Effects of exercise training on mobilization and functional activity of blood-derived progenitor cells in patients with acute myocardial infarction.

BACKGROUND: The aim of the present study was to determine whether regular exercise training (ET) is effective at promoting the mobilization of CPCs and improving their functional activity in patients with recently acquired myocardial infarction (STEMI). Regular physical training has been shown to improve myocardial perfusion and cardiovascular function. This may be related in part to a mobilization of bone marrow-derived circulating progenitor cells (CPCs) as well as an enhanced vascularisation. METHODS: 37 patients with STEMI were randomly assigned to an ET group or a non-ET group (controls). Two weeks after STEMI, three weeks after regular ET and three months after ET, BNP levels, exercise echocardiography and exercise spiroergometry were evaluated. The number of CD34+/CD45+ and CD133+/CD45+ CPCs was measured by flow cytometry analysis. The migration capacity of the CPCs was determined with a boyden chamber and the clonogenic capacity by CFU-assay. RESULTS: In the ET-group the number and migration capacity of CPCs increased significantly after regular exercise training. The BNP level decreased significantly from 121 +/- 94 to 75 +/- 47 pg/ml (p<0.001) after the ET period, the left ventricular ejection fraction raised in parallel at peak exercise, and the cardiorespiratory condition improved as demonstrated by an increase of VO2max (from 1641 +/- 522 to 1842 +/- 724 ml/min, p<0.02). These three effects persist till three months after the ET period. CONCLUSIONS: Regular physical activity appears to predispose the mobilization and enhanced functional activity of CPCs, a phenomenon which might lead to an improved cardiac function in patients with recently acquired acute myocardial infarction.

Therapeutic potentials of stem cells in cardiac diseases.

Coronary heart disease and chronic heart failure are common diseases and have an increasing frequency. Although interventional and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available for preventing or even reversing this process. Chronic coronary artery disease and heart failure impair quality of life and are associated with subsequent worsening of the cardiac pump function. Numerous studies carried out in the past few years have demonstrated, that the intracoronary stem cell therapy has to be considered as a safe therapeutic procedure in heart disease, when destroyed and/or compromised heart muscle must be regenerated. This kind of cell therapy with autologous bone marrow cells is completely justified ethically, except for the small numbers of patients with direct or indirect bone marrow disease (e.g. myeloma, leukemic infiltration) in whom there would be lesions of mononuclear cells. Several preclinical as well as clinical trials have shown that transplantation of autologous bone marrow cells or precursor cells improved cardiac function after myocardial infarction and in chronic coronary heart disease. The age of infarction seems to be irrelevant to regenerative potency of stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective in comparison to previous infarcts. Further indications are non-ischemic cardiomyopathy (dilatative cardiomyopathy) and heart failure due to hypertensive heart disease.

[Pathophysiology of the right ventricle in lung diseases]. / Pathophysiologie des rechten Ventrikels bei Lungenerkrankungen.

The thin-walled right heart is characterized by a low mass-volume-relation. Right ventricular function is influenced basically by loading conditions (afterload and preload), myocardial perfusion, contractility and heart rate. Afterload is determined by intrathoracal and pulmonary vascular pressure/resistance. Morphologic adaptions of the right ventricle affect right ventricular function in cor pulmonale. So the normal, not hypertrophied right ventricle is extremely sensitive to increasing pulmonary artery pressure. Otherwise, minor reductions in afterload lead to a substantial decrease of right ventricular wall stress, myocardial oxygen demand and likely the risk of arrhythmia. Therefore clinical consequences and complications of pulmonary hypertension are substantially dependent on right ventricular dynamics.

Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax.

BACKGROUND: The Düsseldorf-based cardiologist Professor Strauer was the first to present a therapeutic concept for the repair of acute infarcted myocardium in 2001: the autologous intracoronary transplantation of unfractionated human bone marrow (BM) mononuclear cells (MNC). The Division of Cardiology, Pneumology and Angiology, University of Duesseldorf Medical School, Duesseldorf, Germany, was also able to show the regenerative potential of BM stem cell transplantation in patients with chronic heart disease (CHD) and peripheral arterial disease (PAD). In the mean time, several clinical trials have been set up worldwide, predominantly by using MNC isolated manually from BM aspirates via density-gradient centrifugation; 374 patients have been treated here with unselected BM MNC since 2001. Altogether 217 BM aspirates have been processed manually. In order to maintain the high standards required for cellular therapeutics, the Sepax cell-separation system was implemented into routine BM processing in 2006. The closed Sepax system provides a reproducible MNC isolation method, and 157 BM samples have been processed with the Sepax device. The results of manual MNC isolation were compared with the Sepax-mediated MNC isolation. METHODS: The manual Ficoll separation method was compared with the Sepax density gradient-based separation (DGBS) protocol using Ficoll with the kit CS-900 and the Sepax S-100 main processing unit from Biosafe. RESULTS: Nucleated cell and MNC recovery were significantly higher after Sepax processing (P<0.0001) whereas no significance was found for red blood cell depletion. DISCUSSION: The Sepax cell-separation system is a time-saving method providing clinical-grade MNC isolated automatically from human BM by Ficoll density centrifugation.

