Ultrastructural and Compositional Changes in Heart Muscle Cells in Mouse Model of Viral Myocarditis as Imaged by Infra-red Spectromicroscopy

Coxsackievirus B3 (CVB3), a member of the Picornaviridae family, is the leading cause of viral myocarditis, of which dilated cardiomyopathy (DCM) is a major sequela. Both direct viral and immune-mediated mechanisms have been shown to contribute to the pathogenesis of acute injury and subsequent cardiac remodelling. As the disease progresses, changes in both the myocytes and the extracellular matrix are detected. In addition to the myocytes, fibroblasts, and vasculature, the myocardium contains also a gel-like extracellular matrix (ECM)50. The extracellular matrix consists of collagens, proteoglycans, basal laminae, fibronectin, laminin, osteopontin, and other molecules. The ECM provides the myocardium with the structural integrity and alignment critical for pressure distribution and contractility, as well as cell growth, differentiation, and survival. Most of the interstitial matrix proteins, especially collagens (predominantly types I and III) are synthesized by the cardiac fibroblasts. Distortion of the extracellular matrix composition and protein architecture has profound implications on myocardial remodelling, plays a relevant role in the pathogenesis of many cardiac pathologies, and was shown to be the case in dilated cardiomyopathy. The present work has sought to determine how the composition of extracellular matrix changes in a murine model of viral myocarditis by applying infra-red microspectroscopy. The primary purpose of this study was to demonstrate the compositional alterations in temporal relations with progression of that disease state. The results of this study showed increased collagen correlations in mouse strains susceptible to progression to overt cardiomyopathy. This correlated with the evidently recognized myocardial fibrosis in chronic stages of cardiomyopathy These data provide an indication of the importance of changes in collagen content in the adverse remodeling of the failing heart and, thus, raise the possibility of pharmacological prevention of the degeneration of myocardial structure and function during the transition from acute phase of myocarditis to chronic cardiomyopathy. Whether these findings are unique to the murine heart and thus not relevant to the human heart can only be answered by appropriate studies on human myocardium. However, previous studies have suggested that the human heart will show responses in the extracellular matrix similar to those in the mouse heart.Myokarditis ist eine inflammatorische, nicht ischämische Kardiomyopathie, welche entsprechend der WHO-Klassifikation zu den spezifischen Kardiomyopathien zählt und mit einer kardialen Dysfunktion einhergeht. Unter Myokarditis versteht man eine Schädigung kardialer Myozyten mit reaktiver Infiltration des Herzmuskels durch Entzündungszellen mit konsekutiver interstitieller Remodellierung. Akute virale Myokarditis kann einen fulminanten klinischen Verlauf nehmen und konnte histologisch bei bis mehr als einem Drittel der jungen Opfer als Ursache des plötzlichen Herztodes nachgewiesen werden. Außerdem ist die 5-Jahres-Mortalitätsrate der Patienten mit bioptisch gesicherter Myokarditis deutlich reduziert (US Myokarditis Trial 1995). Der Übergang von einer klinisch diagnostizierten bzw. bioptisch gesicherten Myokarditis in eine