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Dilated cardiomyopathy (DCM) is a prevalent heart muscle disease characterized by impaired contractility and dilation of the ventricles. Recent clinical research suggests that cardiotropic viruses are important environmental pathogenic factors in human DCM, which may therefore be considered as a chronic viral cardiomyopathy. All virus-positive DCM patients thus come into the focus of virological research and should be considered for antiviral strategies. Interferon-β therapy has been shown to mediate virus elimination in patients with adenovirus or coxsackievirus persistence.We discuss here several possible new molecular targets for patients infected with cardiotropic viruses in (1) the cellular virus uptake system, (2) virus-induced cellular signaling pathways, and (3) interactions between virus-encoded proteins with important cellular target proteins. The potential of these approaches in the setting of a chronic viral infection is significantly different from that in an acute viral infection. Specific problems encountered in a chronic situation and possible solutions are discussed.

Ongoing viral persistence in the myocardium is associated with an adverse prognosis of cardiomyopathy eventually resulting in a reduced capacity for work and thus it is associated with enormous social costs. Experimental and clinical data highlight that an imbalance of the cytokine network and a defect in the cytokine-induced immune response may constitute major causes leading to the development of virus persistence and progression of myocardial dysfunction. Reversibility of cardiac impairment during the early stages of the disease and the arising chance of specific treatment options demand early diagnosis and treatment of the disease. Our pilot data on anti-viral treatment using INF-β showed beneficial clinical effects and suggest that some of the ventricular dysfunction and wall motion abnormalities resolved after elimination of the responsible agents. The data also suggest that elimination of cardiotropic viruses and associated clinical effects may occur even in DCM patients presenting with a long history.

Background—Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)–induced myocarditis.Methods and Results—First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography.Conclusions—Loss of uPA or MMP activity reduces the cardiac inflammatory response after CVB3 infection, thereby protecting against cardiac injury, dilatation, and failure during CVB3-induced myocarditis.

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage. Electronic supplementary material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00109-006-0122-9 and is accessible for authorized users.

Background— Cardiotropic viral infections have been suspected as one possible cause of myocarditis and dilated cardiomyopathy. Although adverse outcomes in dilated cardiomyopathy patients have been documented, the natural course of heart diseases caused by cardiotropic viruses is unknown. Methods and Results— Consecutive patients (n=172) with biopsy-proven viral infection in endomyocardial biopsies (EMBs) were followed up by reanalysis of EMBs and hemodynamic measurements after a median period of 6.8 months (range, 5.4 to 11.9). Nested polymerase chain reaction (PCR) and reverse transcription–PCR were performed to analyze the genomic sequences. Myocardial inflammation was assessed by histology and immunohistology. At baseline, 32.6% of EMBs in the study group contained enteroviral (EV) RNA, 8.1% adenovirus (ADV) DNA, 36.6% parvovirus B19 (PVB19) DNA, and 10.5% human herpesvirus type 6 (HHV6) DNA. In 12.2% of the samples, dual infection with PVB19 and HHV6 was present. Follow-up analysis of EMBs by PCR documented spontaneous clearance of viral genomes in 36.2% (55/151) of all patients with single infections. Virus-specific clearance rates were 50% for EV, 35.7% for ADV, 22.2% for PVB19, and 44.4% for HHV6. In patients with dual infection with PVB19 + and HHV6 + -, HHV6 was cleared in 42.8% (9/21), whereas PVB19 persisted in all 21 patients. Clearance of viral genomes was associated with a significant improvement in left ventricular ejection fraction (LVEF), improving from 50.2±19.1% to 58.1±15.9% ( P P Conclusions— In this first biopsy-based analysis of the course of viral heart disease, we show that EV, ADV, PVB19, and HHV6 persistence detected in the myocardium of patients with LV dysfunction was associated with a progressive impairment of LVEF, whereas spontaneous viral elimination was associated with a significant improvement in LV function.

Recently, it has been demonstrated that myocardial inflammation plays a pivotal role in the development and progression of congestive heart failure. The myocardial inflammatory reaction not only affects myocardial hypertrophy and apoptosis, but it has a major influence on the regulation of extracellular matrix turnover. The balance between collagen synthesis and degradation is of crucial relevance in maintaining the structural integrity of the heart. Therefore, the overwhelming inflammatory response, as seen in acute myocarditis or inflammatory cardiomyopathy, could lead to a breakdown of this tightly regulated system. This is an additional key factor in the development and progression of heart failure. This review summarizes the importance of myocardial inflammation in respect to extracellular matrix remodeling and its possible patho-physiological role in the development and progression of left ventricular dysfunction in inflammatory heart disease.