[Inflammatory cardiac diseases by primary extracardial diseases]. / Entzündliche Herzerkrankungen bei primär extrakardialen Erkrankungen.

As systemic immunological disorders, internal diseases in gastroenterology, rheumatology and infectiology can, in addition to the bowels, potentially involve the musculo-skeletal system, the immunological system and heart structures. All structures and functions of the heart can be affected. Pericarditis in lupus erythematosus and chronic inflammatory bowel disease, myocarditis in HIV infection and lyme disease are examples of cardiac manifestations of internal diseases. The pathogenetic causes can be manifold, such as direct cytotoxic effects in HIV or Borrelia burgdorferi infections, induced vasculitis and local activation of coagulation factors as in lupus erythematosus or chronic inflammatory bowel disease. Improved treatment options have led to more long-lasting courses of internal diseases, such as in infectious diseases, lupus erythematosus and chronic inflammatory bowel disease, thus cardiovascular complications such as pericarditis and myocarditis gain increasing importance as a consequence of chronic disease and therapy-related damage.

Diagnostics in pulmonary hypertension.

Pulmonary hypertension is a serious disease with a poor prognosis. Pulmonary hypertension is defined by a mean pulmonary arterial pressure over 25 mm Hg at rest or over 30 mm Hg during activity. According to the recent WHO classification from 2003 pulmonary hypertension can be categorized as pulmonary arterial hypertension, pulmonary venous hypertension, hypoxic pulmonary hypertension, chronic thromboembolic pulmonary hypertension and pulmonary hypertension from other causes. Pulmonary arterial hypertension is characterized histopathologically by vasoconstriction, vascular proliferation, in situ thrombosis, and remodeling of all 3 levels of the vascular walls. These pathologic changes result in progressive increases in the mean pulmonary artery pressure and pulmonary vascular resistance, which, if untreated leads to right-ventricular failure and death. Early in the disease process, the signs and symptoms of PAH are often nonspecific, making diagnosis challenging. Patients often present with progressively worsening dyspnea and fatigue. Patients with severe pulmonary arterial hypertension die of right heart failure. The diagnostic procedures include clinical history and physical examination, a standard chest radiography, electrocardiography, transthoracic Doppler echocardiography, pulmonary function tests, arterial blood gas analysis, ventilation and perfusion lung scan, high-resolution computed tomography of the lungs, contrast-enhanced spiral computed tomography of the lungs and pulmonary angiography, blood tests and immunology, abdominal ultrasound scan, exercise capacity assessment, and hemodynamic evaluation. Invasive and non-invasive markers of disease severity, either biomarkers or physiological parameter and tests that can be widely applied, have been proposed to reliably monitor the clinical course. Pulmonary biopsy is rarely indicated. Transthoracic echocardiography is a key screening tool in the diagnostic algorithm. Because transthoracic echocardiography is an inexpensive, easy, and reproducible method, it is the most commonly used noninvasive diagnostic tool to determine pulmonary arterial pressure. But it not only provides an estimate of pulmonary pressure at rest and during exercise, but it may also help to exclude any secondary causes of pulmonary hypertension, predict the prognosis, monitor the efficacy of specific therapeutic interventions, and detect the preclinical stage of the disease. In addition, the measurement of serum markers, such as brain natriuretic peptide (BNP), are diagnostically useful and of prognostic significance. Once the diagnosis and etiology of pulmonary hypertension have been established, several parameters can predict outcome in these patients: functional class, right ventricular function, pulmonary hemodynamics, and certain laboratory parameters. Also, exercise parameters such as walking distance, peak oxygen uptake or peak systolic blood pressure can reliable predict prognosis in these patients.

Signal-averaged P-wave ECG as a marker of atrial electrical instability in patients with right ventricular dysfunction.

