Atrial Fibrillation Risk Assessment after Embolic Stroke of Undetermined Source.

OBJECTIVE: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non-invasive AF risk assessment after ESUS. METHODS: Catch-Up ESUS is an investigator-initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received ≥72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni- and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow-up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tübingen, Germany. RESULTS: A total of 297 ESUS patients were followed for 15.6 ± 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31-33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable-adjusted analyses identified the rhythm irregularity burden as the strongest AF-predictor (hazard ratio 3.12, 95% confidence interval 1.62-5.80, p < 0001) while accounting for the known risk factors age, CHA2 DS2 -VASc-Score, and NT-proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF-predictor (hazard ratio 2.20, 95% confidence interval 1.45-3.33, p < 0001). INTERPRETATION: The novel, non-invasive, electrocardiogram-based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF-detection after ESUS. Clinical trials need to clarify if high-AF risk patients benefit from tailored secondary stroke prevention. ANN NEUROL 2023;93:479-488.

Association of bone morphogenetic protein 10 and recurrent atrial fibrillation after catheter ablation.

AIMS: Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients. METHODS AND RESULTS: We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30 s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend). CONCLUSION: The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF. CLINICALTRIALS.GOV IDENTIFIER: NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364.

Silent brain infarcts impact on cognitive function in atrial fibrillation.

AIMS: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. METHODS AND RESULTS: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. CONCLUSION: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844.

Bedside autonomic risk stratification after myocardial infarction by means of short-term deceleration capacity of heart rate.

Aims: Twenty-four-hour deceleration capacity (DC24h) of heart rate is a strong predictor of mortality after myocardial infarction (MI). Assessment of DC from short-term recordings (DCst) would be of practical use in everyday clinical practice but its predictive value is unknown. Here, we test the usefulness of DCst for autonomic bedside risk stratification after MI. Methods and results: We included 908 patients after acute MI enrolled in Munich and 478 patients with acute (n = 232) and chronic MI (n = 246) enrolled in Tuebingen, both in Germany. We assessed DCst from high-resolution resting electrocardiogram (ECG) recordings (<30 min) performed under standardized conditions in supine position. In the Munich cohort, we also assessed DC24h from 24-h Holter recordings. Deceleration capacity was dichotomized at the established cut-off value of ≤ 2.5 ms. Primary endpoint was 3-year mortality. Secondary endpoint was 3-year cardiovascular mortality. In addition to DC, multivariable analyses included the Global Registry of Acute Coronary Events score >140 and left ventricular ejection fraction ≤ 35%. During follow-up, 48 (5.3%) and 48 (10.0%) patients died in the Munich and Tuebingen cohorts, respectively. On multivariable analyses, DCst ≤ 2.5 ms was the strongest predictor of mortality, yielding hazard ratios of 5.04 (2.68-9.49; P < 0.001) and 3.19 (1.70-6.02; P < 0.001) in the Munich and Tuebingen cohorts, respectively. Deceleration capacity assessed from short-term recordings ≤ 2.5 ms was also an independent predictor of cardiovascular mortality in both cohorts. Implementation of DCst ≤ 2.5 ms into the multivariable models led to a significant increase of C-statistics and integrated discrimination improvement score. Conclusion: Deceleration capacity assessed from short-term recordings is a strong and independent predictor of mortality and cardiovascular mortality after MI, which is complementary to existing risk stratification strategies.