dilatative Kardiomyopathie (DCM) ist in mehreren Studien gezeigt worden. Die Diagnostik einer Myokarditis ist klinisch durch eine unzureichende Sensitivität bzw. Spezifität der bislang verwendeten Methoden erschwert, und die Diagnose einer Myokarditis erfolgt auf der Grundlage der 1996 etablierten Dallas-Kriterien. Die Richtlinien der Dallas- Kriterien erfordern, dass die kardiopathologische Diagnose ausschließlich auf der Grundlage morphologischer Befunde erfolgt. Neue diagnostische Methoden bei der Interpretation von Endomyokardbiopsien (z. B. die immunohistochemische quantatitive Evaluation der intramyokardialen Entzündung sowie die in situ- Hybridisierung und hochsensitiven PCR-Methoden zum Nachweis einer Virusinfektion des Herzmuskels und erregerspezifischen Nukleinsäuren in Endomyokardbiopsien) haben zu diagnostischem Fortschritt beigetragen. Dennoch gibt es keinen allgemeinen akzeptierten Konsensus hinsichtlich der Diagnostik der inflammatorischen Kardiomyopathien. Humanpathogene Enteroviren, insbesondere Coxsackieviren der Gruppe B (CVB) sind klassischerweise ursächliche Erreger einer Myokarditis, ein pathologischer Prozess initiiert durch die Bindung des Virus an zelluläre Rezeptorproteine, [hauptsächlich das sogenannte „CAR“-Protein (Coxsackie-Adenovirus-Rezeptorprotein)]. In Abhängigkeit von bislang unbekannten genetischen Faktoren gelingt es dem Virus sich der Überwachung durch das Immunsystem zu entziehen und bei einem Teil der Patienten über das Stadium der akuten Virusreplikation hinaus zu persistieren und hierdurch eine chronische Infektion auszulösen. Diese infektiologisch relevante Suszeptibilität, welche die Induktion und Aufrechterhaltung einer chronischen enteroviralen inflammatorischen Kardiomyopathie betrifft, wurde bei Patienten sowie beim Mausmodell erkannt (Kandolf, Tübingen). Virus- induzierte Myokardititis im Mausmodell kann pathogenetisch in 3 Phasen konzeptualisiert werden: (1) Virämie-Phase in den ersten 3 Tagen post infectionem, (2) Inflammatorische Reaktion von Tag 5 bis Tag 14 post infectionem, und (3) Remodellierungsphase beginnend 14 Tagen post infectionem. In dieser Studie wurden mittels Infrarot-Spektromikroskopie die Veränderungen im Myokard von Mäusen mit Coxsackievirus-Myokarditis untersucht. Zwei Mäusestämme (C57BL/6 und ABY/SnJ) wurden mit Coxsackievirus B3 (CVB3) infiziert. Der Protein- (insbesondere Kollagen-) und Lipidgehalt wurden im Myokard prae infectionem, nach 4 Tagen, 8 Tagen und 28 Tage post infectionem untersucht. Diese Studie konnte zeigen, dass der Kollagengehalt in der akuten Phase der CVB3-induzierten Myokarditis erhöht ist, parallel mit der Reduktion der Lipid/Protein Ratio in beiden Mäusestämmen. Dieser Veränderungen erscheinen nur in dem permissiven Mäusestamm (ABY/SnJ) zu persistieren. Dies korreliert mit der Beobachtung, dass die Coxsackievirus-Infektion mit zwei verschieden Immunreaktionen einhergeht. Tiere aus dem resistenten Stamm können das Virus eliminieren, wobei permissive Mäuse eine Persistenz der Infektion und damit den Übergang in die chronische Phase der Myokarditis zeigen. Es scheint in dieser Studie auch, dass die zwei Mäusestämme in dem nicht- infizierten Status verschiedene Kompositionen der extrazellulären Matrix aufweisen. Diese Eigenschaft könnte eine weitere Erklärung der Mechanismen der Induktion und Aufrechterhaltung der chronischen enteroviralen inflammatorischen Kardiomyopathie sein

