Optimierte Diagnostik durch molekulare Biomarker bei sekundären Kardiomyopathien

Mein Forschungsbereich war bisher auf die Entwicklung von Biomarkern im Bereich Herzinsuffizienz und sekundäre Kardiomyopathien fokussiert. Zusammen mit meiner Arbeitsgruppe haben wir einen Transkriptombiomarker für die Diagnose und Prognose bei Patienten mit neu diagnostizierter Herzinsuffizienz entwickelt, als auch einen Marker zum Monitoring des Ansprechens auf Beta-Blocker Therapie. Hierbei haben wir wichtige individuelle Unterschiede im Genexpressionsprofil von Patienten mit Herzinsuffizienz beschrieben, welche im Zeitalter der Präzisionsmedizin berücksichtigt werden sollten, insbesondere geschlechtsspezifische Unterschiede, aber auch Unterschiede basierend auf Krankheitsstadium und funktionelle Parameter. Robuste statistische Analysen sind notwendig, wenn Big-Data-Analysen angewandt werden, um Fehlerquellen wie „Overfitting“ und zufällige Assoziation von Parametern mit einem Phänotyp auf Grund sehr hoher Anzahl von Variablen im Experiment zu vermeiden. Entsprechende statistische Algorithmen wurden bereits entwickelt. Unsere Forschung im Bereich der Magnetresonanztomografie bei Myokarditis bestätigt nochmals, dass eine genaue Diagnose und prognostische Evaluation nicht durch einen einzelnen Biomarker möglich ist, da wie bereits erwähnt kein Biomarker perfekt ist. Zusätzlich zeigt sie auf, dass die Bildgebung in der Myokarditis auch im Rahmen der Verlaufskontrolle eine relevante Rolle spielt und dass die Magnetresonanztomografie eine wichtige Funktion bei der Identifikation von Patienten mit Myokarditis bei “Myocardial infarction and non-obstructive coronary artery disease” hat. Außerdem hat uns Magnetresonanztomografie ermöglicht, die Sicherheit von nicht-steroidalen Antirheumatika bei akuter Myoperikarditis zu montiorisieren und zeigte sogar einen möglichen therapeutischen Vorteil bei dieser Patientengruppe. Im Bereich der stabilen koronaren Gefäßerkrankung haben wir mit Hilfe von Proteomanalysen das kardiovaskuläre Risiko von individuellen Patienten mit hoher Genauigkeit berechnet.Hierzu wurde ein Proteommarker in einer Kohorte von 938 Patienten entwickelt und bei weiteren 971 Patienten erfolgreich validiert. Zusammenfassend steht uns aktuell eine Vielzahl an diagnostischen Methoden im Bereich der kardiovaskulären Medizin zur Verfügung von Genetik, über Transkriptom- und Proteombiomarker und modernste Bildgebungstechniken. Im Zeitalter der Präzisionsmedizin sollten wir alle vorhandenen Daten eines Patienten auf integrative Weise berücksichtigen, um eine individualisierte und optimierte Therapie zu ermöglichen

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

Transthyretin amyloidosis (ATTR) is a rare, yet underdiagnosed disease characterized by progressive impairment of neurologic and cardiac function due to deposition of misfolded transthyretin. Despite great efforts, such as the introduction of orthotopic liver transplant, the devastating prognosis for both variant and wild-type ATTR patients remained unchanged over the last decades, mainly due to a lack of specific therapies. Fortunately, recent years saw the introduction of promising targeted therapies, which aim to interfere with the deposition of misfolded transthyretin (TTR) at various stages of the cascade underlying ATTR progression. These include TTR tetramer stabilizers (tafamidis, diflunisal, epigallocatechin-3-gallate), TTR silencers (inotersen, patisiran) and fibril disruptors (monoclonal antibodies, doxycycline and tauroursodeoxycholic acid). In the context of this review we explain their mechanisms of action, analyse their efficacy on neurologic and cardiac function based on all clinical trials conducted to date and discuss their clinical applicability. Eventually suggestions for future clinical research into the field are provided

Case report: Magnetocardiography as a potential method of therapy monitoring in amyloidosis

