Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function.

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter-induced by MG or AGE-BSA-was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation.

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms.

PURPOSE: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. METHODS: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. RESULTS: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. CONCLUSIONS: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.

Cost-effectiveness of noninvasive telemedical interventional management in patients with heart failure: health economic analysis of the TIM-HF2 trial.

BACKGROUND: Noninvasive remote patient management (RPM) in patients with heart failure (HF) has been shown to reduce the days lost due to unplanned cardiovascular hospital admissions and all-cause mortality in the Telemedical Interventional Management in Heart Failure II trial (TIM-HF2). The health economic implications of these findings are the focus of the present analyses from the payer perspective. METHODS AND RESULTS: A total of 1538 participants of the TIM-HF2 randomized controlled trial were assigned to the RPM and Usual Care group. Health claims data were available for 1450 patients (n = 715 RPM group, n = 735 Usual Care group), which represents 94.3% of the original TIM-HF2 patient population, were linked to primary data from the study documentation and evaluated in terms of the health care cost, total cost (accounting for intervention costs), costs per day alive and out of hospital (DAOH), and cost per quality-adjusted life year (QALY). The average health care costs per patient year amounted to € 14,412 (95% CI 13,284-15,539) in the RPM group and € 17,537 (95% CI 16,179-18,894) in the UC group. RPM led to cost savings of € 3125 per patient year (p = 0.001). After including the intervention costs, a cost saving of € 1758 per patient year remained (p = 0.048). CONCLUSION: The additional noninvasive telemedical interventional management in patients with HF was cost-effective compared to standard care alone, since such intervention was associated with overall cost savings and superior clinical effectiveness.

Trained immunity as a novel approach against COVID-19 with a focus on Bacillus Calmette-Guérin vaccine: mechanisms, challenges and perspectives.

COVID-19 is a severe health problem in many countries and has altered day-to-day life in the whole world. This infection is caused by the SARS-CoV-2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID-19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette-Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non-specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID-19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS-CoV-2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID-19 severity.

Hyperglycaemia-induced methylglyoxal accumulation potentiates VEGF resistance of diabetic monocytes through the aberrant activation of tyrosine phosphatase SHP-2/SRC kinase signalling axis.

Diabetes mellitus (DM) is a major cardiovascular risk factor contributing to cardiovascular complications by inducing vascular cell dysfunction. Monocyte dysfunction could contribute to impaired arteriogenesis response in DM patients. DM monocytes show blunted chemotactic responses to arteriogenic stimuli, a condition termed as vascular endothelial growth factor (VEGF) resistance. We hypothesize that methylglyoxal (MG), a glucose metabolite, induces monocyte dysfunction and aimed to elucidate the underlying molecular mechanisms. Human monocytes exposed to MG or monocytes from DM patients or mice (db/db) showed VEGF-resistance secondary to a pro-migratory phenotype. Mechanistically, DM conditions or MG exposure resulted in the upregulation of the expression of SHP-2 phosphatase. This led to the enhanced activity of SHP-2 and aided an interaction with SRC kinase. SHP-2 dephosphorylated the inhibitory phosphorylation site of SRC leading to its abnormal activation and phosphorylation of cytoskeletal protein, paxillin. We demonstrated that MG-induced molecular changes could be reversed by pharmacological inhibitors of SHP-2 and SRC and by genetic depletion of SHP-2. Finally, a SHP-2 inhibitor completely reversed the dysfunction of monocytes isolated from DM patients and db/db mice. In conclusion, we identified SHP-2 as a hitherto unknown target for improving monocyte function in diabetes. This opens novel perspectives for treating diabetic complications associated with impaired monocyte function.

Extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities: A retrospective study of 352 patients.

