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Introduction The identification of clinically silent strokes in patients with atrial fibrillation (AF) is of high clinical relevance as they have been linked to cognitive impairment. Overt strokes have been associated with disturbances of the autonomic nervous system. Purpose We therefore hypothesize that impaired heart rate variability (HRV) can identify AF patients with clinically silent strokes. Methods We enrolled 1358 patients with AF without a history of stroke or transient ischemic attack from the multicenter SWISS-AF cohort study who were in sinus rhythm (SR-group, n=816) or AF (AF-group, n=542) on a 5 minute resting ECG recording. HRV triangular index (HRVI), the standard deviation of normal-to-normal intervals (SDNN) and the mean heart rate (MHR) were calculated. Brain MRI was performed at baseline to assess the presence of large non-cortical or cortical infarcts, which were considered silent strokes without history of stroke or transient ischemic attack. We constructed binary logistic regression models to analyze the association between HRV parameters and silent strokes. Results At baseline, silent strokes were detected in 10.5% in the SR group and 19.9% in the AF group. In the SR-group, HRVI Conclusions Reduced HRVI is independently associated with the presence of clinically silent strokes in an AF population, both when assessed during SR and during AF. Our data suggest that a short-term measurement of HRV in routine ECG recordings might contribute to identifying AF patients with clinically silent strokes. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Swiss National Science Foundation

Background Risk prediction in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) is challenging. Development of novel markers for patient risk assessment is of great clinical value. Deceleration capacity (DC) of heart rate is a strong risk predictor in post-infarction patients. Hypothesis DC provides prognostic information in patients undergoing TAVI. Methods We enrolled 374 consecutive patients with severe AS undergoing TAVI. All patients received 24-hour Holter recording or continuous heart-rate monitoring to assess DC before intervention. Primary endpoint was all-cause mortality after 1 year. Results Forty-nine patients (13.1%) died within 1 year. DC was significantly lower in nonsurvivors than in survivors (1.2 ± 4.8 ms vs 3.3 ± 2.9 ms; P < 0.001), whereas the logistic EuroSCORE and EuroSCORE II were comparable between groups (logistic EuroSCORE: 27.3% ± 17.0% vs 22.9% ± 14.2%; P = 0.122; EuroSCORE II: 8.0% ± 6.9% vs 6.7% ± 4.8%, P = 0.673). One-year mortality in the 116 patients with impaired DC (

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

Impaired cardiac autonomic function has been linked to adverse outcomes in patients with acute coronary syndromes (ACS) but is not included in clinical risk models. This is the first study to investigate whether point-of-care testing of cardiac autonomic function by means of short-term deceleration capacity (DC) of heart rate improves risk assessment in patients with suspected ACS. 1821 patients with suspected ACS were prospectively enrolled if they were older than 17 years and in sinus rhythm. Short-term DC was automatically assessed from monitor recordings at hospital admission. The Global Registry of Acute Coronary Events (GRACE) score was used as gold standard risk predictor. Primary endpoint was the composite of intrahospital and 30-day mortality. Secondary endpoint was 180-day mortality. Of the 1,821 patients with suspected ACS, 28 (1.5%) and 60 (3.3%) reached the primary and secondary endpoints, respectively. DC was a highly significant predictor of both endpoints, yielding areas under the curve (AUC) of 0.784 (95% CI 0.714–0.854) and 0.781 (0.727–0.832) (p

BACKGROUND: A small proportion of patients undergoing primary prophylactic implantation of implantable cardioverter defibrillators (ICDs) experiences malignant arrhythmias. We postulated that periodic repolarisation dynamics, a novel marker of sympathetic-activity-associated repolarisation instability, could be used to identify electrically vulnerable patients who would benefit from prophylactic implantation of ICDs by way of a reduction in mortality. METHODS: We did a prespecified substudy of EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD), a prospective, investigator-initiated, non-randomised, controlled cohort study done at 44 centres in 15 EU countries. Patients aged 18 years or older with ischaemic or non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (≤35%) were eligible for inclusion if they met guideline-based criteria for primary prophylactic implantation of ICDs. Periodic repolarisation dynamics from 24-h Holter recordings were assessed blindly in patients the day before ICD implantation or on the day of study enrolment in patients who were conservatively managed. The primary endpoint was all-cause mortality. Propensity scoring and multivariable models were used to assess the interaction between periodic repolarisation dynamics and the treatment effect of ICDs on mortality. FINDINGS: Between May 12, 2014, and Sept 7, 2018, 1371 patients were enrolled in our study. 968 of these patients underwent ICD implantation, and 403 were treated conservatively. During follow-up (median 2·7 years [IQR 2·0-3·3] in the ICD group and 1·2 years [0·8-2·7] in the control group), 138 (14%) patients died in the ICD group and 64 (16%) patients died in the control group. We noted a 43% reduction in mortality in the ICD group compared with the control group (adjusted hazard ratio [HR] 0·57 [95% CI 0·41-0·79]; p=0·0008). Periodic repolarisation dynamics significantly predicted the treatment effect of ICDs on mortality (adjusted p=0·0307). The mortality benefits associated with ICD implantation were greater in patients with periodic repolarisation dynamics of 7·5 deg or higher (n=199; adjusted HR 0·25 [95% CI 0·13-0·47] for the ICD group vs the control group; p

