Atrialfibrillation is the leading cause of morbidity however, the pathophysiological mechanisms of AF are not well investigated. Molecular mechanisms to understand the underlying genetic aetiologies still needs to be identified. Various studies have concluded a definite relation between miRNAs and AF. miRNAs are substances that can be easily measured in available body fluids like blood and serum, making them perfect candidates for biomarker analysis. The method to establish the relationship between the miRNA and the disease begins with a wide range microarray search that might provide insights about dysregulated miRNAs. AF, as a disease, has other cardiovascular diseases as its risk factors and this arises complications in identifying a miRNA biomarker specific to AF only. The targets of these miRNAs are analysed through miRNA databases such as TargetScan, miRBase, etc. Based on a pathway analysis and possible role in heart function, a miRNA can be established as a personalised global biomarker for AF.
The detection of atrialfibrillation with smartwatches could offer the opportunity for increased participation of the user in his health management. By actively using the ECG-feature, the user takes a proactive role in preventive self-care. Patients who have already been diagnosed with atrialfibrillation could proactively engage in the surveillance of their current therapy and find the best therapy with their doctors ( 21 ). Smartwatches give patients more and easier access to their health data compared to normal home monitoring devices, such as Holter- ECG or implantable devices. If the patient has a smartwatch and can operate it, stigma could be reduced compared to visible monitoring devices. In addition, they offer flexibility and comfort for the patient and thus increase acceptance for long term home monitoring ( 22 ). This could lead to an informed patient gaining a deeper understanding of his illness and thereby gaining greater autonomy. PewInternetResearch showed that 69% of US adults track at least one health indicator. Forty six percentage of the participants said that tracking changed their approach to maintaining their health. In people with chronic diseases, such as atrialfibrillation, tracking even had a greater impact ( 23 ). Informed Consent
Since the introduction of novel direct oral anticoagulants (DOACs) into clinical practice for stroke prevention in atrialfibrillation (AF), the measurement of the intensity of anti- coagulation has been challenging. A precise determination of anticoagulation intensity is vital in the clinical manage- ment of vitamin K antagonists (VKA), which dominated the landscape of anticoagulation for the past decades, to find the ideal therapeutic window between efficacious prevention of stroke and systemic embolism and safety from bleeding complications [ 1 ]. The specific assays that exist to determine the drug concentrations while on treatment with DOACs in patient plasma, including chromogenic anti-Xa assays and diluted thrombin time assays [ 2 – 5 ], neither indicate the effect of anticoagulation on hemostatic capacity nor are Electronic supplementary material The online version of this
Even though the dose-volume limits for the heart were exceeded, it should be noted that the heart is also the target volume in this feasibility studied. Further analysis of the maximal point dose, the maximal irradiated volume as well as the median dose were in good agreement to lim- itations stated in literature [Gag10, Mar98, Wei08, Han93] and hence no pericarditis should be expected. Concerning the irradiated cardiac substructures it was found that three beam direc- tions yielded a lower mean dose to the LCA. A mean dose over all patient cases of up to 1.5 Gy for 7 mm safety margin was found. According to a study by Darby et al. [Dar13] major coronary events increase by 7.4 % per Gy photon irradiation after five years post radiotherapy. Due to the advanced age of the atrialfibrillation patient cohort the irradiation of the coronary arteries might hence play a less significant role. Moreover, recent studies indicate that an irradiation of the heart with carbon ions might even lead to beneficial effects in the intercellular communcia- tion. Studies by Amino et al. indicate that single fraction carbon ion irradiations of more than 10 Gy lead to an increased expression of Connexin 43 (Cx43) [Ami06, Ami10]. This protein is involved in the