Recent insights into the role of host innate and acquired immunity responses.

Viral myocarditis can present as dramatic heart failure in the young, and chronic indolent cardiomyopathy in the older adult. The outcome of the disease is still poor, associated with high mortality during long-term follow-up. Enteroviral myocarditis serves as an excellent model to understand virus and host interactions. The virus enters the target cells via collaborating receptors, and this process triggers an inflammatory response in the host. The immune reaction is a two-edged sword, with appropriate activation of the immune system capable of clearing the virus, but excessive activation leads to a chronic inflammatory process that triggers the remodeling of the heart and consequent clinical heart failure. Through genetic dissection strategies, we have identified that the acquired immune system is activated through the T cell receptor and signaling amplification systems, such as the tyrosine kinase p56lck, phosphatase CD45 and downstream ERK1/2, and the family of cytokines. This signaling system not only promotes inflammatory cell clonal expansion but paradoxically also promotes viral proliferation. The innate immune system is now recognized as playing an ever-expanding role in coordinating the host immune response through the Toll-like receptors, triggering downstream signaling adaptors such as MyD88, IRAK, and TRIF/IRFs. These lead to activation of cytokines or interferons, depending on the balance of the signal contributions. The ongoing research in this area should help us to understand the immune response of the heart to viral infection, while identifying potential targets for therapy.

[Spinal cord ischemia after surgery for arch and aortic valve replacement with elephant trunk for plural thoracic aneurysms].

A 62-years old man had plural aneurysms from the aortic arch to the descending aorta. Y-grafting had been performed twice for an abdominal aortic aneurysm. We performed the first operation which involved aortic valve and arch replacement under deep hypothermia with selective cerebral perfusion. During the operation, hemodynamics was stable, but after the operation he developed paraplegia due to ischemic change in the spinal cord. It was considered that the cause of the ischemia might have been the changing of the blood supply to the spinal cord. In patients with severe atherosclerosis, the blood supply for the spinal cord needs to be very strictly determined.

Multilevel cycle of anthropogenic copper.

A comprehensive contemporary cycle for stocks and flows of copper is characterized and presented, incorporating information on extraction, processing, fabrication and manufacturing, use, discard, recycling, final disposal, and dissipation. The analysis is performed on an annual basis, ca. 1994, at three discrete governmental unit levels--56 countries or country groups that together comprise essentially all global anthropogenic copper stocks and flows, nine world regions, and the planet as a whole. Cycles for all of these are presented and discussed, and a "best estimate" global copper cycle is constructed to resolve aggregation discrepancies. Among the most interesting results are (1) transformation rates and recycling rates in apparently similar national economies differ by factors of two or more (country level); (2) the discard flows that have the greatest potential for copper recycling are those with low magnitude flows but high copper concentrations--electronics, electrical equipment, and vehicles (regional level); (3) worldwide, about 53% of the copper that was discarded in various forms was recovered and reused or recycled (global level); (4) the highest rate of transfer of discarded copper to repositories is into landfills, but the annual amount of copper deposited in mine tailings is nearly as high (global level); and (5) nearly 30% of copper mining occurred merely to replace copper that was discarded. The results provide a framework for similar studies of other anthropogenic resource cycles as well as a basis for supplementary studies in resource stocks, industrial resource utilization, waste management, industrial economics, and environmental impacts.

Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats.