Several investigations showed that in addition to genetic factors also virological and chronic inflammatory aspects are relevant pathogenic mechanisms for the development of dilated cardiomyopathy (DCM). Based on the etiopathogenic importance of viral persistence and chronic myocardial inflammation for disease progression, novel rational therapeutic strategies have been developed. The diagnosis of chronic myocardial inflammation and viral persistence has been a controversial issue for a long time due to diagnostic pitfalls. Detection of persistence of viral genomes with adequate sensitivity and specificity succeeded only by the establishment of sensitive molecular biological techniques such as in situ hybridization and nested polymerase chain reaction (nPCR). By the use of these molecular biological methods, further viruses have been detected in DCM patients in addition to the classic cardiotropic viruses (entero- and adenoviruses), particularly parvovirus B19, human herpes virus type 6 (HHV-6), and Epstein-Barr virus. Considering these different cardiotropic viruses, viral persistence can be proven in50% of the DCM patients, consistent with the diagnosis of viral heart disease. This differentiated diagnosis enables, in addition to symptomatic therapy of heart failure, novel rational therapeutic regimens (e. g., beta-interferon) in the setting of randomized trials such as the BICC Study (Betaferon In Patients with Chronic Viral Cardiomyopathy).

Background— For a long time, enteroviruses have been considered to be the most common cause of acute viral myocarditis (MC), with possible transition from MC to dilated cardiomyopathy (DCM). Recent investigations have shown, however, that other viruses are also frequently encountered in MC patients, suggesting that persistence of various virus species may play a pathogenic role in the transition from MC to DCM. The purpose of this study was to screen endomyocardial biopsies (EMBs) from patients with “idiopathic” DCM for the presence of viral genomes by using polymerase chain reaction (PCR) to assess the frequency of cardiac viral infections that may be involved in the pathogenesis of the disease. Methods and Results— EMBs were obtained for PCR analysis from 245 consecutive patients (median left ventricular ejection fraction, 35.0%; range, 9% to 59%). PCR and reverse transcription–PCR were performed to detect the genomic sequences of enterovirus (EV), adenovirus (ADV), human cytomegalovirus (HCMV), herpes simplex virus, Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), parvovirus B19 (PVB19), and influenza A and B viruses. Myocardial inflammation was assessed by histological and immunohistological analyses. Viral genomes could be amplified from EMBs of 165 (67.4%) of the 245 DCM patients: EV=23 (9.4%), ADV=4 (1.6%), PVB19=126 (51.4%), HHV-6=53 (21.6%), EBV=5 (2.0%), HCMV=2 (0.8%), including n=45 cases (27.3%) with multiple infections. Active or borderline myocarditis according to the Dallas classification did not exist in any case. Lymphocyte and macrophage infiltrates were not significantly different in virus-positive versus virus-negative patients. Conclusions— Viral genomes were frequently detected in EMBs of patients with systolic left ventricular dysfunction. Our data suggest that myocardial persistence of various viruses, often presenting as multiple infections, may play a role in the pathogenesis of DCM far more frequently than suspected so far.

Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT(1)) receptor antagonist candesartan and the selective beta(1)-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague-Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22(phox) and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22(phox) and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+46.3% vs. placebo treatment; P0.05). Angiotensin AT(1) receptor antagonism, but not beta(1)-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin-angiotensin system in the development of diabetic complications.

Background: The cardiac troponin T I79N mutation, linked to familial hypertrophic cardiomyopathy, carries a high risk of sudden cardiac death even in the absence of significant cardiac hypertrophy. The pathology underlying this mechanism has not yet been identified. Aims: To study the underlying mechanism of this phenomenon we characterized the left ventricular (LV) performance of transgenic mice carrying the human troponin T mutation I79N under basal and isoproterenol-induced stress conditions. Methods and results: LV function was analyzed by recording pressure—volume loops using a microconductance catheter. Despite a hypercontractile systolic function under basal conditions TnT-I79N mice showed a diastolic dysfunction indicated by an increase in end-diastolic pressure—volume relationship (EDPVR), a load-independent factor of LV stiffness (0.06±0.01 vs. 0.02±0.01; P

To the Editor: In patients with ST-segment elevation myocardial infarction (STEMI), direct intracoronary as compared with standard intravenous bolus administration of the glycoprotein IIb/IIIa receptor antagonist abciximab acutely causes higher local drug concentrations, greater glycoprotein IIb/

