Successful catheter ablation of a left posterolateral accessory bypass tract and periinterventional management in a patient with MELAS syndrome.

MELAS syndrome is defined as a combination of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes resulting from mutations in mitochondrial DNA. All medical interventions in these patients appear challenging due to a high risk of lactate acidosis or anesthesiological complications. Of note, previous reports suggest that these patients have a higher incidence of Wolff-Parkinson-White (WPW) syndrome. Here, a case of successful catheter ablation of a posteroseptal bypass tract using analgosedation in a patient with MELAS syndrome combined with WPW syndrome is presented.

Ten years of non-vitamin K antagonists oral anticoagulants for stroke prevention in atrial fibrillation: is warfarin obsolete?

Currently, four non-vitamin K antagonists oral anticoagulants (NOACs) are available for stroke prevention in atrial fibrillation (AF). These have been in clinical use for up to 10 years now. Besides data of the initial phase III clinical trials, now clinical data, several sub-studies, meta-analyses, and studies in special clinical settings and specific patient populations are available. This review shall give an overview on the history of NOAC development, sum up study data and 'real-world' clinical data as well as discuss several special clinical settings like NOAC treatment in patients that require coronary artery stenting or cardioversion (CV). Furthermore, treatment considerations in special patient populations like patients with renal impairment, obesity, or patients requiring NOACs for secondary prevention are discussed. The significance of NOAC treatment will be discussed under consideration of the recently published 2020 ESC/EACTS Guidelines for the diagnosis and management of AF.

COVID-19-Induced Cytokine Release Syndrome Associated with Pulmonary Vein Thromboses, Atrial Cardiomyopathy, and Arterial Intima Inflammation.

Coronavirus disease 2019 (COVID-19) is a viral disease induced by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which may cause an acute respiratory distress syndrome (ARDS). First reports have shown that elevated levels of inflammatory cytokines might be involved in the development of organ dysfunction in COVID-19. Here, we can present a case of cytokine release syndrome induced by SARS-CoV-2 causing multiorgan failure and death. Of note, we can report on pulmonary vein thromboses as potential source of cerebrovascular embolic events. Furthermore, we present a specific form of an isolated inflammatory atrial cardiomyopathy encompassing atrial myocardium, perivascular matrix, as well as atrial autonomic nerve ganglia, causing atrial fibrillation, sinus node arrest, as well as atrial clot formation in the right atrial appendage. An associated acute glomerulonephritis caused acute kidney failure. Furthermore, all the described pathologies of organs and vessels were associated with increased local expression of interleukin-6 and monocyte chemoattractant protein-1 (MCP-1). This report provides new evidence about fatal pathologies and summarizes the current knowledge about organ manifestations observed in COVID-19.

German Cardiac Society Working Group on Cellular Electrophysiology state-of-the-art paper: impact of molecular mechanisms on clinical arrhythmia management.

Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.

Clinical importance of atrial cardiomyopathy.

Atrial fibrillation (AF) is the most common cause of thromboembolic complications. The risk of suffering a thromboembolic complication correlates with the CHA2DS2-VASc score identifying patients at increased risk. It is based on patient age, prior thromboembolic events, and clinical comorbidities, but not based on pathophysiological changes in different types of atrial cardiomyopathy (ACM) as classified in the expert consensus on ACM published in 2016. The impact of different types of ACM has also been acknowledged in the expert consensus statement on catheter ablation of atrial fibrillation. The aim of this review is to review data on clinical importance of ACMs.

Atrial thrombogenesis in atrial fibrillation : Results from atrial fibrillation models and AF-patients.

Atrial fibrillation (AF) is the most common cause of thromboembolic complications. The risk of suffering a thromboembolic complication depends on the accompanying cardiac risk factors and the patient's age. For patients who have an increased risk, which is now classified using the CHA2DS2-VASc score, initiation of long-term oral anticoagulation is the first-line treatment. In AF, thrombi arise in the left atrial appendage. The present review will summarize the basic pathophysiology of thrombogenesis in AF and will provide the molecular basis of a process called prothrombotic endocardial remodeling. Despite oral anticoagulation being a central component of therapy, the present results can be used to support concomitant therapy with statins, angiotensin II blockers, etc. to inhibit atrial thromogenesis.

The safety of edoxaban for treating atrial fibrillation.

