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Background: Risk stratification for transcatheter procedures in patients with severe mitral regurgitation is challenging. Deceleration capacity (DC) has already proven to be a reliable risk predictor in patients undergoing transcatheter aortic valve implantation. We hypothesized, that DC provides prognostic value in patients undergoing transcatheter edge‐to‐edge mitral valve repair (TEER). Methods: We retrospectively analyzed electrocardiogram signals from 106 patients undergoing TEER at the University Hospital of Tübingen. All patients received continuous heart‐rate monitoring to assess DC following the procedure. One‐year all‐cause mortality was defined as the primary end point. Results: Sixteen patients (15.1%) died within 1 year. The DC in nonsurvivors was significantly reduced compared to survivors (5.1 ± 3.0 vs. 3.0 ± 1.6 ms, p = 0.002). A higher EuroSCORE II and impaired left ventricular function were furthermore associated with poor outcome. In Cox regression analyses, a DC < 4.5 ms was found a strong predictor of 1‐year mortality (hazard ratio: 0.10, 95% confidence interval: 0.13–0.79, p = 0.029). Finally, a significant negative correlation was found between DC and residual mitral regurgitation after TEER (r = −0.41, p < 0.001). Conclusion: In patients with severe mitral regurgitation undergoing TEER, DC may serve as a new predictor of follow‐up mortality. [ABSTRACT FROM AUTHOR]

Background. Enhanced sympathetic activity at the ventricular myocardium can destabilize repolarization, increasing the risk of death. Sympathetic activity is known to cluster in low-frequency bursts; therefore, we hypothesized that sympathetic activity induces periodic low-frequency changes of repolarization. We developed a technique to assess the sympathetic effect on repolarization and identified periodic components in the low-frequency spectral range (≤ 0.1 Hz), which we termed periodic repolarization dynamics (PRD). Methods. We investigated the physiological properties of PRD in multiple experimental studies, including a swine model of steady-state ventilation (n = 7) and human studies involving fixed atrial pacing (n = 10), passive head-up tilt testing (n = 11), low-intensity exercise testing (n = 11), and beta blockade (n = 10). We tested the prognostic power of PRD in 908 survivors of acute myocardial infarction (MI). Finally, we tested the predictive values of PRD and T-wave alternans (TWA) in 2,965 patients undergoing clinically indicated exercise testing. Results. PRD was not related to underlying respiratory activity (P < 0.001) or heart-rate variability (P = 0.002). Furthermore, PRD was enhanced by activation of the sympathetic nervous system, and pharmacological blockade of sympathetic nervous system activity suppressed PRD (P < 0.005 for both). Increased PRD was the strongest single risk predictor of 5-year total mortality (hazard ratio 4.75, 95% CI 2.94-7.66; P < 0.001) after acute MI. In patients undergoing exercise testing, the predictive value of PRD was strong and complementary to that of TWA. Conclusion. We have described and identified low-frequency rhythmic modulations of repolarization that are associated with sympathetic activity. Increased PRD can be used as a predictor of mortality in survivors of acute MI and patients undergoing exercise testing. Trial registration. ClinicalTrials.gov NCT00196274. Funding. This study was funded by Angewandte Klinische Forschung, University of Tubingen (252-1-0)., Introduction Sudden cardiac death (SCD) is the single most common cause of death in the industrialized world (1). A substantial proportion of SCD cases occur in patients after myocardial infarction [...]