Severe pulmonary hypertension (PAH) leads to right ventricular dysfunction and is associated with different atrial arrhythmias. In PAH patients, the echocardiographic Tei-index is used for monitoring right heart function. The P-wave signal-averaged ECG (SA-ECG) has been shown to have a potential role in identifying patients at risk of developing paroxysmal atrial fibrillation and those likely to change from paroxysmal to chronic atrial fibrillation. The aim of the present study was to define the correlation of the Tei-Index with parameters of P-wave triggered and bidirectional P-wave SA-ECG. A total of 18 patients (14 men, 4 women) with normal sinus rhythm and a mean age of 67+/-10 years (BMI 27.6+/-5.1 kg/m2) were included into the study. Right ventricular (RV) Tei-index was calculated from the sum of isovolumetric contraction time and relaxation time divided by ejection time. Furthermore, P-wave triggered P-wave signal averaged ECG was performed from an X, Y, and Z lead system. The results show that there was a statistically significant correlation between Tei-index and filtered P-wave duration (r=0.53; P=0.023). Teiindex did not correlate with the root mean square voltage of the last 20 ms of the P wave (r=-0.16; P=0.52). In conclusion, a correlation of RV Tei index with P-wave duration indicates that this echocardiographic measurement is not only a marker of right heart function, but also an indicator of electrical instability that could be useful to detect patients at risk for atrial arrhythmias.

Effects of continuous positive airway pressure on exercise capacity in chronic heart failure patients without sleep apnea.

Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea. It is known, that there are beneficial effects on cardiac function, which might be explained by suppression of apnea and specific hemodynamic effects of CPAP. Therefore, CPAP might act as an adjunct therapy in heart failure, even in the absence of sleep apnea. In the present study, 11 patients with congestive heart failure (EF=23.1+/-6.9%) without sleep apnea (AHI 3.0+/-1.2/h) were treated with nocturnal CPAP. Cardiopulmonary exercise testing was performed at baseline and after 8.6 +/-1.3 months. All patients underwent heart catheterization and myocardial biopsy to exclude myocarditis at baseline. Five (46%) of the 11 patients did not complete the study because of poor compliance and irregular use of the CPAP device. Six (54%) of the patients used CPAP regularly (>6 h/night) and completed the study. Cardiopulmonary exercise testing showed an improvement of work load (96+/-36 Watt vs. 112+/-34 Watt; P=0.025) and VO2 peak (1227+/-443 ml vs. 1525+/-470 ml; P=0.01). Oxygen-pulse was increased, although that did not reach significance (11.2+/-4.8 ml/beat vs. 12.6+/-3.9 ml/beat). In conclusion, CPAP might have beneficial effects on exercise capacity in patients with congestive heart failure even in the absence of sleep apnea. Nevertheless, poor compliance seems to be a limiting factor.

Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption.

BACKGROUND: Plaque disruption is the central pathophysiological mechanism underlying acute coronary syndromes and the progression of coronary atherosclerosis. There exists only scant information about the factors that are associated with its development. The aim of the current study was to analyze the contribution of hemodynamic forces in the pathogenesis of plaque disruption. Plaque disruption was diagnosed by coronary angiography of stenosed but not completely occluded coronary arteries. METHODS AND RESULTS: This study retrospectively analyzed 106 patients who underwent 2 coronary angiography procedures within 6 months. We investigated 53 patients with initially smooth stenoses who developed plaque disruption by the time of the second coronary angiogram and compared these patients with 53 age- and sex-matched individuals with smooth stenoses without angiographic signs of plaque disruption. The 2 groups were compared by analyzing central hemodynamics, echocardiographic measurements, and cardiovascular medication use. Logistic regression analysis identified positive associations between plaque disruption, left ventricular muscle mass >270 g, and a mean heart rate >80 bpm and a negative association with the use of beta-blockers. CONCLUSIONS: The associations documented by our investigation indicate that hemodynamic forces may play a crucial role in the pathogenesis of plaque disruption. These findings may help to identify patients who are at an increased risk of plaque disruption and who might gain benefit from pharmacological interventions aimed at reducing heart rate, for example, by the use of beta-blockers, or a reduction of left ventricular hypertrophy.

Impaired coronary flow reserve in NIDDM: a possible role for diabetic cardiopathy in humans.