Background The aim of this study was to assess the prevalence and clinical significance of extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities. Materials and methods Three hundred fifty-two patients underwent abdominal, pelvic and lower extremity 1.5 T magnetic resonance angiography. Clinically relevant vascular and extra-vascular findings were identified. Relevant vascular findings were classified as stenosis, occlusion, aneurysm, sclerosis, dissection or vasculitis. Relevant extra-vascular findings were categorized as 'safe' (Group A), intermediate - requiring additional investigation - (Group B) and malignant/endangering - requiring change of therapy (Group C). Results A total of 2152 clinically relevant vascular findings was identified (6.1/patient). The most frequent vascular finding was femoral artery stenosis (10.6%). Four hundred fifty-one extra-vascular findings were observed (1.3/patient) and classified into Group A (78%), Group B (19.5%) and Group C findings (2.4%). The most frequent malignant findings were lung cancer, lymphoma, osteosarcoma, hepatocellular carcinoma and renal cell carcinoma (7/352 patients). Conclusions Extravascular findings are frequently encountered in magnetic resonance angiography performed for vascular indications. Clinically relevant findings are seen in a substantial part of patients and should prompt further diagnostic work-up.

Sex difference in appropriate shocks but not mortality during long-term follow-up in patients with implantable cardioverter-defibrillators.

AIMS: Implantable cardioverter-defibrillators (ICDs) have been shown to improve survival, although a considerable number of patients never receive therapy. Implantable cardioverter-defibrillators are routinely implanted regardless of sex. There is continuing controversy whether major outcomes differ between men and women. METHODS AND RESULTS: In this retrospective single-centre study, 1151 consecutive patients (19% women) undergoing ICD implantation between 1998 and 2010 were followed for mortality and first appropriate ICD shock over 4.9 ± 2.7 years. Sex-related differences were investigated using multivariable Cox models adjusting for potential confounders. During follow-up, 318 patients died, a rate of 5.9% per year among men and 4.6% among women (uncorrected P = 0.08); 266 patients received a first appropriate ICD shock (6.3% per year among men vs. 3.6% among women, P = 0.002). After multivariate correction, independent predictors of all-cause mortality were age (hazard ratio, HR = 1.04 per year of age, 95% confidence interval (CI) [1.03-1.06], P < 0.001), left ventricular ejection fraction (HR = 0.98 per %, 95% CI [0.97-1.00], P = 0.025), renal function (HR = 0.99 per mL/min/1.73 m(2), 95% CI [0.99-1.00], P = 0.009), use of diuretics (HR = 1.81, 95% CI [1.29-2.54], P = 0.0023), peripheral arterial disease (HR = 2.21, 95% CI [1.62-3.00], P < 0.001), and chronic obstructive pulmonary disease (HR = 1.48, 95% CI [1.13-1.94], P = 0.029), but not sex. Female sex (HR = 0.51, 95% CI [0.33-0.81], P = 0.013), older age (HR = 0.98, 95% CI [0.97-0.99], P < 0.001), and primary prophylactic ICD indication (HR = 0.69, 95% CI [0.52-0.93], P = 0.043) were independent predictors for less appropriate shocks. CONCLUSION: Women receive 50% less appropriate shocks than men having similar mortality in this large single-centre population. These data may pertain to individually improved selection of defibrillator candidates using risk factors, e.g. sex as demonstrated in this study.

DEGRO/DGK guideline for radiotherapy in patients with cardiac implantable electronic devices.

An increasing number of patients undergoing radiotherapy (RT) have cardiac implantable electronic devices [CIEDs, cardiac pacemakers (PMs) and implanted cardioverters/defibrillators (ICDs)]. Ionizing radiation can cause latent and permanent damage to CIEDs, which may result in loss of function in patients with asystole or ventricular fibrillation. Reviewing the current literature, the interdisciplinary German guideline (DEGRO/DGK) was developed reflecting patient risk according to type of CIED, cardiac condition, and estimated radiation dose to the CIED. Planning for RT should consider the CIED specifications as well as patient-related characteristics (pacing-dependent, previous ventricular tachycardia/fibrillation). Antitachyarrhythmia therapy should be suspended in patients with ICDs, who should be under electrocardiographic monitoring with an external defibrillator on stand-by. The beam energy should be limited to 6 (to 10) MV CIEDs should never be located in the beam, and the cumulative scatter radiation dose should be limited to 2 Gy. Personnel must be able to respond adequately in the case of a cardiac emergency and initiate basic life support, while an emergency team capable of advanced life support should be available within 5 min. CIEDs need to be interrogated 1, 3, and 6 months after the last RT due to the risk of latent damage.