The mechanisms of progression, remission and relapse of myocarditis remain unclear. To clarify these mechanisms, we focused on T helper-1 (Th1)/T helper-2 (Th2) subsets balance of peripheral lymphocytes and serum cytokine levels during disease progression in rats with experimental autoimmune myocarditis (EAM). Lewis rats were immunized with cardiac myosin on day 0. Blood samples were collected on days 0, 7, 15, 18, 21, 28, 35, 42, 49 and 56 following immunization. We examined percentages of interferon (IFN)-gamma and/or interleukin (IL)-4 producing cells in stimulated peripheral CD4-positive lymphocytes using flow cytometry analysis. Serum IFN-gamma, IL-2, IL-6 and IL-10 levels were measured by enzyme-linked immunosorbent assay (ELISA). The percentage of Th1/Th2 subsets in EAM on days 0, 15, 28 and 56 were 2.5 +/- 0.5/0.5 +/- 0.1%, 19.4 +/- 3.2/1.6 +/- 0.3%, 2.0 +/- 0.5/22.1 +/- 5.7% and 3.0 +/- 0.4/1.7 +/- 0.3%, respectively. Serum levels of Th1 cytokines, IFN-gamma and IL-2 significantly increased in the acute phase (from day 15-18) and immediately decreased in the early recovery phase. On the other hand, serum levels of Th2 cytokine, IL-10 significantly increased in the early recovery phase (from day 24-30). These results suggest that induction of acute myocarditis might be associated with systemic Th1 dominance, while recovery is related to systemic Th2 polarity. Thus, analysis of Th1/Th2 balance in peripheral T cells may be useful in disease monitoring in patients with myocarditis and postmyocarditic dilated cardiomyopathy.

[Sinus of Valsalva dilatation after replacement of the ascending aorta and aortic valve].

A 52-year-old woman, height, 149 cm; weight, 40 kg, was admitted because of anterior chest discomfort and palpitations. There was no family history of Marfan syndrome. She had undergone replacement of the ascending aorta and aortic valve 10 years prior for DeBakey II aortic dissection. Postoperative pathological examination of the resected aortic wall revealed cystic medionecrosis. Computed tomography(CT) 4 years after the surgery showed moderate enlargement of the preserved sinuses of Valsalva, and CT 10 years after the surgery showed enlargement of the sinus. She consented to a reoperation. The prostheses were explanted, and the aortic root was replaced with a composite graft. The right coronary artery ostium was completely closed, and no graftable portions of the distal right coronary artery were detected. Thus, the left coronary artery alone was reimplanted. The patient required extracorporeal membrane oxygenation for 10 days postoperatively, after which she recovered fully without complications. This case may indicate that the complete aortic root should be replaced during initial surgery of the ascending aorta or aortic valve in patients with potential risk of sinus of Valsalva dilatation.

[Reconstruction of aortic branches after total aortic replacement in Marfan syndrome; report of a case].

A 34-year-old man with Marfan syndrome finished to replace the total aorta in consecutive 4 operations for 7 years. Two years later, he was diagnosed as bilateral common iliac artery aneurysms and performed a reconstruction of both arteries in September 7, 1998. Then 2 years later, innominate artery was dilated and Y-type grafting was performed in March 14, 2001. Now we have a scheduled operation for celiac artery aneurysm. In patients with Marfan syndrome, aortic dissection and aneurysms are common complications, but progressive dilatations of aortic branches are rear. Regular follow-up is important even though total aortic replacement was completed.

Fourteen year experience with the omnicarbon prosthetic heart valve.

The Omnicarbon prosthetic valve was implanted in 168 patients (mean age, 53 years); 84 had aortic valve replacement (AVR), 57 had mitral valve replacement (MVR), and 27 had both aortic and mitral valve replacement (DVR). The mean follow-up period was 6.8 years, with a maximum of 13.7 years. Three patients (1.8%) were lost to follow-up. There were 4 (2.4%) early deaths and 26 late deaths. Survival at 10 years was 76% in the AVR and MVR groups, and 85% in the DVR group. Freedom from thromboembolism at 10 years was 94% in the AVR group, 80% in the MVR group, and 92% in the DVR group. Freedom from hemorrhagic complications at 10 years was 86% in the AVR group and 92% in the MVR group. At 10 years, 97% in the AVR group and 96% in the MVR group were free from endocarditis. One patient in the DVR group suffered a paravalvular leak. At 10 years, 97% in the AVR group and 95% in the MVR group had not needed reoperation. Elevation of the postoperative serum lactate dehydrogenase levels were acceptable in the three groups. In conclusion, the Omnicarbon prosthetic valve has shown excellent long-term clinical results.

