High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.

High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.

Ursodeoxycholic acid impairs atherogenesis and promotes plaque regression by cholesterol crystal dissolution in mice.

Atherosclerosis is a chronic inflammatory disease driven primarily by a continuous retention of cholesterol within the subendothelial space where it precipitates to form cholesterol crystals (CC). These CC trigger a complex inflammatory response through activation of the NLRP3 inflammasome and promote lesion development. Here we examined whether increasing cholesterol solubility with ursodeoxycholic acid (UDCA) affects vascular CC formation and ultimately atherosclerotic lesion development. UDCA mediated intracellular CC dissolution in macrophages and reduced IL-1ß production. In ApoE(-/-) mice, UDCA treatment not only impaired atherosclerotic plaque development but also mediated regression of established vascular lesions. Importantly, mice treated with UDCA had decreased CC-depositions in atherosclerotic plaques compared to controls. Together, our data demonstrate that UDCA impaired CC and NLRP3 dependent inflammation by increasing cholesterol solubility and diminished atherosclerosis in mice.

Cardiac glycosides are not associated with increased mortality or hospitalization rates in ICD and CRT-ICD patients after adjustment for baseline-characteristics at one-year follow-up: Results from the German DEVICE registry.

AIMS: Despite lacking supporting randomized trials, cardiac glycosides (CGs) are widely used in heart failure and/or atrial fibrillation. Moreover, several pro- and retrospective studies and registry-data have recently raised serious concerns in terms of efficacy and safety of CGs in this field. We have therefore examined the association between CGs and clinical outcome of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization (CRT-ICD) patients of the large German DEVICE registry. METHODS AND RESULTS: Between 2007 and 2014, 3782 ICD and 1529 CRT-ICD patients were enrolled in the German DEVICE registry. Those two groups were analyzed independently according to medication with or without CGs. After adjustment for patient characteristics, CGs were not significantly associated with increased one-year mortality (HR 1.27, 95%-CI 0.91-1.76, p = 0.162), major adverse cardiac and cerebrovascular events (OR 1.36, 95%-CI 0.98-1.89, p = 0.063), ICD-shocks (OR 1.29, 95%-CI 0.95-1.74, p = 0.104) or the need for rehospitalization in ICD patients at one-year-follow-up. Similar findings were obtained in CRT-ICD patients. Regarding possible determinants for glycoside treatment, atrial fibrillation at enrollment was found to be most strongly associated with the prescription of glycosides in ICD (adjusted OR 3.25, 95%-CI 2.63-4.02) and CRT-ICD patients (adjusted OR 3.17, 95%-CI 2.39-4.19). CONCLUSION: Overall harmful effects of CGs in ICD- and CRT-ICD patients could not be confirmed in DEVICE. Further large and randomized-controlled trials that investigate dose-dependent effects of CGs in addition to contemporary therapy of heart failure and atrial fibrillation are needed.

Improvement of Retinal Microcirculation after Pulmonary Vein Isolation in Patients with Atrial Fibrillation-An Optical Coherence Tomography Angiography Study.

PURPOSE: To evaluate retinal and optic nerve head (ONH) perfusion in patients with atrial fibrillation (AF) before and after catheter ablation of AF with pulmonary vein isolation (PVI). METHODS: 34 eyes of 34 patients with AF and 35 eyes of 35 healthy subjects were included in this study. Flow density data were obtained using spectral-domain OCT-A (RTVue XR Avanti with AngioVue, Optovue, Inc, Fremont, California, USA). The data of the superficial and deep vascular layers of the macula and the ONH (radial peripapillary capillary network, RPC) before and after PVI were extracted and analysed. RESULTS: The flow density in the superficial OCT-angiogram (whole en face) and the ONH (RPC) in patients with AF was significantly lower compared to healthy controls (OCT-A superficial: study group: 48.77 (45.19; 52.12)%; control group: 53.01 (50.00; 54.25)%; p < 0.001; ONH: study group: 51.82 (48.41; 54.03)%; control group: 56.00 (54.35; 57.70)%; p < 0.001;). The flow density in the ONH (RPC) improved significantly in the study group following PVI (before: 51.82 (48.41; 54.03)%; after: 52.49 (50.34; 55.62)%; p = 0.007). CONCLUSIONS: Patients with AF showed altered ocular perfusion as measured using OCTA when compared with healthy controls. Rhythm control using PVI significantly improved ocular perfusion as measured using OCT-A. Non-contact imaging using OCTA provides novel information about the central global microperfusion of patients with AF.

