Peter L. Schwimmbeck

High Prevalence of Cardiac Parvovirus B19 Infection in Patients With Isolated Left Ventricular Diastolic Dysfunction

Background—The etiology of left ventricular (LV) isolated diastolic dysfunction often remains unclear. In the present study, we report a strong association between parvovirus B19 (PVB19) genomes and isolated LV diastolic dysfunction. Methods and Results—In 70 patients (mean±SD age, 43±11 years) admitted with exertional dyspnea and/or reduced exercise tolerance despite preserved LV systolic contractility (ejection fraction=68%), isolated diastolic dysfunction was clinically suspected. Patients with classic risk factors for diastolic dysfunction such as hypertension, coronary heart disease, diabetes mellitus, or pulmonary disease had been excluded. Diastolic function was assessed by echocardiography and LV and RV catheterization. Endomyocardial biopsies (EMBs) were analyzed for the presence of storage or infiltrative diseases or myocarditis, including molecular screening for cardiotropic virus genomes. In a substudy of 24 patients who reported atypical angina, coronary endothelial function was additionally investigated with a coronary Doppler flow-wire technique. In 37 of 70 patients (53%), isolated diastolic dysfunction was confirmed as the cause of their clinical symptoms. No evidence for cardiac storage or infiltrative diseases was found in these cases, but in 35 of 37 of these patients (95%), cardiotropic virus genomes were detected in EMBs (P<0.001). PVB19 was the most frequent pathogen in 31 of 37 patients (84%). In a subgroup of 10 patients with diastolic dysfunction and coexisting endothelial dysfunction, all 10 (100%) were PVB19 positive. Conclusions—PVB19 genomes were predominant in patients with unexplained, isolated diastolic dysfunction. A strong association with the incidence of endothelial dysfunction was obvious, consistent with the hypothesis that PVB19-induced endothelial dysfunction may be a possible pathomechanism underlying diastolic dysfunction.

Enteroviral RNA Replication in the Myocardium of Patients With Left Ventricular Dysfunction and Clinically Suspected Myocarditis

BACKGROUND Previous studies dealing with the detection of enteroviral RNA in human endomyocardial biopsies have not differentiated between latent persistence of the enteroviral genome and active viral replication. Enteroviruses that are considered important factors for the development of myocarditis have a single-strand RNA genome of positive polarity that is transcribed by a virus-encoded RNA polymerase into a minus-strand mRNA during active viral replication. The synthesis of multiple copies of minus-strand enteroviral RNA therefore occurs only at sites of active viral replication but not in tissues with mere persistence of the viral genome. METHODS AND RESULTS We investigated enteroviral RNA replication versus enteroviral RNA persistence in endomyocardial biopsies of 45 patients with left ventricular dysfunction and clinically suspected myocarditis. Using reverse-transcriptase polymerase chain reaction in conjunction with Southern blot hybridization, we established a highly sensitive assay to specifically detect plus-strand versus minus-strand enteroviral RNA in the biopsies. Plus-strand enteroviral RNA was detected in endomyocardial biopsies of 18 (40%) of 45 patients, whereas minus-strand RNA as an indication of active enteroviral RNA replication was detected in only 10 (56%) of these 18 plus-strand-positive patients. Enteroviral RNA was not found in biopsies of the control group (n=26). CONCLUSIONS These data demonstrate that a significant fraction of patients with left ventricular dysfunction and clinically suspected myocarditis had active enteroviral RNA replication in their myocardium (22%). Differentiation between patients with active viral replication and latent viral persistence should be particularly important in future studies evaluating different therapeutic strategies. In addition, molecular genetic detection of enteroviral genome and differentiation between replicating versus persistent viruses is possible in a single endomyocardial biopsy.

Differential Aspects of Endothelial Function of the Coronary Microcirculation Considering Myocardial Virus Persistence, Endothelial Activation, and Myocardial Leukocyte Infiltrates