An unusual complication associated with the Carpentier-Edwards porcine bioprosthesis.

Primary tissue failure of bioprosthetic heart valves refers primarily to calcification of the leaflets of the bioprosthesis. A 75 year old patient underwent reoperation 15 years after mitral valve replacement with a Carpentier-Edwards porcine bioprosthesis. The extracted bioprosthetic valve was found to have one prolapsed leaflet and a small amount of calcification on all three leaflets without tear or perforation. The two commissures suspending the prolapsed leaflet were detached, causing mitral valve regurgitation.

Protection against autoimmune myocarditis by gene transfer of interleukin-10 by electroporation.

BACKGROUND: Although immunosuppressive therapy for myocarditis has attracted a great deal of attention, its effectiveness is controversial. Interleukin (IL)-10 has a variety of immunomodulatory properties. Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. METHODS AND RESULTS: We examined the applicability of murine IL-10 (mIL-10) gene transfer to the treatment of rats with experimental autoimmune myocarditis. Nine-week-old Lewis rats were inoculated with pig myosin (day 0). A plasmid vector expressing mIL-10 cDNA (800 microgram per rat) was transferred into the tibialis anterior muscles by electroporation 3 times (5 days before immunization and at days 4 and 13); control rats received empty plasmid. Electroporation increased the serum mIL-10 levels to >250 pg/mL. The 21-day survival rate in rats treated with mIL-10 cDNA was higher (15 of 15; 100%) than that of the control group (9 of 15; 60%). Furthermore, mIL-10 treatment significantly attenuated myocardial lesions and improved hemodynamic parameters. CONCLUSIONS: These findings showed that gene transfer into muscle by electroporation in vivo is an effective means of delivery of IL-10 for the treatment of autoimmune myocarditis.

Changes in the occurrence of mechanical alternans after long-term beta-blocker therapy in patients with chronic heart failure.

Mechanical alternans has been observed in patients with severe congestive heart failure, and the phenomenon is considered to be a terminal sign. Therapeutic strategies for chronic heart failure have significantly developed, but it is uncertain whether patients with mechanical alternans can be effectively treated or not. Seventeen consecutive patients with dilated cardiomyopathy were enrolled: 11 were treated with beta-blockers on conventional therapeutic regimens and 6 patients were not indicated for or were unable to continue beta-blockade. Mechanical alternans was detected during cardiac catheterization in the patients under physiologic tachycardia (110 beats/min) and stepwise dobutamine loading. In the initial study, mechanical alternans occurred in 70.6% of the patients: 8 of the 11 being treated with beta-blockers and 4 of the 6 without beta-blockade therapy. In the second study, none of the patients taking beta-blockers showed mechanical alternans under the same protocol; the occurrence of mechanical alternans did not change in the patients who were not being treated with beta-blockers. The left ventricular ejection fraction increased in patients whose mechanical alternans could not be induced during the follow up, but decreased in the patients in whom mechanical alternans was repeatedly inducible. It is concluded that mechanical alternans is associated with the failing myocardium and may be potentially correctable.

Pitfalls in the development of a rotary blood pump controller.

The controller presents a major obstacle in the development of the rotary blood pump as a left ventricular assist device (LVAD). Clinically, LVAD flow is a good indicator in the regulation of circulatory conditions and pump flow changes, depending on pump preload and afterload. Many investigators have tried estimating pump flow by referencing the motor current. There have been pitfalls in in vitro experimental settings, however. Using a test loop with a pneumatically driven LV chamber and a centrifugal pump as an LVAD, we monitored pump flow and pressure head to evaluate the pump performance curve (H-Q curve). Under pulsatile LV conditions, the H-Q curve was a loop that changed, depending on LV contractility. The pneumatically driven LV chamber cannot mimic the Starling phenomenon, so the developed LV pressure does not change according to the LV preload. Rotary pump flow estimation is the most effective control method. In pulsatile conditions, however, the H-Q curve is a loop that changes under various LV contractility conditions, complicating determination of linear equation for calculating flow. In addition, the LV chamber in the test loop cannot mimic native heart contractility as described by Starling's law. This finding can lead to a misanalysis of the H-Q curve under pulsatile conditions.

