Low on-clopidogrel ADP- and TRAP-6-induced platelet aggregation in patients with atrial fibrillation undergoing percutaneous coronary intervention: an observational pilot study.

High on-clopidogrel platelet reactivity (HPR) associates with ischemic risk in patients after percutaneous intervention (PCI). This study aimed to evaluate the association of HPR as assessed by multiple electrode aggregometry (MEA) with ischemic, thromboembolic, and bleeding risk in patients with atrial fibrillation (AF) undergoing PCI. Patients with AF and an indication for oral anticoagulation (OAC) were included in this prospective cohort study on day 1-3 after PCI. Platelet aggregation [U] was analyzed by MEA. HPR and low platelet reactivity (LPR) were defined as ADP-induced aggregation ≥ 46 U and ≤ 18 U, respectively. TRAP-6-induced aggregation reference was 94-156 U. The primary outcome was time to all-cause death, myocardial infarction, or stroke at 6 months. The secondary outcome was time to non-major clinically relevant bleedings or major bleedings. 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range 72-82) and 111 (70%) were male. Median ADP- and TRAP-induced aggregation were 12 (6-17) and 49 (35-68) U, respectively. 147 (93%) patients had a low overall aggregability. HPR was detected in 2 patients (1%) and 125 (79%) had LPR. ADP-induced aggregation did not significantly associate with the primary outcome (r = 0.081, p = 0.309) but correlated inversely with bleeding risk (r = - 0.201, p = 0.011). HPR status as assessed by MEA among patients with AF after PCI was rare and overall aggregability was low. Conventional cut-off values for HPR might be inappropriate for these patients. ADP-induced aggregation might be helpful to identify patients at risk for bleeding.

[Cardiovascular pharmacotherapy in old age]. / Kardiovaskuläre Pharmakotherapie im Alter.

Cardiovascular diseases are the most frequent cause of disability and death. Evidence-based pharmacotherapy is the basis for successful treatment of common diseases, such as hypertension, heart failure, coronary artery disease, and atrial fibrillation. The proportion of older people with several diseases (multimorbidity) who need five or more drugs daily (polypharmacy) is steadily increasing. Evidence on the efficacy and safety of drugs in these patients is, however, limited because they are often excluded or underrepresented in clinical trials. In addition, clinical guidelines mostly focus on single diseases and only occasionally deal with the challenges in the pharmacotherapy of older multimorbid patients with polypharmacy. This article describes the options and special features of pharmacotherapy for hypertension, chronic heart failure and dyslipidemia, as well as antithrombotic treatment in (very) old people.

Impact of body mass on P2Y12-inhibitor de-escalation in acute coronary syndromes-a substudy of the TROPICAL-ACS trial.

AIMS: Clinical guidelines recommend de-escalation antiplatelet strategies to reduce bleeding risk in acute coronary syndrome (ACS) patients, albeit with a weak recommendation. This substudy of the TROPICAL-ACS trial aimed to determine the impact of body mass on the efficacy of a platelet function testing-guided de-escalation regimen in ACS patients after percutaneous coronary intervention. METHODS AND RESULTS: Patients were randomized to prasugrel (control group) or a platelet function testing-guided regimen with clopidogrel or prasugrel defined after 1-week clopidogrel. The primary endpoint was the net clinical benefit [cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium (BARC) 2-5 bleeding] for 12 months. Overweight was defined as a body mass index >25 kg/m2.Patients without overweight showed a significant net clinical benefit from the de-escalation strategy, while in overweight cases de-escalation was comparable to prasugrel treatment [hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.31-0.88; P = 0.013 and HR: 0.95; 95% CI: 0.69-1.31, P = 0.717, P-non-inferiority = 0.03, respectively, P-interaction = 0.053]. The benefit of de-escalation in terms of the risk of bleeding or of the ischaemic events did not reach statistical significance. Bleeding events with de-escalation were less frequent in non-overweight patients but comparable in overweight patients (HR: 0.55; 95% CI: 0.30-1.03; P = 0.057 and HR: 0.95; 95% CI: 0.64-1.41, respectively, P-interaction = 0.147). Non-overweight patients had lower ischaemic event rates with de-escalation, while overweight cases had slightly less (HR: 0.47; 95% CI: 0.18-1.25; P = 0.128 and HR: 0.89; 95% CI: 0.53-1.50, respectively, P-interaction = 0.261). CONCLUSION: The strategy of guided dual antiplatelet therapy de-escalation was associated with a significant net clinical benefit in non-overweight patients, while the two strategies were equivalent in overweight patients.