Autonomic Nervous System Activity for Risk Stratification of Emergency Patients With Pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) causes appreciable morbidity and mortality in adults, especially in those ≥65 years of age. At hospital admission, an immediate and reliable risk assessment is necessary to detect patients with possible fatal outcome. OBJECTIVE: We aimed to evaluate markers of the autonomic nervous system based on an electrocardiogram to predict mortality in patients with CAP. METHODS: For this purpose, the deceleration capacity (DC) of heart rate was calculated in 253 patients who presented to the emergency department with CAP. The 30-day mortality rate was defined as the primary endpoint (PEP). The secondary endpoint was the total mortality within 180 days. RESULTS: PEP was reached in 33 patients (13%). The DC, measured in milliseconds, was significantly lower in patients who reached the PEP than in those who did not (2.3 ± 1.5 ms vs. 3.6 ± 2.3 ms, p = 0.004). The DC was also significantly lower in nonsurvivors than in survivors at the time of the secondary endpoint (2.3 ± 1.5 ms vs. 3.7 ± 2.4 ms, p < 0.001). Our results indicate that DC is an independent predictor of 30- and 180-day mortality. CONCLUSION: DC was independently associated with death from CAP in our study. As a practical consequence, DC could be useful in triage decisions. Patients with certain high risks could benefit from adjuvant treatment and special medical attention.

Emergency Coagulation Assessment During Treatment With Direct Oral Anticoagulants: Limitations and Solutions.

BACKGROUND AND PURPOSE: In patients receiving direct oral anticoagulants (DOACs), emergency treatment like thrombolysis for acute ischemic stroke is complicated by insufficient availability of DOAC-specific coagulation tests. Conflicting recommendations have been published concerning the use of global coagulation assays for ruling out relevant DOAC-induced anticoagulation. METHODS: Four hundred eighty-one samples from 96 DOAC-treated patients were tested using prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT), DOAC-specific assays (anti-Xa activity, diluted TT), and liquid chromatography-tandem mass spectrometry. Sensitivity and specificity of test results to identify DOAC concentrations <30 ng/mL were calculated. Receiver operating characteristic analyses were used to define reagent-specific cutoff values. RESULTS: Normal PT and aPTT provide insufficient specificity to safely identify DOAC concentrations <30 ng/mL (rivaroxaban/PT: specificity, 77%/sensitivity, 94%; apixaban/PT: specificity, 13%/sensitivity, 94%, dabigatran/aPTT: specificity, 49%/sensitivity, 91%). Normal TT was 100% specific for dabigatran, but sensitivity was 26%. In contrast, reagent-specific PT and aPTT cutoffs provided >95% specificity and a specific TT cutoff enhanced sensitivity for dabigatran to 84%. For apixaban, no cutoffs could be established. CONCLUSIONS: Even if highly DOAC-reactive reagents are used, normal results of global coagulation tests are not suited to guide emergency treatment: whereas normal PT and aPTT lack specificity to rule out DOAC-induced anticoagulation, the low sensitivity of normal TT excludes the majority of eligible patients from treatment. However, reagent-specific cutoffs for global coagulation tests ensure high specificity and optimize sensitivity for safe emergency decision making in rivaroxaban- and dabigatran-treated patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02371044 and NCT02371070.

Point-of-care testing for emergency assessment of coagulation in patients treated with direct oral anticoagulants.

BACKGROUND: Point-of-care testing (POCT) of coagulation has been proven to be of great value in accelerating emergency treatment. Specific POCT for direct oral anticoagulants (DOAC) is not available, but the effects of DOAC on established POCT have been described. We aimed to determine the diagnostic accuracy of Hemochron® Signature coagulation POCT to qualitatively rule out relevant concentrations of apixaban, rivaroxaban, and dabigatran in real-life patients. METHODS: We enrolled 68 patients receiving apixaban, rivaroxaban, or dabigatran and obtained blood samples at six pre-specified time points. Coagulation testing was performed using prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and activated clotting time (ACT+ and ACT-low range) POCT cards. For comparison, laboratory-based assays of diluted thrombin time (Hemoclot) and anti-Xa activity were conducted. DOAC concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Four hundred and three samples were collected. POCT results of PT/INR and ACT+ correlated with both rivaroxaban and dabigatran concentrations. Insufficient correlation was found for apixaban. Rivaroxaban concentrations at <30 and <100 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.0 and ≤1.1 and ACT+ POCT ≤120 and ≤130 s. Dabigatran concentrations at <30 and <50 ng/mL were detected with >95% specificity at PT/INR POCT ≤1.1 and ≤1.2 and ACT+ POCT ≤100 s. CONCLUSIONS: Hemochron® Signature POCT can be a fast and reliable alternative for guiding emergency treatment during rivaroxaban and dabigatran therapy. It allows the rapid identification of a relevant fraction of patients that can be treated immediately without the need to await the results of much slower laboratory-based coagulation tests. TRIAL REGISTRATION: Unique identifier, NCT02371070 . Retrospectively registered on 18 February 2015.

