PET/CT-identified atrial hypermetabolism is an index of atrial inflammation in patients with atrial fibrillation.

BACKGROUND: Although atrial inflammation has been implicated in the pathophysiology of atrial fibrillation (AF), the identification of atrial inflammation remains challenging. We aimed to establish a positron emission tomography/computed tomography (PET/CT) protocol with 18Fluor-labeled fluorodeoxyglucose (18F-FDG) for the detection of atrial hypermetabolism as surrogate for inflammation in AF. METHODS: We included n = 75 AF and n = 75 non-AF patients undergoing three common PET/CT protocols (n = 25 per group) optimized for the detection of (a) inflammation and (b) malignancy in predefined fasting protocols, and (c) cardiac viability allowing for maximized glucose uptake. 18F-FDG-uptake was analyzed in predefined loci. RESULTS: Differences of visual atrial uptake in AF vs non-AF patients were observed in fasting (inflammation [13/25 vs 0/25] and malignancy [10/25 vs 0/25]) protocols while viability protocols showed non-specific uptake in both the groups. In the inflammation protocol, AF patients showed higher uptake in the right atrium [(SUVmax: 2.5 ± .7 vs 2.0 ± .7, P = .01), atrial appendage (SUVmax: 2.4 ± .7 vs 2.0 ± .6, P = .03), and epicardial adipose tissue (SUVmax: 1.4 ± .5 vs 1.1 ± .4, P = .04)]. Malignancy and viability protocols failed to differentiate between AF and non-AF. CONCLUSION: Glucose uptake suppression protocols appear suitable in detecting differential atrial 18F-FDG uptake between AF and non-AF patients. Imaging-based assessment of inflammation might help to stratify AF patients offering individualized therapeutic approaches.

Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling.

BACKGROUND: Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging. METHOD AND RESULTS: Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model. From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUVmax 2.2 ± .6 vs 1.5 ± .4, P < .05 and SUVmean 1.6 ± .4 vs 1.2 ± .3, P < .05, respectively). Univariate regression demonstrated a significant correlation of coronary artery disease (CAD), age and left ventricular ejection fraction (LVEF) with remote SUVmean uptake, the latter with a very strong correlation with remote uptake (R2 = .74, P < .01). CONCLUSION: Our study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.

ANTECEDENTES: Proteína de activación de fibroblastos (FAP) como marcador específico de fibroblastos maduros activados se puede visualizar mediante tomografía por emisión de positrones (PET) usando inhibidores de Ga-68-FAP (FAPI). El FAPI marcado con galio 68 se usa cada vez más en la estatificación de varios tipos de cáncer.Además, se han reportado los primeros casos de abordajes teranósticos. En este trabajo describimos el fenómeno de la captación de FAPI miocárdica en pacientes que recibieron Ga-68 FAPI PET para estatificación tumoral. MéTODO Y RESULTADOS: Los exámenes de PET Ga-68 FAPI para estadificación de cáncer se analizaron retrospectivamente con respecto a la captación del marcador cardíaco. Los valores de absorción estandarizados (SUV) se correlacionaron con covariables clínicas en un modelo de regresión univariante. Del 09/2018 al 11/2019 con una n = 32 pacientes fueron sometidos a PET FAPI en nuestra institución. Seis de 32 pacientes (18.8%) demostraron un aumento de acumulación del marcador localizado en el miocardio, con la captación remota de FAPI siendo significativamente mayor en pacientes con aumento de la captación vs sin captación focalizada de miocardio (SUVmax 2.2 ± 0.6 vs. 1.5 ± 0.4, p <0.05 y SUV mean 1.6 ± 0.4 vs. 1.2 ± 0.3, p <0.05, respectivamente). La regresión univariante demostró una correlación significativa de la enfermedad de la arteria coronaria (CAD), la edad y la fracción de eyección ventricular izquierda (FEVI) con absorción SUV remota, esta última con una muy fuerte correlación con la captación remota (R² = 0.74, p <0.01). CONCLUSIóN: Nuestro estudio indica una asociación de CAD, edad y FEVI con la captación de FAPI. Se necesitan más estudios para evaluar si la activación de fibroblastos se puede medir de manera confiable y se puede usar para la estratificación de riesgo con respecto a la detección temprana o la progresión de la CAD y la remodelación ventricular izquierda.