INTRODUCTION: Atrial Fibrillation (AF) has a worldwide increasing incidence and prevalence, putting patients at risk for atrial thrombus formation and consecutive thromboembolic events. Morbidity and mortality have become a significant global public health care burden. Thus, there is increasing need for safe and effective medical prophylaxis of thromboembolic events. Edoxaban is the fourth approved non-vitamin K oral anticoagulant (NOAC) that has been introduced into the market for the prophylaxis of stroke or systemic embolism in non valvulär AF patients after dabigatran, rivaroxaban, and apixaban. The pivotal phase III clinical trial evaluating safety and efficacy of edoxaban included more than 21,000 patients. Areas covered: The aim of this expert opinion drug safety review is to introduce edoxaban as a compound, to discuss its development, and its pharmacologic properties. Furthermore, efficacy and safety data of edoxaban - with emphasis on a comparison to oral anticoagulation with warfarin and the other currently available NOACs - are discussed. Ongoing studies that further evaluate edoxaban in special patient populations and disease entities are summarized. Expert opinion: Concerning safety and efficacy, medical compliance, adherence and concomitant diseases like renal impairment are of utmost importance in daily clinical practice, why in the expert opinion part of this review emphasis is put on that issue.

The Impact of Novel Anticoagulants: Should All AF Patients Now Be Anticoagulated?

Atrial Fibrillation (AF) is accompanied by an increased risk for thromboembolic events in most affected patients. Current guidelines therefore recommend antithrombotic therapy with vitamin K antagonist (VKA) or non VKA oral anticoagulant (NOAC) in the majority of AF patients. Current AF treatment guidelines recommend that only patients younger than 65 years of age with lone AF, meaning without further concomitant risk factors for thromboembolic events should not be anticoagulated. NOACs, like the direct thrombin inhibitor dabigatran and the factor X inhibitors rivaroxaban, apixaban, and edoxaban have undergone large phase III clinical trials concerning treatment efficacy and bleeding risk in comparison to the VKA warfarin. In most cases, treatment with NOACs has been shown to decrease thromboembolic risk and/or decrease bleeding risk when compared with warfarin. Especially, as major hemorrhages like life threatening or intracranial bleeds are reduced, the question arises, if due to favourable adverse event ratios the indication for oral anticoagulation therapy should be broadened and all patients with diagnosed AF should be anticoagulated. This article gives a review on currently used thromboembolic and bleeding risk scores. Furthermore, the impact of NOAC therapy on stroke and bleeding risk is summarized, especially taking pharmacological interactions of NOAC therapy altering thromboembolic or bleeding risk into consideration. Differences of currently available guidelines are discussed. Finally, ongoing recent studies on treatment of low risk patients are debated.

[Upstream therapy for atrial fibrillation]. / Upstream-Therapie bei Vorhofflimmern.

In recent years a tremendous amount has been learned about the pathophysiology of atrial fibrillation (AF) which induces electrophysiological changes in the right and left atrium. Besides calcium-dependent tissue changes which are induced by activation of proteases and phosphatases, such as calpain and calcineurin, concomitant cardiac diseases activate the atrial angiotensin II system. Experiments have shown positive effects of statins in AF models. In contrast, clinical studies have provided heterogeneous results. Of note, several studies have shown that therapy with angiotensin II receptor blockers or statins does not influence the recurrence of AF.

Enzymatic activity of DPIV and renin-angiotensin system (RAS) proteases in patients with left ventricular dysfunction and primary prevention implantable cardioverter/defibrillator (ICD).