Analysis of the amplified p-wave enables identification of patients with atrial fibrillation during sinus rhythm.

Aim: This study sought to develop and validate diagnostic models to identify individuals with atrial fibrillation (AF) using amplified sinus-p-wave analysis. Methods: A total of 1,492 patients (491 healthy controls, 499 with paroxysmal AF and 502 with persistent AF) underwent digital 12-lead-ECG recording during sinus rhythm. The patient cohort was divided into training and validation set in a 3:2 ratio. P-wave indices (PWI) including duration of standard p-wave (standard PWD; scale at 10 mm/mV, sweep speed at 25 mm/s) and amplified sinus-p-wave (APWD, scale at 60-120 mm/mV, sweep speed at 100 mm/s) and advanced inter-atrial block (aIAB) along with other clinical parameters were used to develop diagnostic models using logistic regression. Each model was developed from the training set and further tested in both training and validation sets for its diagnostic performance in identifying individuals with AF. Results: Compared to standard PWD (Reference model), which achieved an AUC of 0.637 and 0.632, for training and validation set, respectively, APWD (Basic model) importantly improved the accuracy to identify individuals with AF (AUC = 0.86 and 0.866). The PWI-based model combining APWD, aIAB and body surface area (BSA) further improved the diagnostic performance for AF (AUC = 0.892 and 0.885). The integrated model, which further combined left atrial diameter (LAD) with parameters of the PWI-based model, achieved optimal diagnostic performance (AUC = 0.916 and 0.902). Conclusion: Analysis of amplified p-wave during sinus rhythm allows identification of individuals with atrial fibrillation.

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes.

BACKGROUND: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. OBJECTIVE: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). METHODS: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. RESULTS: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. CONCLUSIONS: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03504982.

Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.

Drug-Drug Interaction between Antiplatelet Therapy and Lipid-Lowering Agents (Statins and PCSK9 Inhibitors).

Lipid-lowering agents and antiplatelet drugs are guideline-recommended standard treatment for secondary prevention of acute thrombotic events in patients with increased cardiovascular risk. Aspirin is the most frequently used antiplatelet drug, either alone or in combination with other antiplatelet agents (P2Y12 inhibitors), while statins are first-line treatment of hypercholesterolemia. The well-established mode of action of aspirin is inhibition of platelet-dependent thromboxane formation. In addition, aspirin also improves endothelial oxygen defense via enhanced NO formation and inhibits thrombin formation. Low-dose aspirin exerts in addition anti-inflammatory effects, mainly via inhibition of platelet-initiated activation of white cells.Statins inhibit platelet function via reduction of circulating low-density lipoprotein-cholesterol (LDL-C) levels and a more direct inhibition of platelet function. This comprises inhibition of thromboxane formation via inhibition of platelet phospholipase A2 and inhibition of (ox)LDL-C-mediated increases in platelet reactivity via the (ox)LDL-C receptor (CD36). Furthermore, statins upregulate endothelial NO-synthase and improve endothelial oxygen defense by inhibition of NADPH-oxidase. PCSK9 antibodies target a serine protease (PCSK9), which promotes the degradation of the LDL-C receptor impacting on LDL-C plasma levels and (ox)LDL-C-receptor-mediated signaling in platelets similar to but more potent than statins.These functionally synergistic actions are the basis for numerous interactions between antiplatelet and these lipid-lowering drugs, which may, in summary, reduce the incidence of atherothrombotic vascular events.

Validating left atrial fractionation and low-voltage substrate during atrial fibrillation and sinus rhythm-A high-density mapping study in persistent atrial fibrillation.