Normal values and clinical relevance of left atrial myocardial function analysed by speckle-tracking echocardiography: multicentre study.

AIMS: The aim of this multicentre study was to determine the normal range and the clinical relevance of the myocardial function of the left atrium (LA) analysed by 2D speckle-tracking echocardiography (2DSTE). METHODS AND RESULTS: We analysed 329 healthy adult subjects prospectively included in 10 centres and a validation group of 377 patients with left ventricular diastolic dysfunction (LVDD). LA myocardial function was analysed by LA strain rate peak during LA contraction (LA-SRa) and LA strain peak during LA relaxation (LA-Strain). The range of values of LA myocardial function in healthy subjects was LA-SRa -2.11 ± 0.61 s(-1) and LA-Strain 45.5 ± 11.4%, and the lowest expected values of these LA analyses (calculated as -1.96 SD from the mean of healthy subjects) were LA-SRa -0.91 s(-1) and LA-Strain 23.1%. Concerning the clinical relevance of these LA myocardial analyses, LA-SRa and LA-Strain detected subtle LA dysfunction in patients with LVDD, even though LA volumetric measurements were normal. In addition, in these patients we found that the functional class (dyspnoea-NYHA classification) was inversely related to both LA-Strain and LA-SRa. CONCLUSION: In the present multicentre study analysing a large cohort of healthy subjects and patients with LVDD, the normal range and the clinical relevance of the myocardial function of the LA using 2DSTE have been determined.

Potential cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension.

BACKGROUND: Nonadherence to drug therapy poses a significant problem in the treatment of patients with presumed resistant hypertension. It has been shown that therapeutic drug monitoring (TDM) is a useful tool for detecting nonadherence and identifying barriers to treatment adherence, leading to effective blood pressure (BP) control. However, the cost-effectiveness of TDM in the management of resistant hypertension has not been investigated. METHOD: A Markov model was used to evaluate life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in resistant hypertension patients receiving either TDM optimized therapy or standard best medical therapy. The model ran from the age of 30 to 100 years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Cost analyses were performed from a payer's perspective. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of €3854 and €3922, respectively. Given a willingness-to-pay threshold of €35,000 per QALY gained, the probability of TDM being cost-effective was 95% or more in all age groups from 30 to 90 years. Results were influenced mostly by the frequency of TDM testing, the rate of nonresponders to TDM, and the magnitude of effect of TDM on BP. CONCLUSION: Therapeutic drug monitoring presents a potential cost-effective healthcare intervention in patients diagnosed with resistant hypertension. Importantly, this finding is valid for a wide range of patients, independent of sex and age.

Vascular and extravascular findings on magnetic resonance angiography of the thoracic aorta and the origin of the great vessels.

PURPOSE: To investigate the presence of relevant vascular and incidental extravascular findings in patients undergoing magnetic resonance angiography (MRA) of the thoracic aorta and origin of the great vessels. MATERIALS AND METHODS: In all, 165 consecutive patients (mean age 61 ± 12 years) underwent 1.5 T MRA of the thorax. Two researchers identified vascular and incidental extravascular findings. Clinically relevant vascular findings were defined. Extravascular findings were categorized as minor (Group A, without change in patient treatment), intermediate (Group B, unclear clinical relevance, requiring additional investigations), and major (Group C, causing a change in patient treatment). RESULTS: A total of 306 relevant vascular findings were found in our cohort. A total of 397 extravascular findings were observed among the patients and were classified as Group A findings in 81.9% (325/397 findings, observed in 146 of 165 patients), as Group B findings in 15.4% (61/397 findings, observed in 52 of 165 patients), and as Group C in 2.8% of findings (11/397). The clinically relevant Group C findings were observed in 6.7% of patients (11/165), comprising eight previously unknown neoplasms (4.8% of 165), two patients with hemodynamically relevant pericardial effusion (1.2% of 165), and one patient with spondylodiscitis (0.6% of 165) detected by MRA. CONCLUSION: Relevant vascular and extravascular findings were found in patients referred for thoracic MRA. Most extravascular findings can be categorized by MRA as minor, while others required further diagnostics since they may be malignant or otherwise clinically relevant.

