An experimental model for dilated cardiomyopathy after rabbit coronavirus infection.

A rabbit model for coronavirus-induced dilated cardiomyopathy is described. Acute rabbit coronavirus infection results in virus-induced myocarditis and congestive heart failure. Of the survivors of rabbit coronavirus infection, 41% had increased heart weight and heart weight-to-body weight ratios, biventricular dilation, myocyte hypertrophy, myocardial fibrosis, and myocarditis consistent with the development of dilated cardiomyopathy. These changes were also seen in the remaining 59% of the survivors, except that the degree of myocyte hypertrophy was reduced and only right ventricular dilation was present. In most survivors, myocarditis was usually mild (1-5 foci/transverse section), but in some cases it was severe (> 20 foci/transverse section). Interstitial and replacement fibrosis was more pronounced in the papillary muscles. These data suggest that rabbit coronavirus infection may progress to dilated cardiomyopathy.     

ECG changes after rabbit coronavirus infection

This study examines the electrocardiographic (ECG) changes following rabbit coronavirus (RbCV) infection. We have shown that infection with RbCV results in the development of myocarditis and congestive heart failure and that some survivors of RbCV infection go on to develop dilated cardiomyopathy in the chronic phase. Serial ECGs were recorded on 31 RbCV-infected rabbits. Measurements of heart rate; P-R interval; QRS duration; QTc interval; and P-, QRS-, and T-wave voltages were taken. The recordings were also examined for disturbances of conduction, rhythm, and repolarization. The acute and subacute phases were characterized by sinus tachycardia with depressed R- and T-wave voltages as well as disturbances of conduction, rhythm, and repolarization. In most animals in the chronic phase, the sinus rate returned to near-baseline values with resolution of the QRS voltage changes. The ECG changes observed during RbCV infection are similar to the spectrum of interval/segment abnormalities, rhythm disturbances, conduction defects, and myocardial pathology seen in human myocarditis, heart failure, and dilated cardiomyopathy. Because animals often died suddenly in the absence of severe clinical signs of congestive heart failure during the acute phase, RbCV infection may increase ventricular vulnerability, resulting in sudden cardiac death. RbCV infection may provide a rare opportunity to study sudden cardiac death in an animal model in which the ventricle is capable of supporting ventricular fibrillation, and invasive techniques monitoring cardiac function can be performed.     

Mural thrombus in experimental viral myocarditis in mice: relation between thrombosis and congestive heart failure

In a study of the time of appearance of mural thrombus and the relation between thrombosis and congestive heart failure in acute viral myocarditis 180 BALB/c mice were inoculated intraperitoneally with the M variant of encephalomyocarditis virus. Thirty mice were killed on day 5 and 50 mice each on days 7, 10, and 14. Of the 176 mice with myocarditis, 25 (14.2%) developed congestive heart failure after day 9 and 22 (12.5%) showed thrombi after day 6. Most of the thrombi were at the sites of endocardial lesions in the atria. The total incidence of thrombosis in mice with congestive heart failure was significantly higher than that in mice without. None of the 50 uninoculated control mice developed thrombi. The present study suggests that acute viral myocarditis carries an appreciable risk of thromboembolism and that congestive heart failure is a risk factor for thrombosis.     

Left ventricular pressure-volume relationship in a murine model of congestive heart failure due to acute viral myocarditis