CONTEXTE: La protéine d'activation des fibroblastes (FAP) activés et matures peut être visualisée par tomographie à émission de positons (TEP) à l'aide d'inhibiteurs de l'activation des fibroblastes (FAPI). FAPI marqué au gallium 68 est de plus en plus utilisé dans la stratification de divers cancers. De plus, les premiers exemples d'approches théranostiques ont été rapportés. Dans ce travail nous décrivons la captation myocardique de FAPI chez les patients qui bénéficié d'une TEP au Ga-68 FAPI pour stratification tumorale. MéTHODE ET RéSULTATS: Les examens TEP Ga-68 FAPI pour la stratification oncologique ont été analysés rétrospectivement pour l'absorption du traceur au niveau cardiaque. Les valeurs d'absorption normalisées (SUV) font été corrélées aux variables cliniques selon un modèle de régression univarié. A partir de septembre 2018 jusqu'en novembre 2019, 32 patients ont bénéficié d'une TEP FAPI dans notre établissement. Six de nos 32 patients (18,8%) ont démontré une augmentation focale de captation du tracer au niveau myocardique. Les foyers systémiques se sont révélés significativement plus élevé chez les patients avec foyers myocardiques localisés (SUV max 2,2 ± 0,6 vs 1,5 ± 0,4, p <0,05 et SUV mean 1,6 ± 0,4 vs 1,2 ± 0,3, p <0,05, respectivement). Nous avons observé une corrélation significative entre la maladie coronarienne, l'âge, la fraction d'éjection du ventricule gauche et la présence de foyer myocardiques FAPI (R² = 0,74, p <0,01) CONCLUSION: Notre étude indique une association entre la maladie cardiovasculaire coronarienne, l'âge et la FEVG et la captation myocardique de FAPI. Des études additionnelles sont nécessaires pour déterminer si l'activation des fibroblastes peut être mesurée de manière fiable et utilisée pour la détection et la progression de la maladie coronarienne et le remodelage du ventricule gauche.

Critical inflammatory mechanisms underlying arrhythmias.

During the past few decades, cardiovascular research has increasingly focused on systemic inflammatory mechanisms, particularly in the field of atherosclerosis but also in association with cardiac arrhythmogenesis. Objective inflammatory markers including C­reactive protein and cytokines, also called "biomarkers," seem to serve as predictors of onset and prognosis of cardiac arrhythmias. This review gives an overview of potential mechanisms underlying inflammatory processes and arrhythmias, especially atrial fibrillation, which is the most common sustained arrhythmia in daily clinical routine. The association between inflammatory pathways and cardiac arrhythmia is highly complex and includes direct as well as indirect pathways. While past research into arrhythmia focused on fibrosis, altered action potential properties, and ischemia, novel concepts include coagulation and inflammation in cardiac tissue. The underlying mechanisms are altered electrophysiological properties, including ion channel disturbance, early and late afterdepolarizations, as well as enhanced fibrosis and structural remodeling in cardiomyopathies. These pathophysiological factors favor the occurrence of ectopic pacemakers as well as re-entry tachycardia. Further studies are essential to better understand the main inflammatory signal cascades and the exact proarrhythmic effect of interacting key mediators. This will facilitate the evaluation of future anti-inflammatory therapeutic approaches for arrhythmias, analogous to recent developments in atherosclerosis.

Remote monitoring of implantable cardioverter-defibrillators. Problems and implications using a telemonitoring system.

The rising number of implantable devices has led to an increase in device-related workload, e.g., regular interrogation follow-up visits. Telemonitoring systems for implantable cardioverter-defibrillators (ICDs) seem to be a promising tool for reducing workload and costs, and they have the potential of optimizing patient care. However, issues such as practical functionality of ICD telemonitoring in daily routine may affect its broad implementation. The objective of this study was to evaluate potential problems during the implementation of a telemonitoring system, Medtronic CareLink™ (CL™) with respect to the installation and data transmission process. A total of 159 patients with ICDs who were equipped with the CL™ system were evaluated and followed up for 16 months regarding the success rate of the first data transmission via the telemonitoring system. In this cohort, a high rate of nontransmission of 23.9 % was observed after the 16-month follow-up. A detailed interview of these patients (no transmission) revealed that the main reasons for failed transmissions were due to the patients' loss of interest in the concept (approximately 50 %) as well as technical problems (approximately 25 %) with setting up the system. These results indicate that telemonitoring systems bear potential problems and that the evaluation of patient motivation and technical support options seems to play an important role in establishing the functionality of these systems.