Eine schwerwiegende Komplikation nach akutem Herzinfarkt ist die Ruptur des infarzierten Myokards. Bei einer kompletten Ruptur der freien linksventrikularen Wand kommt es akut zu einer kardialer Tamponade mit nahezu immer todlichem Ausgang. Bei der subakuten Form infolge partieller Ruptur verlauft die Hamorrhagie langsamer, so dass Patienten mit einer gedeckten Perforation Tage bis Wochen uberleben konnen. Das Uberleben dieser Patienten hangt wesentlich ab von der raschen Diagnosestellung und chirurgischen Intervention. Die Echokardiographie ist die Untersuchung der Wahl um Wandrupturen mit konsekutivem Hamatoperikard darzustellen. Aber nicht immer lassen sich Wanddefekte echokardiographisch eindeutig erkennen. Wir berichten von einem Patienten mit inferiorem Myokardinfarkt, bei dem mit Hilfe von Linksherz–Echokontrastmittel die Diagnose einer partiellen Myokardwandruptur gesichert und der Patient einer raschen chirurgischen Intervention zugefuhrt werden konnte. Dieser Fall zeigt, dass die fruhzeitige Durchfuhrung einer Echokardiographie nach akutem Myokardinfarkt sinnvoll ist zur Erkennung von periinfarziellen Komplikationen und die Anwendung von Linksherz–Echokontrastmittel den Nachweis und die Lokalisierung einer Wandruptur ermoglichen kann.

Diabetic cardiomyopathy includes fibrosis. Kallikrein (KLK) can inhibit collagen synthesis and promote collagen breakdown. We investigated cardiac fibrosis and left ventricular (LV) function in transgenic rats (TGR) expressing the human kallikrein 1 (hKLK1) gene in streptozotocin (STZ) - induced diabetic conditions. Six weeks after STZ injection, LV function was determined in male Sprague-Dawley (SD) rats and TGR(hKLK1) (n = 10/group) by a Millar tip catheter. Total collagen content ( Sirius Red staining) and expression of types I, III, and VI collagen were quantified by digital image analysis. SD-STZ hearts demonstrated significantly higher total collagen amounts than normoglycemic controls, reflected by the concomitant increment of collagen types I, III, and VI. This correlated with a significant reduction of LV function vs. normoglycemic controls. in contrast, surface-specific content of the extracellular matrix, including collagen types I, III, and VI expression, was significantly lower in TGR( hKLK1)- STZ, not exceeding the content of SD and TGR( hKLK1) controls. This was paralleled by a preserved LV function in TGR( hKLK1)- STZ animals. the kallikrein inhibitor aprotinin and the bradykinin (BK) B2 receptor antagonist icatibant reduced the beneficial effects on LV function and collagen content in TGR( hKLK1)- STZ animals. Transgenic expression of hKLK1 counteracts the progression of LV contractile dysfunction and extracellular matrix remodeling in STZ-induced diabetic cardiomyopathy via a BK B2 receptor-dependent pathway. Free Univ Berlin, Charite Univ Med, Dept Cardiol & Pneumonol, D-12220 Berlin, Germany Universidade Federal de São Paulo, Dept Biophys, São Paulo, Brazil Max Delbruck Ctr Mol Med, Berlin, Germany Universidade Federal de São Paulo, Dept Biophys, São Paulo, Brazil Web of Science

Background Proinflammatory cytokines induce the expression of matrix metalloproteinases that play a crucial role in myocardial remodeling. Beta-adrenergic receptor stimulation influences the production of cytokines heralding the possibility of modulating cytokine production by beta-adrenergic blockers. Methods and results In a coxsackievirus B3 murine myocarditis model (BALB/c), effects of carvedilol and metoprolol on myocardial cytokine expression, inflammatory cell infiltration and MMP/TIMP profiles were investigated. In carvedilol-treated mice, a significant improvement in left ventricular function was documented 10 days post infection. In infected mice (n=10), IL-1β, TNF-α, TGF-β1 and IL-10 myocardial mRNA abundance were increased significantly (240%, 200%, 161%, and 230%) compared to controls (n=10), while IL-15 mRNA was markedly reduced (70%). Infected mice showed significantly increased infiltrations with CD3-, CD4- and CD8-T-lymphocytes (730%, 1110%, 380%). In the infected mice, myocardial MMP/TIMP profiles presented a significant upregulation of membrane type-1 MMP, MMP-9, MMP-8 and MMP-3 (150%, 160%, 340%, and 270%) and a significant decrease in TIMP-4 levels (75%). Carvedilol attenuated over-expression of myocardial TGF-β1, IL-1β and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice (n=10). By an unchanged infiltration with CD3-T-lymphocytes, carvedilol showed a representative reduction in CD4-T-lymphocytes. Conclusion Carvedilol treatment in experimental myocarditis leads to reduced expression of proinflammatory cytokines and MMPs, which contributes to reduced matrix degradation and ultimately to improved structural integrity of the heart. Besides the antiadrenergic potential, carvedilol is beneficial due to a wide range of biological activities (antiinflammatory, antifibrotic, antioxidative and immunomodulatory).