BACKGROUND: Patients (pts) with severely decreased left ventricular ejection fraction (LV-EF ≤ 35%) are at high risk for sudden cardiac death (SCD). We sought to investigate, if pts with primary prevention ICD hold alterations in enzyme-activities of the dipeptidyl-aminopeptidase IV (DPIV) and the renin-angiotensin system (RAS) before VT/VF occurrence. METHODS: 57 Pts (53 male, mean age 64.9 [42-84] years, mean LV-EF 26 ± 5%) with ischemic (n=49) or non-ischemic cardiomyopathy (n=8) who had received an ICD/CRT-D for primary prevention, were included. Pts were assessed for appropriate ICD intervention for VT/VF during a mean follow-up of 365 ± 90 days. Serum levels of dipeptidyl-aminopeptidase IV (DPIV), aminopeptidase N (APN), aminopeptidase B (APB), insulin-regulated aminopeptidase (IRAP), and angiotensin-converting enzyme 2 (ACE2) were determined. RESULTS: Pts with appropriate ICD intervention (n=16) had higher serum activities of IRAP (mean difference=12.681 pkat/mL; p=0.007), and DPIV (mean difference=117.557 pkat/mL; p=0.032) than pts without appropriate ICD intervention. Furthermore, ACE2 activity was significantly higher (median: 223.7 RFU/smL vs. 169.10 RFU/smL; p=0.037). A Cox regression analysis indicated DPIV activity >50th centile to have a hazard ratio (HR) of 5.955 (CI 95%: 1.670-21.241; p=0.006) for prediction of appropriate ICD intervention. In a multivariate Cox regression model, DPIV and IRAP >50th centile remained predictive for appropriate ICD intervention. CONCLUSION: Our prospective study shows that pts with primary prevention ICD, who receive appropriate ICD intervention during follow-up, can be identified by elevated activities of DPIV and several RAS proteases. Hence, theses biomarkers seem to be of prognostic relevance in a primary prevention collective. Our data has to be proven in larger cohorts.

Induction of ventricular tachycardia during radiofrequency ablation via pulmonary vein ablation catheter in a patient with an implanted pacemaker.

Pulmonary vein isolation in a dual-chamber pacemaker patient using the pulmonary vein ablation catheter (PVAC) system resulted in perpetual induction of ventricular tachycardia (VT) during radio frequency energy application. Induction of VT was abolished by programming the PVAC-system to a pure bipolar ablation mode. Patients with implanted devices should be closely monitored when using the PVAC system in unipolar modes.

The impact of rapid atrial pacing on ADMA and endothelial NOS.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a well-established risk factor for oxidative stress, vascular dysfunction, and congestive heart failure. The aim of the present study was to determine the impact of rapid atrial pacing (RAP) on ADMA levels and eNOS expression. METHODS AND RESULTS: ADMA levels were studied in 60 age- and gender-matched patients. Thirty five patients had persistent atrial fibrillation (AF)≥ 4months. In AF-patients, parameters were studied before and 24h after electrical cardioversion. Moreover, ADMA, eNOS expression, and calcium-handling proteins were studied in pigs subjected to RAP as well as in endothelial cell (EC) cultures. ADMA level was significantly higher in AF compared to sinus rhythm patients (p=0.024). ADMA was highest in AF-patients, who also showed elevated troponin T (TnT) levels. Moreover, ADMA showed a significant linear correlation to TnT (r=0.47; p<0.01). After electrical cardioversion ADMA returned to normal within 24h. In pigs, RAP for 7h increased ADMA levels (p=0.018) and TnI (p<0.05), and reduced mRNA expression of ventricular and aortic eNOS (-80%; p<0.05) compared to sham-control. However, ADMA per se did not affect eNOS mRNA level in EC cultures. CONCLUSION: The current study shows that acute and persistent episodes of atrial tachyarrhythmia are associated with elevated ADMA levels accompanied by increased ischemic myocardial markers. Moreover, RAP increases ADMA and down-regulates eNOS expression in an ADMA-independent manner. We conclude that the combination of these two separate and potentially synergistic mechanisms may contribute to long-term vascular injury during atrial tachyarrhythmia.

Asymmetric dimethylarginine predicts appropriate implantable cardioverter-defibrillator intervention in patients with left ventricular dysfunction.