Deceleration capacitiy for rapid risk stratification in stroke patients Cerebral ischemia is a major cause of neurologic deficit and patients suffering from ischemic stroke bear a relevant risk of mortality. Identifying stroke patients at high mortality risk is of crucial clinical relevance. Deceleration capacity of heart rate (DC) as a parameter of cardiac autonomic function is an excellent predictor of mortality in myocardial infarction and heart failure patients. The aim of our study was to evaluate whether DC provides prognostic information regarding mortality risk in patients with acute ischemic stroke. From September 2015 to March 2018 we prospectively enrolled consecutive patients presenting at the Stroke Unit of our university hospital with acute ischemic stroke who were in sinus rhythm. In these patients 24 hours-Holter-ECG recordings and evaluation of National Institute of Health Stroke Scale (NIHSS) were performed. DC was calculated according to a previously published algorithm. Primary endpoint was intrahospital mortality. Eight hundred seventy eight stroke patients were included in the study. Intrahospital mortality was 2.8% (25 patients). Both DC and NIHSS were significantly different between non-survivors and survivors (Mean ± SD: DC: 4.1 ± 2.8 ms vs 6.3 ± 3.3 ms, P

Recurrent laryngeal palsies are relatively common. Frequently, surgical procedures precede paresis. In rare cases a compression of the recurrent laryngeal nerve can be caused by enlarged cardiovascular structures. The phenomenon of compression of the left recurrent laryngeal nerve is explicitly designated as Ortner's syndrome, first described in 1897 by Norbert Ortner. Nowadays the compression of the right recurrent laryngeal nerve by cardiovascular structures is also associated with Ortner's syndrome. We report two cases of an 82- and a 71-year-old patient who presented with hoarseness and each right- and left-sided vocal cord paralysis for further diagnosis. The ear, nose, and throat (ENT) examinations revealed no clarifying findings besides the vocal cord palsy, so extensive imaging techniques were used. The cause of left-sided recurrent laryngeal nerve palsy was a penetrated aortic ulcer caused by large thrombosed aneurysm of the aortic arch. The right-sided paresis arose due to aneurysmal enlargement of the brachiocephalic trunk and an aneurysm of right subclavian artery. These cases demonstrate that interdisciplinary medical work is important. The internal medical presentation of a patient with hoarseness without ENT medical findings should be considered.

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.We aimed to evaluate markers of the autonomic nervous system based on an electrocardiogram to predict mortality in patients with CAP.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.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.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.

Lactobacillus species are Gram-positive, facultative anaerobic, rod-shaped bacteria. They belong to the lactic acid bacteria group and are also known as a usual part of the normal flora of the gastrointestinal tract as well as of the urinary and genital tracts. They are an infrequent human pathogen but can induce several infections such as bacteremia and infectious endocarditis. We report the case of an 81-year-old woman with Lactobacillus bacteremia and mitral valve endocarditis as well as splenic abscesses.

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.Prospective cohort study.Medical emergency department of a large university hospital.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.None.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; p0.001) and yielded an area under the receiver-operator 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; p0.001 for difference). Deceleration capacity was also a highly significant predictor of 30-day and 180-day mortality as well as transfer to the ICU.Deceleration capacity is a strong and independent predictor of short-term mortality among patients admitted to a medical emergency department.

