Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction

Recent molecular studies have suggested that viral myocarditis frequently underlies human congestive cardiomyopathy; however, only moderately sensitive and specific techniques were used. Polymerase chain reaction (PCR) gene amplification is a sensitive, specific technique ideally suited for the diagnosis of viral disease in small tissue samples where low copy numbers of the viral genome may be present. Using PCR and high stringency condition, we screened biopsies taken from 48 patients with clinically suspected myocarditis or dilated cardiomyopathy. Five patients demonstrated positive enteroviral signals by PCR; two of them had myocarditis by pathology, whereas the other three had changes consistent with cardiomyopathy. Four other patients had myocarditis diagnosed by pathology from 3 months to 1 year earlier but were now negative by both PCR and pathology. Both pathology and PCR were negative for active myocarditis in all other patients. Ventricular samples taken from left ventricular myectomy in four additional patients with hypertrophic cardiomyopathy, normal human ventricle samples, and uninfected monkey kidney cells were also negative by PCR. This study supports a link between viral infection and dilated cardiomyopathy in some patients. PCR gene amplification provides a new diagnostic approach to patients with suspected myocarditis.     

A case of biopsy-proven myocarditis progressing to autopsy-proven dilated cardiomyopathy

A 22-year-old man presented with congestive heart failure following flulike symptoms. The diagnosis of acute myocarditis was confirmed by endomyocardial biopsy, which revealed mild infiltration of inflammatory cells. A favorable response to beta-adrenergic receptor blockade was seen, and the patient was discharged without symptoms. Five months later, however, congestive heart failure recurred, and intracardiac thrombi were demonstrated. The patient died after two months. Postmortem examination revealed left ventricular dilatation with slight interstitial fibrosis; the diagnosis was dilated cardiomyopathy. Thus, progression of biopsy-proven myocarditis to dilated cardiomyopathy 10 months after the onset of disease was documented.     

Recurrent left ventricular mural thrombi in a patient with acute myocarditis

Summary A case of acute myocarditis with recurrent left ventricular mural thrombi in a 59-year-old man is reported. Two-dimensional echocardiogram demonstrated left ventricular mural thrombus with apical dyskinesis on the 2nd day after the onset of chest oppression. No hemoagglutination abnormalities were present. Anticoagulation treatment with heparin was initiated. A two-dimensional echocardiogram obtained on the 15th day showed that the left ventricular wall motion had become normal and that the thrombus had disappeared. However, on the 38th day, a new pedunculated free mobile thrombus was found in the apical part of the left ventricle despite the normal wall motion. By the 46th day, the new thrombus had disappeared.The present case suggests that mural thrombi can occur in the absence of left ventricular dyskinesis and dilatation. Anticoagulation therapy resolved the mural thrombi but could not prevent the recurrence at the apex. Thus, in acute myocarditis, a mural thrombus may appear as a result of the endocardial damage, even when blood stasis is absent.     

Dilated Cardiomyopathy With Left Ventricular Thrombi as a Presenting Feature of Cushing Disease

We report on a 20-year-old man with dilated cardiomyopathy and intracardiac thrombi associated with Cushing disease (CD). The patient presented with symptomatic heart failure. Follow-up echocardiography showed 2 thrombi in the apex of the left ventricle, which resolved after intravenous heparin therapy. The patient was first treated symptomatically, and then trans-sphenoidal adenomectomy was performed. Although cortisol excess alone may not be sufficient to produce severe cardiomyopathy, progressive improvement of cardiac function was observed within 3 years after surgery.     