Periodic repolarization dynamics in patients with moderate to severe aortic stenosis.

BACKGROUND: Periodic repolarization dynamics (PRD) refers to low-frequency oscillations of cardiac repolarization, most likely related to phasic sympathetic activation. Increased PRD is a validated predictor of mortality after myocardial infarction and in ischemic heart disease, but has not been tested in aortic valve stenosis (AS). Here, we assessed PRD in patients with AS and tested its correlation with clinical and hemodynamic parameters as well as markers of heart rate variability (HRV). MATERIALS AND METHODS: We prospectively enrolled 139 consecutive patients with moderate to severe AS in sinus rhythm. In all patients we performed a 24-h Holter ECG in Frank-leads configuration. We assessed PRD according to previously published technologies from the nocturnal hours (0am-6am) and dichotomized PRD at the established cut-off value of ≥5.75deg2. In addition to clinical and hemodynamic markers, we also assessed deceleration capacity (DC) of heart rate, heart rate turbulence and standard HRV parameters. RESULTS: In the patients studied, PRD was 6.55±3.96deg2. Seventy-three patients (52.5%) had increased PRD. Among them, 36 (49.9%) patients were classified as being asymptomatic. There was no association between increased PRD and clinical or hemodynamic markers, including presence of symptoms, NYHA-classification, aortic valve area, and left-ventricular ejection fraction. Thirty-three of the 73 (45.2%) patients with PRD ≥5.75deg2 also suffered from decreased vagal tonic activity by means of abnormal DC (≤2.5ms) indicating severe autonomic dysfunction. CONCLUSION: Prevalence of increased PRD is high among patients with moderate to severe AS. Patients with increased PRD cannot be identified by clinical or hemodynamic markers Future studies should test the prognostic value of PRD in patients with AS.

One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry.

AIMS: The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort-which is the largest published to date. METHODS AND RESULTS: Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001). CONCLUSIONS: Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality.

Point-of-Care Testing of Coagulation in Patients Treated With Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: Specific coagulation assays for non-vitamin K antagonist oral anticoagulants (NOAC) are relatively slow and often lack availability. Although specific point-of-care tests (POCT) are currently not available, NOAC are known to affect established coagulation POCT. This study aimed at determining the diagnostic accuracy of the CoaguChek POCT to rule out relevant concentrations of rivaroxaban, apixaban, and dabigatran in real-life patients. METHODS: We consecutively enrolled 60 ischemic stroke patients newly started on NOAC treatment and obtained blood samples at 6 prespecified time points. Samples were tested using the CoaguChek POCT, laboratory-based coagulation assays (prothrombin time and activated partial thromboplastin time, anti-Xa test and Hemoclot), and liquid chromatography-tandem mass spectrometry for direct determination of NOAC concentrations. RESULTS: Three hundred fifty-six blood samples were collected. The CoaguChek POCT strongly correlated (r=0.82 P<0.001) with rivaroxaban concentrations but did not accurately detect dabigatran or apixaban. If used to estimate the presence of low rivaroxaban concentrations, POCT was superior to predictions based on normal prothrombin time and activated partial thromboplastin time values even if sensitive reagents were used. POCT-results≤1.0 predicted rivaroxaban concentrations<32 and <100 ng/mL with a specificity of 90% and 96%, respectively. CONCLUSIONS: If anti-Xa test is not available, we propose the use of the CoaguChek POCT to guide thrombolysis decisions after individual risk assessment in rivaroxaban-treated patients having acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02371044.

Anticoagulation after catheter ablation of atrial fibrillation guided by implantable cardiac monitors.

BACKGROUND: Discontinuation of oral anticoagulation (OAC) after catheter ablation of atrial fibrillation (AF) is not recommended in patients with elevated CHADS2 scores. However, a low incidence of thromboembolic events is reported when OAC is stopped in these patients. We introduce an algorithm for discontinuation of OAC after ablation based on the AF burden documented by implantable cardiac monitors (ICM). METHODS: Sixty-five patients with CHADS2 scores 1-3 free from AF 3 months after ablation (AF ablation [n = 49] or ablation of possible AF triggers [n = 16]) were included. One day after implantation of the ICM, OAC was stopped. Patients performed a daily interrogation of the ICM which was programmed to alarm the patient if daily AF burden exceeded 1 hour. Study end point was the first recurrence of a daily AF burden ≥1 hour or a thromboembolic event, which both triggered reinitiation of OAC. RESULTS: During a follow-up time of 32 ± 12 months (126 patient-years), 41 of the 65 patients (63%) had an AF burden <1 h/day and were able to stay off OAC. Twenty-one patients (32%) had to reinitiate OAC due to an AF burden ≥1 hour and three patients due to other reasons. No stroke, transitory ischemic attack, or other thromboembolic event was observed during follow-up. CONCLUSIONS: Rhythm monitoring by ICM in patients who have stopped OAC after catheter ablation of AF or ablation of possible AF triggers seems to be a safe and promising method to monitor for AF recurrence. Within 1.3 years after ablation, about two-thirds of patients were able to stay off OAC.

Automated assessment of cardiac autonomic function by means of deceleration capacity from noisy, nonstationary ECG signals: validation study.

BACKGROUND: Assessment of heart rate variability by means of deceleration capacity (DC) provides a noninvasive probe of cardiac autonomic activity. However, clinical use of DC is limited by the need of manual review of the ECG signals to eliminate artifacts, noise, and nonstationarities. OBJECTIVE: To validate a novel approach to fully automatically assess DC from noisy, nonstationary signals METHODS: We analyzed 100 randomly selected ECG tracings recorded for 10 minutes by routine monitor devices (GE DASH 4000, sample size 100 Hz) in a medical emergency department. We used a novel automated R-peak detection algorithm, which is mainly based on a Shannon energy envelope estimator and a Hilbert transformation. We transformed the automatically generated RR interval time series by phase-rectified signal averaging (PRSA) to assess DC of heart rate (DCauto ). DCauto was compared to DCmanual , which was obtained from the same manually preprocessed ECG signals. RESULTS: DCauto and DCmanual showed good correlation and agreement, particularly if a low-pass filter was implemented into the PRSA algorithm. Correlation coefficient between DCauto and DCmanual was 0.983 (P < 0.0001). Average difference between DCauto and DCmanual was -0.23±0.49 ms with limits of agreement ranging from -1.19 to 0.73 ms. Significantly lower correlations were observed when a different R-peak detection algorithm or conventional heart rate variability (HRV) measures were tested. CONCLUSIONS: DC can be fully automatically assessed from noisy, nonstationary ECG signals.

Heart rate variability and stroke or systemic embolism in patients with atrial fibrillation.

BACKGROUND: Stroke remains one of the most serious complications in atrial fibrillation (AF) patients and has been linked to disturbances of the autonomic nervous system. OBJECTIVE: The purpose of this study was to test the hypothesis that impaired cardiac autonomic function might be associated with an enhanced stroke risk in AF patients. METHODS: A total of 1922 AF patients who were in either sinus rhythm (SR group; n = 1121) or AF (AF group; n = 801) on a 5-minute resting electrocardiographic (ECG) recording were enrolled in the study. Heart rate variability triangular index (HRVI), standard deviation of normal-to-normal intervals, root mean square root of successive differences of normal-to-normal intervals, mean heart rate, 5-minute total power, and power in the high-frequency, low-frequency, and very-low-frequency ranges were calculated. Cox regression models were constructed to examine the association of heart rate variability (HRV) parameters with the composite endpoint of stroke or systemic embolism. RESULTS: Mean age was 71 ± 8 years in the SR group and 75 ± 8 years in the AF group. Thirty-seven patients in the SR group (3.4%) and 60 patients in the AF group (8.0%) experienced a stroke or systemic embolism during follow-up of 5 years. In patients with SR, HRVI <15 was the strongest HRV parameter to be associated with stroke or systemic embolism (hazard ratio 3.04; 95% confidence interval 1.3-7.0; P = .009) after adjustment for multiple confounders. In the AF group, no HRV parameter was found to be associated with the composite endpoint. CONCLUSION: HRVI measured during SR on a single 5-minute ECG recording is independently associated with stroke or systemic embolism in AF patients. HRV analysis in SR may help to improve risk stratification in AF patients.

Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Gremlin-1 identifies fibrosis and predicts adverse outcome in patients with heart failure undergoing endomyocardial biopsy.

BACKGROUND: Gremlin-1 (Grem1), an antagonist of bone morphogenetic proteins, is involved in fibrotic tissue formation in kidney and lung. The impact of myocardial Grem1 expression is unknown. We investigated the prognostic value of Grem1 expression in 214 consecutive patients with nonischemic heart failure (HF) undergoing endomyocardial biopsy. METHODS: In all patients, the following risk factors were assessed: Grem1 expression (semiquantitative score scheme ranging from 1 to 4), presence of inflammatory markers, detection of viral genome, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), New York Heart Association functional class (NYHA), troponin I, and B-type natriuretic peptide. Degree of myocardial fibrosis was defined as an index. Study end point was a combination of all-cause death and HF-related rehospitalization within 3 years of follow-up. RESULTS: Grem1 expression significantly correlated with the degree of myocardial fibrosis (correlation coefficient r = 0.619; P < .0001). Patients with the highest Grem1 expression (score 4) showed the most severely impaired LVEF and highest LVEDD (P < .0001 and P = .030, respectively, for comparison of semiquantitative scores). During follow-up, 33 patients (15.4%) reached the study end point. Grem1 expression and NYHA ≥II were independent predictors of the end point (Grem1: hazard ratio [HR] 7.5, 95% confidence interval [CI] 1.8-32.2; P = .006; NYHA ≥II: HR 2.0, 95% CI 1.0-4.1; P = .048). CONCLUSIONS: Grem1 correlates with the degree of myocardial fibrosis and left ventricular dysfunction and is an independent predictor of adverse outcome in patients with nonischemic HF.

Case report: mRNA-1273 COVID-19 vaccine-associated myopericarditis: Successful treatment and re-exposure with colchicine.

Introduction: Vaccine-induced myocarditis is a rare complication of messenger RNA (mRNA) COVID-19 vaccines. Case presentation: We report a case of acute myopericarditis in a recipient of allogeneic hematopoietic cells following the first dose of the mRNA-1273 vaccine and the successful administration of a second and third dose while on prophylactic treatment with colchicine to successfully complete the vaccination. Conclusion: Treatment and prevention of mRNA-vaccine-induced myopericarditis represent a clinical challenge. The use of colchicine is feasible and safe to potentially reduce the risk of this rare but severe complication and allows re-exposure to an mRNA vaccine.

Assessment of the atrial fibrillation burden in Holter electrocardiogram recordings using artificial intelligence.