Syncope is a common cause for admission to the emergency department (ED). Due to limited clinical resources there is great interest in developing risk stratification tools that allow identifying patients with syncope who are at low risk and can be safely discharged. Deceleration capacity (DC) is a strong risk predictor in postinfarction and heart failure patients. The aim of this study was to evaluate whether DC provides prognostic information in patients presenting to ED with syncope. We prospectively enrolled 395 patients presenting to the ED due to syncope. Patient's electrocardiogram (ECG) for the calculation of DC was recorded by monitoring devices which were started after admission. Both the modified early warning score (MEWS) and the San Francisco syncope score (SFSS) were determined in every patient. Primary endpoint was mortality after 180 days. Eight patients (2%) died after 180 days. DC was significantly lower in the group of nonsurvivors as compared with survivors (3.1 ± 2.5 ms vs 6.7 ± 2.4 ms; P

Plasma Galectin-3 is a marker of myocardial inflammation and fibrosis, was associated with left ventricular (LV) reverse remodeling after conventional surgical mitral valve repair (MVR) and predicted clinical events in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to evaluate the association between pre-interventional Galectin-3 levels and (1) reverse LV remodeling and (2) major adverse cardiovascular events (MACE) in patients undergoing percutaneous MVR.Forty-four consecutive patients (median age 79 years, LV ejection fraction 39.5 ± 11.4%, 91% in NYHA functional class ≥III) with symptomatic moderate to severe mitral regurgitation undergoing percutaneous MVR were prospectively included. Plasma Galectin-3 levels were measured before the procedure. Echocardiographic and clinical assessment was performed at baseline and after 3 months. LV reverse remodeling was prospectively defined as a ≥10% increase in global longitudinal strain. MACE included death, myocardial infarction, heart failure related rehospitalization and stroke and was assessed after a mean follow-up time of 2 years.72.7% of the patients showed LV reverse remodeling. Pre-interventional Galectin-3 10 ng/ml was an independent predictor of LV reverse remodeling (OR 10.3, 95% CI 1.2-83.9, p = 0.036). 25 patients (56.8%) experienced a MACE. Patients with Galectin-3 levels ≥ 10 ng/ml had significantly more MACE than patients with Galectin-3 levels 10 ng/ml (100% vs. 45.5%, p = 0.003). Diabetes independently predicted MACE (HR 3.1, 95% CI 1.0-9.4, p = 0.049); Galectin-3 ≥ 10 ng/ml was of borderline significance (HR 2.2, 95% CI 0.9-5.4, p = 0.088).Pre-interventional plasma Galectin-3 levels are associated with LV reverse remodeling and with clinical outcome after percutaneous MVR.

BACKGROUND: Risk prediction in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) is challenging. Development of novel markers for patient risk assessment is of great clinical value. Deceleration capacity (DC) of heart rate is a strong risk predictor in post‐infarction patients. HYPOTHESIS: DC provides prognostic information in patients undergoing TAVI. METHODS: We enrolled 374 consecutive patients with severe AS undergoing TAVI. All patients received 24‐hour Holter recording or continuous heart‐rate monitoring to assess DC before intervention. Primary endpoint was all‐cause mortality after 1 year. RESULTS: Forty‐nine patients (13.1%) died within 1 year. DC was significantly lower in nonsurvivors than in survivors (1.2 ± 4.8 ms vs 3.3 ± 2.9 ms; P < 0.001), whereas the logistic EuroSCORE and EuroSCORE II were comparable between groups (logistic EuroSCORE: 27.3% ± 17.0% vs 22.9% ± 14.2%; P = 0.122; EuroSCORE II: 8.0% ± 6.9% vs 6.7% ± 4.8%, P = 0.673). One‐year mortality in the 116 patients with impaired DC (

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.

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.

Optimal timing of elective aortic valve replacement (AVR) for severe aortic stenosis (AS) is challenging. Hence, a sensitive marker in AS patients indicating increasing risk after AVR would be of great clinical value. In the present study, we hypothesized that mild-to-moderate pulmonary hypertension (PH) assessed prior to AVR is a sensitive marker for adverse events in patients after successful AVR.We enrolled 200 consecutive patients with severe AS undergoing AVR. Among them, 176 patients (88%) were symptomatic. Patients were divided according to systolic pulmonary artery pressure (PAP(sys)) into three groups: no PH (PAP(sys) 30 mmHg), mild-to-moderate PH (PAP(sys) ≥30 and PAP(sys) 60 mmHg) and severe PH (≥60 mmHg). Multivariable analyses were adjusted for age and gender and included PH, left ventricular ejection fraction ≤35%, renal insufficiency and logistic EuroSCORE ≥20%. Primary endpoint was death of any cause within 5 years after AVR.During follow-up, 23 patients died (cumulative 5-year mortality rate 14.6%). Patients without (n = 78), mild-to-moderate (n = 99) and severe PH (n = 23) had 5-year mortality rates of 2.6, 15.2 and 26.1% (p = 0.001). PAPsys ≥30 mmHg yielded an excellent level of sensitivity of 92.8%. On multivariable analysis, mild-to-moderate PH was the only independent risk factor (hazard ratio 4.9, 95% confidence interval 1.1-21.8).In patients with severe AS undergoing AVR, mild-to-moderate PH is a strong and independent predictor of late mortality. Conversely, patients with normal PAP(sys) have an extremely good prognosis.