AIMS: More precise characterization of risk factors for occurring ventricular arrhythmia in patients (pts) with primary prevention implantable cardioverter-defibrillator (ICD) therapy is critical. We sought to investigate whether biomarkers of nitric oxide metabolism can predict the occurrence of ventricular tachyarrhythmias and might be used as risk markers in these pts. METHODS AND RESULTS: Plasma levels of l-arginine (Arg), asymmetric dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), monomethyl l-arginine, and nitrite/nitrate were examined in 106 consecutive pts (mean age 65 years, 97 male, mean LV-EF 24 ± 6%), with ischaemic (n= 82) or non-ischaemic cardiomyopathy (n= 24) who underwent ICD implantation for primary prevention of SCD. Appropriate ICD intervention was assessed during a mean follow-up of 344 days, and occurred in 18 of 106 (17%) pts. Asymmetric dimethylarginine plasma levels were significantly higher in pts with appropriate ICD intervention compared with those without any ICD intervention (0.564 ± 0.083 µmol/L vs. 0.513 ± 0.088 µmol; P= 0.027). The Arg/ADMA ratio was found lower in pts with appropriate ICD intervention than in those without ICD intervention (144.71 ± 32.50 vs. 175.29 ± 41.29; P= 0.002). Univariate Cox regression showed that ADMA (P = 0.028) and the Arg/ADMA ratio (P = 0.003) were associated with a higher incidence of appropriate ICD intervention. In a multivariable Cox regression analysis, an ADMA concentration above the 50th centile was independently associated with appropriate ICD intervention, revealing a hazard ratio (HR) of 4.21 (CI 95 %: 1.14-15.63; P = 0.028, Table 4). An Arg/ADMA ratio below the 25th centile had a HR of 3.83 (1.360-10.87; P = 0.011). CONCLUSION: Asymmetric dimethylarginine and the Arg/ADMA ratio seem to be new biomarkers for the prediction of ventricular tachycardia/ventricular fibrillation episodes and of appropriate ICD intervention in pts with left ventricular ejection fraction dysfunction (LV-EF ≤ 35%), suggesting a value for risk stratification in these pts.

Atrial expression of endothelial nitric oxide synthase in patients with and without atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with oxidative stress within the fibrillating atrial myocardium. Experimental studies suggest that reduced levels of nitric oxide (NO) caused by down-regulation of the NO synthase (eNOS) contribute to the development of prothrombotic endocardial remodeling in AF. This study was designed to determine the endocardial expression of eNOS in atrial tissue samples from patients with and without AF. METHODS: Tissue microarrays were used to analyze right atrial tissue specimens obtained from 234 patients (38 with AF; 196 with sinus rhythm) for differences in atrial eNOS expression. In selected patients, immunohistological results were confirmed by Western blotting. RESULTS: Immunohistochemical analyses showed that eNOS is expressed by endocardial cells and myocytes. However, endocardial expression of eNOS was not independently related to AF per se. There was no difference between paroxysmal and persistent AF. Clinical factors like gender (P=.05) and coronary artery disease (P=.06) were associated with down-regulation of eNOS. Interestingly, diabetes mellitus (P=.02) was associated with an up-regulation of endocardial eNOS, whereas other risk factors for thromboembolic events did not influence eNOS levels. Multivariable analysis showed that eNOS expression is influenced by interactions between diabetes mellitus and AF (P=.09) as well as by interactions between gender and AF (P=.04). Lowest levels of eNOS were found in women with AF. CONCLUSION: AF does not independently effect atrial eNOS expression in humans. Due to the nonuniform regulation of endocardial eNOS expression, it appears unlikely that down-regulation of eNOS is a final common pathway for the development of prothrombotic endocardial remodeling, since classical risk factors for thromboembolic events do not reduce endocardial eNOS protein.

Recent advances in the pharmacological treatment of cardiac arrythmias.

Atrial and ventricular arrhythmias are associated with substantial morbidity and mortality and thus are a significant economic burden for healthcare systems. Currently available pharmacological agents have limited efficacy or the risk of relevant side effects, such as drug toxicity and proarrhythmic potential. Recent scientific developments have added new aspects and approaches to this field meriting a fresh review of treatment options. These include novel ion-channel blockers (e.g. dronedarone, celivarone, vernakalant, ranolazine), non-ion channel blockers (e.g. GsMtx4) such as gap junction modulators (rotigaptide) and drugs antagonizing the angiotensin system (ACE-inhibitors, angiotensin II receptor blockers), which appear to have various effects on cardiac electrophysiology. Special emphasis is placed on new antiarrhythmic drugs (e.g. dantrolene) targeting molecular, proarrhythmogenic and structural remodeling. Finally, new developments in the prevention of thromboembolic complications of atrial fibrillation are discussed (dabigatran).

Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation.

Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.

New drugs for atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Epidemiologic studies suggest that the number of patients with AF will triple in the next 30 years, and therefore, its impact on medical and economic issues will further increase. Due to the limited efficacy and significant side effects of antiarrhythmic drugs, much effort has been made to develop alternative pharmacologic treatments for AF. Novel approaches include new antiarrhythmic drugs and novel drug targets involved in molecular, proarrhythmogenic, atrial remodeling. Furthermore, novel anticoagulants are now clinically studied. This review briefly summarizes new developments in the pharmacotherapy for AF.