Dilated cardiomyopathy update: infectious-immune theory revisited

Dilated cardiomyopathy is characterized by dilatation of the left or right ventricle, or both ventricles. The degree of myocardial dysfunction is not attributable to abnormal loading conditions. The infectious-immune theory has long been hypothesized to explain the pathogenesis of many etiologically unrecognized dilated cardiomyopathies. Inflammations followed by immune reactions, which may be excessive, in the myocardium, evoked by external triggers such as viral infections and/or autoimmune antibodies, continue insidiously, and lead to the process of cardiac remodeling with ventricular dilatation and systolic dysfunction. This ultimately results in dilated cardiomyopathy. Hepatitis C virus-associated heart diseases are good examples of cardiac lesions definitely induced by viral infections in humans that progress to a chronic stage through complicated immune mechanisms. Therapeutic strategies for myocarditis and dilated cardiomyopathy have been obtained through analyses of the acute, subacute, and chronic phases of experimental viral myocarditis in mice. The appropriate modulation of excessive immune reactions during myocarditis, rather than their complete elimination, appears to be a key option in the prevention and treatment of dilated cardiomyopathy. The clinical application of an NF-κB decoy and immune adsorption of IgG3 cardiac autoantibodies have been used as immunomodulating therapies and may provide novel approaches for the treatment of refractory patients with dilated cardiomyopathy. Conventional therapeutic agents for chronic heart failure such as β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in particular should be re-evaluated on the basis of their anti-inflammatory properties in the treatment of dilated cardiomyopathy.     

Surgical treatment of left ventricular thrombi: two-dimensional echocardiographic diagnosis

Two cases of successful surgical removal of left ventricular thrombi are presented. Two-dimensional echocardiography revealed in the first case multiple masses of thrombi in the dilated ventricle consistent with congestive cardiomyopathy and emergency surgery was performed for cerebral embolism. In the second case the thrombus was pedunculated and calcified, a probable sequel of a 17-year old myocardial infarction. The pertinent literature of echocardiographic and surgical aspects of left ventricular thrombi is reviewed.     

Increased thrombocyte activation in dilated cardiomyopathy: a risk factor for development of ventricular thrombosis despite anticoagulant therapy?

HISTORY AND CLINICAL FINDINGS: A 48-year-old patient with dilated cardiomyopathy complained of dyspnea at rest, severe sleeplessness and a slight pain in the stomach. The clinical examination was normal except for a murmur at the apex of the heart. There was no evidence of edema or congestion of the jugular veins. INVESTIGATION: The echocardiography demonstrated a dilated left ventricle with severely compromised function. No ventricular thrombi were present at this time. Coronary artery disease was excluded by coronary angiography. Endomyocardial biopsies were obtained from the right ventricular septum. The immunohistological analysis of the endomyocardial biopsy specimens revealed pathologically increased lymphocytic infiltrates and increased expression of interstitial and endothelial MHC I and II antigens. Flow cytometric analysis of platelets surface antigens (P-selectin, GP53, thrombospondin) was performed as a measure for intravasal platelet activation. Our patient compared to a healthy control group (> 4 SD) and to other patients with dilated cardiomyopathy (> 2 SD). A high grade increase of platelet activation was found. TREATMENT AND COURSE: ACE inhibitor, diuretics, spironolactone and digitalis were used to treat the heart insufficiency. Due to the severe left ventricular dysfunction phenprocoumone and aspirin were also prescribed. A follow-up echocardiography was performed 6 months later. Comparable to the first examination left ventricular contractility was found to be severely reduced. In addition, a marginal thrombus was now present in the left ventricle despite antithrombotic therapy. DISCUSSION: An increased platelet activation was found in the peripheral circulation of our patient with dilated cardiomyopathy. After 6 months, ventricular thrombi were found in the dilated ventricle, although aspirin and phenprocoumone had been administred. We speculate that an additional thrombotic treatment with clopidogrel is necessary in patients with dilated cardiomyopathy and increased platelet activation.     

Study of dilated cardiomyopathies using gallium 67 myocardial scintigraphy

Twenty-seven patients were diagnosed as having dilated cardiomyopathies, based on increases in the cardiothoracic index greater than 0.50, in the diastolic and systolic diameters of the left ventricle, and in the telediastolic volume of the left ventricle, which was indexed by body surface determined by contrast ventriculography. They underwent gallium 67 scintigraphic examination of the myocardium, in order to non-invasively detect the presence of an inflammatory infiltrate. Fifteen of them also had endomyocardial biopsies and all had virology check-up. The results were disappointing. Only in one case was the scintigraphic image undeniably positive; in 20 other patients the findings were dubious or negative. This technique did not demonstrate the presence of an inflammatory infiltrate and thus we could not establish an association between myocarditis and dilated cardiomyopathy.     

Intraventricular thrombosis complicating peri-partum idiopathic myocardiopathy

Ventricular thrombosis can complicate the development and worsen the prognosis in any case of hypokinetic dilated cardiomyopathy. In the present article, a study has been made of 6 reports of ventricular thrombosis selected out of 58 medical files on women with peri-partum idiopathic cardiomyopathy. Patient age ranged from 22 to 55 years. The clinical picture showed hypokinetic dilated cardiomyopathy, complicated by cardiac failure; with its onset during the last trimester of gestation or in the 6 months post-partum. In all patients, overall cardiac failure was observed, and in all cases the diagnosis of intracardiac thrombosis was made by echocardiography. In all 6 patients, a left ventricular apical thrombosis was detected. In 2 subjects, 2 and 3 left ventricular thrombi were respectively found. In 1 case, a left ventricular thrombosis was present. In another case, a right thrombosis associated with a left ventricular thrombosis was detected. Treatment was initiated with a combination of anticoagulants (heparin and K antivitamins), diuretic and vasodilatory treatment. The clinical outcome was favorable, with the disappearance of thrombi and signs of cardiac failure (between the 15th and 54th day). No embolic complication was observed. These findings clearly show the importance of prescribing an anticoagulant treatment as a preventive measure during PPICM. Even if severe embolic complications are a potential risk, anitcoagulant treatment can ensure a favorable outcome.     

Hypertrophic cardiomyopathy evolving into a hypokinetic and dilated left ventricle: coronary embolization as a probable pathogenetic mechanism

A long-term follow-up (9 years) in a patient with hypertrophic cardiomyopathy revealed an evolution to a hypokinetic and dilated left ventricle. The patient underwent heart transplantation, and therefore the native heart was available for morphologic studies. Gross and microscopic stigmata of hypertrophic cardiomyopathy were present, as well as evidence of left ventricular dilatation. Multiple myocardial scars in both ventricles indicated past ischemic episodes, most probably due to coronary embolization from left ventricular mural thrombi. Other possible pathogenetic mechanisms for the progression of hypertrophic cardiomyopathy to a dilated one are discussed.     

Intracardiac thrombi and systemic embolization

Recent progress has been made in diagnosing and tracing the natural history of intracardiac thrombi by echocardiography. Left ventricular thrombi occur and cause emboli in three clinical conditions: acute myocardial infarction, left ventricular aneurysm as a sequel to infarction, and idiopathic dilated cardiomyopathy. Echocardiographic studies have shown that one third of patients with acute anterior myocardial infarction have left ventricular thrombi; only a small percentage of these patients have emboli. Administration of anticoagulants decreases the prevalence of left ventricular thrombi and the frequency of embolization in this group. Thrombi that are protruding and mobile are most likely to embolize. Anticoagulation treatment decreases the prevalence of embolization in idiopathic dilated cardiomyopathy and should be instituted regardless of whether atrial or ventricular thrombi are detected by two-dimensional echocardiography. In patients with chronic left ventricular aneurysm, thrombi occur commonly, but emboli, infrequently. Therefore, data are insufficient to suggest that anticoagulation treatment is indicated, even if left ventricular thrombi are detected by two-dimensional echocardiography.     

Intracardiac thrombosis diagnosed by echocardiography in childhood: predisposing and etiological factors

Eleven cases of intracardiac thrombi caused by different factors including protein-C deficiency are presented for discussion of the etiology and predisposing factors of intracardiac thrombi during infancy and childhood, and to stress the importance of protein-C deficiency as an etiological factor. Thrombi were localised in the left heart in five patients and right heart in five patients. One patient had both-sided thrombi. Four of our patients had dilated cardiomyopathy, one had mitral valve hypoplasia, and one had pulmonary valvar stenosis as the predisposing factors for thrombus formation. In three patients whose cardiac anatomies were completely normal, we determined protein-C deficiency as an etiological factor of thrombus formation. One of these had congenital protein-C deficiency and the other two had acquired temporary protein-C deficiency due to sepsis. In conclusion we recommend that protein-C deficiency should be investigated as an etiological factor in all cases of intracardiac thrombi irrespective of whether or not another predisposing factor is identified.     

The arrhythmogenic right ventricle. Dysplasia versus cardiomyopathy

Summary Twenty-four patients presenting with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ventricular tachycardia of right ventricular origin associated with structural abnormalities of the right ventricle) were divided into two groups with left ventricular ejection fraction (LVEF) above or below 45%. The distribution of LVEF in the group with LVEF below 45% was comparable with the distribution in 6 patients with idiopathic dilated cardiomyopathy who had ventricular tachycardia originating in the left ventricle (P = 0.2). They also had the same unfavorable long-term prognosis. Therefore, it is suggested that the term, arrhythmogenic right ventricular cardiomyopathy (ARVC), be restricted to patients with a LVEF below 45%. Histological data obtained in the ARVC group showed signs of acute or chronic myocarditis (in the right and left ventricles). It can be hypothesized that patients with arrhythmogenic right ventricular dysplasia (ARVD) may be prone to develop infectious myocarditis. In patients in whom an abnormal host immune response had been seen, progressive deterioration of right and left ventricular function could be observed. This pattern may be superimposed on the genetically determined background of ARVD. This could explain the wide spectrum of clinical presentation observed in patients with tachycardia originating in an abnormal right ventricle.Presented at the ISFC International Symposium on Cardiomyopathies, Warsaw (Poland) October 1993     

Pathogenesis of dilated cardiomyopathy: a study based on comparison of the clinical features with other related conditions

To investigate the pathogenesis and pathophysiology of dilated cardiomyopathy (DCM), we studied 28 patients with DCM by echocardiography and endomyocardial biopsy, and compared their findings with those of 34 patients including eight with myocarditis, seven with alcoholics, 12 with hypertensives and seven patients with hypertrophic cardiomyopathy. All 12 patients in the hypertensive group had congestive heart failure without accompanying high blood pressure, and prominent dilatation and uniform wall motion abnormality of the left ventricle observed echocardiographically on admission. After medical management, both heart failure and the echocardiographic abnormalities gradually resolved. Those in the alcoholic group had larger left ventricles and uniform wall motion abnormality compared to those in the other groups. The myocarditis and hypertrophic cardiomyopathy groups had smaller left ventricles, non-uniform wall motion and larger % myocardial fibrosis. Both ventricles in the hypertrophic cardiomyopathy group were thicker than those of the other three groups. Each patient with DCM had individual echocardiographic abnormalities, which could be categorized as two subsets depending on the degree of left ventricular dilatation and uniformity of the wall motion. The one was characterized by a prominently dilated left ventricle and uniform wall motion abnormality similar to the alcoholic group, and the other had less marked left ventricular dilatation and heterogeneous wall motion abnormality similar to the myocarditis group. From these findings, it was suggested that there are common factors to specific myocardial disease in the pathogenesis and pathophysiology of DCM, and thus, DCM might include many subsets of different etiologies.     

Ventricular thrombi and thromboembolism in dilated cardiomyopathy: a prospective follow-up study.

To determine the prevalence and natural history of left ventricular thrombus in dilated cardiomyopathy, we prospectively performed two-dimensional echocardiograms in 25 patients with nonischemic dilated cardiomyopathy who were not receiving anticoagulation. Eighty-five echocardiograms were performed serially over a 9- to 30-month period (mean follow-up 21.5 months). A left ventricular thrombus was present on initial echocardiogram in 11 (44%) patients, became present during follow-up in an additional four, and disappeared in two. Thrombus was significantly more common in patients with fractional shortening of less than or equal to 10% (12 of 15) than in those with a fractional shortening 11% to 25% (3 of 10) (p less than 0.02). Five embolic events (four cerebral) occurred over the follow-up period, four of which were associated with a previously visualized left ventricular thrombus. Three of five thrombi that protruded into the left ventricular cavity subsequently embolized. We conclude that in nonanticoagulated patients with dilated cardiomyopathy left ventricular thrombus and thromboembolism are common. Echocardiography may be helpful in predicting which patients are at risk of thromboembolism.     

Findings on endomyocardial biopsy in infants and children with dilated cardiomyopathy

Fifteen infants and children with dilated cardiomyopathy underwent transvascular endomyocardial biopsy. The light and electron microscopic findings were reviewed to evaluate the presence of lymphocytes as an indicator of active myocarditis. Both ventricles were biopsied in 13 patients, and the right ventricle only was biopsied in 2. None of the endomyocardial specimens obtained by biopsy revealed an inflammatory process. Interstitial fibrosis, myofiber hypertrophy, degeneration and necrosis were found. Ultrastructural abnormalities of the mitochondria, T tubules or Z bands were noted in approximately one-third of patients. Persistent, active myocarditis is an uncommon cause of dilated cardiomyopathy in children. Immunosuppressive therapy, which may be harmful, should be considered only after myocardial inflammation has been documented by endomyocardial biopsy.     