Outcome after ablation of atypical atrial flutter: Is induction a feasible approach?

Background: Atypical atrial flutter (AAF) is an increasingly relevant clinical problem. Despite advancements in mapping and ablation techniques, the general management of these patients remain challenging especially when mapping cannot be performed during ongoing arrhythmia. There are no data whether induction of AAF is a feasible approach in these cases. Methods: We retrospectively analyzed patients who underwent catheter ablation of AAF and compared procedural results between patients with ongoing tachycardia when starting the procedure and patients with induced AAF. Results: We analyzed 97 ablation procedures performed in 76 patients with a mean follow-up of 13.2 ± 12.2 months. In 68 procedures (70.1 %) AAF was ongoing at the beginning of the procedure and in 29 cases (29.9 %) AAF had to be induced.There was no statistically significant difference regarding acute procedural success. The recurrence rate of any arrhythmia during follow-up was significantly higher after ablation of ongoing AAF compared to induced AAF (63.2 % vs. 42.9 %; p = 0.047) driven by a significant higher rate of AAF-recurrence (57.4 % vs. 34.5 %; p = 0.039). The number of ablated tachycardias per patient as well as the number of de-novo tachycardias found during re-ablation showed no significant difference between both groups. Conclusion: Starting a procedure with ongoing arrhythmia did not result in better short- or mid-term outcome in patients undergoing AAF ablation. Furthermore, based on our results inducing AAF seems a legitimate approach for AAF ablation in patients presenting in sinus rhythm.

[Molecular mechanisms of atrial fibrillation: potential role of microRNAs as new therapeutic targets and potential biomarkers]. / Molekulare Mechanismen von Vorhofflimmern: Potenzielle Rolle der microRNAs als neues therapeutisches Ziel und als möglicher Biomarker.

Atrial fibrillation represents the most common form of clinical arrhythmia in daily routine. However, current therapeutic options are still limited and a better understanding of the underlying molecular mechanisms is expected to contribute to the development of new therapeutic strategies. The scientific field of microRNA research has received a lot of attention in recent years, especially regarding cardiovascular research. This article gives a brief overview of the most recent developments in microRNA research in the field of atrial fibrillation and atrial remodelling processes. Furthermore, the clinical perspective of microRNAs as new therapeutic targets and as potential biomarkers is discussed.

[A rest or arrest--asystolic episodes of 7 seconds in a 22-year-old athlete]. / 22-jähriger Sportler mit Sinusarrest und Pausen bis 7 Sekunden.

A 22-year-old athlete with nocturnal asymptomatic episodes of transient sinus arrest/sinoatrial block up to 7.3 s and recurrent inappropriate sinus tachycardias which had been incidentally found during Holter electrocardiography diagnostics is presented. In spite of extensive diagnostic work-up including invasive procedures like coronary angiography and electrophysiological study, no causal etiology was found. Based on the normal findings and the lack of symptoms, we decided not to implant a permanent pacemaker. After 14 months, the patient is still asymptomatic. Howerver, the 24-h Holter electrocardiography shows unchanged frequency of nocturnal transient sinus arrest episodes.

[Catheter ablation : Developments and technique selection]. / Katheterablation : Entwicklung und Auswahl verschiedener Verfahren.

Atrial fibrillation (AF) is the most common arrhythmia and an important risk factor for the occurrence of cardiovascular events. According to current guidelines, rhythm-controlling therapy is recommended only for symptomatic AF. Even in symptomatic AF there is still only a class IIa-recommendation for catheter ablation as initial therapy in paroxysmal AF. Meanwhile, current studies have shown an advantage of the early rhythm control compared to a rate control, as well as a benefit of catheter ablation compared to antiarrhythmic drug (AAD) treatment. The gold standard of catheter ablation for AF therapy is pulmonary vein isolation, which has been mainly radiofrequency-based in the past. However, cryoablation as a first-line therapy of paroxysmal AF is increasingly gaining importance, as the latest studies showed shorter procedure times, lower reintervention rates and improved life quality after cryoablation. Nevertheless, using these standard techniques, the risk of adverse events is still given through collateral damage. The field high-power short duration ablation is currently topic of ongoing AF research, which describes a radiofrequency ablation with higher energy levels, given over shorter duration, with a consecutive lower recurrence rate as well as procedure time. The new ablation techniques also include the pulsed field ablation, which allows ablation through very fast delivery of electrical pulses and causes isolated damage to myocardial cells without collateral damage. This promising technique passed the efficiency and safety testing in preclinical studies. To validate this technique further randomized trials are needed.

