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This study investigated whether an activated R-mode in patients carrying a cardiac implantable electronic device (CIED) is associated with worse prognosis during and after an episode of acutely decompensated heart failure (AHF). Six hundred and twenty-three patients participating in an ongoing prospective cohort study that phenotypes and follows patients admitted for AHF were studied. We compared CIED carriers with activated R-mode stimulation (CIED-R) to CIED carriers not in R-mode (CIED-0) and patients without CIEDs (no-CIED). The independent impact of R-mode activation on 12-month all-cause death was examined using uni- and multivariable Cox proportional hazards regression taking into account potential confounders, and hazard ratios (HR) with their 95% confidence intervals (CI) were reported. Mean heart rate on admission was lower in CIED-R (n = 37, 16% women) vs. CIED-0 (n = 64, 23% women) or no-CIED (n = 511, 43% women): 70 bpm vs. 80 bpm or 82 bpm; both p<0.001. In-hospital mortality was similar across groups, but age- and sex-adjusted all-cause 12-month mortality risk was differentially affected by R-mode activation; CIED-R vs. CIED-0: HR 2.44, 95%CI 1.25-4.74; CIED-R vs. no-CIED: HR 2.61, 95%CI 1.59-4.29. These effects persisted after multivariable adjustment for potential confounders. Within CIED-R, mortality risk was similar in patients with pacemakers vs. ICDs and in subgroups with left ventricular ejection fraction (LVEF) <50% vs. ≥50%. In patients admitted with AHF, R-mode stimulation was associated with a significantly increased 12-month mortality risk. Our findings shed new light on \"admission heart rate\" as a potentially treatable target in AHF. Our data are compatible with the concept that chronotropic incompetence contributes to an adverse outcome in these patients and may not be adequately treated through accelerometer-based R-mode stimulation.

Objectives The study aims to investigate the impact of COVID-19 pandemic on physical activity and frequency of implantable cardioverter-defibrillator (ICD) therapies of patients with cardiac implantable electronic devices. Methods and results Physical activity, heart rate and ICD-therapies were assessed via routine remote monitoring over two years. We focussed on a 338-day period during COVID-19 pandemic that was divided in 6 time-intervals defined by public health interventions and compared to the previous regular year. Paired nonparametric longitudinal analysis was performed to detect differences between time-intervals. To model effects of age, sex and time we applied a nonparametric ANOVA-type-statistic. 147 patients with cardiac implantable electronic devices were analysed. Longitudinal analysis of physical activity in 2019 and 2020 showed a specific weekly and seasonal pattern. Physical activity was reduced during the pandemic (mean daily physical activity 2019: 12.4% vs. 2020: 11.5%; p<0.0001) with the strongest reductions (fold changes 0.885/0.889, p<0.0001/p70 years), physical activity was decreased in every time-interval of the year 2020. In time-intervals of eased restrictions, physical activity of younger patients ([less than or equal to]70 years) was not different compared to 2019. No variation in mean heart rate, arrhythmia-burden and count of ICD-therapies was found. Conclusion Physical activity shows fluctuations dependent on days of the week and time of the year. During the pandemic, physical activity was reduced in patients with cardiac implantable electronic devices with the strongest reductions during lockdown-periods. Younger patients resumed former levels of physical activity in times of eased restrictions while older patients remained less active. Thus, activation of the elderly population is important to prevent long-term health impairments due to the pandemic.

There is evidence that the benefit of a primary prophylactic ICD therapy is not equal in all patients. To evaluate risk factors of appropriate shocks and all- cause mortality in patients with a primary prophylactic ICD regarding contemporary studies. PubMed, LIVIVO, Cochrane CENTRAL between 2010 and 2016. Studies were eligible if at least one of the endpoints of interest were reported. All abstracts were independently reviewed by at least two authors. The full text of all selected studies was then analysed in detail. Our search strategy retrieved 608 abstracts. After exclusion of unsuitable studies, 36 papers with a total patient number of 47282 were included in our analysis. All-cause mortality was significantly associated with increasing age (HR 1.41, CI 1.29-1.53), left ventricular function (LVEF; HR 1.21, CI 1.14-1.29), ischemic cardiomyopathy (ICM; HR 1.37, CI 1.14-1.66) and co-morbidities such as impaired renal function (HR 2.30, CI 1.97-2.69). Although, younger age (HR 0.96, CI 0.85-1.09), impaired LVEF (HR 1.26, CI 0.89-1.78) and ischemic cardiomyopathy (HR 2.22, CI 0.83-5.93) were associated with a higher risk of appropriate shocks, none of these factors reached statistical significance. Individual patient data were not available for most studies. In this meta-analysis of contemporary clinical studies, all-cause mortality is predicted by a variety of clinical characteristics including LVEF. On the other hand, the risk of appropriate shocks might be associated with impaired LVEF and ischemic cardiomyopathy. Further prospective studies are required to verify risk factors for appropriate shocks other than LVEF to help select appropriate patients for primary prophylactic ICD-therapy.