Left ventricular apical thrombus after systemic thrombolysis with recombinant tissue plasminogen activator in a patient with acute ischemic stroke

BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established treatment in acute stroke. To prevent rethrombosis after rtPA therapy, secondary anticoagulation with heparin is commonly performed. However, the recommended time-point and extent of heparin treatment vary and are not well investigated. CASE PRESENTATION: We report a 61-year-old man who developed an acute global aphasia and right-sided hemiparesis. Cranial CT was normal and systemic thrombolytic therapy with tPA was started 120 minutes after symptom onset. Low-dose subcutaneous heparin treatment was initiated 24 hours later. Transthoracic echocardiography (TTE) 12 hours after admission showed slightly reduced left ventricular ejection fraction (LVEF) but was otherwise normal. 48 hours later the patient suddenly deteriorated with clinical signs of dyspnea and tachycardia. TTE revelead a large left ventricular apical thrombus as well as a reduction of LVEF to 20 %. Serial further TTE investigations demonstrated a complete resolution of the thrombus and normalisation of LVEF within two days. CONCLUSION: Our case demonstrates an intracardiac thrombus formation following rtPA treatment of acute stroke, probably caused by secondary hypercoagulability. Rethrombosis or new thrombus formation might be an underestimated complication of rtPA therapy and potentially explain cases of secondary stroke progression

Cardiac and renal function in a large cohort of amateur marathon runners

Background Participation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners. Methods A total of 167 participants of the BERLIN-MARATHON (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT- proBNP and cystatin C). Results Among the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon. Conclusions The increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function

Single beat 3D echocardiography for the assessment of right ventricular dimension and function after endurance exercise: Intraindividual comparison with magnetic resonance imaging

<p>Abstract</p> <p>Background</p> <p>Our study compares new single beat 3D echocardiography (sb3DE) to cardiovascular magnetic resonance imaging (CMR) for the measurement of right ventricular (RV) dimension and function immediately after a 30 km run. This is to validate sb3DE against the "gold standard" CMR and to bring new insights into acute changes of RV dimension and function after endurance exercise.</p> <p>Methods</p> <p>21 non-elite male marathon runners were examined by sb3DE (Siemens ACUSON SC2000, matrix transducer 4Z1c, volume rates 10-29/s), CMR (Siemens Magnetom Avanto, 1,5 Tesla) and blood tests before and immediately after each athlete ran 30 km. The runners were not allowed to rehydrate after the race. The order of sb3DE and CMR examination was randomized.</p> <p>Results</p> <p>Sb3DE for the acquisition of RV dimension and function was feasible in all subjects. The decrease in mean body weight and the significant increase in hematocrit indicated dehydration. RV dimensions measured by CMR were consistently larger than measured by sb3DE.</p> <p>Neither sb3DE nor CMR showed a significant difference in the RV ejection fraction before and after exercise. CMR demonstrated a significant decrease in RV dimensions. Measured by sb3DE, this decrease of RV volumes was not significant.</p> <p>Conclusion</p> <p>First, both methods agree well in the acquisition of systolic RV function. The dimensions of the RV measured by CMR are larger than measured by sb3DE. After exercise, the RV volumes decrease significantly when measured by CMR compared to baseline.</p> <p>Second, endurance exercise seems not to induce acute RV dysfunction in athletes without rehydration.</p

Galectin-3 increase in endurance athletes

Background Galectin-3 is a new and promising biomarker for heart failure and myocardial fibrosis. Although endurance exercise is a crucial element in cardiovascular disease prevention, the relationship between exercise and plasma levels of galectin-3 is still unknown. To date, the relationship between regular exercise and myocardial fibrosis is not fully understood. This study investigates the relationship between endurance exercise and plasma levels of galectin-3. Methods Twenty-one male, healthy non-elite marathon runners were examined before and within 1 hour after a strenuous run of 30km after 4-day training abstinence. Examination included blood samples for galectin-3, echocardiography, and cardiac magnetic resonance imaging (CMR). In addition, to distinguish between cardiac or skeletal muscular origin of galectin-3, 27 C57Bl/6J mice performing voluntary wheel running and 25 sedentary mice were analysed. Results Plasma galectin-3 in endurance athletes increased from baseline to post exercise (12.83.4ng/ml to 19.9 +/- 3.9ng/ml, p Conclusions Plasma galectin-3 is substantially elevated in endurance athletes after running but does not correlate with cardiac function, other biomarkers, or myocardial fibrosis. In mice, we demonstrate that galectin-3 increase during endurance exercise originates primarily from skeletal muscle