Different patterns of fibroblast-mediated remodeling of the extracellular matrix (ECM) might be expected between patients with pressure- and volume-induced left ventricular hypertrophy.Patients with chronic pressure-overload due to aortic stenosis (AS, n = 19) and chronic volume-overload due to either aortic regurgitation (AR, n = 9) or mitral regurgitation (MR, n = 10) were examined. The amount of interstitial collagen was quantified by using circular-polarization-microscopy in picrosirius red-stained biopsies. Biopsies from 10 patients with mild cardiomyopathy served as controls. In a subgroup, collagen type-I (Coll-I) and collagen type-III (Coll-III) gene expression was evaluated by quantitative RT-PCR. After immunohistological staining, procollagen-I/procollagen-III ratio and density of fibroblasts (FB) per vision-field were analyzed.The amount of interstitial cardiac fibrosis (ICF) was significantly higher in AS (5.7 +/- 4.1 g/m2), AR (8.8 +/- 4.9 g/m2) or MR (4.7 +/- 2.8 g/m2) than in controls (2.3 +/- 1.5 g/m2) (p = 0.003). The amount of thick collagen fibers was higher in AR than in AS, where-by density of fibroblasts did not differ. In volume-overloaded ventricles, the Coll-I/Coll-III ratio was shifted towards Coll-I, and in pressure-overloaded ventricles towards Coll-III. The severity of ECM remodeling was positively correlated with wall stress and impaired diastolic function, but not with systolic function or clinical symptoms.Remodeling of the ECM is specific for left ventricular volume and pressure overload, and may serve as an early indicator for inadequate adaptation.

Background— Enteroviruses (EVs) and adenoviruses (ADVs) have been considered common causes of myocarditis and dilated cardiomyopathy. In the present study, we report on the association of parvovirus B19 (PVB19) genomes in the clinical setting of acute myocarditis. Methods and Results— This study included 24 consecutive patients admitted to our hospital within 24 hours after onset of chest pain. Acute myocardial infarction had been excluded in all patients by coronary angiography. Endomyocardial biopsies were analyzed by nested polymerase chain reaction/reverse transcriptase-polymerase chain reaction for EV, ADV, PVB19, human cytomegalovirus, Epstein-Barr virus, Chlamydia pneumoniae , influenza virus A and B, and Borrelia burgdorferi genomes, respectively, followed by direct sequencing of the amplification products. All patients presented with acute onset of angina pectoris and ST-segment elevations or T-wave inversion mimicking acute myocardial infarction. Mean baseline peak creatinine kinase and creatine kinase-isoenzyme fraction were 342±241 U/L and 32±20 U/L, respectively. Mean troponin T was increased to 7.5±15.0 ng/mL and C-reactive protein to 91±98 mg/mL. Eighteen patients had global or regional wall motion abnormalities (ejection fraction 62.5±15.5%). Histological analysis excluded the presence of active or borderline myocarditis in all but one patient. PVB19, EV, and ADV genomes were detected in the myocardium of 12, 3, and 2 patients, respectively (71%). Follow-up biopsies of virus-positive patients (11 of 17) demonstrated persistence of PVB19 genomes in 6 of 6 patients, EV genomes in 2 of 3 patients, and ADV genomes in 1 of 2 patients, respectively. Conclusions— Virus genomes can be demonstrated in 71% of patients with normal coronary anatomy, clinically mimicking acute myocardial infarction. In addition to EVs and ADVs, PVB19 was the most frequent pathogen.

To phenotypically characterize cytotoxic T-lymphocytes (CTLs: Perforin+ and TIA-1+ phenotypes) and to study the interactions with cell adhesion molecules (CAMs) in dilated cardiomyopathy (DCM).DCM is linked to intramyocardial inflammation, being characterized by T-lymphocytic infiltration and CAMs abundance. However, the pathogenic significance of increased CD3+ lymphocytes remains obscure as these do not correlate with CTLs (perforin+ and TIA1+ phenotypes). CAMs participate in the phenotypic repertoire and effector pathways of CTLs.CAMs-expression (ICAM-1, VCAM-1, LFA-3, CD29, CD62E and CD62P and beta(2)-integrins), CD3+ (T-lymphocytes), CD57+ (NK-cells) and adhesion related (CD18+, CD11a+, CD11b+, CDw49d+) phenotyped infiltrates were investigated in endomyocardial biopsies (EMBs) from 89 DCM patients (33 female; LVEF40%) using immunohistochemisty. The enteroviral genome was identified by nested RT-PCR.CAMs abundance was confirmed in 55 DCM patients (62%) and 29 EMBs (33%) were graded CTLs+ (1.5 TIA-1+ and/or2.0 perforin+ infiltrates/hpf). CTLs correlated with all endothelial CAMs-markers studied (P0.01), the adhesion related phenotypes of infiltrates (LFA-1, VLA-4, CD18) and CD57+ NK-cells (P0.02). There was no correlation of CTLs with CD3+ T-lymphocytes, CD11b+ macrophages, enteroviral infection (present in n=16/18%), clinical history and LVEF (P0.05). Phenomena suggestive of CTLs mediated myocytolysis were observed in 10 patients (11%).CTLs-infiltrates are associated with endothelial CAMs-abundance and co-express adhesion related (beta2-integrins, VLA-4) and NK-cellular antigens (CD57) in DCM. Endothelial CAMs expression also reflects cytotoxic activation of intramyocardial infiltrates, which is not reflected by immunologically nai;ve CD3 T-lymphocytes.