OBJECTIVES: This study, performed in a murine model of encephalomyocarditis virus myocarditis, used a new Millar 1.4F conductance-micromanometer system for the in vivo determination of the left ventricular (LV) pressure-volume relationship (PVR). BACKGROUND: Viral myocarditis is an important cause of congestive heart failure and may lead to dilated cardiomyopathy. However, the hemodynamic changes associated with its acute phase have not been analyzed in detail. METHODS: Four-week-old DBA/2 mice were inoculated with EMCV (day 0). Serial hemodynamic measurements, compared with uninfected control mice were made on days 0, 1, 3, 4, 5, 7, 9, 12, and 14. RESULTS: On day 1, the hearts of infected mice manifested enhanced contractile function, decreased LV compliance, and abnormal diastolic function with increased LV end-diastolic pressure (EDP). Mean stroke index, ejection fraction (EF), and cardiac index (CI) were significantly higher than in uninfected control mice (p < 0.05). Contractile function decreased from days 4 to 14. On day 7, when hemodynamic abnormalities consistent with heart failure culminated, end-diastolic volume (EDV), EDP, and EDPVR were significantly higher, and CI, EF, end-systolic pressure (ESP), and ESPVR significantly lower in the infected than in control mice. Heart rate remained comparable in both groups. Although heart failure receded between day 9 and day 14, ESPVR, ESP, and EF remained significantly depressed up to day 14, and EDV and EDP remained significantly higher. CONCLUSIONS: These hemodynamic data provide new insights into the pathophysiology of acute viral myocarditis and may be useful in the development of therapeutic interventions.     

Therapy for pediatric myocarditis

Optional statement Pediatric myocarditis is most often associated with the acute or subacute onset of congestive heart failure in a previously healthy child. Myocarditis presenting with acute, severe symptomatology, termed fulminant myocarditis, has a high rate of recovery. Aggressive supportive care is indicated in fulminant myocarditis, including mechanical circulatory support. For subacute heart failure, supportive care remains the mainstay of therapy for myocarditis. A number of uncontrolled pediatric studies using both immunosuppressive therapy and/or immunomodulating therapy with intravenous gamma globulin have suggested these therapies are safe and useful in treating pediatric myocarditis. However, translating these results into recommended, routine therapy for pediatric myocarditis is complicated by the high rate of spontaneous improvement of myocarditis with supportive care, and the lack of demonstrable benefit for immunosuppressive and immunomodulating therapies in blinded, randomized, placebo-controlled trials in adult myocarditis. Heart transplantation remains the final therapeutic option for children with myocarditis and intractable severe heart failure.     

Clinical findings in acute viral myocarditis. With special attention to experimental and immunological evidence

According to analysis of 40,000 autopsies, the incidence of myocarditis is approximately 3.5%, the diagnosis of which had not been established in the majority prior to death. The clinical characteristics of myocarditis encompass a wide spectrum from an asymptomatic course to sudden cardiac death. Symptoms and findings of congestive heart failure or an inflammatory virus disease may be present. There is usually evidence of nonspecific clinical, radiologic, electrocardiographic, echocardiographic and blood chemistry abnormalities. In the presence of myocarditis, gallium scintigrams are generally pathologic. Virologic and serologic studies may have an important, albeit not decisive, role in establishing the diagnosis. In the acute phase, endomyocardial biopsy can document inflammatory changes. For the most part, treatment is symptomatic. Ventricular arrhythmias and high-grade conduction disturbances prerequisite vigilant monitoring as well as adequate medical and, if indicated, electrical therapy. In addition to conventional treatment, steroids, more recently, in combination with azathioprine, have been employed in patients with subacute and chronic myocarditis. The course of myocarditis is frequently benign although, in some cases, congestive heart failure may develop. Laboratory studies in DBA/2 mice with congestive heart failure subsequent to surviving myocarditis have shown myocardial fibrosis and hypertrophy without mononuclear cell infiltrates indicative of transition to dilated cardiomyopathy.     

Nonspecific myocarditis: a statistical and clinicopathological study of autopsy cases

Among a total of 634,440 autopsy cases in "The Annuals of Pathological Autopsy Cases in Japan" from 1958 to 1984, 929 cases with nonspecific myocarditis were registered. The average incidence was 0.15%, fluctuating around 3- to 5-year intervals with a remarkable rise observed after 1974. The major complications in cases of myocarditis were pneumonitis, hepatitis or hepatic cirrhosis, pancreatitis, malignancies, lymphatic or thymic involvements. A clinicopathological study of 36 cases of myocarditis and 27 cases of postmyocarditic cardiomegaly indicated a classification of acute, subacute, healing and chronic or recurrent stages as well as dilatation-hypertrophy- and right ventricle-dominant types. Acute myocarditis was characterized by diffuse inflammatory cell infiltration and showed various types of arrhythmias and shock. Subacute myocarditis showed ventricular dilatation, edematous interstitium and severe congestive heart failure. Chronic myocarditis with dilatation and/or hypertrophy and irregular fibrosis included right ventricular involvement, endomyocardial disease, sick sinus syndrome in selected cases, congestive heart failure in most cases, and showed a male predominancy. Postmyocarditic cardiomegaly was similar to chronic myocarditis but showed more hypertrophy, preexcitation waves and prominent negative T waves in electrocardiography and sudden death.     