Background: Low-voltage-substrate (LVS)-guided ablation for persistent atrial fibrillation (AF) has been described either in sinus rhythm (SR) or AF. Prolonged fractionated potentials (PFPs) may represent arrhythmogenic slow conduction substrate and potentially co-localize with LVS. We assess the spatial correlation of PFP identified in AF (PFP-AF) to those mapped in SR (PFP-SR). We further report the relationship between LVS and PFPs when mapped in AF or SR. Materials and methods: Thirty-eight patients with ablation naïve persistent AF underwent left atrial (LA) high-density mapping in AF and SR prior to catheter ablation. Areas presenting PFP-AF and PFP-SR were annotated during mapping on the LA geometry. Low-voltage areas (LVA) were quantified using a bipolar threshold of 0.5 mV during both AF and SR mapping. Concordance of fractionated potentials (CFP) (defined as the presence of PFPs in both rhythms within a radius of 6 mm) was quantified. Spatial distribution and correlation of PFP and CFP with LVA were assessed. The predictors for CFP were determined. Results: PFPs displayed low voltages both during AF (median 0.30 mV (Q1-Q3: 0.20-0.50 mV) and SR (median 0.35 mV (Q1-Q3: 0.20-0.56 mV). The duration of PFP-SR was measured at 61 ms (Q1-Q3: 51-76 ms). During SR, most PFP-SRs (89.4 and 97.2%) were located within LVA (<0.5 mV and <1.0 mV, respectively). Areas presenting PFP occurred more frequently in AF than in SR (median: 9.5 vs. 8.0, p = 0.005). Both PFP-AF and PFP-SR were predominantly located at anterior LA (>40%), followed by posterior LA (>20%) and septal LA (>15%). The extent of LVA < 0.5 mV was more extensive in AF (median: 25.2% of LA surface, Q1-Q3:16.6-50.5%) than in SR (median: 12.3%, Q1-Q3: 4.7-29.4%, p = 0.001). CFP in both rhythms occurred in 80% of PFP-SR and 59% of PFP-AF (p = 0.008). Notably, CFP was positively correlated to the extent of LVA in SR (p = 0.004), but not with LVA in AF (p = 0.226). Additionally, the extent of LVA < 0.5 mV in SR was the only significant predictor for CFP, with an optimal threshold of 16% predicting high (>80%) fractionation concordance in AF and SR. Conclusion: Substrate mapping in SR vs. AF reveals smaller areas of low voltage and fewer sites with PFP. PFP-SR are located within low-voltage areas in SR. There is a high degree of spatial agreement (80%) between PFP-AF and PFP-SR in patients with moderate LVA in SR (>16% of LA surface). These findings should be considered when substrate-based ablation strategies are applied in patients with the left atrial low-voltage substrate with recurrent persistent AF.

Apixaban and Valve Thrombosis After Transcatheter Aortic Valve Replacement: The ATLANTIS-4D-CT Randomized Clinical Trial Substudy.

BACKGROUND: Subclinical obstructive valve thrombosis after transcatheter aortic valve replacement (TAVR) is of uncertain frequency and clinical impact. OBJECTIVES: The aim of this study was to determine the effects of apixaban vs standard of care on post-TAVR valve thrombosis detected by 4-dimensional (4D) computed tomography. METHODS: The randomized ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial demonstrated that apixaban 5 mg twice daily was not superior to standard of care (vitamin K antagonists or antiplatelet therapy) after successful TAVR and was associated with similar safety but with more noncardiovascular deaths. Three months after randomization, 4D computed tomography was proposed to all patients to determine the percentage of patients with ≥1 prosthetic valve leaflet with grade 3 or 4 reduced leaflet motion or grade 3 or 4 hypoattenuated leaflet thickening (the primary endpoint) in the intention-to-treat population. RESULTS: Seven hundred sixty-two participants had complete multiphase datasets and were included in the 4D computed tomographic analysis. The primary endpoint occurred in 33 (8.9%) and 51 (13.0%) patients in the apixaban and standard-of-care groups, respectively. It was reduced with apixaban vs antiplatelet therapy (OR: 0.51; 95% CI: 0.30-0.86) but not vs vitamin K antagonists (OR: 1.80; 95% CI: 0.62-5.25) (Pinteraction = 0.037). The composite of death, myocardial infarction, any stroke, or systemic embolism at 1 year occurred in 10.7% (n = 9 of 84) and 7.1% (n = 48 of 178) of patients with and without subclinical valve thrombosis at 90 days, respectively (HR: 1.68; 95% CI: 0.82-3.44). CONCLUSIONS: Apixaban reduced subclinical obstructive valve thrombosis in the majority of patients who underwent TAVR without having an established indication for anticoagulation. This study was not powered for clinical outcomes. (Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis [ATLANTIS]; NCT02664649).