The purpose of this study was to analyze cardiac tissue and blood for viral genomes using polymerase chain reaction (PCR) to define the common viral etiologies of myocarditis by age group.Enteroviruses are considered the most common cause of myocarditis at all ages. Diagnosis relies on viral cultures, serology, and cardiac histology, which lack sensitivity, as well as PCR. However, in many cases enteroviruses are not detected.Cardiac samples were obtained for PCR analysis from patients with myocarditis (n = 624) and dilated cardiomyopathy (DCM) (n = 149). Patients were analyzed by age group, including neonates (n = 116), infants (n = 191), toddlers (n = 87), children (n = 110), adolescents (n = 92), and adults (n = 177). After nucleic acids had been extracted from an endomyocardial biopsy, an explant, or autopsy samples, PCR and reverse transcription PCR were performed to detect the genomic sequences of enterovirus, adenovirus, cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), parvovirus, respiratory syncytial virus (RSV), and influenza A virus.Viral genome was amplified (adenovirus = 142, enterovirus = 85, CMV = 18, parvovirus = 6, influenza A = 5, HSV = 5, EBV = 3, RSV = 1) from 239 (38%) of the 624 samples from myocarditis patients, including 26 patient samples in which dual infection was found. Virus was detected in 30 (20%) of 149 DCM patient samples; only adenovirus (n = 18) and enterovirus (n = 12) were detected.Polymerase chain reaction identified adenovirus as the most common virus in the myocardium of children and adults with myocarditis and DCM. Although enteroviruses are also found in these patients, they appear to be a less common cause of myocarditis than adenovirus.

Myocardial rupture is a major complication after acute myocardial infarction. With complete rupture of the free left ventricular wall cardiac tamponade occurs with fatal outcome in most cases. With partial rupture, however, hemorrhage is slower, allowing days or weeks for diagnosis. Survival of these patients strongly depends on early recognition of this complication followed by immediate surgical intervention. Echocardiography is the diagnostic tool of choice to detect myocardial rupture with consecutive hemopericardium but diagnosis remains difficult even if suspected. We describe the case of a patient with inferior infarction who presented with cardiogenic shock, echocardiographic signs of pericardial effusion and abnormal motion and myocardial irregularities of the inferior wall. With Doppler echocardiography no flow across the wall was detected. Left heart contrast echocardiography confirmed the diagnosis of suspected myocardial rupture by clear deliniation of the defect. Immediate surgical repair was successfully performed in this patient with favorable long-term outcome. Thus, echocardiography early after acute myocardial infarction is useful in detecting subsequent complications and the use of contrast echocardiography should be considered in suspected myocardial rupture.

Persistence of cardiotropic viruses (enterovirus, adenovirus) and anticardiac autoimmunity constitute the predominant etiopathogenic pathways of dilated cardiomyopathy (DCM). The diagnosis of inflammatory cardiomyopathy (InfCM) imposes sensitivity and specificity requirements, which are not fulfilled by the histological Dallas Criteria. The immunohistological quantification and characterization of immunocompetent infiltrates and cell adhesion molecule (CAM) expression has endorsed a new entity of secondary cardiomyopathies acknowledged by the World Health Organization (WHO), InfCM, in approximately 50% of DCM patients. In the absence of viral persistence, InfCM patients benefit from immunosuppressive treatment. Enteroviral and adenoviral genomes have been detected in a significant proportion of DCM patients. Enteroviral persistence is associated with an adverse prognosis. The induction of the coxsackie-adenovirus receptor (CAR) exclusively in 63% of DCM patients, but not in other cardiomyopathies, might constitute a key molecular determinant for cardiotropic viral infections in DCM. In InfCM patients with enterovirus or adenoviral persistence, interferon-beta administration leads to viral elimination and cessation of the intramyocardial inflammation, paralleled by a significant improvement of left ventricular systolic function and heart failure symptoms. The biopsy-guided etiopathogenic differentiation of DCM has endorsed specific treatment strategies: immunosuppressive regimens are favorable in autoimmune InfCM, whereas patients with viral persistence benefit from antiviral immunomodulation.