Extended ECG monitoring with an implantable loop recorder in patients with cryptogenic stroke: time schedule, reasons for explantation and incidental findings (results from the TRACK-AF trial).

BACKGROUND: Implantable loop recorders (ILR) may be used to detect occult atrial fibrillation (AF) in patients with cryptogenic stroke. At present, there has been no description on the incidental findings of stored episodes in these patients. Furthermore, no standard practice has been established with respect to the duration of continued ECG monitoring in these patients. MATERIALS AND METHODS: In the prospective monocentric study (TRACK-AF), a total of 173 patients with cryptogenic stroke received an ILR for detection of AF between November 2010 and December 2014. Before implantation all patients had undergone recommended protocols for detection of stroke causes. RESULTS: During a mean follow-up of 24.8 ± 11.5 months, atrial tachyarrhythmias were detected in n = 33 pts (19.1%). Diagnosis of AF was made after a mean of 10.7 ± 11.4 months, time to first AF detection ranged between 0.2 and 39.8 months. In 15 patients (8.7%), other incidental findings were stored in the ILR memory. Short episodes of sinus arrest at night not requiring a permanent pacemaker were present in 8 pts (4.6%). DDD-pacemaker implantation due to sinus arrest or symptomatic bradyarrhythmias occurred in 5 patients (2.9%) after a median monitoring period of 23.1 ± 7.4 months. Further incidental findings were atrial flutter and an AV-nodal-reentry tachycardia in one patient, respectively. Both patients underwent successful catheter ablation. So far, ILR were explanted in 111 pts, and 71 ILR were explanted before end of service status of the battery. Main reason for ILR explantation was patients' preference (51%), followed by battery depletion (24%) and diagnosis of AF (15%). CONCLUSION: The present study revealed a significant number of ECG findings during continued ECG monitoring for AF in patients with cryptogenic stroke. Apart from AF (17.5% during the first 1.5 years), other clinical relevant arrhythmias requiring, e.g., pacemaker implantations, were observed. With respect to these findings, we recommend to extend ILR monitoring to the end of battery life. However, acceptance of continued ECG monitoring until battery depletion was poor; in 71 patients (64%), the ILR were explanted before the end of battery life. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT02641678.

[Management of inappropriate shocks/T-wave-oversensing in S-ICD®-patients]. / Management von inadäquaten Schocks/T-Wellen-Oversensing bei S-ICD®-Patienten.

Inappropriate shocks are a feared complication after implantable cardioverter-defibrillator (ICD) implantation and have a tremendous impact on quality of life. Inappropriate shocks in patients with subcutaneous ICD (S-ICD®, Boston Scientific, Marlborough, MA, USA) have various underlying causes. This review summarizes the current literature on this topic and lists possible treatment options.

Direct comparison of the novel automated screening tool (AST) versus the manual screening tool (MST) in patients with already implanted subcutaneous ICD.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has evolved as a valuable alternative to the transvenous ICD, especially in young patients. Unfortunately, some of these patients are ineligible for S-ICD implantation due to specific electrocardiographic features. So far, these patients were identified by mandatory pre-implantation screening using the manual screening tool (MST), which lacks objective value. Therefore, a novel automated screening tool (AST) has been introduced recently for objective screening, which has not been evaluated yet. METHODS/RESULTS: We here first investigate the novel AST, in direct comparison to MST, in 33 consecutive patients with already implanted S-ICD system to compare predicted eligibility by screening tools with true sensing of the S-ICD system. Both screening tools reliably predicted true ineligible single vectors, but also suggested overall ineligibility in a similar fraction of patients (MST: 3.0%; AST: 6.1%), albeit the implanted S-ICD worked flawlessly in these patients. AST did not predict the finally selected sensing vector better than MST. There was a surprising mismatch between AST and MST for the predicted eligibility of single vectors; only in 49% of patients did both screening tools predict eligibility for the same vectors. CONCLUSIONS: The novel AST predicted overall eligibility approximately similar to MST. Both tools predicted ineligibility in a few patients, who were actually eligible. There was a striking mismatch between both screening tools when eligibility of single vectors was predicted. Thus, the AST seems to be a valuable advance, due to its standardized and objective process, but it still lacks specificity.

Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.