Enhanced expression and production of monocyte chemoattractant protein-1 in myocarditis.

Monocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family that has been shown to play a major role in the migration of monocytes and T cells to an inflammatory focus. To clarify the role of MCP-1 in the pathogenesis of myocarditis, we have examined the expression of MCP-1 in rat hearts with experimental autoimmune myocarditis (EAM), and have also measured serum levels of MCP-1 in patients with histology-proven acute myocarditis. Lewis rats were immunized with cardiac myosin and were killed 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 42 and 56 days after immunization. Large mononuclear cells in the myocardial interstitium were stained with an anti-MCP-1 antibody. mRNA of MCP-1 increased in the hearts of EAM rats from days 15--27 as shown by quantitative reverse transcription-polymerase chain reaction. Serum MCP-1 levels of the rats with EAM were significantly elevated from days 15--24. In the clinical study, serum levels of MCP-1 in 24 patients with acute myocarditis at the time of admission (165.2 +/- 55.8 pg/ml) were significantly (P = 0.0301) elevated compared with those of 20 healthy volunteers (61.8 +/- 10.7 pg/ml). Serum MCP-1 levels of 8 fatal cases (371.8 +/- 145.2 pg/ml) were significantly (P = 0.0058) higher than those of 16 cases who survived (65.5 +/- 12.8 pg/ml). In conclusions, MCP-1 may play an important role in the pathogenesis of human acute myocarditis as well as in the progression of rat EAM.

Mechanical alternans in patients with chronic heart failure.

BACKGROUND: Clinical implications of mechanical alternans in patients with chronic heart failure have remained uncertain. In this study, prevalence, characteristics, and prognostic implications of mechanical alternans were investigated. METHODS AND RESULTS: Consecutive 51 patients with dilated cardiomyopathy underwent diagnostic cardiac catheterization using a micromanometer-tipped catheter. Under basal conditions, 7 of 35 patients with sinus rhythm showed mechanical alternans. Physiologic tachycardia (110 bpm) induced mechanical alternans in another 15 patients with sinus rhythm and in another 10 of 16 patients with atrial fibrillation. Low doses of dobutamine also induced mechanical alternans in another 8 patients, but a high dose of dobutamine eliminated mechanical alternans. Consequently, 40 patients (78%) showed mechanical alternans. Mechanical alternans was always accompanied by alternating changes of positive dP/dt, a parameter of contractility during isovolumetric contraction time, but negative dP/dt was occasionally constant. Concordant mechanical alternans between both ventricles was more prevalent than discordant alternans. The left ventricular end-diastolic volume indices and end-systolic volume indices of patients with mechanical alternans were larger than those of patients without. The left ventricular ejection fraction of patients with alternans was significantly lower than that of patients without. CONCLUSIONS: Mechanical alternans was highly prevalent in patients with chronic heart failure. The origin of mechanical alternans seems to exist before or at the isovolumetric contraction time.

Organized thrombus of the tricuspid valve mimicking valvular tumor.

We report on a case of organized thrombus of the tricuspid valve mimicking a valve tumor. Preoperative transesophageal echocardiography showed the mass to have originated from the septal leaflet of the tricuspid valve. A pouch of the tricuspid valve and a ventricular septal defect were observed perioperatively, with the mass attached to the septal leaflet. Histologic examination revealed the mass to be an organized thrombus without tumor components.

Platelet activation and aggregation during normothermic cardiopulmonary bypass.

OBJECTIVE: The usefulness of heparin-bonded circuits under normothermic cardiopulmonary bypass has not been elucidated. We studied platelet activation and aggregation differences between heparin-bonded and nonheparin-bonded circuits in patients undergoing surgery involving normothermic cardiopulmonary bypass. METHODS: Eight patients underwent coronary artery bypass grafting with non heparin-bonded circuits (controls) and 7 the same with heparin-bonded circuits (heparin group). Heparin bonding was applied to the blood contact surface of our system, including the oxygenator and connecting tubes. Patient body temperature was kept between 36 and 37 degrees C. Beta-thromboglobulin and platelet factor 4 were measured before, during, and after cardiopulmonary bypass, and platelet aggregation was evaluated by laser-light scattering. RESULTS: Changes in beta-thromboglobulin and platelet factor 4 during and after cardiopulmonary bypass were similar in both groups. Small particle formation was the primary aggregate induced during and after cardiopulmonary bypass in both groups, and serial changes in particle formation up to 24 hours after cardiopulmonary bypass were similar in both groups. CONCLUSIONS: Our results indicate that in 2-3 hours of normothermic cardiopulmonary bypass, heparin-bonded circuits are similar to nonheparin-bonded ones in platelet compatibility.

Inhibition of progression of heart failure and expression of TGF-beta 1 mRNA in rats with heart failure by the ACE inhibitor quinapril.

The cardioprotective effects of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of heart failure. Twenty-six rats were divided into two groups: one given 20 mg/kg/day quinapril (n = 11), and controls given 0.5% methylcellulose (n = 15). After oral administration for 1 month, quinapril reduced heart weight (from 1.28+/-0.05 to 0.87+/-0.02 g; p < 0.05) without changing body weight. Quinapril lowered left ventricular end-diastolic pressure (from 14.1+/-2.0 to 6.6+/-1.5 mmHg; p < 0.05) and central venous pressure (from 2.7+/-0.9 to 0.7+/-0.4 mmHg), and increased +/- dP/dt (from +2409+/-50 to +3569+/-169 mmHg/s, and from -2318+/-235 to -3960+/-203 mmHg/s; both p < 0.01). The area of myocardial fibrosis was markedly reduced by quinapril (6+/-3%) as compared with controls (29+/-6%; p < 0.01). Expression of transforming growth factor (TGF)-beta1 mRNA was markedly increased in controls as compared with age-matched normal rats. The increase in level of TGF-beta1 mRNA was significantly suppressed by quinapril (from 17.1+/-6.2 to 9.00+/-2.40; p < 0.05). These observations indicated that quinapril has cardioprotective effects on heart failure, and that the beneficial effects may be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 mRNA expression.

Bisoprolol improves survival in rats with heart failure.

The cardioprotective effects of bisoprolol were studied in a rat model of severe heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization, Lewis rats were divided into four groups: 0.1 mg/kg/day bisoprolol (Group 0.1), 1.0 mg/kg/day bisoprolol (Group 1) and 10 mg/kg/day bisoprolol (Group 10), and vehicle (0.5% methylcellulose; Group V) (all groups, n = 13). After oral administration for 1 month, heart weight, mean blood pressure, heart rate, central venous pressure, peak left ventricular pressure, left ventricular end-diastolic pressure, +/- dP/dt, and area of fibrosis were measured. Although bisoprolol reduced heart rate (399+/-11/min in Group V, 382+/-10/min in Group 0.1, 348+/-8/min in Group 1 and 302+/-9/min in Group 10) and increased survival (62% in Group V, 69% in Group 0.1, and 100% in Group 1 and Group 10) in a dose-dependent manner, this drug did not change heart weight, the area of myocardial fibrosis or hemodynamic parameters. These observations suggested that bisoprolol may improve survival independently of its effect on left ventricular function by reducing sudden death in patients with severe heart failure.