construction of gap junctions in mammalian hearts, which are intercellular channels enabling current flow and hence the propagation of action potentials (see chapter 1, section 1.3.1). It has been shown that remodelling of connexin expression and gap junction organization are featured in pathological conditions of the heart, including ischemia and heart failure [Sev04, Sev08]. Recent studies indicate that connexin expression is also implied in the induction and sustaining of AF [Kan04, Pol01, Yeh01, Bik11]. Amino et al. could show in animal models that a cardiac irradiation with carbon ions led to a dose-dependent upregulation of Cx43 expression [Ami06], lasting for at least one year [Ami10]. It was found that this result improved the conductivity and repolarization of the animal hearts, hence having the potential for an ad- diational antiarrhythmic effect. The clinical relevance of these findings needs to be investigated. Due to the anatomical differences of pigs compared to humans and due to the larger dis- tance of the AV node to critical structures (esophagus, trachea and aorta) dose depositions
Atrialfibrillation (AF) is the most common cardiac arrhythmia requiring clinical practice and also the leading cause of hospitalisations among arrhythmia patients. Although not immediately life threatening, AF increases the risk of stroke approximately fivefold and the risk of all-cause mortality about twofold. Additionally, AF is also related to the emergence of heart failure. In order to prevent thromboembolic events from happening, a long-time antithrombotic therapy with oral anticoagulants (OAC) is recommended for most non-valvular AF patients. It reduces the risk of systemic embolisation by nearly 70%. Despite the recent advances in the therapy of AF, the high mortality and morbidity remain. The prevalence of AF increases with age; young healthy adults are at low risk. Due to the growing proportion of elderly individuals, the number of patients with AF will likely increase 2.5-fold during the next 50 years (1 –3).
RK, Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppala I, Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH, Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Theriault S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Volker U, Wang B, Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA, Lunetta KL and Ellinor PT, Multi- ethnic genome-wide association study for atrialfibrillation. Nat Genet, 2018. 11. Mohanty S, Santangeli P, Bai R, Di Biase L, Mohanty P, Pump A, and Natale A,
Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common type of supraventricular tachycardia. Slow pathway (SP) ablation is the treatment of choice with a high acute success rate and a negligible periprocedural risk. However, long-term outcome data are scarce. The aim of this study was to assess long-term outcome and arrhythmia free survival after SP ablation. In this study, 534 consecutive patients with AVNRT, who underwent SP ablation between 1994 and 1999 were included. During a mean follow-up of 15.5 years, 101 (18.9%) patients died unrelated to the procedure or any arrhythmia. Data were collected by completing a questionnaire and/or contacting patients. Clinical information was obtained from 329 patients (61.6%) who constitute the final study cohort. During the electrophysiological study, sustained 1:1 slow AV nodal pathway conduction was eliminated in all patients. Recurrence of AVNRT was documented in 9 patients (2.7%), among those 7 patients underwent a successful repeat ablation procedure. New-onset atrialfibrillation (AF) was documented in 39 patients (11.9%) during follow-up. Pre-existing arterial hypertension (odds ratio 2.61, 95% CI 1.14–5.97, p = 0.023), age (odds ratio 1.05, 95% CI 1.02–1.09, p = 0.003) and the postinterventional AH interval (odds ratio 1.02, 95% CI 1.00–1.04, p = 0.038) predicted the occurrence of AF. The present long- term observational study after successful SP ablation of AVNRT confirms its clinical value reflected by low recurrence and complication rates. The unexpectedly high incidence of new-onset AF (11.9%) may impact long-term follow-up and requires further clinical attention.
20 Huo Y, Gaspar T, Pohl M, Sitzy J, Richter U, Neudeck S, Mayer J, Kronborg MB, Piorkowski C: Prevalence and predictors of low voltage zones in the left atrium in patients with atrialfibrillation. Europace 2017; DOI:10.1093/europace/eux082.