Background—Viral cardiomyopathy resulting from myocardial virus persistence can be associated with inflammatory immune responses that involve the myocardium and coronary blood vessels. The aim of this study was to investigate the differential impact of myocardial virus persistence and inflammation on endothelial function of the coronary microcirculation. Methods and Results—In 71 patients with nonischemic cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the coronary microcirculation was examined during heart catheterization by measuring diameter (by quantitative coronary angiography) and velocity changes (by intracoronary Doppler) of the left anterior descending artery in response to acetylcholine. Coronary blood flow (CBF) was calculated. Endothelium-independent vasoreactivity to adenosine was assessed. Mean age of the patients (37 men, 34 women) was 43±13 years; mean ejection fraction was 64±11%. In 43 patients, adenovirus, enterovirus, parvovirus, or HHV-6 was detected; 28 had no virus. Endothelial function of the coronary microcirculation was significantly impaired in patients with myocardial virus persistence (V) compared with patients without virus (Co) (&Dgr;CBF-V, 22±86%; &Dgr;CBF-Co, 110±113%; P=0.001), which was confirmed in 51 patients with myocardial inflammation (MC) (32 with virus, 19 with no virus) (&Dgr;CBF-MC-V, 12±89%; &Dgr;CBF-MC-Co, 81±109%; P=0.034) and in 20 patients with normal immunohistology of the myocardial biopsies (Co) (11 with virus, 9 with no virus) (&Dgr;CBF-Co-V, 51±72%; &Dgr;CBF-Co-Co, 175±97%; P=0.006). Endothelial function of the coronary microcirculation was also significantly impaired in patients with myocardial inflammation/endothelial activation compared with patients without inflammatory immune response. Endothelium-independent vasodilation was not influenced significantly. Conclusions—Myocardial virus persistence and myocardial inflammation/endothelial activation are associated with endothelial dysfunction of the coronary microcirculation. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of myocardial inflammation/endothelial activation but is more pronounced in patients with concurrent inflammation.

Endothelium-Dependent Flow-Mediated Vasodilation of Systemic Arteries Is Impaired in Patients With Myocardial Virus Persistence

Background—Myocardial virus persistence is frequently observed in patients with cardiomyopathy. Endothelial dysfunction in patients with cardiomyopathy is associated with inflammatory immunoresponses in myocardial biopsies. The aim of this study was to investigate the impact of myocardial virus persistence on endothelial function. Methods and Results—In 124 patients with suspected cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the radial artery was examined by high-resolution ultrasound. Diameter changes in response to reactive hyperemia (flow-mediated dilation [FMD]) compared with glycerol trinitrate (GTN-MD) were measured. Mean age of the patients (55 men, 69 women) was 45±13 years; ejection fraction was 57±17%. In 73 patients, adenovirus, enterovirus, parvovirus, or HHV6 virus (V) was detected; in 51, no virus was detected. FMD was significantly impaired in patients with myocardial virus persistence compared with control subjects (Co): FMD-V, 3.38±2.67%; FMD-Co, 7.34±3.44 (P<0.001). In 86 patients, myocardial inflammation was confirmed (Inf). Of those, 57 had virus, and 29 did not. FMD was significantly impaired in patients with virus compared with controls: FMD-Inf-V, 3.24±2.66%; FMD-Inf-Co, 6.07±3.00 (P<0.001). In 38 patients, immunohistology of the myocardial biopsies was normal (Co); of those, 16 had virus, and 22 did not. FMD was impaired in patients with virus compared with control subjects: FMD-Co-V, 3.88±2.72%; FMD-Co-Co, 9.00±3.32% (P<0.001). Endothelium-independent vasodilation (GTN-MD) was not significantly affected. Conclusions—Myocardial virus persistence is associated with endothelial dysfunction. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of endothelial activation or myocardial inflammation but is more pronounced in patients with concurrent inflammation.

An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy

Impaired mitochondrial ADP/ATP transport and altered adenine nucleotide translocase (ANT) isoform expression characterized by enhanced ANT1 and decreased ANT2 expression have been implicated in the pathophysiology of dilated cardiomyopathy (DCM). It is still unknown whether restricted ANT function results from exogenous factors, or mutations in the ANT genes, or whether the imbalance in the isoform composition causes the reduced ADP/ATP transport. We performed DNA mutation screening of ANT genes and analyzed the kinetic properties of ANT protein isolated from DCM hearts and controls in a reconstituted system excluding natural environmental influences.

Remodeling der extrazellulären Matrix bei dilatativer Kardiomyopathie

Hintergrund: Die extrazelluläre Matrix des Myokards spielt eine bedeutende Rolle für den Erhalt der Integrität und der Funktion des Herzens. Kollagen Typ I und Typ III sind die wesentlichen Bestandteile der myokardialen extrazellulären Matrix. In verschiedenen Arbeiten konnte gezeigt werden, dass es bei dilatativer Kardiomyopathie (DCM) zu einer Zunahme des Fibroseindexes kommt. Darüber hinaus ist auch der Quotient Kollagen Typ I/Typ III signifikant erhöht. Aufgrund der unterschiedlichen physikalischen Eigenschaften von Kollagen Typ I (steif) und Typ III (elastisch) sind diese Veränderungen für die Myokardfunktion von essenzieller Bedeutung. Pathogenetische Mechanismen: Die exakten molekularen Mechanismen, die für die Umgestaltung der extrazellulären Matrix von Bedeutung sind, konnten bisher noch nicht eindeutig aufgeschlüsselt werden. So ist auch noch nicht geklärt, inwieweit die chronisch entzündlichen myokardialen Veränderungen, die bei ca 50% der Patienten mit dilatativer Kardiomyopathie nachgewiesen werden können, das myokardiale Remodeling beeinflussen. Auch die Veränderungen der nicht kollagenen Komponenten der extrazellulären Matrix bei dilatativer Kardiomyopathie konnten bisher noch nicht klar definiert werden. Schlussfolgerung: Daher ist es essenziell, die Pathomechanismen der Regulation dieser komplexen Umbauprozesse der extrazellulären Matrix bei Herzinsuffizienz exakt zu erfassen, um daraus möglicherweise neue Therapiestrategien zur Verhinderung der Progression der Herzinsuffizienz entwickeln zu können.Background: 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. Pathogenetic Mechanisms: 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. Conclusion: 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.

Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry

BACKGROUND Prasugrel compared to clopidogrel has been shown to improve outcome in patients with ST elevation myocardial infarction (STEMI) in the TRITON-TIMI 38 trial. Little is known about the use, efficacy and safety of prasugrel in patients with STEMI in clinical practice. METHODS We conducted a prospective registry including patients with STEMI scheduled for primary percutaneous coronary intervention (PCI). Between October 2009 and February 2013 a total of 3291 patients with STEMI receiving a loading dose of either clopidogrel or prasugrel were included in this analysis. RESULTS Prasugrel was predominantly used in patients <75 years, body weight >60 kg and those without prior stroke. In-hospital mortality was numerically lower in the prasugrel group (1.7% vs. 4.4%), as well as non-fatal reinfarction (0.2% vs. 0.5%), non-fatal stroke (0.1% vs. 0.3%) and major cardiac and cerebrovascular events (MACCE) (2.1% vs. 5.2%), while there was no difference in major bleeding complications (0.8% vs. 0.9%). In the multivariate analysis the MACCE-rate tended to be lower in prasugrel treated patients (odds ratio 0.71, 95% confidence intervals 0.42-1.08) but bleeding-rates tended to be higher. CONCLUSIONS In this real life experience in patients with STEMI scheduled for primary PCI, prasugrel was almost exclusively used in the label-recommended patient population and tended to be more effective but associated with more bleedings compared to clopidogrel. These results support the findings in the STEMI population in the randomized TRITON-TIMI 38 study.

Coronary vasospasm–induced acute diastolic dysfunction in a patient with Raynaud’s phenomenon

SummaryWe present the case of a patient with severe dyspnea and Raynaud’s phenomenon. We could clarify, using invasive techniques including left ventricular conductance catheterization and coronary ergonovine provocation, that isolated diastolic dysfunction induced by coronary vasospasm were responsible for the symptoms. Systolic function was not affected. Short–term infusions with the prostacyclin analogue iloprost, known to act as a disease–modifying agent in patients suffering from Raynaud’s phenomenon, led to an improvement of cardiac function. Thus, episodes of dyspnea in patients with Raynaud’s phenomenon might be also interpretated as a coronary ischemia equivalent, which may belong to a visceral form of Raynaud’s phenomenon and which are sensitive to iloprost infusions.

Myocardial Infarction Caused by Occlusion of Cabrol Conduit Graft

A 73-year-old man presented with new onset of chest pain and left bundle-branch block. He reported a surgical valve repair 5 years ago but did not know additional details. The chest x-ray demonstrated broad appearance of the thoracic aorta, indicative of thoracic dissection; therefore, a chest CT examination was performed. The CT finding was initially interpreted by the radiologist as a focal dissection or pseudoaneurysm in the aortic root because of contrast media outside the aortic graft (Figure 1). Because his troponin T level was found to be elevated, the patient underwent cardiac catheterization. An initial aortography demonstrated the …

Enteroviral and immune mediated myocarditis in SCID mice.