Thrombelastography Compared with Multiple Impedance Aggregometry to Assess High On-Clopidogrel Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

Background: High on-clopidogrel platelet reactivity (HPR) following percutaneous coronary intervention (PCI) is associated with increased ischemic risk. It is unclear whether conventional definitions of HPR apply to patients with concomitant oral anticoagulation (OAC). This study aimed to compare the performance of multiple platelet aggregometry (MEA) and thrombelastography (TEG) to detect HPR in patients with atrial fibrillation (AF) and indication for an OAC. Methods: In this observational single-center cohort study, MEA and TEG were performed in patients with AF with an indication for OAC on day 1 to 3 after PCI. The primary outcome was HPR as assessed by MEA (ADP area under the curve ≥ 46 units [U]) or TEG (MAADP ≥ 47 mm), respectively. The secondary exploratory outcomes were a composite of all-cause death, myocardial infarction (MI) or stroke and bleeding, as defined by the International Society on Thrombosis and Hemostasis, at 6 months. Results: Platelet function of 39 patients was analyzed. The median age was 78 (interquartile range [IQR] was 72−82) years. 25 (64%) patients were male, and 19 (49%) presented with acute coronary syndrome. All patients received acetylsalicylic acid and clopidogrel prior to PCI. Median (IQR) ADP-induced aggregation, MAADP, TRAP-induced aggregation, and MAthrombin were 9 (6−15) U, 50 (43−60) mm, 54 (35−77) U and 65 (60−67) mm, respectively. The rate of HPR was significantly higher if assessed by TEG compared with MEA (25 [64%] vs. 1 [3%]; p < 0.001). Within 6 months, four (10%) deaths, one (3%) MI and nine (23%) bleeding events occurred. Conclusion: In patients with AF undergoing PCI, the rates of HPR detected by TEG were significantly higher compared with MEA. Conventional cut-off values for HPR as proposed by consensus documents may need to be re-evaluated for this population at high ischemic and bleeding risk. Further studies are needed to assess the association with outcomes.

Impact of On-Clopidogrel Platelet Reactivity on Incidence of Peri-Interventional Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation.

Dual anti-platelet therapy (DAPT) with clopidogrel and acetylsalicylic acid (ASA) has previously been recommended after transcatheter aortic valve implantation (TAVI) and is still the standard of care in patients who underwent coronary stent placement within 3 months prior to TAVI. This study sought to evaluate whether on-treatment platelet reactivity is a predictor for the occurrence of bleeding events after TAVI. This study enrolled 484 patients undergoing TAVI from November 2013 until April 2018. Patients were either on long-term DAPT with clopidogrel and ASA or received loading doses of both drugs before TAVI, reflecting the standard of care at the time of the patient's enrollment. Platelet reactivity was determined by multi-electrode impedance aggregometry before TAVI, at days 1 and 5 thereafter. Peri-interventional bleeding was assessed up to 5 days following TAVI and coded according to BARC-classification. Bleeding events were seen in 199 (41.1%) patients. The most frequent were BARC 2 bleeding cases (24.2%), followed by BARC 1 (6.0%), BARC 3b (5.2%), and BARC 3a (4.5%) cases. Low on-clopidogrel platelet reactivity before TAVI was present in 243 patients, of which 44.4% had a bleeding event. In contrast, the incidence of bleeding was 30.5% in the 95 patients with high on-clopidogrel platelet reactivity. Multivariate logistic regression analysis identified low/normal/high on-clopidogrel platelet reactivity (OR: 0.533; CI: 0.309-0.917; p = 0.023) and use of oral anticoagulation (OR: 1.766; CI: 1.209-2.581; p = 0.003) as strongest predictors for peri-interventional bleeding events. These findings support current recommendations advocating against the routine use of dual antiplatelet therapy following TAVI.

Echocardiographic and Electrocardiographic Determinants of Atrial Cardiomyopathy Identify Patients with Atrial Fibrillation at Risk for Left Atrial Thrombogenesis.