Catheter ablation has become the first line of therapy in patients with symptomatic, recurrent, drug-refractory atrial fibrillation. However, catheter ablation of persistent atrial fibrillation is still a challenge. Various rather complex ablation strategies exist and their results are not very favorable. Therefore, the aim of our study was to evaluate a well-defined reasonable approach to catheter ablation of persistent atrial fibrillation. The strategy consisted of a circumferential pulmonary vein ablation in combination with a potential-guided segmental approach to achieve complete pulmonary vein isolation and a linear lesion at the roof of the left atrium. A total of 43 patients (30 men, 13 women; mean age 55 years (SD ± 9 years)) with symptomatic persistent atrial fibrillation were enrolled in this study. All patients underwent catheter ablation of persistent atrial fibrillation using the above-mentioned approach (with the CARTO or the NAVX system). Additionally, catheter ablation of the mitral isthmus and the right atrial isthmus was performed in selected cases. In all patients, cardiac MRI or multi-detector spiral computed tomography was performed prior to the ablation procedure and a surface rendered model of the left atrium was created. After discharge, patients were scheduled for repeated visits at the arrhythmia clinic at 1, 3, 6, 9, and 12 months after the ablation procedure. The ablation procedure could be performed as planned in all 43 patients. Nine patients had to undergo a repeat ablation procedure, so that a total of 52 procedures were evaluated. An additional linear lesion was created at the mitral isthmus in three patients (7%) during the initial procedure and in one patient (2.3%) during the second procedure. Catheter ablation of the right atrial isthmus was performed in 11 patients (25.6%) during the first procedure and in four additional patients during the redo procedure (9.3%). Twenty-four out of 43 patients (55.8%) experienced an arrhythmia recurrence within the first 3 months after ablation requiring an electrical cardioversion. At 1-year follow-up, analysis of a 7-day Holter monitoring revealed no evidence for an arrhythmia recurrence in 26 of 43 patients (60.5%). In nine of 43 patients (20.9%), only short episodes of paroxysmal atrial fibrillation were documented. In eight patients (18.6%), a recurrence of persistent atrial fibrillation (>48 h) was revealed by the long-term recordings. A duration of persistent atrial fibrillation >3 months was the most powerful predictor for arrhythmia recurrences at 1-year follow-up. A subgroup analysis revealed a markedly higher rate of stable sinus rhythm at 1-year follow-up in patients with a short duration of atrial fibrillation (≤3 months) compared to patients with a longer duration of AF (>3 months) prior to the procedure (72.0% versus 44.4%). There were no major complications. Catheter ablation of persistent atrial fibrillation can be performed safely and effectively using this ablation strategy (especially in patients with short-lasting persistent atrial fibrillation (≤3 months)).

Aims Atrial fibrillation (AF) leads to electrical atrial remodeling including alterations of various ion channels early after arrhythmia onset. The beneficial effects of statins in AF treatment due to their influence on oxidative stress and inflammation are discussed. Our hypothesis was that statins might also alter atrial ion currents and their early tachycardia-induced remodeling. Main methods Effects of an atorvastatin treatment (7 days) on atrial ion currents and their tachycardia-induced alterations were studied in a rabbit model of tachycardia-induced electrical remodeling (rapid atrial pacing (600 min) for 24 and 120 h). Ion currents (L-type calcium channel [I Ca,L ], transient outward current [I to ]) were measured using whole cell patch clamp method and were compared with previous experiments in untreated but also tachypaced animals. Key findings Atorvastatin treatment alone decreased I Ca,L similar to rapid atrial pacing alone, currents were also further reduced by additional atrial tachypacing. I to and its pacing-induced down-regulation after 24 h were not influenced by atorvastatin treatment. However, I to was still reduced after 120 h in atorvastatin-treated animals and did not return to control values as expected. Significance The present study establishes that an atorvastatin treatment can affect atrial ion currents and their tachycardia-induced remodeling in a rabbit model. These results show that—amongst other positive effects on oxidative stress and inflammation—the impact of statins on ion currents and their tachycardia-induced alterations might also play a role in “upstream” treatment of AF with HMG-CoA reductase inhibitors.

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.