Introduction Wolff–Parkinson–White (WPW) syndrome is a congenital heart disorder marked by an accessory electrical pathway (AP) causing reentrant tachycardias. This report presents a case of WPW successfully treated with catheter ablation but followed by transient symptomatic premature ventricular contractions (PVCs). Case Summary A 27‐year‐old WPW patient was referred due to paroxysmal tachycardias. The baseline electrocardiogram confirmed ventricular pre‐excitation, and the patient underwent radiofrequency ablation targeting a right septal AP. Some days later, the patient experienced palpitations distinct from preablation symptoms. A 24‐h Holter ECG and exercise testing revealed frequent, monomorphic PVCs originating from the previously pre‐excited region. Low‐dose beta‐blocker therapy alleviated symptoms, and there was no evidence of PVC recurrence after tapering temporary beta‐blocker medication. Discussion This case illustrates a new onset of PVC after ablation of septal AP in WPW syndrome. We postulate that transient electric instability due to AP‐associated cardiac memory led to enhanced local automatic activity resulting in PVC.

Rap1b, an abundant small GTPase in platelets, becomes rapidly activated upon stimulation with agonists. Though it has been implicated to act downstream from G protein-coupled receptors (GPCRs) and upstream of integrin alpha IIbbeta3, the precise role of Rap1b in platelet function has been elusive. Here we report the generation of a murine rap1b knockout and show that Rap1b deficiency results in a bleeding defect due to defective platelet function. Aggregation of Rap1b-null platelets is reduced in response to stimulation with both GPCR-linked and GPCR-independent agonists. Underlying the defective Rap1b-null platelet function is decreased activation of integrin alphaIIbbeta3 in response to stimulation with agonists and signaling downstream from the integrin alpha IIbbeta3. In vivo, Rap1b-null mice are protected from arterial thrombosis. These data provide genetic evidence that Rap1b is involved in a common pathway of integrin activation, is required for normal hemostasis in vivo, and may be a clinically relevant antithrombotic therapy target.

Background Macrophages are the dominant phagocyte at sites of wound healing and inflammation, and the cellular and acellular debris encountered by macrophages can have profound effects on their inflammatory profile. Following interaction with apoptotic cells, macrophages are known to switch to an anti-inflammatory phenotype. Activated platelets, however, are also a major component of inflammatory lesions and have been proposed to be pro-inflammatory mediators. In the present study, we tested the hypothesis that macrophage interaction with activated platelets results in an inflammatory response that differs from the response following phagocytosis of apoptotic cells. Methods Human monocyte-derived macrophages (hMDMs) were co-incubated with autologous activated platelets (AAPs) and the platelet-macrophage interaction was examined by electron microscopy and flow cytometry. The cytokines TNF-α, IL-6, and IL-23 were also measured during LPS-activated hMDM co-incubation with AAPs, which was compared to co-incubation with apoptotic lymphocytes. Cytokine secretion was also compared to platelets pre-treated with the gluococorticoid dexamethasone. Results Macrophages trapped and phagocytized AAPs utilizing a mechanism that was significantly inhibited by the scavenger receptor ligand fucoidan. LPS-induced macrophage secretion of TNF-α, IL-6, and IL-23 was inhibited by co-incubation with apoptotic cells, but enhanced by co-incubation with AAPs. The platelet-dependent enhancement of LPS-induced cytokines could be reversed by pre-loading the platelets with the glucocorticoid dexamethasone. Conclusions The interaction of human macrophages with autologous platelets results in scavenger-receptor-mediated platelet uptake and enhancement of LPS-induced cytokines. Therefore, the presence of activated platelets at sites of inflammation may exacerbate pro-inflammatory macrophage activation. The possibility of reversing macrophage activation with dexamethasone-loaded platelets is a promising therapeutic approach to treating unresolved inflammation.