Recurrent reversible dilated cardiomyopathy secondary to viral and streptococcal pneumonia vaccine-associated myocarditis

Myocarditis is inflammation of cardiac muscle, which may be acute, subacute, or chronic with either focal or diffuse involvement of the myocardium. This leads to a cardiomyopathy with clinical features of heart failure as well as echocardiographic evidence of global dilation of the cardiac chambers. There are numerous reports in the literature of viral myocarditis causing dilated cardiomyopathy; however, there are no reports of recurrent viral myocarditis and vaccine-associated myocarditis in a single patient with complete reversal of the cardiomyopathy and return to normal cardiac function. We present a case of recurrent myocarditis in a female patient caused by a viral upper respiratory infection and streptococcal pneumonia vaccination who presented with recurrent episodes of reversible cardiomyopathy.     

An experimental model for congestive heart failure after encephalomyocarditis virus myocarditis in mice

Severe myocarditis was induced in inbred BALB/c mice inoculated with the M variant of encephalomyocarditis (EMC) virus. The mortality rate was maximal on the fourth day, then decreased gradually, but increased again between the eleventh and fourteenth days. Gross myocardial lesions were seen on the surface of the ventricles in 62 of 125 mice (49.6%) after the fifth day. These myocardial lesions were observed more frequently in the dead mice (46 of 49, 93.9%). Cavity dimensions and wall thickness were measured in two groups of mice with myocarditis. On days 5-7, the cavity dimensions of the right (RV) and left (LV) ventricles in inoculated mice (0.92 +/- 0.51 mm and 1.21 +/- 0.18 mm, respectively) were significantly larger than those in controls (RV 0.54 +/- 0.17, LV 1.01 +/- 0.15; p less than 0.05). The wall thickness of the RV (0.46 +/- 0.09, controls 0.64 +/- 0.11; p less than 0.001) and the LV (0.97 +/- 0.13, controls 1.12 +/- 0.19; p less than 0.05) was significantly decreased. On days 8-14, dilatation of the LV was more pronounced (1.48 +/- 0.37, p less than 0.005) than during days 5-7, and the interventricular septum was also thinner. Pleural effusion, ascites and congestion of the lungs and liver were noted, and death seemed due to congestive heart failure. This study is the first documentation of congestive heart failure after viral infection is an experimental animal.     

The effect of alpha 1-blocker, bunazosin on a murine model of congestive heart failure induced by viral myocarditis.

The purpose of this study was to investigate the therapeutic effect of an alpha 1-blocker, bunazosin, using an experimental murine model of congestive heart failure induced by viral myocarditis. This model is characterized by a high incidence of severe myocarditis and subsequent congestive heart failure, and is suitable for the evaluation of the effect of drugs. To estimate myocardial damage objectively and quantitatively, we used antimyosin monoclonal antibody in addition to histopathological grading. Four-week-old BALB/c mice were inoculated with encephalomyocarditis virus. The mice were injected daily with bunazosin or saline as a placebo from the day of viral inoculation until day 7 (protocol-I) or day 14 (protocol-II), or from day 4 to day 14 (protocol-III). They were then injected with 1.5 microCi of indium-111 labeled antimyosin antibody and were killed 24 h later. The antimyosin cardiac uptake was counted and histopathological grading was performed. The heart-weight to body-weight ratio, left ventricular dimension, histopathological grades and antimyosin cardiac uptake were significantly lower in the bunazosin group than in the placebo group in protocol-II, but not in protocol-I or protocol-III. Bunazosin showed a protective effect against viral myocarditis only when it was started early after infection and continued until the stage of congestive heart failure.     

Reversible asymmetric septal hypertrophy in acute myocarditis. Serial findings of two-dimensional echocardiogram and thallium-201 scintigram

Serial two-dimensional echocardiographic and thallium-201 scintigraphic findings are described in a patient with acute myocarditis diagnosed by endomyocardial biopsy. On the 4th day of illness, just before the onset of congestive heart failure, the echocardiogram showed asymmetric septal hypertrophy (IVS/PW = 16 mm/10 mm = 1.6) and thallium-201 scintigram showed the ventricular septal thickening. On the 8th day of illness, when severe congestive heart failure was seen, asymmetric septal hypertrophy disappeared (IVS/PW = 8 mm/8 mm = 1.0), the left ventricle dilated markedly (LVDd = 63 mm), and the wall motion became poor (EF = 0.24). After one month, when congestive heart failure and clinical inflammatory findings disappeared, the contractility somewhat improved (EF = 0.43), although marked left ventricular dilatation remained. Thallium-201 scintigram showed some scattered persistent perfusion defects, thinning of the ventricular septal thickening, and dilatation of the left ventricle. The right ventricular endomyocardial biopsy revealed the histologic findings of the late stage of acute myocarditis. It is concluded that transient thickening of the ventricular wall may represent early changes in acute myocarditis.     

Pathological substratum for clinical features of fatal myocarditis

Heart autopsies in six cases of fatal myocarditis were examined clinicopathologically. Included were 2 cases in the acute stage, 1 in the subacute stage and 3 in the chronic stage. As to microscopical dating changes, at the acute stage, numerous inflammatory cells were found in the edematous interstitium after 2 days from onset and degeneration, i.e., destruction of myocardial cells without fibrous replacement, was also noted after 11 days. At the subacute stage, irregular patchy and slightly loose fibrosis with inflammatory cells and vascularization was found after 50 days. At the chronic stage, loose fibrosis with inflammatory cells and tight fibrosis without the cells, that is, active and healed myocarditis co-existed. All cases showed heart failure of varying degrees, and also showed, respectively, complete AV block and ventricular fibrillation at the acute stage, and complete AV block and sustained ventricular tachycardia at the chronic stage. In myocarditis, which often was difficult to diagnose clinically, the pathological findings corresponded well to the clinical features retrospectively.     

Varicella zoster myocarditis progressing to cardiomyopathy and cardiac transplantation.

The case of a 12 year old schoolgirl with heart failure due to varicella myocarditis is reported. Heart failure and cardiogenic shock were evident 21 days after the appearance of the rash, and cardiac transplantation was performed two weeks later. Myocarditis is a serious complication of varicella zoster infection and heart failure may be fulminant. Endomyocardial biopsy changes consistent with myocarditis were documented six days after the start of heart failure. The histological changes, however, developed into those of idiopathic dilated cardiomyopathy (with anisonucleosis and fibre width variation) over a seven day period. This case provides further evidence for the link between viral myocarditis and idiopathic cardiomyopathy and underlines the value of immediate endomyocardial biopsy in heart failure of recent onset. Cardiac transplantation led to a rapid and full recovery.     

Influenza-induced rhabdomyolysis after autologous peripheral blood stem cell transplantation for malignant lymphoma

We report influenza-induced rhabodmyolysis and congestive heart failure after high-dose therapy and hematopoietic stem cell transplantation for malignant lymphoma. Four months after autologous peripheral blood stem cell transplantation for the treatment of malignant lymphoma, a 65-year-old Japanese man developed acute congestive heart failure requiring artificial ventilation and rahbdomyolysis. Since influenza A virus was documented from his nasal cavity, he was diagnosed as rhabdomyolysis and congestive heart failure induced by influenza A infection. Neuraminidase inhibitor (oseltamivir 150 mg/ day for 5 days) was administrated, and heart failure and respiratory status were improved. Our experience suggests that early treatment with neuraminidase inhibitor may improve the clinical outcome of influenza-induced rhabdomyolysis and congestive heart failure.     