Role of catheter location on local impedance measurements and clinical outcome with the new direct sense technology in cardiac ablation procedures.

Background: A novel catheter technology (direct sense, DS) enables periprocedural local impedance (LI) measurement for estimation of tissue contact during radiofrequency ablation (RFA) for real-time assessment of lesion generation. This measure reflects specific local myocardial conduction properties in contrast to the established global impedance (GI) using a neutral body electrode. Our study aimed to assess representative LI values for the cardiac chambers, to evaluate LI drop in response to RF delivery and to compare those values to established GI measures in patients undergoing RFA procedures. Methods and Results: Seventy-three patients undergoing RFA with the DS technology were included. Within the cardiac chambers, baseline LI was significantly different, with the highest values in the left atrium (LA 107.5 ± 14.3 Ω; RV 104.6 Ω ± 12.9 Ω; LV 100.7 Ω ± 11.7 Ω, and RA 100.5 Ω ± 13.4 Ω). Baseline LI was positively correlated to the corresponding LI drop during RF delivery (R2 = 0.26, p = 0.01) representing a promising surrogate of lesion generation. The observed mean LI drop (15.6 ± 9.5 Ω) was threefold higher as GI drop (4.9 ± 7.4 Ω), p < 0.01. We evaluated the clinical outcome in a subgroup of patients undergoing DS-guided pulmonary vein isolation, which was comparable regarding arrhythmia recurrence to a conventional ablation cohort (57 % vs 50 %, p = 0.2). Conclusion: We provide detailed information on LI measures in electrophysiological procedures with significant differences within the cardiac chambers highlighting that RFA-related LI drop can serve as a promising surrogate for real-time assessment of lesion generation. Guiding the electrophysiologist in RFA procedures, this additional information promises to improve safety profile and success rates in the interventional treatment of arrhythmias.

Mapping strategies and ablation of premature atrial complexes.

Premature atrial complexes (PACs) are a common finding in patients with structural heart disease, as well as in healthy subjects. In addition to the clinical spectrum ranging from asymptomatic patients to irritating palpitations, PACs are suggested to be associated with an increased risk of atrial fibrillation and stroke. Medical treatment leads to a significant reduction in PACs with clear symptom relief in a large proportion of patients, but is limited in cases of PACs that are refractory to antiarrhythmic drug (AAD) treatment. Furthermore, proarrhythmic effects of AAD or the patient's refusal of AAD treatment due to side effects need to be considered. Ablation of PACs is a good alternative to medical therapy with a comparable safety profile and at least comparable efficacy. In recent years, ultra-high-density (UHD) mapping with multiple improvements for successful ablation has been evolving. Before the introduction of UHD mapping, ablation strategies included activation mapping with single-tip catheters or conventional mapping aiming for the earliest activation of the PAC locally, with the earliest activation suspected to be the origin of the PAC and targeted by radiofrequency (RF) ablation. Using UHD mapping, a three-dimensional local activation map of the atrium can be acquired, identifying the point of earliest activation within the high-resolution map. PAC ablation has therefore developed into a true alternative for the treatment of symptomatic PACs.

High-density Mapping Guided Pulmonary Vein Isolation for Treatment of Atrial Fibrillation - Two-year clinical outcome of a single center experience.