Calcium (Ca2+) and 3',5'-cyclic adenosine monophosphate (cAMP) play a critical role for cardiac excitation-contraction-coupling. Both second messengers are known to interact with each other, for example via Ca2+-dependent modulation of phosphodiesterase 1 (PDE1) and adenylyl cyclase 5/6 (AC 5/6) activities, which is supposed to occur especially at the local level in distinct subcellular microdomains. Currently, many studies analyze global and local cAMP signaling and its regulation in resting cardiomyocytes devoid of electrical stimulation. For example, Förster resonance energy transfer (FRET) microscopy is a popular approach for visualization of real time cAMP dynamics performed in resting cardiomyocytes to avoid potential contractility-related movement artifacts. However, it is unknown whether such data are comparable with the cell behavior under more physiologically relevant conditions during contraction. Here, we directly compare the cAMP-FRET responses to AC stimulation and PDE inhibition in resting vs. paced adult mouse ventricular cardiomyocytes for both cytosolic and subsarcolemmal microdomains. Interestingly, no significant differences in cAMP dynamics could be detected after β-adrenergic (isoproterenol) stimulation, suggesting low impact of rapidly changing contractile Ca2+ concentrations on cytosolic cAMP levels associated with AC activation. However, the contribution of the calcium-dependent PDE1, but not of the Ca2+-insensitive PDE4, to the regulation of cAMP levels after forskolin stimulation was significantly increased. This increase could be mimicked by pretreatment of resting cells with Ca2+ elevating agents. Ca2+ imaging demonstrated significantly higher amplitudes of Ca2+ transients in forskolin than in isoproterenol stimulated cells, suggesting that forskolin stimulation might lead to stronger activation of PDE1. In conclusion, changes in intracellular Ca2+ during cardiomyocyte contraction dynamically interact with cAMP levels, especially after strong AC stimulation. The use of resting cells for FRET-based measurements of cAMP can be justified under β-adrenergic stimulation, while the reliable analysis of PDE1 effects may require electric field stimulation.

In patients treated with implantable cardioverter defibrillator (ICD), prediction of both overall survival and occurrence of shocks is important if improved patient selection is desired. We prospectively studied the predictive value of biomarkers and indexes of cardiac and renal function and spectral microvolt T-wave alternans testing and 24-hour Holter variables in a population who underwent first ICD implantation. Consecutive patients in sinus rhythm with ischemic or dilated cardiomyopathy scheduled for primary or secondary prophylactic ICD implantation were enrolled. Exercise microvolt T-wave alternans and 24-hour Holter for number of ventricular premature contractions (VPCs), deceleration capacity, heart rate variability, and heart rate turbulence were done. Death of any cause and first appropriate ICD shock were defined as end points. Over 33 ± 15 months of follow-up, 36 of 253 patients (14%) received appropriate shocks and 39 of 253 patients (15%) died. Only 3 of 253 patients (1%) died after receiving at least 1 appropriate shock. In univariate analyses, New York Heart Association class, ejection fraction, N-terminal pro brain-type natriuretic peptide (NT-proBNP), renal function, ICD indication, deceleration capacity, heart rate variability, and heart rate turbulence were predictive of all-cause mortality and VPC number and deceleration capacity predicted first appropriate shock. NT-proBNP (≥1,600 pg/ml) was identified as the only independent predictor of all-cause mortality (hazard ratio 3.0, confidence interval 1.3 to 7.3, p = 0.014). In contrast, VPC number predicted appropriate shocks (hazard ratio 2.3, confidence interval 1.0 to 5.5, p = 0.047) as the only independent risk marker. In conclusion, NT-proBNP is a strong independent predictor of mortality in a typical prospective cohort of newly implanted patients with ICD, among many electrocardiographic and clinical variables studied. Number of VPCs was identified as a predictor of appropriate shocks (clinicaltrials.gov: NCT02010515).

The study aims to investigate the impact of COVID-19 pandemic on physical activity and frequency of implantable cardioverter-defibrillator (ICD) therapies of patients with cardiac implantable electronic devices. Physical activity, heart rate and ICD-therapies were assessed via routine remote monitoring over two years. We focussed on a 338-day period during COVID-19 pandemic that was divided in 6 time-intervals defined by public health interventions and compared to the previous regular year. Paired nonparametric longitudinal analysis was performed to detect differences between time-intervals. To model effects of age, sex and time we applied a nonparametric ANOVA-type-statistic. 147 patients with cardiac implantable electronic devices were analysed. Longitudinal analysis of physical activity in 2019 and 2020 showed a specific weekly and seasonal pattern. Physical activity was reduced during the pandemic (mean daily physical activity 2019: 12.4% vs. 2020: 11.5%; p<0.0001) with the strongest reductions (fold changes 0.885/0.889, p<0.0001/p70 years), physical activity was decreased in every time-interval of the year 2020. In time-intervals of eased restrictions, physical activity of younger patients ([less than or equal to]70 years) was not different compared to 2019. No variation in mean heart rate, arrhythmia-burden and count of ICD-therapies was found. Physical activity shows fluctuations dependent on days of the week and time of the year. During the pandemic, physical activity was reduced in patients with cardiac implantable electronic devices with the strongest reductions during lockdown-periods. Younger patients resumed former levels of physical activity in times of eased restrictions while older patients remained less active. Thus, activation of the elderly population is important to prevent long-term health impairments due to the pandemic.

Aims Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca2+ cycling remain elusive. Methods and results Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca2+ leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca2+‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca2 leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca2+ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics including SERCA activity (kSERCA) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca2+ leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end‐stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3). Conclusion This study demonstrates that neprilysin inhibitor Sac directly improves Ca2+ homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca2+ leak without acutely affecting systolic Ca2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial.