Effects of cyclosporine, prednisolone and aspirin on rat autoimmune giant cell myocarditis.

OBJECTIVES: Preventive effects of cyclosporine, prednisolone and aspirin on autoimmune giant cell myocarditis in rats were investigated. BACKGROUND: The therapeutic efficacy of immunosuppressants for human myocarditis is controversial. Although harmful effects of immunosuppressive therapy on experimental viral myocarditis have been reported, the effects on autoimmune myocarditis have not been investigated. Recently, a novel experimental autoimmune myocarditis model characterized by congestive heart failure and multinucleated giant cell has been established. Using this model, the preventive effects of cyclosporine, prednisolone and aspirin on autoimmune myocarditis were investigated. METHODS: Lewis rats were immunized with cardiac myosin in complete Freund's adjuvant on days 0 and 7. In experiment 1, four groups of seven rats each were established. Rats in each group received for 21 days intraperitoneal injections of either 1) phosphate-buffered saline solution, 1 ml/day (control); 2) cyclosporine, 20 mg/kg body weight per day (cyclosporine 20); 3) prednisolone, 4 mg/kg per day; or 4) aspirin, 15 mg/kg per day. In experiment 2, two additional groups (five rats each) received for 21 days an injection of cyclosporine, 1 or 5 mg/kg per day (cyclosporine 1 and cyclosporine 5, respectively). All rats were killed on day 21, when histopathologic studies were performed and the titers of antimyosin antibodies were measured. RESULTS: The rats in the control, prednisolone and aspirin groups became ill and immobile in week 3. In comparison, rats in the cyclosporine 5 and 20 groups were still active until death was induced. Heart weight/body weight, lung weight/body weight and liver weight/body weight ratios in the rats in the cyclosporine 5 and cyclosporine 20 groups were significantly lower than those in the control group, and no differences were detectable among rats in the control, prednisolone and aspirin groups. The rats in the latter three groups and the cyclosporine 1 groups showed severe myocarditis with multinucleated giant cells. However, myocarditis was effectively prevented in the rats in the cyclosporine 5 and 20 groups. The histologic scores in each group were 2.91 in the control group, 2.14 in the prednisolone group, 2.91 in the aspirin group and 0.02, 2.58 and 0.07, respectively, in the cyclosporine 20, 1 and 5 groups. Production of antimyosin antibodies was remarkably suppressed in rats in the cyclosporine 5 and 20 groups in comparison with values in all other groups. CONCLUSIONS: Autoimmune myocarditis is preventable by cyclosporine but not by prednisolone or aspirin in usual dosages.

A case of giant cell myocarditis with evidence of cardiac autoimmunity.

A 45-year-old-woman with giant cell myocarditis showing high titer of circulating antiheart antibodies is reported. She experienced two recurrences of myocarditis and repeatedly responded to immunosuppressive therapy using prednisolone. The titer of antiheart antibodies went up and down appropriately according to the clinical responses to immunosuppressive therapy. This case suggested that giant cell myocarditis might be related to autoimmunity.

Ethanol ingestion on allylamine-induced experimental subendocardial fibrosis.

Effects of ethanol ingestion on allylamine-induced subendocardial fibrosis of the myocardium and intimal hyperplasia of the intramyocardial coronary artery were investigated in male Wistar rats. The toxic effect of allylamine is ascribed to acrolein produced from allylamine by benzylamine oxidase. Animals were forced to drink allylamine solution for 12 weeks. Incidence and size of subendocardial fibrosis were examined, and the lesions of the intramyocardial artery were scrutinized. Effects of ethanol on the systemic blood pressure and benzylamine oxidase activity were investigated in another experiment. Treatment with allylamine resulted in subendocardial fibrosis (size = 4.2%) in 4 of 12 rats. The incidence of fibrosis was increased (up to 6/12) and the area of fibrosis was augmented (to 6.8%) in animals additionally treated with epinephrine. The lesions in the intramyocardial vasculature were also augmented. Ethanol ingestion reduced allylamine-induced subendocardial fibrosis and intramyocardial coronary lesions. The effects were significant in animals additionally treated with epinephrine. Systemic blood pressure and benzylamine oxidase activity were not significantly affected by allylamine or by ethanol. The vasodilatory effect of ethanol may have prevented the development of microvascular spasm induced by allylamine.

Clustered lipid droplets in the endomyocardial biopsies from a patient with neuroleptic malignant syndrome.

Neuroleptic malignant syndrome is caused by serious adverse effects of antipsychotic agents and occurs only rarely. Endomyocardial biopsies documented unique clustered lipid droplets in a Japanese man with this disease. After administration of haloperidol, he had symptoms of high fever, respiratory dysfunction, and cardiogenic shock, and subsequently suffered from multiple organ failure. Fortunately, he was completely cured with intensive therapy. In the convulsant stage, left ventricular endomyocardial biopsies were performed that yielded the interesting discovery of unique clustered lipid droplets among the myofibrils. It was suggested that although the pathomechanism of neuroleptic malignant syndrome is unknown, this disease may be characterized by a lipid metabolic disorder of the cardiac muscle cell.

[Nutritional myocardial disorders].

It is well known that the nutritional deficiency possibly causes cardiac dysfunction. Although social hygiene has successfully diminished these cardiac dysfunction in developed countries, patients could be found in certain number under altered clinical profiles than before. Excess intake of carbohydrate drinks and carbohydrates should make beri-beri heart in youth. Not only deficiency but recent dietary habits of excessive nutrition in these developed countries are causing new types of nutritional cardiac dysfunctions such as obesity cardiomyopathy in morbid obese. On the other hand, anorexia nervosa which sometimes shows heart failure and sudden death combines with psychosomatic disorders. In this article, the pathogenesis and treatments are discussed focusing on these three cardiac disorders.

Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study.

The myocardial layer of the pulmonary vein of adult rats was examined by electron microscopy. Among ordinary myocardial cells resembling those of the atrial myocardium, clear cells with structural features similar to those of sinus node cells were identified. They were distributed in the intrapulmonary, preterminal portion of the pulmonary vein. They appeared singly or in small groups among the ordinary myocardial cells. Their cytoplasm was characterised by a paucity of myofilaments, irregular disposition of myofilament bundles, small and oval mitochondria, absence of atrial specific granules and a wide cytoplasmic matrix between intracellular organelles. The intercalated discs of node-like cells were composed of small junctional specialisations. Nerve fibres containing small and large vesicles with and without dense cores were juxtaposed to the node-like cells over an intercellular space of more than 200 nm. Taking into consideration physiological data, the possibility is discussed that the node-like cells may have a potential pacemaking activity and represent an ectopic pacemaker centre in the pulmonary vein.

Immunohistochemical demonstration of S-100 protein in fibroblast-like cells of the guinea-pig heart.

The immunocytochemical localization of S-100 protein was examined in the hearts of adult guinea-pigs. In addition to Schwann cells, adipose cells and chondrocytes, fibroblast-like cells densely distributed in the cardiac skeleton, all of the four valves and tendinous chordae were immunoreactive for S-100 protein. The S-100-positive fibroblast-like cells were conspicuously rounded in shape and extended their thin, thread-like cell processes in opposite directions; the cytoplasm was restricted to perinuclear region. In these morphological features, the cells were distinctly different from ordinary fibroblasts which were immunonegative for S-100 protein. Electron microscopic observation revealed that the S-100-like immunoreactivity was distributed throughout the cytoplasmic matrix in the cell body and processes, but absent from the nuclei and cell organelles. The significance of the S-100 immunopositive fibroblast-like cells was discussed in relation to cartilaginous tissues, which have the potential to form in the region of the cardiac skeleton and valves under both normal and abnormal conditions.

An ultrastructural study on arrhythmogenic right ventricular dysplasia with special reference to lipid droplets.

Myocardial tissues in arrhythmogenic-right ventricular dysplasia (ARVD), which were surgically resected from the site of origin of ventricular tachycardia (VT), were investigated optically and electron-microscopically. The site of origin was found to be occupied by an abundance of adipose cells. In the marginal zone, lipid droplets were obviously increased in count in the cytoplasm of both myocytes and blood capillary-endothelium, rather more than in distant areas. Lipid droplets in the endothelial cells also occurred at a higher frequency in the ARVD group than in any other myocardial disease showing VT. A mechanism which increases lipid droplets in the cytoplasm of cardiomyocytes and endothelial cells operates at the VT origin site in ARVD. Intraendothelial lipids may be an important diagnostic finding in the histology of ARVD.

Left ventricular free wall rupture in acute fulminant myocarditis during long-term cardiopulmonary support.

A 77-year-old woman with acute myocarditis developed cardiogenic shock soon after admission and was given mechanical cardiopulmonary support. Echocardiography revealed severe global left ventricular hypokinesia. After 5 days of mechanical support, left ventricular wall motion gradually began to improve, but the patient died of cardiac tamponade on day 13. At necropsy, a free wall rupture was found where the apical akinetic area bordered the basal portion, an area which had shown better wall motion. Left ventricular free wall rupture in acute myocarditis has not been reported, but this case indicates that it may occur in fulminant myocarditis when a cardiopulmonary support system is used.

Effects of long-term xamoterol in idiopathic dilated cardiomyopathy.

In prospective study, the beta 1-partial agonist xamoterol (200 mg daily) was given to 26 patients with idiopathic dilated cardiomyopathy (DCM) in addition to conventional therapy with digitalis, diuretics and vasodilators. The patients were followed for 35 +/- 15 months (6-53 months). Cardiothoracic ratio (CTR), left ventricular end-diastolic dimension (LVDD) and exercise heart rate decreased, and exercise duration, fractional shortening (FS) and ejection fraction (EF) increased after xamoterol therapy. Twenty-one patients survived and one patient dropped out at 7 months. Twelve of the 20 patients improved their NYHA functional class. Blood norepinephrine concentration (NE), LVDD, FS, EF and pulmonary capillary wedge pressure (PCWP) after xamoterol were significantly better in survivors than in non-survivors. Survival rate at 3 years was 83%. The results suggest that adjunctive xamoterol therapy in DCM has a beneficial effect on hemodynamics and symptoms. Prognosis will be satisfactory if improvement in parameters such as NE, LVDD, FS, EF and PCWP is seen during xamoterol therapy.

Risk factors and the effects of xamoterol in idiopathic dilated cardiomyopathy.

A long-term follow-up study was performed for 110 patients with idiopathic dilated cardiomyopathy (DCM) for 34 +/- 12 months (range 3-122 months). Thirteen patients died of heart failure, 15 of sudden death and one of non-cardiac death. The 3- and 5-year survival rates were 78 and 62%, respectively. The important factors in predicting the 3-year survival rate were left ventricular end-diastolic volume index (LVEDVI > or = 150 ml/m2 = 66%, < 150 ml/m2 = 93%, p < 0.01), myocardial cell diameter (> 25 microns = 42%, < or = 25 microns = 87%, p < 0.05) and sustained ventricular tachycardia (VT present = 32%, absent = 85%, p < 0.01). In a prospective study, 26 patients with DCM were given a beta 1-partial agonist, xamoterol (200 mg daily) and were followed for 35 +/- 15 months (6-53 months). The cardiothoracic ratio, left ventricular end-diastolic dimension and exercise heart rate decreased, and the exercise duration, fractional shortening and ejection fraction increased after xamoterol therapy. The 3-year survival rate was 83%. These results suggest that the important factors in predicting the survival rate of DCM patients were LVEDVI, myocardial cell diameter and the occurrence of VT. Adjunctive xamoterol therapy in DCM had a beneficial effect on hemodynamics and symptoms.

Possible intramural site of reentrant circuit in ventricular tachycardia of nonischemic cause. Pre and intraoperative mapping studies.

A patient with a drug-refractory sustained ventricular tachycardia (VT) of nonischemic cause was mapped for the site of VT origin. The intraoperative mapping showed the earliest site of activation of VT on the epicardial surface at which the initial deflection of the local electrogram preceded the onset of the QRS complex of VT by 45 msec. The endocardial mapping could not indicate the site at which the electrogram was found prior to the onset of the QRS complex of VT. However, at the earliest site of the endocardial mapping, VT was entrained without change in the configuration of the QRS complex. After cessation of the rapid pacing, VT resumed at the intrinsic rate and the first post-paced return cycle was identical to each paced cycle length. The interval from the stimulus to the orthodromically captured local electrogram at the pacing site was identical to the cycle length of VT. Catheter ablation from the endocardial side and a cryoablative procedure from the epicardial side failed to eradicate the VT. These findings suggest an intramural site of VT origin and reentrant circuit of which the exit and the entrance face the epicardial and the endocardial surfaces, respectively.

A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction.

It is suspected that autoimmune disease processes are involved in the pathogenesis of a part of giant cell myocarditis. However, evidence for autoimmunity has rarely been demonstrated in clinical investigations. In this study, we have demonstrated a new animal model of autoimmune myocarditis characterized by the appearance of multinucleated giant cells. Lewis rats were immunized twice with human cardiac myosin fraction in complete Freund's adjuvant. Cardiac myosin fraction was prepared from the ventricular muscle of human hearts. Three weeks after the first immunization, acute and severe myocarditis was elicited in all rats. This myocarditis was characterized by massive pericardial effusion, enlargement of the heart, and gray discoloration of the cardiac muscle. Microscopically, there was marked cellular infiltration consisting of mononuclear cells, neutrophils, fibroblasts, and a considerable number of multinucleated giant cells. Extensive myocardial necrosis was also present. The heart weights increased from the third week to the fourth week and then gradually decreased. The titer of anti-myosin antibodies began to elevate from the second week and remained high until the sixth week. In the sixth week, inflammation became smoldering and the multinucleated giant cells disappeared. These findings indicate that the cardiac myosin fraction contains myocarditogenic antigen and that giant cell myocarditis can be induced by autoimmune involvement. To our knowledge, this is the first report of experimental giant cell myocarditis, which is closely similar to human giant cell myocarditis in its histology and clinical course.

Catheter-type defibrillation electrode using glassy carbon: results of electrode implantation.

The implantable defibrillator, developed by Dr Michel Mirowski, is a remarkable electric therapeutic device which has been in clinical use since 1980 in the treatment of life-threatening arrhythmia. However, as the present life span of this device is only 3 years, research is being carried on to extend the lifetime with improved stimulation methods, circuits and electrodes. In particular, the electrode system which is inserted into the right ventricle has more than 50 times the electrode area of a pacing electrode and is prone to degradation. What is needed is biocompatibility and electrical stability, similar to that of cardiac pacemaker electrodes, which can be used for more than 10 years. For this purpose, we focused on a conductive ceramic as a new material for the defibrillation electrode instead of the previously-used metal. We selected glassy carbon as our electrode material and tested the surface condition through acute and chronic animal experiments. No clots formed around the electrodes after a 3-month implantation, nor were there surface disorders after the defibrillation stimulations. We concluded that glassy carbon is a promising material for future defibrillation electrodes.

[Myocardial involvement in female Fabry's disease: evaluation by thallium-201 myocardial scintigraphy].

Fabry's disease is characterized by an inherited X-linked disorder of glycosphingolipid catabolism, and heterozygous women affected with this disease who show overt symptoms including cardiac manifestations have rarely been reported. To elucidate the features of myocardial involvement in female patients, noninvasive techniques including exercise stress thallium-201 myocardial scintigraphy were performed. Three female patients, Cases 1-3, 26, 29 and 50 years of age, were documented low leucocytic alpha-galactosidase activities of less than 48% of normal (67.92-16.2 nmol/mg protein/h). They were examined using ECG, two-dimensional echocardiography (2-D Echo), Holter ECG, treadmill test and stress scintigraphy. On the ECG, negative T waves were shown in leads III and aVF in Cases 1 and 2. Left ventricular high voltage, giant negative T waves and short PR intervals were seen in Case 3. The 2-D Echo revealed neither valvular change nor left ventricular hypertrophy. On the Holter ECG, monofocal ventricular premature beats were occasionally observed in Cases 1 and 3. The treadmill test showed positive ST changes only in Case 2. On the exercise stress scintigraphy, uptake of thallium-201 was enhanced in the apex of the heart in Cases 2 and 3. Low uptake areas of thallium-201 were observed in Case 3. The ventricular angiogram revealed slight hypertrophy of the wall of the apical portion. In endocardial biopsies from the right ventricle, myelinoid lamellar inclusions were demonstrated in myocardial cells electron microscopically. Increased uptake of thallium-201 in the apex was noted in two of the three patients, but no apical thickening was noticed in any of the three cases by 2-D Echo. From the result of the biopsy of Case 3, the increased apical uptake of thallium-201 seems to reflect thickening caused by the deposition of glycosphingolipid. It was concluded that myocardial involvement in female Fabry's disease may occur early in the third decade and that the lesions could be detected with high sensitivity by thallium-201 myocardial scintigraphy.