Background: Emerging evidence indicates that a high atrial fibrillation (AF) burden is associated with adverse outcome. However, AF burden is not routinely measured in clinical practice. An artificial intelligence (AI)-based tool could facilitate the assessment of AF burden. Objective: We aimed to compare the assessment of AF burden performed manually by physicians with that measured by an AI-based tool. Methods: We analyzed 7-day Holter electrocardiogram (ECG) recordings of AF patients included in the prospective, multicenter Swiss-AF Burden cohort study. AF burden was defined as percentage of time in AF, and was assessed manually by physicians and by an AI-based tool (Cardiomatics, Cracow, Poland). We evaluated the agreement between both techniques by means of Pearson correlation coefficient, linear regression model, and Bland-Altman plot. Results: We assessed the AF burden in 100 Holter ECG recordings of 82 patients. We identified 53 Holter ECGs with 0% or 100% AF burden, where we found a 100% correlation. For the remaining 47 Holter ECGs with an AF burden between 0.01% and 81.53%, Pearson correlation coefficient was 0.998. The calibration intercept was -0.001 (95% CI -0.008; 0.006), and the calibration slope was 0.975 (95% CI 0.954; 0.995; multiple R2 0.995, residual standard error 0.017). Bland-Altman analysis resulted in a bias of -0.006 (95% limits of agreement -0.042 to 0.030). Conclusion: The assessment of AF burden with an AI-based tool provided very similar results compared to manual assessment. An AI-based tool may therefore be an accurate and efficient option for the assessment of AF burden.

Omega-3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation.

Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations of n-3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n-3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n-3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha-linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS-AF (Swiss Atrial Fibrillation cohort). Individual and total n-3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n-3 FA (odds ratio [OR], 0.97 [95% CI, 0.89-1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82-1.06]), whereas other individual n-3 FAs showed no association with nonparoxysmal AF. Higher total n-3 FAs (estimate 0.99 [95% CI, 0.98-1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97-1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89-0.99]). Conclusions We found no strong evidence for an association of n-3 FA blood levels with AF type, but higher total n-3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.

Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Prevalence and predictors of severe autonomic failure in patients with insulin-dependent type 2 diabetes mellitus and coronary artery disease: pilot study.

BACKGROUND: Presence of severe autonomic failure (SAF), defined as coincidence of abnormal heart rate turbulence and abnormal deceleration capacity, identifies a group of patients with very poor prognosis among post-infarction patients with diabetes mellitus. However, factors contributing to development of SAF are entirely unknown. Here, we aimed to identify clinical, biochemical, and hemodynamic factors predicting SAF in a consecutive cohort of diabetic patients with coronary artery disease (CAD). METHODS: Between January 2010 and July 2011, we prospectively enrolled 97 patients with insulin-dependent type 2 diabetes mellitus and stable CAD in sinus rhythm. Heart rate turbulence (as marker of autonomic reflex activity) and deceleration capacity (as marker of autonomic tonic activity) were calculated from 24-hour Holter recordings. Uni- and multivariable logistic regression analysis included duration of diabetes mellitus, diabetic neuropathy, retinopathy, nephropathy, level of HbA(1c), left ventricular ejection fraction (LVEF), brain natriuretic peptide, presence of multivessel disease, and history of myocardial infarction. RESULTS: Ten (10.3%) of the 97 patients exhibited signs of SAF. Patients with SAF were characterized by longer duration of diabetes (25 years vs 15 years), higher prevalence of diabetic neuropathy (70% vs. 36%), retinopathy (80% vs 45%) and nephropathy (90% vs 55%), significantly higher levels of HbA(1c) (9.0% vs 7.4%; P = .002) and a lower LVEF (30% vs.55%; P = .001). On multivariable analysis, LVEF ≤ 35% and HbA(1c) >8% were the only factors which were independently associated with SAF (odds ratios of 23.1 [95% CI, 1.8-287.0]; P = .015 and 6.6 [1.1-40.1]; P = .043). DISCUSSION: In patients with insulin-dependent type 2 diabetes mellitus and CAD, presence of SAF correlates with both glycemic control and diabetic complications. Impaired LVEF and increased level of HbA(1c) were independently associated with SAF.