21 Heinzmann D, Bangert A, Muller AM, von Ungern-Sternberg SN, Emschermann F, Schonberger T, Chatterjee M, Mack AF, Klingel K, Kandolf R, Malesevic M, Borst O, Gawaz M, Langer HF, Katus H, Fischer G, May AE, Kaya Z, Seizer P: The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis. PLoS One 2015;10:e0124606.
cells proved to be predictive for the development of POAF after cardiac surgery. Our results potentially indicate an auto-immune impact of this preexisting, highly cytotoxic T cell subset in the pathogenesis of POAF, which might be modified via the anti-inflammatory potential of a pre-operative statin-therapy. Already in 2010 the total estimated burden of atrialfibrillation (AF) amounted to 33.5 million affected individ- uals worldwide, representing to most common cardiac arrhythmia in the western society 1 . While various types
increase in HbA1c the risk of stroke increased 1.7-fold (95% CI 1.20–2.45, p = 0.003) (Table 2). For every one point added to the CHA2DS2-Vasc score the risk of stroke doubled (HR 2.06, 95% CI 1.27–3.35, p = 0.004). One myocardial infarction occurred while on VKA, and 6 VTE events occurred (4 DVT, 2 PE), corresponding to an event-rate of 2.8 per 100 patient-years. One VTE event occurred while on rivaroxaban therapy, 2 during rivaroxaban pause, 1 during VKA treatment, 1 during VKA pause, and 1 after discontinuation of rivaroxaban. Major bleeding events occurred in 6 patients (3 intraocular hemorrhages, 2 intraabdominal bleedings with massive blood loss and/or transfusions, 1 subdural hematoma) and CRNM bleeding events occurred in 9 patients (5 gastrointestinal [GI] bleeds, 4 other bleeds requiring hospitalization). The event rate for major bleeding was 2.8 per 100 patient-years and for CRNM bleeding 4.1 per 100 patient-years. Minor bleeding events oc- curred in 43 patients and 15 patients died during follow-up of causes unrelated to atrialfibrillation or anticoagulation. The results of our analysis revealed no statistically significant risk factor for bleeding that occurred during follow-up.
Atrialfibrillation (AF) is a frequent comorbid condition in patients with end‐stage renal disease on hemodialysis (HD) with a prevalence of up to 27%. The incidence rate of stroke in AF patients on HD is approximately 5%. The AF‐associated risk of stroke is a major clinical challenge because current evidence for anticoagulation in HD patients with AF is based on observational data. Results from these observa‐ tional studies is largely contradictory because they do not show a clear benefit of vi‐ tamin K antagonists over no treatment in terms of stroke prevention, and they show an increased risk of hemorrhage associated with anticoagulation treatment in HD patients. HD patients were not included in randomized trials of the direct oral antico‐ agulants (DOACs), and therefore there is no evidence to support efficacy and safety of DOACs compared to vitamin K antagonists in HD patients. The pharmacological characteristics of DOACs are of particular interest in the HD setting. The factor Xa inhibitors rivaroxaban, apixaban, and edoxaban are not predominantly eliminated via the kidneys. The thrombin inhibitor dabigatran is 80% eliminated via the kidneys but is dialyzable due to its low protein binding. In this narrative review, we examine the current state of evidence regarding the prevalence of AF in patients on HD, the asso‐ ciated risk of stroke, and the efficacy and safety of anticoagulation for stroke preven‐ tion in the HD setting. Further, based on the pharmacokinetic properties of DOACs, we discuss their potential use in patients on HD and ongoing randomized trials. K E Y W O R D S
However, while IL-6 proved to be linked to both endothelial activation and tissue damage, it also showed to impact in the activation and aggregation of thrombocytes as well modulation of thrombin sensitivity. In this context, the CD40-CD40L pathway of thrombocyte-leucocyte interaction needs further attention. The CD40-CD40L pathway suggests that activated platelets in AF might contribute to both the pro-thrombotic state and inflammation. [71-72] Thrombocytes represent the main source of the soluble CD40L. Due to binding on CD40 + surface protein expressed on Leucocytes, the expression of tissue factor is initiated. However, while the exact pathway in AF has not been elucidated further, the CD40-CD40L complex – especially soluble CD40L – was found to be significantly associated with elevated platelet aggregation and formation of thrombi. Moreover, values of soluble CD40L were strongly elevated in individuals presenting with AF and were found to decrease after ablation- procedure in paroxysmal and persistent cases, but remained high in individuals with recurrence of AF. Interestingly, soluble CD40L values measured prior to cardiovascular surgery, proved to predict the development of post-operative atrialfibrillation and the incidence of stroke and fatal cardiovascular events. [73-76]
ing risk. In randomized trials, the benefit of the newer anti- coagulants (non-vitamin K antagonist oral anticoagulants [NOACs]) vs warfarin was apparent regardless of age and maintained in elderly patients. 7 However, concerns on the utilization of NOACs in older patients may exist due to the high prevalence of comorbid conditions, potentially influ- encing the clinical effects of these agents. 8 Thus, more evi- dence on NOAC utilization and outcomes in older populations with atrialfibrillation should be welcome to date, where no extensive real-world data are currently available. Moreover, an assessment of the net clinical bene- fit with different anticoagulant approaches appears crucial in elderly patients with atrialfibrillation, especially in those at higher bleeding risk.