Pulmonary vein isolation (PVI) as interventional treatment for atrial fibrillation (AF) aims to eliminate arrhythmogenic triggers from the PVs. Improved signal detection facilitating a more robust electrical isolation might be associated with a better outcome. This retrospective cohort study compared PVI procedures using a novel high-density mapping system (HDM) with improved signal detection vs. age- and sex-matched PVIs using a conventional 3D mapping system (COM). Endpoints comprised freedom from AF and procedural parameters. In total, 108 patients (mean age 63.9 ± 11.2 years, 56.5% male, 50.9% paroxysmal AF) were included (n = 54 patients/group). Our analysis revealed that HDM was not superior regarding freedom from AF (mean follow-up of 494.7 ± 26.2 days), with one- and two-year AF recurrence rates of 38.9%/46.5% (HDM) and 38.9%/42.2% (COM), respectively. HDM was associated with reduction in fluoroscopy times (18.8 ± 10.6 vs. 29.8 ± 13.4 min; p < 0.01) and total radiation dose (866.0 ± 1003.3 vs. 1731.2 ± 1978.4 cGy; p < 0.01) compared to the COM group. HDM was equivalent but not superior to COM with respect to clinical outcome after PVI and resulted in reduced fluoroscopy time and radiation exposure. These results suggest that HDM-guided PVI is effective and safe for AF ablation. Potential benefits in comparison to conventional mapping systems, e.g. arrhythmia recurrence rates, have to be addressed in randomized trials.

Diagnostic and prognostic value of miR-1 and miR-29b on adverse ventricular remodeling after acute myocardial infarction - The SITAGRAMI-miR analysis.

BACKGROUND: MicroRNAs (miRs) have shown to exert fibrotic and anti-fibrotic effects in preclinical models of acute myocardial infarction (AMI). The aim of this study was to evaluate miR-1, miR-21, miR-29b and miR-92a as circulating biomarkers for adverse ventricular remodeling (AVR) in post-AMI patients. METHODS: Plasma levels of miR-1, miR-21, miR-29b and miR-92a were measured in 44 patients of the SITAGRAMI trial population at day 4, day 9 and 6month after AMI and in 18 matched controls (CTL). MiR expression patterns were correlated with magnetic resonance imaging (MRI) parameters for AVR (absolute change (Δ) in infarct volume (IV), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) between day 4 and 6months after AMI) and a combined cardiovascular endpoint. RESULTS: Expression of miR-1, miR-21 and miR-29b but not miR-92a was increased in AMI vs. CTL cohort showing highest miR levels at d9. However, only miR-1 and miR-29b levels significantly correlated with ΔIV and showed a trend for correlation with ΔLVEF. Only miR-29b levels at day 9 correlated with ΔLVEDV at 6-month follow-up. There was no correlation of miR levels with an adverse outcome. CONCLUSION: Mir-1 and miR-29b plasma levels post-AMI correlate with IV changes. In addition, miR-29b levels are associated with changes of LVEDV over time. These results provide insights into the role of miRs as diagnostic AVR surrogate markers. Further large scale clinical trials will be needed to evaluate the real prognostic relevance of these miRs with respect to a clinical implication in the future.

Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation.

BACKGROUND: The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). METHODS: 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference. RESULTS: Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI. CONCLUSION: Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.

Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length.

BACKGROUND: We studied the effects of angiotensin II (Ang II) and diastolic overstretch on the induction of cardiac growth in isometrically contracting muscle preparations from human right atria and left ventricles. We used the gene expression of brain natriuretic peptide (BNP) as a molecular marker of cardiac hypertrophy. METHODS AND RESULTS: Northern blot analysis was performed in human atrial muscle preparations, which were either incubated in 10(-6) mol/L Ang II for 45 minutes or diastolically stretched to 120% of optimum muscle length. Similar experiments were performed with human left ventricular muscle preparations. Results were as follows: (1) BNP gene expression increased in human atrial myocardium 4-fold when stimulated by Ang II (n=7, P<0.001). (2) Diastolic overstretch increased BNP expression in a time-dependent manner. The linear regression equations for the BNP/GAPDH ratio as a function of time (hours) were y=1.21+0.62x (P:<0.001) for overstretched preparations and y=1.07-0.01x (P:=NS) for atrial preparations kept at physiological muscle length. (3) In left ventricular human muscle preparations, diastolic overstretch and Ang II increased BNP gene expression as well. (4) In addition, the Ang II subtype 1 receptor blocker losartan was able to block the effects of Ang II and diastolic overstretch. CONCLUSIONS: Cardiac hypertrophy can be induced in isolated human atrial and left ventricular intact myocardium by Ang II and diastolic overstretch but not by isometric afterload. The fact that the induction of cardiac growth is inhibited by the blockade of Ang II subtype 1 receptors is of scientific and clinical importance.