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. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate heart rate deceleration capacity, an electrocardiogram- based marker of autonomic nervous system activity, as risk predictor in a medical emergency department and to test its incremental predictive value to the modified early warning score. Design: Prospective cohort study. Setting: Medical emergency department of a large university hospital. Patients: Five thousand seven hundred thirty consecutive patients of either sex in sinus rhythm, who were admitted to the medical emergency department of the University of Tübingen, Germany, between November 2010 and March 2012. Interventions: None. Measurements and Main Results: Deceleration capacity of heart rate was calculated within the first minutes after emergency department admission. The modified early warning score was assessed from respiratory rate, heart rate, systolic blood pressure, body temperature, and level of consciousness as previously described. Primary endpoint was intrahospital mortality; secondary endpoints included transfer to the ICU as well as 30-day and 180-day mortality. One hundred forty-two patients (2.5%) reached the primary endpoint. Deceleration capacity was highly significantly lower in nonsurvivors than survivors (2.9 ± 2.1 ms vs 5.6 ± 2.9 ms; p < 0.001) and yielded an area under the receiveroperator characteristic curve of 0.780 (95% CI, 0.745-0.813). The modified early warning score model yielded an area under the receiver-operator characteristic curve of 0.706 (0.667-0.750). Implementing deceleration capacity into the modified early warning score model led to a highly significant increase of the area under the receiver-operator characteristic curve to 0.804 (0.770- 0.835; p < 0.001 for difference). Deceleration capacity was also a highly significant predictor of 30-day and 180-day mortality as well as transfer to the ICU. Conclusions: Deceleration capacity is a strong and independent predictor of short-term mortality among patients admitted to a medical emergency department. [ABSTRACT FROM AUTHOR]

Abstract: 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 HbA1c, 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 HbA1c (9.0% vs 7.4%; P = .002) and a lower LVEF (30% vs.55%; P = .001). On multivariable analysis, LVEF ≤35% and HbA1c >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 HbA1c were independently associated with SAF. [Copyright &y& Elsevier]

Background: In patients with arterial hypertension, increased blood pressure (BP) variability contributes to end organ damage independently from mean levels of arterial BP. Increased BP variability has been linked to alterations in autonomic function including sympathetic overdrive. We hypothesized that catheter-based renal sympathetic denervation (RDN) confers beneficial effects on BP variability. Methods and Results: Eleven consecutive patients with therapy-refractory arterial hypertension (age 68.9 ± 7.0 years; baseline systolic BP 189 ± 23 mmHg despite medication with 5.6 ± 2.1 antihypertensive drugs) underwent bilateral RDN. Twenty-four hour ambulatory BP monitoring (ABPM) was performed before RDN and 6 months thereafter. BP variability was primarily assessed by means of standard deviation of 24-h systolic arterial BP (SDsys). Secondary measures of BP variability were maximum systolic BP (MAXsys) and maximum difference between two consecutive readings of systolic BP (Δmaxsys) over 24 h. Six months after RDN, SDsys, MAXsys, and Δmaxsys were significantly reduced from 16.9 ± 4.6 to 13.5 ± 2.5 mmHg (p = 0.003), from 190 ± 22 to 172 ± 20 mmHg (p < 0.001), and from 40 ± 15 to 28 ± 7 mmHg (p = 0.006), respectively, without changes in concomitant antihypertensive therapy. Reductions of SDsys, MAXsys, and Δmaxsys were observed in 10/11 (90.9%), 11/11 (100%), and 9/11 (81.8%) patients, respectively. Although we noted a significant reduction of systolic office BP by 30.4 ± 27.7 mmHg (p = 0.007), there was only a trend in reduction of average systolic BP assessed from ABPM (149 ± 19 to 142 ± 18 mmHg; p = 0.086). Conclusion: In patients with therapy-refractory arterial hypertension, RDN leads to significant reductions of BP variability. Effects of RDN on BP variability over 24 h were more pronounced than on average levels of BP. [ABSTRACT FROM AUTHOR]