Lymphocyte subsets in patients with acute myopericarditis, arrhythmias and dilated cardiomyopathy

To investigate the role of immunoregulatory function in determining the clinical course of acute myopericarditis, lymphocyte subsets were analysed by laser flow cytometry in 20 patients with acute myopericarditis, 30 with various arrhythmias or atrio-ventricular block and 31 with dilated cardiomyopathy. During the healing stage of acute myopericarditis, patients with residual electrocardiographic or left ventricular wall motion abnormalities presented altered frequencies of lymphocyte subsets, increased B 1 and reduced OKT 8 positive cells with an elevated OKT 4/8 ratio. The abnormal pattern was not evident in patients with acute pericarditis nor in those with acute myocarditis who recovered completely without residual abnormalities. This observation suggested that an imbalance of helper/suppressor T cells could modulate the clinical course of acute myopericarditis, either by producing extensive and irreversible myocardial damage during acute illness or by inducing chronic smoulding myocardial inflammation. Patients with ventricular arrhythmias and left ventricular wall motion abnormalities also presented reduced suppressor/cytotoxic T cells, implying that they had been suffering from chronic smoulding myocarditis mediated by immunoregulatory dysfunction. However, we could not determine whether the imbalance of helper/suppressor T cells could mediate the progression from myocarditis to dilated cardiomyopathy, since no association was demonstrated between the abnormal lymphocyte subsets and mononuclear cell infiltration in endomyocardial biopsy sample from patients with dilated cardiomyopathy.     

Dilated cardiomyopathy: emerging role of endomyocardial biopsy

The development of safe techniques of endomyocardial biopsy has led to a significant increase in our understanding of the etiology and pathogenesis of dilated cardiomyopathy. The scope of patients for whom this technique is absolutely clinically indicated, however, remains quite narrow and should be restricted to those centers with active cardiac transplant programs, large oncology practices, or those involved with active research into the etiology and treatment of patients with heart muscle disease. The most exciting concept to emerge from the use of EMB is the role of myocarditis in the development of dilated cardiomyopathy. It can accurately be stated that a subset of patients with the clinical presentation of dilated cardiomyopathy may in fact have histologic evidence of myocarditis. Although there is a suspicion that immunosuppressive therapy may be helpful, a randomized trial of large numbers of patients is necessary before definitive conclusions may be drawn. If immunosuppressive therapy proves to be efficacious in active myocarditis, then one could argue that all patients with heart failure of unknown cause with no evidence of valvular or coronary artery disease should undergo endomyocardial biopsy as part of the routine diagnostic workup. However, this recommendation must be considered premature. Since routine histologic findings are nonspecific in dilated cardiomyopathy, biochemical, pharmacologic, and cell culture techniques may provide more definitive information regarding the functional state of the heart muscle. In conclusion, endomyocardial biopsy is rapidly emerging as a useful diagnostic tool in the evaluation of patients with heart failure of unknown cause.     

Laminin distribution and autoantibodies to laminin in dilated cardiomyopathy and myocarditis

With the use of the enzyme-linked immunosorbent assay technique and indirect immunofluorescence, we determined the frequency of antibodies to laminin (a noncollagenous protein of basement membrane) and their influence on endomyocardial laminin distribution in 132 patients suffering from dilated cardiomyopathy and myocarditis. Seventy-eight percent of 91 patients with dilated cardiomyopathy and 73% of 41 patients with myocarditis exhibited significantly elevated anti-laminin antibody levels compared with 68 apparently healthy persons. A positive correlation was found between hemodynamic data and irregular myocardial immunofluorescence laminin staining patterns in dilated cardiomyopathy and myocarditis. With regard to recent studies, these data suggest that antibodies to laminin in dilated cardiomyopathy and myocarditis enhance clusters of cell-surface laminin, inducing an alteration of the cytoskeleton, which may account for functional abnormalities in dilated cardiomyopathy and myocarditis. Considering the fact that optical microscopy is unable to resolve sarcolemmal structures proper from the basement membranes, the high prevalence of laminin autoantibodies in dilated cardiomyopathy and myocarditis raises doubts as to the diagnostic value of direct immunofluorescence findings.     

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.