Amyloidosis is characterized by a disorder of protein conformation and metabolism, resulting in deposits of insoluble fibrils in various organs causing functional disturbances. Amyloidosis can also affect the heart. Cardiac amyloidosis tends to have a poor prognostic outcome if diagnosed at a late stage. Therefore, early diagnosis and initiation of therapy as well as monitoring of treatment response are crucial to improve outcomes and to learn more about its pathophysiology and clinical course. We present an 83-year-old woman with cardiac transthyretin amyloidosis (ATTR) who was treated with tafamidis. The patient significantly improved 18 months after initiation of therapy with regards to exercise capacity and quality of life. In addition to standard diagnostic methods, we used magnetocardiography (MCG) to monitor potential treatment response by detecting changes in the magnetic field of the heart. MCG is a non-invasive method that detects the cardiac magnetic field generated by electrical currents in the heart with high sensitivity. We have recently shown that this magnetic field changes in various types of cardiomyopathies may be used as a non-invasive screening tool. We determined previously that an MCG vector ≥0.052 was the optimal threshold to detect cardiac amyloidosis. The patient's MCG was measured at various time points during therapy. At the time of diagnosis, the patient's MCG vector was 0.052. After starting therapy, the MCG vector increased to 0.090, but improved to 0.037 after 4 months of therapy. The MCG vector reached a value of 0.017 after 5 months of therapy with tafamidis, and then increased slightly after 27 months to a value of 0.027 (<0.052). Data from this case support our previous findings that MCG may be used to monitor treatment response non-invasively. Further research is needed to understand the unexpected changes in the MCG vector that were observed at the beginning of therapy and later in the course. Larger studies will be necessary to determine how these changes in the electromagnetic field of the heart are related to structural changes and how they affect clinical outcomes

Case report: Recurrence of inflammatory cardiomyopathy detected by magnetocardiography

BackgroundThe diagnosis of inflammatory cardiomyopathies remains challenging. Life-threatening conditions such as acute coronary syndrome (ACS) always have to be considered as differential diagnoses due to similarities in presentation. Diagnostic methods for inflammatory cardiomyopathy include endomyocardial biopsy (EMB), cardiac magnetic resonance imaging (CMR), and positron emission tomography-computed tomography (PET-CT). We report a case in whom magnetocardiography (MCG) led to an initial diagnosis of inflammatory cardiomyopathy and in whom MCG was used for subsequent monitoring of treatment response under immunosuppression.Case presentationA 53-year-old man presented with two recurrent episodes of inflammatory cardiomyopathy within a 2-year period. The patient initially presented with reduced exercise capacity. Echocardiography revealed a moderately reduced left ventricular ejection fraction (LVEF 40%). Coronary angiography ruled out obstructive coronary artery disease (CAD) and an EMB was performed. The EMB revealed inflammatory cardiomyopathy without viral pathogens or replication. Moreover, we performed MCG, which confirmed a pathological Tbeg-Tmax vector of 0.108. We recently established a cutoff value of Tbeg-Tmax of 0.051 or greater for the diagnosis of inflammatory cardiomyopathy. Immunosuppressive therapy with prednisolone was initiated, resulting in clinical improvement and an LVEF increase from 40% to 45% within 1 month. Furthermore, the MCG vector improved to 0.036, which is considered normal based on our previous findings. The patient remained clinically stable for 23 months. During a routine follow-up, MCG revealed an abnormal Tbeg-Tmax vector of 0.069. The patient underwent additional testing including routine laboratory values, echocardiography (LVEF 35%), and PET-CT. PET-CT revealed increased metabolism in the myocardium—primarily in the lateral wall. Therapy with prednisolone and azathioprine was initiated and MCG was used to monitor the effect of immunosuppressive therapy.ConclusionIn addition to diagnostic screening, MCG has the potential to become a valuable method for surveillance monitoring of patients who have completed treatment for inflammatory cardiomyopathy. Furthermore, it could be used for treatment monitoring. While changes in the magnetic vector of the heart are not specific to inflammatory cardiomyopathy, as they may also occur in other types of cardiomyopathies, MCG offers a tool of broad and efficient diagnostic screening for cardiac pathologies without side effects