Objective: Atrial cardiomyopathy (ACM) is associated with development of AF, left atrial (LA) thrombogenesis, and stroke. Diagnosis of ACM is feasible using both echocardiographic LA strain imaging and measurement of the amplified p-wave duration (APWD) in digital 12-lead-ECG. We sought to determine the thresholds of LA global longitudinal strain (LA-GLS) and APWD that identify patients with AF at risk for LA appendage (LAA) thrombogenesis. Methods: One hundred and twenty-eight patients with a history of AF were included. Left atrial appendage maximal flow velocity (LAA-Vel, in TEE), LA-GLS (TTE), and APWD (digital 12-lead-ECG) were measured in all patients. ROC analysis was performed for each method to determine the thresholds for LA-GLS and the APWD, enabling diagnosis of patients with LAA-thrombus. Results: Significant differences in LA-GLS were found during both rhythms (SR and AF) between the thrombus group and control group: LA-GLS in SR: 14.3 ± 7.4% vs. 24.6 ± 9.0%, p < 0.001 and in AF: 11.4 ± 4.2% vs. 16.1 ± 5.0%, p = 0.045. ROC analysis revealed a threshold of 17.45% for the entire cohort (AUC 0.82, sensitivity: 84.6%, specificity: 63.6%, Negative Predictive Value (NPV): 94.3%) with additional rhythm-specific thresholds: 19.1% in SR and 13.9% in AF, and a threshold of 165 ms for APWD (AUC 0.90, sensitivity: 88.5%, specificity: 75.5%, NPV: 96.2%) as optimal discriminators of LAA-thrombus. Moreover, both LA-GLS and APWD correlated well with the established contractile LA-parameter LAA-Vel in TEE (r = 0.39, p < 0.001 and r = −0.39, p < 0.001, respectively). Conclusion: LA-GLS and APWD are valuable diagnostic predictors of left atrial thrombogenesis in patients with AF.

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study.

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Comparison of various late gadolinium enhancement magnetic resonance imaging methods with high-definition voltage and activation mapping for detection of atrial cardiomyopathy.

AIMS: Atrial cardiomyopathy (ACM) is associated with increased arrhythmia recurrence rates after pulmonary vein isolation (PVI). We compare the most common left atrial (LA) late gadolinium enhancement magnetic resonance imaging (LGE-MRI)-methods [Utah-method and image intensity ratio (IIR)-methods] and endocardial voltage mapping for ACM-detection and outcome prediction after PVI for atrial fibrillation (AF). METHODS AND RESULTS: In this prospective observational study, 37 ablation-naive patients (66 ± 9 years, 84% male) with persistent AF underwent LA-LGE-MRI and high-definition voltage and activation mapping (2129 ± 484 sites) in sinus rhythm prior to PVI. The MRI-post-processing-analyses were performed by two independent expert laboratories. Arrhythmia recurrence was recorded within 12 months following PVI. The global ACM-extent was highly variable: median LA low-voltage substrate (LA-LVS) was 12.9% at <1.0 mV and 2.7% at <0.5 mV; median LA-LGE-extent using the Utah-method was 18.3% and 0.03-93.1% using the IIR-methods. The LA activation time was significantly correlated with LA-LVS (r = 0.76 at <0.5 mV and r = 0.82 at <1.0 mV, both P < 0.0001), but not with LA-LGE-extent. The highest regional matching between LA-LVS <0.5 mV and LA-LGE was found for the anterior wall in 57% of patients using the Utah-method and in 59% using IIR 1.20. The corresponding values for the posterior wall were 19% and 38%, respectively. Arrhythmia recurrence occurred in 15(41%) patients. Freedom from arrhythmia was significantly lower in those with LA-LVS ≥2 cm2 at 0.5 mV but not in those with LGE ≥20% (Utah-stages III and IV): 43% vs. 81%, P = 0.009 and 50% vs. 67%, P = 0.338, respectively. CONCLUSION: Comparison of the most common LA-LGE-MRI methods and endocardial voltage mapping revealed large discrepancies in global and regional ACM-extent.

Rotational thromboelastometry and conventional coagulation tests in patients undergoing major cardiac or aortic surgery: a retrospective single-center cohort study.

Algorithms for treatment of diffuse bleeding in cardiac surgery are based on intervention thresholds of coagulation tests, such as rotational thromboelastometry (ROTEM) or conventional laboratory tests. The relationship between these two approaches is unclear in patients with increased risk of coagulation abnormalities. We retrospectively analyzed the data of 248 patients undergoing major cardiac and/or aortic surgery. ROTEM and conventional laboratory tests were performed simultaneously after termination of cardiopulmonary bypass and protamine administration to investigate the extrinsic and intrinsic system, and to determine deficiencies in platelets and fibrinogen. We evaluated the association between ROTEM and conventional tests by linear regression analysis and compared the frequency of exceeding established thresholds for clinical intervention. Significant linear associations between ROTEM 10 min after the start of coagulation, and plasma fibrinogen concentration or platelet count (FIBTEM A10, R2 = 0.67, p < 0.001; EXTEM A10, R2 = 0.47, p < 0.001) were obtained. However, the 95% prediction intervals exceeded clinically useful ranges (92-233 mg/dL fibrinogen at the intervention threshold of FIBTEM A10 = 10 mm; 14 × 103-122 × 103/µL platelets at the intervention threshold of EXTEM A10 = 40 mm). The association between EXTEM and INR (R2 = 0.23), and INTEM and aPTT (R2 = 0.095) was poor. The frequency of exceeding intervention thresholds and, consequently, of triggering treatment, varied markedly between ROTEM and conventional tests (p < 0.001 for all comparisons). The predictability of conventional coagulation test results by ROTEM is limited, thus hampering the interchangeability of methods in clinical practice.