Background In some patients, above-average alcohol consumption before occurrence of atrial fibrillation (AF) in terms of a "holiday heart syndrome" (HHS) can be determined. There is evidence that long before development of apparent alcohol-induced cardiomyopathy, above-average alcohol consumption generates an arrhythmogenic substrate which abets the onset of AF. Changes of atrial current densities in terms of an electrical remodeling after sustained short-term ethanol infusion in rabbits as a potential part of HHS pathophysiology were examined in this study. Methods Rabbits of the ethanol group (EG) received sustained short-term intravenous alcohol infusion for 120 hours (during infusion period, blood alcohol level did not fall below 158 mg/dl), whereas NaCl 0.9% was infused in the placebo group (PG). Using patch clamp technique in whole-cell mode, atrial current densities were measured and compared between both groups. Results Ethanol infusion did not alter current densities of I(to) [58.7 +/- 5.0 pA/pF (PG, n = 20 cells) vs. 53.9 +/- 5.0 pA/pF (EG, n = 24)], I(sus) [11.3 +/- 1.4 pA/pF (PG, n = 20) vs. 10.2 +/- 1.0 pA/pF (EG, n = 24)], and I(K1) [-1.6 +/- 0.3 pA/pF (PG, n = 17) vs. -2.0 +/- 0.3 pA/pF (EG, n = 22)]. However, alcohol infusion resulted in a remarkable reduction of I(Ca,L) current densities [-28.4 +/- 1.8 pA/pF (PG, n = 20) vs. -15.2 +/- 1.4 pA/pF (EG, n = 22)] and I(Na) [-75.4 +/- 3.6 pA/pF (PG, n = 17) vs. -35.4 +/- 4.4 pA/pF (EG, n = 21)], respectively. Conclusion Sustained short-term ethanol infusion in rabbits alters atrial current densities. HHS might be favored by alcohol-induced atrial electrical remodeling.

Background and purpose Recently, the CRYSTAL AF trial detected paroxysmal atrial fibrillation (AF) in 12.4% of patients after cryptogenic ischaemic stroke (IS) or cryptogenic transient ischaemic attack (TIA) by an insertable cardiac monitor (ICM) within 1 year of monitoring. Our aim was (i) to assess if an AF risk factor based pre-selection of ICM candidates would enhance the rate of AF detection and (ii) to determine AF risk factors with significant predictive value for AF detection. Methods Seventy-five patients with cryptogenic IS/TIA were consecutively enrolled if at least one of the following AF risk factors was present: a CHA2DS2-VASc score ≥4, atrial runs, left atrium (LA) size >45 mm, left atrial appendage (LAA) flow ≤0.2 m/s, or spontaneous echo contrast in the LAA. The electrocardiographic and echocardiographic criteria were chosen as they have been repeatedly reported to predict AF; the same applies for four of the six items of the CHA2DS2-VASc score. The study end-point was the detection of one or more episodes of AF (≥2 min). Results Seventy-four patients underwent implantation of an ICM; one patient had AF at the date of implantation. After 6 months, AF was detected in 21/75 patients (28%), after 12 months in 25/75 patients (33.3%). 92% of AF episodes were asymptomatic. LA size >45 mm and the presence of atrial runs were independently associated with AF detection [hazard ratio 3.6 (95% confidence interval 1.6–8.4), P = 0.002, and 2.7 (1.2–6.7), P = 0.023, respectively]. Conclusions The detection rate of AF is one-third after 1 year if candidates for an ICM after cryptogenic IS/TIA are selected by AF risk factors. LA dilation and atrial runs independently predict AF.

Hughes-Stovin syndrome (HSS) is a rare autoimmune vasculitis and is characterized by the simultaneous presence of deep venous thrombosis and pulmonary artery aneurysms. The exact etiology and pathogenesis of this life-threatening syndrome is currently unknown. The disease is thought to be a variant of Behcet’s disease with major vascular involvement. Here we report a case of a 19-year-old man from West Africa with a severe cardiovascular manifestation of HSS. The patient was referred to our hospital with dyspnoea, recurrent fever and swelling of the left leg. Echocardiography revealed extensive biventricular thrombi. He responded very well to immunosuppressive therapy in combination with anticoagulation using low-molecular-weight heparins (LMWHs). Thrombolysis was consciously avoided.