[An ultrastructural study of arrhythmogenic right ventricular dysplasia: comparison among islands of myocytes, marginal zone and control zone].

During surgery for intractable ventricular tachycardia, an ultrastructure of cardiac tissue was obtained from two male patients, 54 and 59 years old. On light microscopy, the histopathology was compatible with arrhythmogenic right ventricular dysplasia (ARVD). These myocardial samples were divided into three parts: an island of myocytes (some grouped cardiocytes floating on the fatty layer), a marginal zone (the parts of the myocardium surrounding the fatty infiltration), and a distant zone (as a control muscle). In the island of myocytes and marginal zone, myocardial hypertrophy, variability of cell diameter, degenerative changes of myocytes and interstitial fibrosis were more distinct than in the control zone. In addition, the number and diameter of intrasarcoplasmic lipid droplets detected among interstices of myofibrils also increased in both groups. The variability in number and diameter of the lipid droplets seemed to have a relation to the pathogenesis of fatty infiltration into the myocardium in ARVD. Lipid droplets were also revealed not only in the nuclei of myocytes but in the endothelial cells of capillaries and small vessels. Internuclear inclusion of the lipid was limited to the island and margin, but the lipid droplets in the endothelium spread widely in every zone. These lipid droplets are expected to have diagnostic value in the histological study of ARVD using endomyocardial biopsy.

Juvenile cases of restrictive cardiomyopathy without eosinophilia.

Two cases of juvenile restrictive cardiomyopathy are presented, in which we highlight the useful role of noninvasive diagnostic techniques including the apexcardiogram, echocardiography, and magnetic resonance (MR) imaging.

Electrophysiologic study and ergonovine provocation of coronary spasm in unexplained syncope.

A total of 38 patients with syncope in whom a cause was not assigned or suggested by the initial history, physical examination and electrocardiography (ECG) were studied. Twenty-four patients underwent cardiac examination with Holter ECG, electrophysiologic testing with programmed ventricular stimulation (EPS) and/or coronary arteriography including ergonovine provocation (ergonovine CAG). The study with Holter ECG, EPS and ergonovine CAG yielded a presumptive diagnosis in 36 patients (36/38 = 95%), 11 with vasopastic angina, 7 with ventricular tachycardia, 4 with ischemic heart disease, 9 with sick sinus syndrome (SSS), 1 with drug induced SSS, 3 with A-V block, 1 with supraventricular tachycardia, 1 with hypertrophic cardiomyopathy, 1 with aortic valve stenosis and 1 with carotid sinus syndrome (included are 1 patient with ventricular tachycardia+ischemic heart disease, 1 with SSS+vasopastic angina and 1 with ventricular tachycardia+vasospastic angina). Therapy based on these findings provided complete symptomatic relief in all patients during a mean follow up of 25 +/- 10 months (range 5-45 months). In conclusion, EPS and ergonovine CAG are useful in the diagnosis and therapy of unexplained syncope.

[An echocardiographic study of alcoholic cardiomyopathy after total abstinence].

Left ventricular function of alcoholic cardiomyopathy with congestive heart failure was investigated by echocardiography during total abstinence for six months. In five of 13 cases, left ventricular ejection fraction (LVEF) was normalized to 55% or more and left ventricular end-diastolic dimension (LVEDd) was reduced to 5.7 cm or less during the study. In the remaining eight patients, no improvement was observed. In the responsive group, two patients showed an increase of LVEF and a reduction of LVEDd simultaneously, but three showed an earlier change in LVEDd. This normalization of LVEF and LVEDd was recognized from three to 12 weeks after abstinence. No significant differences were detected between the responsive and non-responsive groups concerning their age, daily intake of alcohol and period of drinking, NYHA cardiac functional class, the period of experiencing cardiac symptoms and the cardiothoracic ratio by chest radiography. The ratio of left ventricular radius to wall thickness (R/Th) remained 2.9 or less in all of the responsive group, but seven of eight in the non-responsive group showed 2.9 or more. Left atrial dimension was reduced to the normal range except in one, but its normalization did not correlate with the change of left ventricular function. Consequently, after total abstinence from alcohol intake, both left ventricular end-diastolic dimension and ejection fraction improved rapidly, and their normalization could be highly expected. Echocardiography is very helpful in predicting the effect of total abstinence on left ventricular function in alcoholic cardiomyopathy.