Acute myocarditis in fulminant systemic sclerosis.

Myositis and myocarditis have been reported in progressive systemic sclerosis, and these patients have had favorable therapeutic responses to intravenous pulse methylprednisolone. Thus far, premortem biopsy documentation of myocarditis and myocardial fibrosis has not been reported in such patients. We report the case of a patient with subacute congestive heart failure six months after she developed Raynaud's phenomenon. Clinical examination was typical of scleroderma but there was no proximal muscle weakness. She had elevated creatine kinase and MB-creatine kinase and laboratory evidence of hypothyroidism. Echocardiogram demonstrated four-chamber dilatation and severe left ventricular dysfunction. Cardiac catheterization revealed normal epicardial coronary arteries and severely decreased cardiac index. A skin biopsy specimen of the forearm was consistent with diffuse systemic sclerosis, and an endomyocardial biopsy specimen demonstrated mild fibrosis and lymphocytic infiltrate. Her heart failure initially improved with digoxin, furosemide, and enalapril. She also received L-thyroxine and intravenous methylprednisolone. The heart failure progressed over the next six weeks and she died. Patients with scleroderma and new-onset heart failure may have acute myocarditis.     

An elderly case of triple-vessel coronary artery disease with alternating bundle branch blocks in serial electrocardiograms

An 82-year-old woman was admitted with severe chest pain and orthopnea on January 17, 1997. Physical examination revealed bilateral leg edema and cyanosis at the periphery of the extremities. The serum CK level was 488 IU/l on admission and increased to a maximum value of 4,866 IU/l 8 hours after admission. An echocardiogram demonstrated diffuse severe hypokinesis in the left ventricle. Serial electrocardiograms showed transient right bundle branch block, left bundle branch block, and normal sinus rhythm. The patient was diagnosed as having congestive heart failure. Artificial ventilation was performed, and furosemide, isosorbide dinitrate and dopamine were administered. A right ventricular endomyocardial biopsy performed on the 13th hospital day demonstrated moderate hypertrophy and disparity of cardiac myocytes and fibrosis around the myocytes, and few inflammatory cells in the specimens. This biopsy finding was not compatible with acute myocarditis but with the chronic stage of myocarditis. The patient was discharged on the 45th hospital day, but returned because of a recurrence of congestive heart failure. After an improvement of the heart failure, a coronary angiography was performed on the 20th hospital day. The coronary angiography revealed significant stenosis in three vessels. This elderly patient had congestive heart failure and triple-vessel coronary artery disease with transient alternating bundle branch blocks on serial electrocardiograms. Alternating bundle branch blocks and diffuse left ventricular dysfunction was considered to be induced by the aging process, postmyocarditic change of myocytes, and triple-vessel coronary artery disease in this case.     

Experimental rat model representing both acute and chronic heart failure related to autoimmune myocarditis

Summary The most important clinical manifestation of myocarditis is congestive heart failure. The precise mechanisms of heart failure during myocarditis have not been elucidated because no animal model that would permit in vivo study of hemodynamics in severe active myocarditis has been available. We monitored hemodynamics and left ventricular function in a rat model of experimental autoimmune myocarditis to determine if this model could be useful for the study of in vivo hemodynamics in severe active myocarditis. Lewis rats were immunized with human cardiac myosin suspended in complete Freund's adjuvant. Baseline hemodynamics were measured using an ultraminiature catheter pressure transducer via the right internal carotid artery, 4 weeks after immunization in one group of rats (acute phase) and 3 months after immunization in another group (chronic phase). Untreated rats served as the control group. Hemodynamic measurements were also obtained after infusion of dobutamine in the acute-phase and chronic-phase groups. The heart weight-to-body weight ratios were significantly higher in both the acute-phase group and the chronic-phase group compared with normal control rats. The baseline left ventricular systolic pressure was significantly lower in the chronic phase group than in the control group. Peak dP/dt and peak -dP/dt were significantly lower in both the acute-phase group and the chronic-phase group compared with the control group. Dobutamine significantly increased left ventricular systolic pressure, peak dP/dt, and peak -dP/dt in the chronic-phase group but caused only minor changes in hemodynamic variables in the acute-phase group. In vivo measurements of hemodynamic variables indicated the presence of left ventricular dysfunction in rats with experimental autoimmune myocarditis. This animal model may be useful for the study of both acute heart failure related to acute myocarditis and chronic heart failure due to diffuse myocardial fibrosis.     