Objective The aim of this study was to find a new and less cardiotoxic conditioning regimen for high-dose chemotherapy and autologous stem cell transplantation (aSCT) in patients with severe SSc and pre-existing cardiac involvement. Methods Six patients with cardiac involvement were treated for SSc with a conditioning regimen including reduced-dose CYC plus the non-cardiotoxic alkylant thiotepa. All patients received an implantable cardioverter defibrillator (ICD) before aSCT. The response at months 6 and 12 was measured according to reduction of the modified Rodnan skin score (mRSS). CT histography was used to monitor pulmonary manifestations, as were echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin for the cardiac involvement. Cardiac events were defined as death or hospitalisation due to heart failure or appropriate discharge of the ICD. Results Between December 2008 and May 2012, four male and two female patients with a median age of 41 years received aSCT. The median mRSS significantly decreased from 26.5 to 18 and 17.5 at month 6 and 12, respectively. The total lung volume also significantly improved. Within the median follow-up of 1.6 years (range 1-3.8) two patients experienced a relapse of SSc, which results in a progression-free survival rate of 66.6%. Three patients experienced ICD discharge. Conclusion For patients with SSc and cardiac involvement, the use of thiotepa and reduced-dose CYC is feasible and effective. The rate of ICD discharge underlines the need for protection in these endangered patients. This preliminary experience allowed us to use this regimen for our currently recruiting prospective trial (NCT01895244).

Identification of new risk markers in aortic valve stenosis (AS) is of great interest. Here, we hypothesized that the presence of severe autonomic failure (SAF) is an important prognostic marker in both, symptomatic patients undergoing invasive treatment for severe AS, and in asymptomatic patients with severe AS who were primarily treated conservatively.We prospectively enrolled 300 patients with severe AS (aortic valve area1.0 cm2 or mean aortic gradient40 mmHg) in sinus rhythm. All patients underwent a 24-h Holter recording for assessment of heart rate turbulence (HRT) and deceleration capacity (DC). Patients with both, abnormal DC and HRT were considered to suffer from SAF.The first hypothesis was tested in 216 symptomatic patients who underwent successful aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI). During follow-up of 2 years, 29 of these patients died. SAF was the strongest independent predictor of mortality (hazard ratio 5.6, 95% confidence interval 2.6-12.0; p0.001) with 2-year mortality rates of 50.0% and 10.7% in SAF-positive and SAF-negative patients, respectively (p0.001). The second hypothesis was tested in 71 patients, who were asymptomatic at study entry and for whom a primarily conservative treatment strategy was proposed. During follow-up, 10 of these patients died. SAF also predicted death in asymptomatic patients with 2-year mortality rates of 52.4% and 8.7% in SAF-positive and SAF-negative patients, respectively (p=0.010).SAF is a strong and independent predictor of mortality in symptomatic and asymptomatic patients with severe AS.

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 {"type":"clinical-trial","attrs":{"text":"NCT00196274","term_id":"NCT00196274"}}NCT00196274. Funding. This study was funded by Angewandte Klinische Forschung, University of Tubingen (252-1-0).

Background: Catheter ablation (CA) of atrial fibrillation (AF) requires an intensified peri-inter­ventional anticoagulation scheme to avoid thromboembolic complications. In patients with cardiac or extracardiac artery disease, an additional antiplatelet treatment (AAT) is at least temporally necessary especially after a percutaneous intervention with stent implantation. This raises the question whether these patients have a higher peri-interventional bleeding risk during CA of AF. Methods: The data of 1235 patients with CA of AF were retrospectively analyzed in terms of bleeding events, ablation type, antithrombotic medication and comorbidities such as coronary artery disease and components of the HAS- BLED score. Peri-interventional bleeding events were classified in accordance with the BARC classification. Differentiations were made between slight femoral bleeding (based on type 1), severe femoral bleeding and pericardial effusion without pericardiocentesis (based on type 2) with the need of further hospitalization, the need of transfusion (based on type 3a) and pericardial tamponades requiring pericardiocentesis (based on type 3b). Results: 1131/1235 (91.6%) patients were exclusively under anticoagulation and 187 (15.3%) patients were also on AAT. There were no statistically significant differences in type 1 and 3b bleeding complica­tions or the occurrence of femoral pseudoaneurysms between both groups. However, type 2/3a bleeding complications, mostly femoral bleedings, were significantly more frequent in the patient group with AAT (3.2% vs. 7.5%, p = 0.006). Conclusions: An additional antiplatelet therapy increases the risk of severe femoral bleeding events during CA of AF. It appears reasonable to perform the elective procedure of AF ablation after the dis­continuation of AAT.