Determinants of fibrotic atrial cardiomyopathy in atrial fibrillation. A multicenter observational study of the RETAC (reseau européen de traîtement d'arrhythmies cardiaques)-group.

AIMS: Despite advances in interventional treatment strategies, atrial fibrillation (AF) remains associated with significant morbidity and mortality. Fibrotic atrial myopathy (FAM) is a main factor for adverse outcomes of AF-ablation, but complex to diagnose using current methods. We aimed to derive a scoring system based entirely on easily available clinical parameters to predict FAM and ablation-success in everyday care. METHODS: In this multicenter, prospective study, a new risk stratification model termed AF-SCORE was derived in 220 patients undergoing high-density left-atrial(LA) voltage-mapping to quantify FAM. AF-SCORE was validated for FAM in an external mapping-validation cohort (n = 220) and for success following pulmonary vein isolation (PVI)-only (without adjunctive left- or right atrial ablations) in an external outcome-validation cohort (n = 518). RESULTS: FAM was rare in patients < 60 years (5.4%), but increased with ageing and affected 40.4% (59/146) of patients ≥ 60 years. Sex and AF-phenotype had additional predictive value in older patients and remained associated with FAM in multivariate models (odds ratio [OR] 6.194, p < 0.0001 for ≥ 60 years; OR 2.863, p < 0.0001 for female sex; OR 41.309, p < 0.0001 for AF-persistency). Additional clinical or diagnostic variables did not improve the model. AF-SCORE (+ 1 point for age ≥ 60 years and additional points for female sex [+ 1] and AF-persistency [+ 2]) showed good discrimination to detect FAM (c-statistic 0.792) and predicted arrhythmia-freedom following PVI (74.3%, 54.7% and 45.5% for AF-SCORE ≤ 2, 3 and 4, respectively, and hazard ratio [HR] 1.994 for AF-SCORE = 3 and HR 2.866 for AF-SCORE = 4, p < 0.001). CONCLUSIONS: Age, sex and AF-phenotype are the main determinants for the development of FAM. A low AF-SCORE ≤ 2 is found in paroxysmal AF-patients of any age and younger patients with persistent AF irrespective of sex, and associated with favorable outcomes of PVI-only. Freedom from arrhythmia remains unsatisfactory with AF-SCORE ≥ 3 as found in older patients, particularly females, with persistent AF, and future studies investigating adjunctive atrial ablations to PVI-only should focus on these groups of patients.

Structural and electrophysiological determinants of atrial cardiomyopathy identify remodeling discrepancies between paroxysmal and persistent atrial fibrillation.