Among various forms of cardiomyopathies, dilated cardiomyopathy has a multifactorial etiology and pathogenicity, its socioeconomic impact is major, and it represents the leading indication for heart transplantation.1 The pathogenic relationship between viral-induced chronic inflammation and dilated cardiomyopathy may best be illustrated by the meta-analytical observation of the evolution of 21% of acute cases of myocarditis to dilated cardiomyopathy within 33 months of follow-up.2 The prognosis of dilated cardiomyopathy remains grave with conventional pharmacological management, which does not consider the underlying pathogenesis.3 Numerous pathogenically significant autoantibodies directed against cryptic myocardial antigens have been identified in patients with dilated cardiomyopathy. Immunohistochemical quantitative analysis of intramyocardial inflammation and refined molecular biological techniques have begun a new era in the diagnosis of intramyocardial inflammation and viral infection, leading to the description of a new specific disease entity, the inflammatory cardiomyopathy, endorsed by the World Health Organization Task Force on the Definition and Classification of Cardiomyopathies. The etiologic and pathogenic differentiation of dilated cardiomyopathy with reference to inflammation, with or without viral persistence, has fostered promising concepts toward scientifically based treatment modalities.

The mechanisms underlying myocardial remodeling during heart failure have historically been attributed as the consequence of intrinsic changes in cardiac myocytes. Nevertheless, over the last several years, it has become increasingly evident that disruption of extracellular matrix (ECM) homeostasis is also a deciding factor for the progression of myocardial failure.Collagens, the chief components of extracellular matrix, are a tightly regulated family of proteins that determine the structural and functional integrity of heart. Synthesis of collagens is regulated at the cellular level while deposition of these proteins depend on a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). Infiltrating inflammatory cells are major producers of MMPs though myocardial cells are also found to synthesize these proteolytic enzymes. However, immune-mediated regulation of myocardial collagen synthesis and deposition during myocardial inflammation remains poorly understood. It seems likely that a paracrine/autorine effect of a repertoire of cytokines on inflammatory cells and myocardial cells may lead to an imbalance in myocardial MMP/TIMP ratio resulting, eventually, in altered myocardial extracellular matrix architecture and contribute significantly to the development of left ventricular remodeling and dysfunction.Attempts to delineate the cross-talk between immune cells, myocardial cells and extracellular matrix are important as chronic myocardial inflammation is documented in about 50% of patients with dilated cardiomyopathy.

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.

Objective: Myocardial collagen degradation is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). The possible relevance of MMPs in association with the inflammatory induction was investigated in a murine coxsackievirus B3 myocarditis model. Methods: Hearts from viral infected and sham-infected BALB/c mice were analyzed by semi-quantitative RT-PCR, picrosirius red staining, Western blot analysis, and immunohistochemistry. Results: In viral infected mice, both mRNA and protein abundance for collagen type I remained unaltered. In addition, picrosirius red staining showed the unchanged total collagen content. However, degraded soluble fraction of collagen type I protein was increased. Moreover, the mRNA abundance for MMP-3 and MMP-9 was upregulated, whereas the mRNAs for TIMP-1 and TIMP-4 were downregulated, respectively. The upregulation of MMP-3/MMP-9 and downregulation of TIMP-4 were confirmed at the protein level, and were associated with significantly increased mRNA levels of interleukin 1β, tumor necrosis factor-α, transforming growth factor-β1 and interleukin-4. Conclusion: The increment of MMPs in the absence of counterbalance by TIMPs may lead to a functional defect of the myocardial collagen network by posttranslational mechanisms. This may contribute significantly to the development of left ventricular dysfunction in murine viral myocarditis. The inflammatory response with induction of cytokines may mediate the dysregulation of the myocardial MMP/TIMP systems.

We attempted to develop a digital image analysis (DIA) system for endomyocardial biopsies (EMBs) to reliably quantify a) biopsy quality, b) immunohistochemically-marked infiltrates, and c) cell adhesion molecules (CAMs) in relation to net heart area (HA) for the semi-automated diagnosis of inflammatory cardiomyopathy (InfCM).140 EMBs from dilated cardiomyopathy (DCM) patients and 14 autopsy heart samples (controls) were immunostained for T-lymphocytes (CD2, CD3, CD4, CD8), beta(2)-integrin+ infiltrates (CD18, LFA-1, Mac-1) and CAMs (immunoglobulin superfamily: ICAM-1, HLA class I, HLA DR, VCAM-1, CD58; selectins: CD62E and CD62P; and the beta(1)-integrin chain CD29). EMB quality was assessed visually on a three-point scale. Infiltrates were quantified visually (per hpf) and by DIA (per mm2 HA). CAM expression was evaluated semiquantitatively and by DIA (area fraction [AF]: stained area relative to HA).DIA-evaluated HA correlated significantly with the visual assessment of EMB quality. The visual evaluation of both infiltrates and CAMs correlated significantly with the respective DIA-based quantification. DIA-quantified CAM-AF and infiltrates were discriminated by the CAM classification (CAMs+: n=87; 62%) compared to controls. DIA-quantified CAM immunoreactivity correlated significantly with the DIA-quantified counter-receptor+ infiltrates. DIA evaluation of biopsy quality, infiltrates, and CAMs was devoid of inter- and intraobserver variability.The DIA system presented here enables standardized and observer-independent assessment of EMB quality and intramyocardial inflammation (density of infiltrates and CAM expression) in DCM biopsies related to HA. Our data confirm that endothelial CAM count and counter-receptor+ immunocompetent infiltration are interdependent pathogenic and diagnostic hallmarks of InfCM.