Background and purpose Studies report on the reversal of electrophysiological parameters altered by atrial tachycardia after cessation of the latter. However, there is no data concerning reversal of tachycardia-induced alterations of ion currents. Reverse remodeling of atrial ion currents ( I Ca,L , I to , I sus ) was studied in our rabbit model of tachycardia-induced electrical remodeling. Methods Three groups each with four animals were built. Rapid atrial pacing (600/min) for 5 days was applied in all groups. Thereafter, different time intervals (5, 10, 20 days) were awaited before the patch clamp experiments. Results Similar to I to remodeling in our model, within 20 days after cessation of atrial tachycardia, time course of I to reverse remodeling was also U-shaped. In contrast, there was no significant recovery of I Ca,L which was initially reduced by rapid atrial pacing. Conclusion Relevance of a missing recovery of I Ca,L is likely as this current is closely linked with intracellular calcium handling.

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 BPV. Methods and Results: Eleven consecutive patients with therapy-refractory arterial hypertension (age 68.9±7.0 years; baseline systolic BP 189±23mmHg despite medication with 5.6±2.1 antihypertensive drugs) underwent bilateral RDN. Twenty-four hour ambulatory blood pressure monitoring (ABPM) was performed before RDN and six months thereafter. BPV was primarily assessed by means of standard deviation of 24-hour systolic arterial blood pressures (SDsys). Secondary measures of BPV were maximum systolic blood pressure (MAXsys) and maximum difference between two consecutive readings of systolic BP (deltamaxsys) over 24 hours. Six months after RDN, SDsys, MAXsys and deltamaxsys were significantly reduced from 16.9±4.6mmHg to 13.5±2.5mmHg (p=0.003), from 190±22mmHg to 172±20mmHg (p

Severe autonomic failure (SAF) refers to combined abnormalities in reflex and tonic autonomic function. SAF indicates increased risk of death in post-infarction and heart failure patients, but has not been studied in aortic stenosis (AS). Here, we investigated SAF in patients with AS and tested its correlation with hemodynamic and biochemical markers. We prospectively enrolled 174 patients with moderate to severe AS in sinus rhythm (age 76 ± 9 years; mean aortic valve area 0.9 ± 0.3 cm2). Heart rate turbulence (as marker of autonomic reflex activity) and deceleration capacity (as marker of autonomic tonic activity) were calculated from 24-h Holter recordings. According to the previously published technology, SAF was considered present if both factors were abnormal. 44 (25.3%) of the 174 patients had signs of SAF. Patients with SAF had lower left ventricular ejection fraction (LVEF: 48.1 vs. 54.8%; p = 0.002), lower mean aortic gradients (28 vs. 34 mmHg, p = 0.019), higher systolic pulmonary artery pressures (46.8 vs. 40.9 mmHg, p = 0.028), higher levels of brain natriuretic peptide (905 vs. 407 ng/l; p = 0.003) and higher levels of high sensitive troponin I (0.65 vs. 0.24 μg/l; p = 0.013). Impaired LVEF (≤50%) was the only independent factor associated with SAF, but only explained autonomic abnormalities in less than half of the patients. In patients with moderate to severe AS prevalence of SAF is high. SAF correlates with hemodynamic and biochemical markers indicating increased risk. Future studies should evaluate the prognostic value of SAF in patients with AS.

Sympathetic activity plays an important role in the pathogenesis of ventricular tachyarrhythmia. Catheter-based renal sympathetic denervation (RDN) is a novel treatment option for patients with resistant hypertension, proved to reduce local and whole-body sympathetic activity.Two patients with chronic heart failure (CHF) (non-obstructive hypertrophic and dilated cardiomyopathy, NYHA III) suffering from therapy resistant electrical storm underwent therapeutic renal denervation. In both patients, RDN was conducted with agreement of the local ethics committee and after obtaining informed consent.The patient with hypertrophic cardiomyopathy had recurrent monomorphic ventricular tachycardia despite extensive antiarrhythmic therapy, following repeated endocardial and epicardial electrophysiological ablation attempts to destroy an arrhythmogenic intramural focus in the left ventricle. The second patient, with dilated nonischemic cardiomyopathy, suffered from recurrent episodes of polymorphic ventricular tachycardia and ventricular fibrillation. The patient declined catheter ablation of these tachycardias. In both patients, RDN was performed without procedure-related complications. Following RDN, ventricular tachyarrhythmias were significantly reduced in both patients. Blood pressure and clinical status remained stable during the procedure and follow-up in these patients with CHF.Our findings suggest that RDN is feasible even in cardiac unstable patients. Randomized controlled trials are urgently needed to study the effects of RD in patients with electrical storm and CHF.