Severe Heart Failure in the Setting of Inflammatory Cardiomyopathy With Likely Pathogenic Titin Variant

No abstract availabl

Benefit of a wearable cardioverter defibrillator for detection and therapy of arrhythmias in patients with myocarditis

Aims: Myocarditis may lead to malignant arrhythmias and sudden cardiac death. As of today, there are no reliable predictors to identify individuals at risk for these catastrophic events. The aim of this study was to evaluate if a wearable cardioverter defibrillator (WCD) may detect and treat such arrhythmias adequately in the peracute setting of myocarditis. Methods and results: In this observational, retrospective, single centre study, we reviewed patients presenting to the Charite Hospital from 2009 to 2017, who were provided with a WCD for the diagnosis of myocarditis with reduced ejection fraction (<50%) and/or arrhythmias. Amongst 259 patients receiving a WCD, 59 patients (23%) were diagnosed with myocarditis by histology. The mean age was 46 +/- 14 years, and 11 patients were women (19%). The mean WCD wearing time was 86 +/- 63 days, and the mean daily use was 20 +/- 5 h. During that time, two patients (3%) had episodes of sustained ventricular tachycardia (VT; four total) corresponding to a rate of 28 sustained VT episodes per 100 patient-years. Consequently, one of these patients underwent rhythm stabilization through intravenous amiodarone, while the other patient received an implantable cardioverter defibrillator. Two patients (3.4%) were found to have non-sustained VT. Conclusions: Using a WCD after acute myocarditis led to the detection of sustained VT in 2/59 patients (3%). While a WCD may prevent sudden cardiac death after myocarditis, our data suggest that WCD may have impact on clinical management through monitoring and arrhythmia detection

Long-Term Mortality after New-Onset Atrial Fibrillation in COVID-19

Background: Atrial fibrillation (AF) has been described as a common cardiovascular manifestation in patients suffering from coronavirus disease 2019 (COVID-19) and has been suggested to be a potential risk factor for a poor clinical outcome. Methods: In this observational study, all patients hospitalized due to COVID-19 in 2020 in the Cantonal Hospital of Baden were included. We assessed clinical characteristics, in-hospital outcomes as well as long-term outcomes with a mean follow-up time of 278 (±90) days. Results: Amongst 646 patients diagnosed with COVID-19 (59% male, median age: 70 (IQR: 59-80)) in 2020, a total of 177 (27.4%) patients were transferred to the intermediate/intensive care unit (IMC/ICU), and 76 (11.8%) were invasively ventilated during their hospitalization. Ninety patients (13.9%) died. A total of 116 patients (18%) showed AF on admission of which 34 (29%) had new-onset AF. Patients with COVID-19 and newly diagnosed AF were more likely to require invasive ventilation (OR: 3.5; p = 0.01) but did not encounter an increased in-hospital mortality. Moreover, AF neither increased long-term mortality nor the number of rehospitalizations during follow-up after adjusting for confounders. Conclusions: In patients suffering from COVID-19, the new-onset of AF on admission was associated with an increased risk of invasive ventilation and transfer to the IMC/ICU but did not affect in-hospital or long-term mortality

A Prospective Pilot Study to Identify a Myocarditis Cohort who may Safely Resume Sports Activities 3 Months after Diagnosis

International cardiovascular society recommendations to return to sports activities following acute myocarditis are based on expert consensus in the absence of prospective studies. We prospectively enrolled 30 patients with newly diagnosed myocarditis based on clinical parameters, laboratory measurements and cardiac magnetic resonance imaging with mildly reduced or pre served left ventricular ejection fraction (LVEF) with a follow-up of 12 months. Cessation of physical activity was recommended for 3 months. The average age was 35 (19–80) years with 73% male patients. One case of non-sustained ventricular tachycardia was recorded during 48-h-Holter electrocardiogram. Except for this case, all patients were allowed to resume physical exercise after 3 months. At 6- (n = 26) and 12-month (n = 19) follow-up neither cardiac events nor worsening LVEF were recorded. The risk of cardiac events at 1 year after diagnosis of myocarditis appears to be low after resumption of exercise after 3 months among patients who recover from acute myocarditis