Expression and distribution of atrial natriuretic polypeptide in the ventricles of children with myocarditis and/or myocardial infarction secondary to Kawasaki disease: immunohistochemical study

We studied the expression and distribution of atrial natriuretic polypeptide in the ventricles of 27 autopsied children with Kawasaki disease. Fourteen of the children had died in the acute stage of the disease. Three without any coronary artery aneurysms died due to myocarditis, while 11 with coronary artery aneurysms also had myocarditis but died of coronary heart disease. Histologic evidence of acute myocardial infarction was noted in three children who died of coronary heart disease. In the 14 children with acute-stage deaths, no abnormal expression of atrial natriuretic polypeptide was noted in the ventricles, despite the presence of heart failure in seven of them for 2 to 22 days before death. The other 13 patients had coronary artery aneurysms and died in the healed stage. In three patients with granulation tissue and congestive heart failure, myocytes in foci around the granulations were moderate to markedly positive for atrial natriuretic polypeptide. These three patients died over 8 days after the onset of their first myocardial infarct. Of 10 patients with old myocardial infarction, four had a history of congestive heart failure. They demonstrated moderate or marked atrial natriuretic polypeptide expression in extensive regions around sites of massive fibrosis, and foci of slight expression in the inner third of the noninfarcted region of the ventricle. In the other six patients without congestive heart failure, there was slight or moderate expression in foci around sites of massive fibrosis. We concluded that the expression of atrial natriuretic polypeptide appeared more than 1 week after the onset of acute myocardial infarction in the ventricles of children with Kawasaki disease who died in the healed stage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome

The prevalence of myocarditis was retrospectively evaluated in 71 consecutive necropsy patients who died from acquired immunodeficiency syndrome (AIDS) between 1982 and 1986. Myocarditis was found in 37 cases (52%). Biventricular dilation at necropsy was present in seven cases (10%) and was accompanied by myocarditis in each case; fatal congestive heart failure occurred in four of these seven cases. Although viral, protozoan, bacterial, fungal and mycobacterial opportunistic pathogens were present in myocardial sections of 7 of 37 myocarditis cases, the etiology of myocarditis in the majority of these patients with AIDS remained idiopathic. Thus, myocarditis is a frequent finding at necropsy in patients with AIDS and may contribute to the development of biventricular dilation.     

降钙素原与白介素-6与急性心力衰竭继发肺部感染的关系

目的观察分析血清降钙素原（PCT）与白介素-6（IL-6）与急性心力衰竭（心衰）并发肺部感染中的关联性。方法：将急性心衰患者184例分别于发病后第1、2、3、5天抽取静脉血,检测血清IL-6、PCT的变化,同时依据患者临床肺部感染评分及痰培养结果将患者分为单纯心衰组与心衰并发肺部感染组,分析两组患者IL-6、PCT动态变化的意义。结果：心衰发生后第1、2天单纯心衰组与并发肺部感染组炎性反应指标较正常值明显增高。单纯心衰组发生后第2天PCT达到高峰,第3、5天PCT明显下降,降低幅度大于50％。但第3天单纯心衰组有59％患者血清PCT≥2．0 μg／L;而继发肺部感染组第1、2天血清PCT水平也表现明显升高,两组比较,差异无统计学意义。但第3天及第5天患者血清PCT水平持续升高或下降幅度〈30％。IL-6的动态变化：单纯心衰组发生后IL-6缓慢上升,第3天白IL-6达到高峰,持续升高至第5天下降不明显;而肺部感染组各时点观察IL-6水平持续升高,两组比较,差异无统计学意义。结论：急性心衰发生后,血清PCT水平的动态变化与继发肺部感染有关联。