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 I(Na) 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 I(Na) and its tachycardia-induced remodeling were studied in a rabbit model.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.Rapid atrial pacing (RAP, 600/min) reduced I(Na) after 24 hours (≈ -50%) with no further reduction after 120 hours. DT reduced I(Na) (≈ -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 I(Na).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.

We appreciate the interest in our paper [(1)][1] and the opportunity to reply to the thoughtful comments by Dr. Hering and colleagues. We agree that testing the effect of renal sympathetic denervation (RDN) on cardiac baroreflex sensitivity (BRS) would provide important insights into the

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.

Long-term atrial fibrillation changes in many regulatory and structural processes may result in stabilization of the arrhythmia. There is evidence that decreased amplitude of L-type Ca(2+) current - probably a key mechanism of atrial remodelling -resulting from changes in expression of regulatory proteins is at least jointly responsible.To assess the expressions of protein phosphatases PP1 and PP2A, as well as the effect of verapamil pretreatment (VPT), in the early phases of atrial fibrillation in a rabbit model.FOUR GROUPS, EACH CONSISTING OF SIX ANIMALS, WERE STUDIED: 'not paced, no drug' group; 'paced, no drug' group (rapid atrial pacing [RAP] 600 beats/min for 24 h); 'not paced, verapamil' (NPV) group (duration of VPT was seven days, verapamil 7.5 mg/kg was administered every 12 h); and 'paced, verapamil' (PV) group (pacemaker stimulation after VPT). Protein expression was evaluated by Western blot analysis.RAP resulted in an augmented (32%) PP1 expression (not paced, no drug group versus paced, no drug group). The increase in PP1 expression was prevented with VPT (NPV group versus PV group). Expression of PP2A was not influenced by RAP. However, VPT led to an increase of PP2A expression (16%) after RAP (NPV group versus PV group).Fortified expression of protein phosphatases might be - besides transcriptional downregulation of channel subunits - another important cause of reduced L-type Ca(2+) current after RAP. Blocking L-type Ca(2+) channels with verapamil to prevent tachycardia-induced changes of PP1 expression might be expedient.

We appreciate the insightful comments of Drs. Ormezzano and Baguet on our paper [(1)][1]. In our proof-of-concept study, we demonstrated for the first time that impaired spontaneous cardiac baroreflex sensitivity (BRS) might be a valuable tool for identification of patients with hypertension who

Background: A substantial number of patients with aortic valve stenosis (AS) suffer from severe cardiac autonomic failure (SAF) defined as combination of abnormal heart rate turbulence and deceleration capacity. Here we hypothesized that presence of SAF is a strong and independent predictor of adverse outcome in patients with severe AS undergoing aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI). Methods: We included 161 consecutive patients with severe AS in sinus rhythm who underwent AVR (n=53) or TAVI (n=108) at our institution. Twenty-four hour Holter recordings were performed prior to operation. SAF was assessed according previously published technologies. SAF was considered present if Turbulence Onset ≥0%, Turbulence Slope ≤2.5ms/RRI and deceleration capacity ≤4.5ms. Multivariable analyses included SAF, age ≥80 years, increased levels of brain natriuretic peptides and the logistic Euro Score. Primary endpoint was two-year all-cause mortality. Results: During a median follow of 312 days, 11 patients died. Twenty-three of 161 patients (14.3%) were SAF-positive prior to operation. SAF-positive patients had a cumulative mortality rate of 32.6% compared to 4.2% in SAF-negative patients (p

Background: In susceptible individuals, enhanced sympathetic activity at the ventricular myocardium can destabilize repolarization resulting in an increased risk of death. To assess the sympathetic effect on repolarization we developed a novel technique and identified low frequency oscillatory waves of the T-wave, which are independent from underlying heart rate. We postulated that increased amplitudes of those waves predict mortality after myocardial infarction (MI) and are linked to the well-known exercise-induced microvolt T-wave alternans (mTWA) phenomenon. Methods: We assessed low frequency (≤ 0.1Hz) waves of the T-wave (LFdT°) from surface ECGs recorded under resting conditions. We tested the technology in 908 survivors of acute MI. LFdT° was dichotomized at the upper quartile. Primary endpoint was 5-year total mortality. Multivariable analyses were adjusted for age and gender and included established risk predictors: left ventricular ejection fraction≤35%, standard deviation of all normal to normal intervals ≤70ms, diabetes mellitus and history of previous MI. We studied the potential link of resting LFdT° to mTWA in 3,223 patients who underwent a clinically indicated exercise test. Results: LFdT° was significantly enhanced in non-surviving compared to surviving patients (6.7 (median) [IQR 3.6 – 12.2] vs 2.7 [1.4 – 5.3]; p