warfarin, aspirin, dabigatran, rivaroxaban, and aspirin + clopidogrel. For the present analysis we report data for apixaban versus warfarin for patients suitable for oral anticoagulant therapy. The model includes 18 mutually exclusive health states for a hypothetical cohort of patients with non-valvular atrialfibrillation (NVAF) considering the occurrence of stroke (both ischemic or heamorrhagic), systemic embolism (myocardial infarction, pulmonary em- bolism), bleeding (intracranial, major bleeding, clinically relevant non-major bleeding) and death (Fig. 1). Transi- tion probabilities between health states were derived from the ARISTOTLE trial  and from the life expectancy table for Argentina obtained from the World Health Organization.  Patients were followed for a lifetime horizon with 6 week cycles, with only allowing for one event per cycle.
Competing interests MR received advisory fees from Daiichi Sankyo and Novarits and lecutring fees from Biotronik and Takeda Pharma. TWW received lecturing fees and advisory honoraria from Daiichi Sankyo, Boehringer Ingelheim and Pfizer/ BMS. LP consultant fees from Daiichi-Sankyo, SOTIO, Beckman Coulter, Novartis. GP speaker/consultant/advisory board for Amgen, Sanofi, Bayer, Boehringer- Ingelheim, BMS-Pfizer, Daiichi Sankyo, Astra Zeneca, Sigma-Tau, Malesci, PIAM and MSD. JMSM lecture or consultant fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Bayer and research grant from Roche Diagnostics. Menarini and lecture fees from AtriCure, all outside the submitted workML is affiliated with the sponsor. KH received lecturing fees and advisory honoraria from Boehringer Ingelheim, Pfizer/ BMS, Bayer, Daiichi Sankyo, Sanofi-Aventis, AstraZeneca, and Eli Lilly. RDC received research grants from Boehringer-Ingelheim, Bayer and BMS/Pfizer. Honoraria for lecturing and participation to Advisory Boards from Boehringer-Ingelheim, Bayer and BMS/Pfizer, Daiichi-Sankyo, Lilly, AstraZeneca, Merck, Novartis, Roche. PK has received research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrialfibrillation, and has received honoraria from several such companies. PK is listed as inventor on two patents held by University of Birmingham (AtrialFibrillation Therapy WO 2015140571, Markers for AtrialFibrillation WO 2016012783).