Background: Progressive atrial fibrotic remodeling has been reported to be associated with atrial cardiomyopathy (ACM) and the transition from paroxysmal to persistent atrial fibrillation (AF). We sought to identify the anatomical/structural and electrophysiological factors involved in atrial remodeling that promote AF persistency. Methods: Consecutive patients with paroxysmal (n = 134) or persistent (n = 136) AF who presented for their first AF ablation procedure were included. Patients underwent left atrial (LA) high-definition mapping (1,835 ± 421 sites/map) during sinus rhythm (SR) and were randomized to training and validation sets for model development and evaluation. A total of 62 parameters from both electro-anatomical mapping and non-invasive baseline data were extracted encompassing four main categories: (1) LA size, (2) extent of low-voltage-substrate (LVS), (3) LA voltages and (4) bi-atrial conduction time as identified by the duration of amplified P-wave (APWD) in a digital 12-lead-ECG. Least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to identify the factors that are most relevant to AF persistency in each category alone and all categories combined. The performance of the developed models for diagnosis of AF persistency was validated regarding discrimination, calibration and clinical usefulness. In addition, HATCH score and C2HEST score were also evaluated for their performance in identification of AF persistency. Results: In training and validation sets, APWD (threshold 151 ms), LA volume (LAV, threshold 94 mL), bipolar LVS area < 1.0 mV (threshold 4.55 cm2) and LA global mean voltage (GMV, threshold 1.66 mV) were identified as best determinants for AF persistency in the respective category. Moreover, APWD (AUC 0.851 and 0.801) and LA volume (AUC 0.788 and 0.741) achieved better discrimination between AF types than LVS extent (AUC 0.783 and 0.682) and GMV (AUC 0.751 and 0.707). The integrated model (combining APWD and LAV) yielded the best discrimination performance between AF types (AUC 0.876 in training set and 0.830 in validation set). In contrast, HATCH score and C2HEST score only achieved AUC < 0.60 in identifying individuals with persistent AF in current study. Conclusion: Among 62 electro-anatomical parameters, we identified APWD, LA volume, LVS extent, and mean LA voltage as the four determinant electrophysiological and structural factors that are most relevant for AF persistency. Notably, the combination of APWD with LA volume enabled discrimination between paroxysmal and persistent AF with high accuracy, emphasizing their importance as underlying substrate of persistent AF.

Left Atrial Hypertension, Electrical Conduction Slowing, and Mechanical Dysfunction - The Pathophysiological Triad in Atrial Fibrillation-Associated Atrial Cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and a significant burden for healthcare systems worldwide. Presence of relevant atrial cardiomyopathy (ACM) is related to persistent AF and increased arrhythmia recurrence rates after pulmonary vein isolation (PVI). OBJECTIVE: To investigate the association of left atrial pressure (LAP), left atrial electrical [invasive atrial activation time (IAAT) and amplified p-wave duration (aPWD)] and mechanical [left atrial emptying fraction (LA-EF) and left atrial strain (LAS)] functional parameters with the extent of ACM and their impact on arrhythmia recurrence following PVI. MATERIALS AND METHODS: Fifty patients [age 67 (IQR: 61-75) years, 78% male] undergoing their first PVI for persistent AF were prospectively included. LAP (maximum amplitude of the v-wave), digital 12-lead electrocardiogram, echocardiography and high-density endocardial contact mapping were acquired in sinus rhythm prior to PVI. Arrhythmia recurrence was assessed using 72-hour Holter electrocardiogram at 6 and 12 months post PVI. RESULTS: Relevant ACM (defined as left atrial low-voltage extent ≥2 cm2 at <0.5 mV threshold) was diagnosed in 25/50 (50%) patients. Compared to patients without ACM, patients with ACM had higher LAP [17.6 (10.6-19.5) mmHg with ACM versus 11.3 (7.9-14.0) mmHg without ACM (p = 0.009)]. The corresponding values for the electrical parameters were 166 (149-181) ms versus 139 (131-143) ms for IAAT (p < 0.0001), 163 (154-176) ms versus 148 (136-152) ms for aPWD on surface-ECG (p < 0.0001) and for the mechanical parameters 27.0 (17.5-37.0) % versus 41.0 (35.0-45.0) % for LA-EF in standard 2D-echocardiography (p < 0.0001) and 15.2 (11.0-21.2) % versus 29.4 (24.9-36.6) % for LAS during reservoir phase (p < 0.0001). Furthermore, all parameters showed a linear correlation with ACM extent (p < 0.05 for all). Receiver-operator-curve-analysis demonstrated a LAP ≥12.4 mmHg [area under the curve (AUC): 0.717, sensitivity: 72%, and specificity: 60%], a prolonged IAAT ≥143 ms (AUC: 0.899, sensitivity: 84%, and specificity: 80%), a prolonged aPWD ≥153 ms (AUC: 0.860, sensitivity: 80%, and specificity: 79%), an impaired LA-EF ≤33% (AUC: 0.869, sensitivity: 84%, and specificity: 72%), and an impaired LAS during reservoir phase ≤23% (AUC: 0.884, sensitivity: 84%, and specificity: 84%) as predictors for relevant ACM. Arrhythmia recurrence within 12 months post PVI was significantly increased in patients with relevant ACM ≥2 cm2, electrical dysfunction with prolonged IAAT ≥143 ms and mechanical dysfunction with impaired LA-EF ≤33% (66 versus 20, 50 versus 23 and 55 versus 25%, all p < 0.05). CONCLUSION: Left atrial hypertension, electrical conduction slowing and mechanical dysfunction are associated with ACM. These findings improve the understanding of ACM pathophysiology and may be suitable for risk stratification for new-onset AF, arrhythmia recurrence following PVI, and development of novel therapeutic strategies to prevent AF and its associated complications.