Purpose: Atrial fibrillation (AF) results in tachycardia-induced ionic remodeling. Pharmacological prevention of tachycardia-induced ionic remodeling not only with "classical" antiarrhythmics but also with drugs which provide a basis for some of the pillars of the so-called "upstream" therapy of AF like corticosteroids or statins has been proposed as a therapeutic strategy. Amongst other ion currents, atrial sodium current INa and its tachycardia-induced alterations play an important role in AF pathophysiology. Thus, effects of a dexamethasone (DT) and atorvastatin treatment (AT) on atrial sodium current INa and its tachycardia-induced remodeling were studied in a rabbit model. Methods: 9 groups with 4 animals were examined. Atrial pacemaker leads were implanted in all animals. No rapid atrial pacing (600/min) was performed in the control group but for 24 or 120 hours in the respective pacing groups. Instrumentation and pacing did not differ from the respective drug groups but an additional treatment with dexamethasone or atorvastatin (7 days) was performed. Results: Rapid atrial pacing (RAP, 600/min) reduced INa after 24 hours (≈ -50%) with no further reduction after 120 hours. DT reduced INa (≈ -20%), current densities in consecutively tachypaced animals did not differ from those in untreated animals. AT reduced INa similar as RAP, subsequent RAP did not further diminish INa. Conclusions: Impact of corticosteroids and statins on INa and its tachycardia-induced alterations also contribute to the mode of action of these substances in upstream treatment of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Certain evidence points to a role of inflammation in AF pathophysiology. Thus, antiinflammatory treatment of AF is discussed. Effects of a dexamethasone treatment (7 days) on atrial ion currents (ICa,L, Ito, Isus) and their tachycardia-induced remodeling were studied in a rabbit model. Methods: 6 groups of 4 animals each were built. Rapid atrial pacing (600 min) was performed for 24 and 120 hours with/ without dexamethasone treatment. Ion currents were measured using whole cell patch clamp method. Results: Rapid atrial pacing reduced (ICa,L, Ito was decreased after 24 hours but almost returned to control values after 120 hours. When dexamethasone-treated animals also underwent atrial tachypacing, pacing-induced reduction of ICa,L was still observed after 24 hours and was even augmented after 120 hours compared to untreated but tachypaced animals. Ito was not influenced by dexamethasone alone. In dexamethasone-treated animals, reduction of Ito was not observed after 24 hours but occurred after 120 hours of atrial tachypacing. Isus was neither influenced by rapid atrial pacing nor by dexamethasone. Biophysical properties of all currents were affected neither by rapid atrial pacing nor by dexamethasone. Conclusion: Dexamethasone influenced tachycardia-induced alterations of atrial Ito. Our experiments give evidence that - amongst other anti-inflammatory action impact of dexamethasone on ion currents and their tachycardia-induced alterations might also play a role in treatment/prevention of AF with steroids. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction. Tachycardia-induced atrial remodelling (as an equivalent to atrial fibrillation) can be influenced by the renin-angiotensin system. Effects of a seven-day enalapril pre-treatment (EPT, 0.16 mg/kg body weight subcutaneously every 24 h) on ionic currents underlying tachycardia-induced early electrical remodelling after 24 h rapid atrial pacing (RAP, 600 beats/min) in rabbit atrium were studied.Materials and methods. Animals were divided into four groups (n=4 each): control; paced only; enalapril only; and enalapril and paced, respectively. Using patch-clamp technique in whole-cell mode, current densities were measured in isolated atrial myocytes. Results. EPT nearly doubled L-type calcium current (ICa,L, −7.7±0.6 pA/pF [control] vs. f −12.3±1.2 pA/pF [enalapril only]). RAP reduced ICa,L to −3.6±0.7 pA/pF (paced only). Also after EPT, RAP led to a significant downregulation of ICa,L by 39% (−7.5±1.3 pA/pF [paced and enalapril]). RAP decreased transient outward potassium current (Ito, −45%, 51.5±3.9 pA/pF [control] vs. 28.5±4.5 pA/pF [paced only]). EPT did not alter Ito (44.2±8.1 pA/pF [enalapril only]). However, RAP did not affect Ito in enalapril-treated animals and averaged 50.4±9.8 pA/pF (paced and enalapril).Conclusions. In summary, EPT has several effects on ion channels in rabbit atrium: 1) EPT increases ICa,L current density, but cannot prevent its downregulation due to RAP; 2) EPT has no influence on Ito current density, but can prevent its downregulation due to RAP. Although changes of single ion channels must be interpreted in context of the complex atrial electrophysiology as a whole, our results provide a possible explanation of the in vivo observation that angiotensin-converting enzyme inhibition is mainly beneficial on the early electrical remodelling due to the atrial fibrillation-equivalent RAP. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Purpose: Silent brain infarcts (SBI) are frequently detected in patients with atrial fibrillation (AF), but it is unknown whether SBI are linked to autonomic dysfunction. We aimed to explore the association of autonomic dysfunction with SBI in AF patients. Methods: 1,358 AF patients without prior stroke or TIA underwent brain MRI and 5-min resting ECG. We divided our cohort into AF patients who presented in sinus rhythm (SR-group, n = 816) or AF (AF-group, n = 542). HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, mean heart rate, root mean square root of successive differences of normal-to-normal intervals, 5-min total power and power in the low frequency, high frequency and very low frequency range were calculated. Primary outcome was presence of SBI in the SR group, defined as large non-cortical or cortical infarcts. Secondary outcomes were SBI volumes and topography. Results: Mean age was 72 ± 9 years, 27% were female. SBI were detected in 10.5% of the SR group and in 19.9% of the AF group ( p < 0.001). HRVI <15 was the only HRV parameter associated with the presence of SBI after adjustment for clinical covariates in the SR group [odds ratio (OR) 1.67; 95% confidence interval (CI): 1.03-2.70; p = 0.037]. HRVI <15 was associated with larger brain infarct volumes [β (95% CI) -0.47 (-0.84; -0.09), p = 0.016] in the SR group and was more frequently observed in patients with right- than left-hemispheric SBI ( p = 0.017). Conclusion: Impaired HRVI is associated with SBI in AF patients. AF patients with autonomic dysfunction might undergo systematic brain MRI screening to initiate intensified medical treatment. Clinical Trials Gov Identifier: NCT02105844., Competing Interests: CSZ reports a research grant from Medtronic and honoraria from Vifor Pharma and Novartis. MK has received grants from the Swiss National Science Foundation, the Swiss Heart Foundation, Daiichi-Sankyo, Bayer, and Pfizer-BMS and lecture/consulting fees from Daiichi-Sankyo, Boehringer Ingelheim, Bayer, Pfizer-BMS, AstraZeneca, Sanofi-Aventis, Novartis, MSD, Medtronic, Boston Scientific, St. Jude Medical, Biotronik, Sorin, Zoll and Biosense Webster. PK is supported by the University of Basel, the Mach-Gaensslen foundation and the Bangerter-Rhyner foundation. SP received research grants from Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, and speakers' honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo and Werfen. JW is CEO of the Medical Image Analysis Center, Basel; has served on advisory boards for Actelion, Biogen, Genzyme-Sanofi, Novartis, Roche, and the Guthy Jackson Charitable Foundation; has received research grants from Novartis; has received speaker honoraria from Bayer, Biogen, Genzyme, Novartis, and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hämmerle, Eick, Poli, Blum, Schlageter, Bauer, Rizas, Eken, Coslovsky, Aeschbacher, Krisai, Meyre, Wuerfel, Sinnecker, Vesin, Beer, Moschovitis, Bonati, Sticherling, Conen, Osswald, Kühne and Zuern.)