A 9-year-old girl presented with systemic infection related to a Port-a-Cath system (PAC); therefore, the urgent removal of the PAC was indicated. However, the catheter was trapped and not extractable by conventional means. Using existing comprehensive experience in the removal of pacemaker and implantable cardioverter defibrillator leads, the entrapped PAC was successfully extracted by laser technique, thus avoiding open heart surgery.

Gene therapy of cancer requires high-level expression of therapeutic transgenes in the target cells. Poor gene transfer is an important limitation to adenovector-mediated cancer gene therapy. We investigated two fundamentally different approaches to improve transgene expression in poorly permissive cancer cells. First, overexpression of the adenovirus attachment receptor CAR to facilitate receptor-mediated adenovector (AdV) uptake into the target cells; second, co-infection of this vector together with traces of replication competent adenovirus (RCA) accidentally arising by back-recombination during large-scale vector preparation. Among eight gastrointestinal cancer cell lines, the colorectal cancer lines showed particularly poor vector-mediated transgene expression (down to 67-fold lower than in HeLa cells). Expression of the adenovirus receptors CAR, alpha(v)beta5- and alpha(v)beta3-integrin were highly variable between cell lines. AdV uptake was significantly associated with CAR levels on the cell surface, but not with those of the integrins. AdV-mediated CAR overexpression increased CAR density on the surface of all investigated tumor cells and led to enhancement of transgene expression by 1.8- to 6.7-fold. The other principle to enhance transgene expression was 'trans-complementation' of the therapeutic vector, ie induction of its replication within the target cells. Traces of RCA in a vector preparation, as well as purified RCA were found to provide sufficient E1-region transcripts to induce replication of the therapeutic vector genome. The number of adenovector-based transgene expression cassettes was greatly amplified by this principle, notably without any influence on the rate of vector entry. Co-infection of four colorectal cancer cell lines with marker vector plus RCA (at around 240:1 particle ratio) resulted in far stronger enhancement of transgene expression (up to 46-fold) as compared with CAR overexpression, even in cancers almost refractory to standard adenovector-mediated gene transfer. Whereas RCAs need to be strictly avoided in gene therapy of non-malignant diseases for safety reasons, the magnitude of helper virus-induced therapeutic transgene expression could possibly warrant application of this principle to overcome the resistance of highly malignant cancers against gene therapy.

Background —It is controversial whether myocardial fibrosis in end-stage dilated cardiomyopathy (DCM) is associated with altered collagen type I/type III (Col I/Col III) ratio. Methods and Results —Patients with DCM (ejection fraction [EF] 50%, n=18) were examined. Col I, Col III, and transforming growth factors-β 1 (TGF-β 1 ) and -β 2 (TGF-β 2 ) gene expression in endomyocardial biopsies was evaluated by quantitative competitive reverse transcriptase–polymerase chain reaction (qRT-PCR). Collagen content was quantified after picrosirius red and immunohistological staining and by hydroxyproline assay. In patients with EF P 50%. The Col III mRNA abundance showed a 2.0-fold increase ( P 50% (Col I/Col III, 6.4). In addition, total collagen content was increased in patients with EF 50% (n=8) (2.7±0.9%) ( P P r =0.77). TGF-β 1 and TGF-β 2 showed elevated myocardial mRNA abundances (1- to 7-fold and 4- to 5-fold, respectively) in DCM patients. Conclusions —Differential increase of Col I and Col III leads to an increased Col I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile strength and stiffness, this may contribute to systolic and in particular diastolic dysfunction in DCM.

Unter einer Myokarditis wird ein sich herdformig oder diffus im Herzmuskel ausbreitender, akut oder chronisch-rezidivierend verlaufender Entzundungsprozes verstanden, der durch direkte oder indirekte Einwirkung von Erregern, von toxischen, chemischen oder physikalischen Agenzien oder bisher nicht verstandenen und somit unbekannten Ursachen hervorgerufen wird. Die Mehrzahl aller Myokarditiden verlauft klinisch inapperent. Dies gilt besonders fur virusinduzierte Myokarditiden, die nach dem Ruckgang bakteriell verursachter Infektionskrankheiten den Hauptanteil aller Myokarditiden ausmachen. Obwohl zahlreiche kardiotrope Viren als Erreger prinzipiell in Betracht kommen, stehen aufgrund epidemiologischer Untersuchungen Enteroviren (RNA-Viren), speziell Coxsackie-Viren der Gruppe B (CBV), als auslosendes Agens an erster Stelle.