Diabetic cardiopathy represents a cardiac disorder with involvement of myocardial, interstitial, coronary, and neural structures. One of the main manifestations refers to coronary microangiopathy, which has not yet been clearly identified. Coronary hemodynamics, including the determination of coronary flow reserve, were therefore analyzed in normal subjects and in nine patients with NIDDM and clinically suspected coronary heart disease but normal coronary arteriogram. Coronary flow reserve was determined as the quotient of baseline and minimal coronary resistance after dipyridamole (0.5 mg/kg i.v.). Coronary blood flow was measured quantitatively by the argon method. Systolic left ventricular function was analyzed by ventriculography and diastolic function by M-mode and Doppler echocardiography. Twelve healthy normotensive subjects served as the control group (CON). In the diabetic patients, maximal coronary flow was significantly reduced (172 +/- 50 vs. 395 +/- 103 ml/min x 100 g; P < 0.001), and minimal coronary resistance was increased (0.60 +/- 0.19 vs. 0.24 +/- 0.06 mmHg x min x 100 g/ml; P < 0.001). Coronary reserve in the diabetic subjects was markedly reduced (1.84 +/- 0.39 vs. 4.23 +/- 0.52; P < 0.001). No difference existed with respect to myocardial oxygen consumption (12.4 +/- 2.3 vs. 11.8 +/- 2.8 ml O2/100 g x min; NS). Global systolic function was normal in all patients (ejection fraction: NIDDM 72 +/- 13 vs. CON 77 +/- 12%, NS; CI: NIDDM 3.2 +/- 0.8 vs. CON 3.3 +/- 1.2 l/min x m2, NS). Diastolic function was impaired in diabetic patients with an increase in relaxation time index (97 +/- 23 vs. 45 +/- 18 ms; P < 0.01) and an impaired diastolic inflow pattern, indicated by the ratio between early and late transmitral flow (0.75 +/- 0.14 vs. 1.66 +/- 0.13; P < 0.05). We conclude that the markedly reduced coronary flow reserve in diabetic patients may play a key role in the induction and perpetuation of coronary insufficiency in myocardial ischemia, in diastolic and systolic dysfunction, and in the initiation of diabetic cardiopathy.

The significance of coronary reserve in clinical heart disease.

The clinical syndrome "coronary insufficiency with normal coronary arteriogram" is found in approximately 10% to 20% of patients with exercise-induced coronary insufficiency. In most of these cases, disturbances of the coronary microcirculation are present. They can appear in vascular diseases (arterial hypertension, systemic immunopathies, immune complex vasculitis), in rheologic diseases (paraproteinemia, hyperlipoproteinemia, polyglobulia) and in disturbances of transport and diffusion of oxygen (carbon monoxide intoxication, methemoglobinemia). The clinical diagnosis is based on the usual diagnostic procedures (electrocardiogram, exercise electrocardiogram, responsiveness to nitroglycerin), as well as on newer functionally oriented diagnostic procedures (determinations of coronary blood flow and coronary vascular reserve, production of lactate, serologic findings, histology and immune histology of peripheral arteries, measurements of viscosities in both plasma and blood). Many clinically relevant disturbances in the coronary microcirculation can thus be detected and treated on a rational basis by management of the underlying main disease, that is, by treatment of the vascular, rheologic and metabolic disorders. Persistent angina pectoris in the presence of a normal coronary arteriogram does not represent an end to coronary diagnostic procedures, but introduces the clinical task of using all diagnostic possibilities to enable functional and therapeutic assessment of the coronary microcirculation.

Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: a possible cause for myocardial ischemia.

OBJECTIVES: The study was designed to investigate the architecture of subendocardial arterioles of patients with hypertrophic cardiomyopathy (HCM) and angina pectoris with respect to coronary vasodilator reserve. BACKGROUND: There is growing evidence that the coronary microvasculature is abnormal in HCM. Arterioles, which mainly regulate intramyocardial blood flow, are especially suspect. METHODS: Thirteen patients with HCM (50.1+/-12.6 years old, mean value +/- SD) were studied after exclusion of any relevant coronary stenoses. Subendocardial arterioles (density [n/mm2], wall area [microm2], percent lumen area [%lumen], periarteriolar collagen area [microm2]), myocyte diameter (microm) and interstitial collagen fraction (Vv%) were evaluated by means of stereologic morphometry of transvenous biopsy samples. Coronary blood flow was measured quantitatively with the inert chromatographic argon method at basal conditions and after dipyridamole (0.5 mg/kg body weight over 4 min intravenously), and coronary vasodilator reserve was calculated as the ratio of coronary resistance at basal conditions and after pharmacologic vasodilation. Data from five normotensive subjects (45.4+/-11 years old, p = NS) served as control data. RESULTS: Arteriolar density was diminished by 38% (p = 0.004) and %lumen by 13% (p = 0.009) in patients with HCM compared with control subjects. Coronary reserve was impaired in patients with HCM (2.28+/-0.6 vs. 5.34+/-1.49, p = 0.003) because of higher coronary resistance after vasodilation (0.48+/-0.14 vs. 0.22+/-0.06 mm Hg x min x 100 g/ml, p = 0.004). Coronary vasodilator reserve correlated with arteriolar density (r = +0.47, p = 0.045) and with %lumen (r = 0.65, p = 0.003). CONCLUSIONS: In HCM, the architecture of preterminal subendocardial arterioles is altered by a reduced total cross-sectional lumen area, corresponding to an impaired coronary vasodilator capacity that may predispose to myocardial ischemia.