Long-term impact of myocardial inflammation on quantitative myocardial perfusion-a descriptive PET/MR myocarditis study

PURPOSE Whether myocardial inflammation causes long-term sequelae potentially affecting myocardial blood flow (MBF) is unknown. We aimed to assess the effect of myocardial inflammation on quantitative MBF parameters, as assessed by 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) late after myocarditis. METHODS Fifty patients with a history of myocarditis underwent cardiac magnetic resonance (CMR) imaging at diagnosis and PET/MR imaging at follow-up at least 6 months later. Segmental MBF, myocardial flow reserve (MFR), and 13N-ammonia washout were obtained from PET, and segments with reduced 13N-ammonia retention, resembling scar, were recorded. Based on CMR, segments were classified as remote (n = 469), healed (inflammation at baseline but no late gadolinium enhancement [LGE] at follow-up, n = 118), and scarred (LGE at follow-up, n = 72). Additionally, apparently healed segments but with scar at PET were classified as PET discordant (n = 18). RESULTS Compared to remote segments, healed segments showed higher stress MBF (2.71 mL*min$^{-1}$*g$^{-1}$ [IQR 2.18-3.08] vs. 2.20 mL*min$^{-1}$*g$^{-1}$ [1.75-2.68], p < 0.0001), MFR (3.78 [2.83-4.79] vs. 3.36 [2.60-4.03], p < 0.0001), and washout (rest 0.24/min [0.18-0.31] and stress 0.53/min [0.40-0.67] vs. 0.22/min [0.16-0.27] and 0.46/min [0.32-0.63], p = 0.010 and p = 0.021, respectively). While PET discordant segments did not differ from healed segments regarding MBF and MFR, washout was higher by ~ 30% (p < 0.014). Finally, 10 (20%) patients were diagnosed by PET-MPI as presenting with a myocardial scar but without a corresponding LGE. CONCLUSION In patients with a history of myocarditis, quantitative measurements of myocardial perfusion as obtained from PET-MPI remain altered in areas initially affected by inflammation. CMR = cardiac magnetic resonance; PET = positron emission tomography; LGE = late gadolinium enhancement

Long-term impact of myocardial inflammation on quantitative myocardial perfusion-a descriptive PET/MR myocarditis study.

PURPOSE Whether myocardial inflammation causes long-term sequelae potentially affecting myocardial blood flow (MBF) is unknown. We aimed to assess the effect of myocardial inflammation on quantitative MBF parameters, as assessed by 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) late after myocarditis. METHODS Fifty patients with a history of myocarditis underwent cardiac magnetic resonance (CMR) imaging at diagnosis and PET/MR imaging at follow-up at least 6 months later. Segmental MBF, myocardial flow reserve (MFR), and 13N-ammonia washout were obtained from PET, and segments with reduced 13N-ammonia retention, resembling scar, were recorded. Based on CMR, segments were classified as remote (n = 469), healed (inflammation at baseline but no late gadolinium enhancement [LGE] at follow-up, n = 118), and scarred (LGE at follow-up, n = 72). Additionally, apparently healed segments but with scar at PET were classified as PET discordant (n = 18). RESULTS Compared to remote segments, healed segments showed higher stress MBF (2.71 mL*min-1*g-1 [IQR 2.18-3.08] vs. 2.20 mL*min-1*g-1 [1.75-2.68], p < 0.0001), MFR (3.78 [2.83-4.79] vs. 3.36 [2.60-4.03], p < 0.0001), and washout (rest 0.24/min [0.18-0.31] and stress 0.53/min [0.40-0.67] vs. 0.22/min [0.16-0.27] and 0.46/min [0.32-0.63], p = 0.010 and p = 0.021, respectively). While PET discordant segments did not differ from healed segments regarding MBF and MFR, washout was higher by ~ 30% (p < 0.014). Finally, 10 (20%) patients were diagnosed by PET-MPI as presenting with a myocardial scar but without a corresponding LGE. CONCLUSION In patients with a history of myocarditis, quantitative measurements of myocardial perfusion as obtained from PET-MPI remain altered in areas initially affected by inflammation. CMR = cardiac magnetic resonance; PET = positron emission tomography; LGE = late gadolinium enhancement