhanced in TG. While both anti- and pro-apoptotic Bcl-2 family genes were constitutively expressed in WT, TNF- alpha overexpression strongly induced anti-apoptotic A1 in the myocardium. Furthermore, TNF- alpha overexpression activated NF- kappa B, a mediator of anti-apoptotic pathways, in the myocardium. Thus, overexpression of TNF- alpha activated both anti- and pro-apoptotic pathways in the myocardium, resulting in an increase of apoptosis, primarily in non-myocytes. These results suggest that TNF- alpha by itself is not sufficient to induce apoptosis in cardiac myocytes in vivo.