Background Impaired heart rate variability (HRV) is associated with increased mortality in sinus rhythm. However, HRV has not been systematically assessed in patients with atrial fibrillation (AF). We hypothesized that parameters of HRV may be predictive of cardiovascular death in patients with AF. Methods and Results From the multicenter prospective Swiss-AF (Swiss Atrial Fibrillation) Cohort Study, we enrolled 1922 patients who were in sinus rhythm or AF. Resting ECG recordings of 5-minute duration were obtained at baseline. Standard parameters of HRV (HRV triangular index, SD of the normal-to-normal intervals, square root of the mean squared differences of successive normal-to-normal intervals and mean heart rate) were calculated. During follow-up, an end point committee adjudicated each cause of death. During a mean follow-up time of 2.6±1.0 years, 143 (7.4%) patients died; 92 deaths were attributable to cardiovascular reasons. In a Cox regression model including multiple covariates (age, sex, body mass index, smoking status, history of diabetes mellitus, history of hypertension, history of stroke/transient ischemic attack, history of myocardial infarction, antiarrhythmic drugs including β blockers, oral anticoagulation), a decreased HRV index ≤ median (14.29), but not other HRV parameters, was associated with an increase in the risk of cardiovascular death (hazard ratio, 1.7; 95% CI, 1.1-2.6; P =0.01) and all-cause death (hazard ratio, 1.42; 95% CI, 1.02-1.98; P =0.04). Conclusions The HRV index measured in a single 5-minute ECG recording in a cohort of patients with AF is an independent predictor of cardiovascular mortality. HRV analysis in patients with AF might be a valuable tool for further risk stratification to guide patient management. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Aims: Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials., Methods and Results: Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16-55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47-0.79; P = 0.0002)., Conclusion: Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.

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.