Apixaban (Eliquis ® ) as second oral factor Xa inhibi- tor was examined in two randomized, multicenter studies in patients with atrialfibrillation. In the Apixaban versus Acetylsalicylic acid to prevent strokes (AVERROES) trial, 5,599 patients with atrialfibrillation and at least one additional risk factor were double-blind randomized. 18 Patients who were not suitable for treatment with VKA and, were either treated with acetylsalicylic acid (ASA) at doses of 81–324 mg once daily or apixaban at a dosing of 5 mg twice daily. It has long been known that ASA has only a limited antithrombotic effect in atrialfibrillation; therefore, apixaban could demonstrate its superior antithrombotic activity compared to ASA. The risk of suffering stroke or embolism was approximately halved under apixaban treatment. Remarkably, the bleeding rates among apixaban were not significantly increased in com- parison to ASA. Due to the superior benefit–risk profile of apixaban, the study has been terminated prematurely. It was finally investigated in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AtrialFibrillation (ARISTOTLE)-trial whether apixaban in the dosing of 5 mg twice daily is non-inferior to warfarin at target-INR of 2–3. 19 The study design was double-blind and randomized, and included patients with nonvalvular AF and one additional risk factor (average CHADS 2 score: 2.1). Patients with increased risk of bleeding and the presence of two risk markers (age .80 years, body weight less than 60 kg, creatinine .1.5 mg/ dL) were treated with the lower dose of apixaban 2.5 mg twice daily. The primary endpoints consisted of stroke and systemic
affiliated critical care unit allowing fast diagnostic work-up and the opportunity to rapidly perform cardioversion at any time. As this was a registry-based study, time to cardioversion attempts and observation periods were not standardized. It is thus conceivable that patients as- signed to the non-spontaneous conversion cohort would have converted spontaneously over the following hours or days if they had not under- gone early cardioversion to restore sinus rhythm. Some related bias cannot be excluded and should be considered when interpreting our findings. However, sensitivity analysis restricting the observational time-window from admission to two hours suggested robustness of the model. Furthermore, the median duration from admission to restoration of sinus rhythm was significantly longer in patients who were finally cardioverted than in those who converted spontaneously. At our in- stitution, cardioversion of hemodynamically stable symptomatic AF patients, who do not early convert spontaneously, is performed as soon as exam results are available and a trial of fluid and/or potassium challenge has been performed to improve the probability of sponta- neous conversion. This might be a common approach and reflect real- world practice in emergency settings, where ED-overcrowding and limited space for observation are common conditions. Yet, a future prospective trial should include a predefined observation schedule and follow-up period. In addition, the single-center design limits our results’ generalizability to different settings and populations. We followed the methodological guidance by Steyerberg and Verguowe and used the most contemporaneous set for validating our score. Geographical or strong external validation may provide more robust model validation, but was not be performed in this single-center study. Further validation of the developed score is needed to conclusively assess its performance. As not only hypokalemia but also potassium levels in the low- normal range may be considered target conditions for potassium re- placement, we included the combined information of low/low-normal potassium level (≤3.9mmol/l) and potassium substitution in the model. Patients with potassium levels exceeding 3.9mmol/l were not counted as potassium replacement. This needs to be noted, as clinical practice on potassium substitution in atrialfibrillation may vary be- tween institutions and clinicians.
FIGURE 1 | Schematic summary of different interactions between atrialfibrillation, oxidative stress, and flow abnormalities. Abbreviations should be
included here are explained in the text.
cardiac arrhythmia. It appears that the oxidative events initiate the disease-dependent tissue remodeling and promote its prop- agation. Oxidative stress is associated with microvascular flow abnormalities and occurs immediately after new-onset AF likely representing key initiator mechanisms of AF-related ventricular remodeling. This has been shown in patients with lone recur- rent AF and for rapid atrial pacing models ( Kochiadakis et al., 2002 ; Bukowska et al., 2008, 2012 ; Goette et al., 2009 ). Irreg- ular RR intervals are considered to be responsible for compro- mised coronary blood flow reserve, thus preventing the adequate attainment of the increased oxygen demand due to tachycardia ( Kochiadakis et al., 2002 ). In addition, increased catecholamine levels via α-adrenergic vasoconstriction may further contribute to AF-induced ischemia ( Heusch et al., 2000 ; Heusch, 2008 ). AF- dependent cardiac remodeling, especially fibrosis, may well con- tribute to long-term restriction of microcirculation ( De Boer et al., 2003 ). Resulting imbalances of myocardial oxygen supply and myocardial oxygen demand lead to the specific activation of redox- sensitive signaling pathways, that are either protective or part of the pathophysiological process causing onset and progression of AF.