Three adenine nucleotide translocase isoforms (ANT1, ANT2 and ANT3) are coded by different genes. The relative amounts of the three ANT isoform mRNAs were determined in detail in various human tissues. ANT isoforms were co-expressed in all tested tissues revealing tissue-specific transcription patterns. The highest ANT1 mRNA proportions were found in terminally differentiated tissues like skeletal muscle, heart and brain, whereas ANT2 was mainly expressed in tissues capable of proliferation and regeneration as in the kidneys, spleen, liver, fibroblasts and lymphocytes. The ANT3 mRNA proportion was not prominently expressed in any of the tissues tested. In conclusion, tissue-specific expression of ANT isoforms is strongly related to the state of cellular differentiation.

Background: Recent trials as FAIR-HF demonstrated an improvement of symptoms and exercise capacity by iron therapy in patients with heart failure (HF) and iron deficiency (ID). We investigated the clinical efforts on diagnostics and therapy of ID in the current "real-world" management of HF-patients. Methods: EVITA-HF is a registry of consecutive patients with chronic HF and left ventricular ejection fraction ≤ 40%. There are 17 recruiting centers in Germany and Switzerland. The RAID-HF substudy focusses on diagnosis and therapy of ID in HF-patients. Results: From 10/2010 until 07/2012 1603 HF-patients were included, only 3.7% received iron therapy (oral or intravenous). Patients with iron therapy were older, in a higher NYHA-class and had lower hemoglobin levels (Table). Diagnostics on iron status (blood levels of iron, ferritin, transferrin saturation) were performed in 434 patients (27.1%) of all HF-patients. In the group of patients with known iron status 220 patients (50.7%) had ID (ID defined as ferritin levels < 100 ng/ml or 100-299 ng/ml, if transferrin saturation < 20%). View this table: Patients with vs. without iron therapy Conclusions: In the current management of HF-patients less than 5% receive iron therapy. In only ¼ of the patients diagnostic measurements of iron status are performed (in spite of participation in an iron registry). Until now diagnosis of ID rarely leads to the initiation of iron supplementation in clinical practice.

Background Data on the prognostic value of cardiac magnetic resonance imaging (CMR) parameters in patients with STelevation myocardial infarction (STEMI) are limited due to analysis of single-center cohorts and small study sample sizes. Aim of the current study was thus to investigate the impact of infarct size, microvascular obstruction (MO) and myocardial salvage index (MSI) on clinical outcome in a large cohort of STEMI patients derived from a multi-center study. Methods STEMI patients (n=795) reperfused by primary percutaneous coronary intervention (PCI) within 12 hours after symptom onset underwent CMR in 8 centers in Germany. CMR was performed at day 1 to 4 after the index event. Infarct size and microvascular obstruction (MO) were measured 15 minutes after gadolinium injection. T2-weighted and contrast-enhanced CMR were used to calculate the MSI. The primary endpoint was defined as a composite of death, non-fatal myocardial reinfarction and congestive heart failure (MACE). Clinical follow-up was conducted after 12 months. Results Infarct size, MO and MSI were significantly associated with MACE in univariable Cox regression analysis (all p

In a recent issue of the Journal , Mahon et al. [(1)][1]added substantially to the pathogenesis of familial dilated cardiomyopathy (DCM), elucidating that intramyocardial inflammation, as assessed by immunohistochemical quantification of CD3+ T-lymphocytes and abundance of endothelial cell adhesion

Objective This propensity-matched study compared clinical and echocardiographic outcomes between patients undergoing transcatheter aortic valve implantation (TAVI) and sutureless aortic valve replacement. Methods From January 2010 to March 2012, 122 patients (age 79.4 ± 5.3 years, logistic euroSCORE 12% ± 8.4%) underwent minimally invasive sutureless aortic valve replacement, and 122 (age 84.6 ± 6.2 years, logistic euroSCORE 20.9% ± 2.5%) underwent TAVI. After propensity matching, 37 matched pairs were available for analysis. Results Preoperative characteristics and risk scores of matched groups were comparable. In-hospital mortalities were 0% in the sutureless group and 8.1% (n = 3) in the TAVI group ( P = .24). Permanent pacemaker implantation was required in 4 patients in the sutureless group and 1 patient in the TAVI group (10.8% vs 2.7%; P = .18). A neurologic event was recorded in 2 patients of each group. Predischarge echocardiographic data showed higher paravalvular leak rate in the TAVI group (13.5% vs 0%; P = .027). At mean follow-up of 18.9 ± 10.1 months, overall cumulative survival was 91.9% and significantly differed between groups (sutureless 97.3% vs TAVI 86.5%; P = .015). In the TAVI group, a significant difference in mortality was observed between patients with (n = 20) and without (n = 17) paravalvular leak (25% vs 0%; P = .036). Conclusions Combining the advantage of standard diseased valve removal with shorter procedural times, minimally invasive sutureless aortic valve replacement may be the first-line treatment for high-risk patients considered in the "gray zone" between TAVI and conventional surgery.