Pharmacologic myocardial protection during percutaneous transluminal coronary angioplasty by intracoronary application of dipyridamole: impact on hemodynamic function and left ventricular performance.

OBJECTIVES: The aim of this study was to investigate whether intracoronary infusion of dipyridamole represents a suitable tool for preventing deterioration of left ventricular performance and hemodynamic function during percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Coronary angioplasty represents a suitable model for establishing myocardial ischemia in humans. Balloon inflation is usually accompanied by significant deterioration in left ventricular systolic and diastolic properties. A brief episode of ischemia followed by reperfusion, termed preconditioning, has been identified as a mechanism for rendering the myocardium more resistant to ischemia. Adenosine is considered an important mediator of preconditioning. Dipyridamole is an important drug that interferes with myocardial adenosine metabolism by inhibiting its cellular reuptake. METHODS: In 20 patients undergoing elective coronary angioplasty of a major vessel, assessment of angiographic left ventricular performance and hemodynamic variables was performed before, during and after PTCA. Patients were randomly allocated to pretreatment with intracoronary infusion of dipyridamole before percutaneous transluminal coronary angioplasty (10 patients) or conventional pretreatment without dipyridamole (10 patients). RESULTS: Dipyridamole pretreatment resulted in significant preservation of systolic and diastolic left ventricular performance during percutaneous transluminal coronary angioplasty, as documented by an unaffected global ejection fraction (vs. a deterioration of 29.2% with conventional pretreatment, p < 0.01) and an increment in diastolic stiffness of only 12.7% (vs. an increment of 57.3% with conventional pretreatment, p < 0.01). Apart from one instance of coronary steal phenomenon, no significant side effects of dipyridamole infusion could be detected. CONCLUSIONS: It is concluded that intracoronary application of dipyridamole may result in the induction of myocardial preconditioning by improving systolic and diastolic ventricular performance during percutaneous transluminal coronary angioplasty, thereby potentially reducing the risk of the angioplasty procedure.

Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis.

OBJECTIVES: The study evaluates the clinical course and the development of systolic and diastolic left ventricular function in patients with chronic myocarditis with or without autoantibodies against cardiac myosin. BACKGROUND: Patients with myocarditis often show autoantibodies against cardiac myosin. The clinical and pathophysiologic significance of these antimyosin autoantibodies (AMAAB) is yet unknown. The results from studies comparing the clinical course and the development of left ventricular function in patients with chronic myocarditis with or without AMAAB are not yet available. METHODS: Thirty-three patients with biopsy proven chronic myocarditis underwent analysis of AMAAB, right and left heart catheterization and left ventriculography at baseline and after six months. Left ventricular volumes and ejection fraction as well as the time constant of left ventricular relaxation "tau" and the constant of myocardial stiffness "b" were determined at baseline and at follow-up. RESULTS: In 17 (52%) patients, AMAAB could be detected at baseline. After six months, AMAAB were still found in 13 (76%) initially antibody-positive patients. No initially antibody-negative (n = 16) patient developed AMAAB during follow-up. Clinical symptoms improved slightly in antibody-negative patients and remained stable in antibody-positive patients. Left ventricular ejection fraction developed significantly better in antibody-negative patients (+8.9 +/- 10.1%) compared with antibody-positive patients (-0.1 +/- 9.4%) (p < 0.012). Stroke volume (SV) and stroke volume index (SVI) also improved in antibody-negative patients (SV: +20 +/- 31 ml; SVI: +10 +/- 17 ml) compared with antibody-positive patients (SV: -14 +/- 43 ml; SVI: -8 +/- 22 ml) (SV: p < 0.015; SVI: p < 0.016). Left ventricular end-diastolic and end-systolic volumes and the time constant of left ventricular relaxation "tau" did not change significantly different in antibody-positive and antibody-negative patients. The constant of myocardial stiffness "b" improved significantly in antibody-negative patients (-6.1 +/- 10.8) compared with antibody-positive patients (+7.3 +/- 22.6) (p < 0.040). Analyzing only the persistently antibody-positive patients yielded essentially the same results. CONCLUSIONS: Antimyosin autoantibodies are associated with worse development of left ventricular systolic function and diastolic stiffness in patients with chronic myocarditis.