Severe combined immune deficiency (SCID) mice have been used as an animal model to study both the direct cytopathic effect of enteroviruses on the heart in the absence of an effective immune system and to investigate the role of immune mediated processes in the pathogenesis of human myocarditis.The infection of SCID mice with coxsackievirus B3 resulted in severe myocarditis with very high titers of the virus in the myocardium and severe necrosis of myocytes. This direct cytopathic effect caused an impairment of the myocardial function and resulted in a high mortality rate of the infected animals.For the study of the immune mechanisms in human myocarditis, peripheral blood leukocytes of patients with myocarditis, having an impaired left ventricular function without viral persistence in the myocardium, were transferred into SCID mice. As controls peripherals blood leukocytes of normal donors were used. At 60 days after transfer, human immunoglobulines could be demonstrated in the peripheral blood of the SCID mice, however, human autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the animals receiving peripheral blood leukocytes from patients with myocarditis. Cellular infiltrates of human leukocytes in the myocardium and an impaired left ventricular function were also only observed in animals reconstituted with peripheral blood leukocytes from patients. These effects were T cell dependent as shown by differential transfer.These results are of interest for the treatment of human myocarditis, suggesting the avoidance of an immunosuppressive therapy in acute or chronic myocarditis with viral persistence to prevent a direct cytophatic effect in the absence of an effective immune system. However, in the setting of a chronic, (auto-)immunological myocarditis with the proven absence of entero- or adneoviral sequences an immunomodulatory therapy seems to be effective and safe.ZusammenfassungDie Bedeutung einer enteroviralen Infektion sowie einer resultierenden Immunreaktion ist immer noch Gegenstand der Forschung in der Pathogenese der humanen Myokarditis. Mäuse mit einer kombinierten Immundefizienz (“severe combined immundeficiency”, SCID-Mäuse), die keinen eigenen funktionstüchtigen peripheren B- und T-Lymphozyten besitzen, wurden im Tiermodell verwendet, um den direkten zytopathischen Effekt von Enteroviren auf Herzmuskelzellen in der Abwesenheit eines effektiven Immunsystems zu untersuchen. Außerdem kann dieses Tiermodell verwendet werden, um die Rolle von immunologischen und autoimmunologischen Prozessen in der Pathogenese der humanen Myokarditis zu analysieren.Die Infektion von SCID-Mäusen mit Coxsackie-B3-Viren führt zu einer ausgeprägten Myokarditis bei sehr hohen Virustitern im Myokardgewebe und schweren Myokardzellnekrosen. Dieser direkte zytopathische Effekt verursacht eine Einschränkung der myokardialen Pumpfunktion und führte zu einer hohen Mortalitätsrate in den infizierten Tieren, während immunkompetente Mäuse praktisch keine Mortalität aufweisen.Zur Untersuchung der Immunmechanismen bei der humanen Myokarditis wurden periphere Blutleukozyten von Patienten mit Myokarditis, die eine eingeschränkte linksventrikuläre Funktion, jedoch keine Viruspersistenz im Myokard aufwiesen, auf SCID-Mäuse übertragen. Als Kontrollen dienten die peripheren Blutleukozyten von gesunden Personen. 60 Tage nach dem Transfer fanden sich humane Immungloboline im peripheren Blut der SCID-Mäuse. Humane Autoantikörper gegen den Adenin-Nukleotid-Translokator, ein myokardiales Autoantigen, fanden sich hingegen nur bei den Tieren, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Zelluläre Infiltrate von humanen Leukozyten im Myokard und eine Einschränkung der linksventrikulären Funktion (verminderte Druckanstiegsgeschwindigkeit) lagen ebenso nur bei den SCID-Mäusen vor, die periphere Blutleukozyten von Patienten mit Myokarditis erhalten hatten. Die Tiere wiesen jedoch keinen Anhalt für eine Graft-versus-Host-Reaktion auf, wie die Untersuchung von verschiedenen anderen Geweben ergab. Der Transfer der humanen Myokarditis in SCID-Mäusen ist ein T-Zell-abhängiger Prozess, wie ein entsprechender differenzieller Transfer von nur CD4-positiven oder CD4-depletierten peripheren Blutleukozyten zeigte.Diese Untersuchungen dürften für die Therapie der humanen Myokarditis von Bedeutung sein. Diese Experimente legen nahe, dass im Rahmen der Myokarditis des Menschen vor allem im Stadium der akuten Erkrankung auf eine immunsuppressive Therapie verzichtet werden sollte, um eine Schwächung des Immunsystems und damit eine erhöhte Virämie und somit auch eine Verstärkung des direkten zytopathischen Effektes auf die Herzmuskelzellen zu verhindern. Aber auch im chronischen Stadium der Erkrankung sollte eine Viruspersistenz durch Entnahme von Myokardbiopsien mit entsprechender molekularbiologischer Analyse (Polymerasekettenreaktion und/oder In-situ-Hybridisierung für Entero- bzw. Adenoviren) untersucht werden, bevor eine immunsuppressive Therapie erwogen wird. In diesem Stadium der Erkrankung sollte bei nachgewiesener Viruspersistenz vielmehr möglicherweise eine Therapie mit subkutanen Gaben von Interferon initiiert werden, wie Untersuchungen unserer eigenen Arbeitsgruppe zwischenzeitlich nahelegen.Zum anderen sprechen die Befunde dieses Tiermodells auch dafür, dass es sich bei der Myokarditis des Menschen im chronischen Stadium der Erkrankung bei Ausschluss einer Viruspersistenz um einen chronischen autoimmunologischen Prozess handelt, der einer immunmodulatorischen Therapie zugeführt werden sollte. Nur durch eine differenzierte histologische, immunhistologische und molekularbiologische Diagnostik ist es jedoch möglich, eine Differenzierung des akuten virologischen Stadiums der Erkrankung von einem chronischen, immunologisch bedingten Stadium vorzunehmen und dementsprechend eine sinnvolle kausale Therapie durchzuführen.