Non-invasive body surface electrocardiographic imaging for diagnosis of atrial cardiomyopathy.

AIMS: Atrial cardiomyopathy (ACM) is associated with new-onset atrial fibrillation, arrhythmia recurrence after pulmonary vein isolation (PVI) and increased risk for stroke. At present, diagnosis of ACM is feasible by endocardial contact mapping of left atrial (LA) low-voltage substrate (LVS) or late gadolinium-enhanced magnetic resonance imaging, but their complexity limits a widespread use. The aim of this study was to assess non-invasive body surface electrocardiographic imaging (ECGI) as a novel clinical tool for diagnosis of ACM compared with endocardial mapping. METHODS AND RESULTS: Thirty-nine consecutive patients (66 ± 9 years, 85% male) presenting for their first PVI for persistent atrial fibrillation underwent ECGI in sinus rhythm using a 252-electrode-array mapping system. Subsequently, high-density LA voltage and biatrial activation maps (mean 2090 ± 488 sites) were acquired in sinus rhythm prior to PVI. Freedom from arrhythmia recurrence was assessed within 12 months follow-up. Increased duration of total atrial conduction time (TACT) in ECGI was associated with both increased atrial activation time and extent of LA-LVS in endocardial contact mapping (r = 0.77 and r = 0.66, P < 0.0001 respectively). Atrial cardiomyopathy was found in 23 (59%) patients. A TACT value of 148 ms identified ACM with 91.3% sensitivity and 93.7% specificity. Arrhythmia recurrence occurred in 15 (38%) patients during a follow-up of 389 ± 55 days. Freedom from arrhythmia was significantly higher in patients with a TACT <148 ms compared with patients with a TACT ≥148 ms (82.4% vs. 45.5%, P = 0.019). CONCLUSION: Analysis of TACT in non-invasive ECGI allows diagnosis of patients with ACM, which is associated with a significantly increased risk for arrhythmia recurrence following PVI.

Echocardiographic diagnosis of atrial cardiomyopathy allows outcome prediction following pulmonary vein isolation.

BACKGROUND: Relevant atrial cardiomyopathy (ACM), defined as a left atrial (LA) low-voltage area ≥ 2 cm2 at 0.5 mV threshold on endocardial contact mapping, is associated with new-onset atrial fibrillation (AF), higher arrhythmia recurrence rates after pulmonary vein isolation (PVI), and an increased risk of stroke. The current study aimed to assess two non-invasive echocardiographic parameters, LA emptying fraction (EF) and LA longitudinal strain (LAS, during reservoir (LASr), conduit (LAScd) and contraction phase (LASct)) for the diagnosis of ACM and prediction of arrhythmia outcome after PVI. METHODS: We prospectively enrolled 60 consecutive, ablation-naive patients (age 66 ± 9 years, 80% males) with persistent AF. In 30 patients (derivation cohort), LA-EF and LAS cut-off values for the presence of relevant ACM (high-density endocardial contact mapping in sinus rhythm prior to PVI at 3000 ± 1249 sites) were established in sinus rhythm and tested in a validation cohort (n = 30). Arrhythmia recurrence within 12 months was documented using 72-h Holter electrocardiograms. RESULTS: An LA-EF of < 34% predicted ACM with an area under the curve (AUC) of 0.846 (sensitivity 69.2%, specificity 76.5%) similar to a LASr < 23.5% (AUC 0.878, sensitivity 92.3%, specificity 82.4%). In the validation cohort, these cut-offs established the correct diagnosis of ACM in 76% of patients (positive predictive values 87%/93% and negative predictive values 73%/75%, respectively). Arrhythmia recurrence in the entire cohort was significantly more frequent in patients with LA-EF < 34% and LASr < 23.5% (56% vs. 29% and 55% vs. 26%, both p < 0.05). CONCLUSION: The echocardiographic parameters LA-EF and LAS allow accurate, non-invasive diagnosis of ACM and prediction of arrhythmia recurrence after PVI.

Ticagrelor or Prasugrel in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI). OBJECTIVES: This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management. METHODS: This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3-5. RESULTS: The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month. CONCLUSIONS: In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800).