Autoantibodies against human ventricular myosin in sera of patients with acute and chronic myocarditis.

OBJECTIVES: The present study investigated the presence of antimyosin autoantibodies in sera of patients with myocarditis and in three control groups: healthy blood donors, patients with alcoholic cardiomyopathy and patients with other cardiac diseases. BACKGROUND: An increasing body of evidence indicates that in the course of myocarditis, autoimmunologic mechanisms may play a pathogenetic role. Animal studies with Coxsackie B3 virus-induced murine myocarditis could demonstrate the appearance of circulating autoantibodies against cardiac myosin. METHODS: Sera were analyzed by enzyme-linked immunosorbent assay (ELISA) and Western blot with human left ventricular myosin as antigen. RESULTS: Seventeen (42%) of 40 serum samples from patients with myocarditis showed antibody-binding against myosin, whereas only 1 (2.5%) of 39 samples from healthy blood donors and 9 (21%) of 43 samples from patients with other cardiac diseases showed autoantibodies against myosin (p < 0.05 vs. myocarditis). In sera from patients with alcoholic cardiomyopathy (n = 12), no antibodies against human ventricular myosin could be detected. In Western blots, the antimyosin antibodies in patients with myocarditis bound to the myosin heavy chain. Using protein-A sepharose chromatography, it could be shown that the antimyosin autoantibodies are of the immunoglobulin G (IgG) type. In ELISA, the antimyosin autoantibodies bind equally to myosin prepared from either cardiac or skeletal muscle, respectively. CONCLUSIONS: These results demonstrate the presence of autoantibodies against human ventricular myosin in patients with myocarditis. The prevalence of these autoantibodies is significantly higher in patients with myocarditis than in patients with other cardiac diseases. No organ specificity of the autoantibodies could be detected.

Cardiac troponin T in patients with clinically suspected myocarditis.

OBJECTIVES: The present study investigated whether myocyte injury can be assessed sensitively by measurement of serum levels of cardiac troponin T (cTnT) in patients with clinically suspected myocarditis and whether cTnT levels may predict the results of histologic and immunohistologic analysis of endomyocardial biopsy specimens. BACKGROUND: Conventionally used laboratory variables often fail to show myocyte injury in patients with clinically suspected myocarditis, possibly because of a low extent of myocardial injury in these patients. Sensitive variables for myocyte injury have not yet been investigated. METHODS: Eighty patients with clinically suspected myocarditis were screened for creatine kinase (CK) activity, MB isoform of CK (CK-MB) activity and cTnT. Endomyocardial biopsy specimens were examined histologically and immunohistologically. RESULTS: cTnT was elevated in 28 of 80 patients with clinically suspected myocarditis, CK in 4 and CK-MB in 1. Histologic analysis alone of the endomyocardial biopsy specimen revealed evidence of myocarditis in only five patients, all with elevated cTnT levels. Twenty-three of 28 patients with elevated cTnT levels had histologically negative findings for myocarditis. Additional immunohistologic analysis revealed evidence of myocarditis in 26 (93%) of 28 patients with elevated cTnT levels and in 23 (44%) of 52 patients with normal cTnT levels. Mean cTnT levels were higher in patients with myocarditis proved histologically or immunohistologically, or both, than in patients without myocarditis (0.59 +/- 1.68 vs. 0.04 +/- 0.05, p < 0.001). CONCLUSIONS: Measurement of serum levels of cTnT provides evidence of myocyte injury in patients with clinically suspected myocarditis more sensitively than does conventional determination of cardiac enzyme levels. Myocardial cell damage may be present even in the absence of histologic signs of myocarditis. Additional immunohistologic analysis often shows lymphocytic infiltrates in these patients. Elevated levels of cTnT are highly predictive for myocarditis in this group.