Detection of intracardiac masses in patients with coronary artery disease using cardiac magnetic resonance imaging: a comparison with transthoracic echocardiography.

We sought to evaluate the diagnostic accuracy of contrast-enhanced cardiac magnetic resonance (CMR) imaging for the detection of intracardiac masses and thrombus formation in patients with history of coronary artery disease (CAD) in comparison to transthoracic echocardiography (TTE) under clinical routine conditions. 171 patients with history of CAD (89 male, aged 34-89 years, median 63 ± 11) underwent TTE and CMR during routine clinical examinations. TTE and CMR were independently analysed regarding the presence of intracardiac thrombus formation, masses and related size, dimensions, shape and signal characteristics. TTE depicted intracavitary thrombus formation in 40/171 patients (23.4 %) and intracardiac mass in 12/171 patients (7.0 %). All masses revealed in TTE were correctly detected on CMR and confirmed by histology. However, CMR showed 15 additional thrombi and 3 additional intracardiac masses (p = 0.001) that were not seen in TTE. Patients with poor systolic function (LVEF <30 %) had misleading results when referred to TTE (19 vs. 27 thrombi detected, p < 0.01). The detection of intracardiac masses or thrombi was not significantly different in patient with LVEF >30 %, whereas CMR was superior when the LVEF was <30 %. Routine TTE in patients with CAD leads to lower detection rates of intracardiac masses and thrombus formation in patients with severely impaired EF. Consequently we are missing a significant amount of clinically relevant diagnosis when only assessing patients with TTE. In patients with CAD and severely impaired LVEF, CMR should be considered as first line imaging tool to detect or rule out intracardiac masses and thrombi.

Passive-fixation lead failure rates and long-term patient mortality in subjects implanted with Sprint Fidelis electrodes.

AIMS: To evaluate passive-fixation lead failure rates and long-term patient survival in subjects implanted with Sprint Fidelis electrodes. METHODS AND RESULTS: We identified 748 subjects who received a Sprint Fidelis (n = 429; Medtronic models 6948: 94.8%, 6949: 2.6%, 6930: 1.9%, 6931: 0.7%) or a Sprint 'non-Fidelis' implantable cardioverter defibrillator lead (n = 319, Medtronic models 6944: 68.6%, 6947: 17.9%, 6942: 7.8%, 6943: 3.4%, 6945: 2.2%) at our centre between 1998 and 2008. Kaplan-Meier patient survival was lower in the Fidelis group than in the Control cohort (68.4 vs. 77.0% at 5 years, P = 0.0061), but multivariate analyses revealed no significant association between mortality and implanted lead type. Passive-fixation lead failure rate at 5 years was 14.4% (95% confidence interval (CI) [9.2, 19.3]) in the Fidelis (n = 414) group and 1.8% (95% CI [0.0-3.8]) in the Control (n = 241) cohort (P < 0.001 upon multivariate comparison). CONCLUSION: Failure rates of passive-fixation Sprint Fidelis leads are increased and similar to those previously reported for active-fixation Fidelis electrodes. Despite the elevated risk for lead failure and its potential sequelae, the Sprint Fidelis has no obvious impact on long-term mortality.

Electromagnetic interference of avalanche transceivers with cardiac pacemakers and implantable cardioverter defibrillators.

BACKGROUND: Avalanche transceivers are essentials tools in locating persons who were buried by an avalanche. In the past few years, avalanche transceivers have become widely available and affordable, but it is largely unknown whether they are a source of electromagnetic interference for implanted cardiac devices. We aimed to determine the potential interaction between avalanche transceivers and pacemakers or implantable cardioverter defibrillators (ICDs). METHODS: One hundred and one patients, 41 with pacemakers and 60 with ICDs, were enrolled (mean age 66 ± 15 years). Four avalanche transceivers (Pieps DSP [Pieps GmbH, Lebring, Austria], Ortovox x1, Ortovox m2, and Ortovox f1 [Otovox Sportartikel GmbH, Taufkirchen, Germany]) were evaluated in transmit as well as in receive mode. Surface electrocardiograms, intracardiac electrograms, and marker channels were continuously recorded and observed by an experienced physician. Electromagnetic interference events were categorized as direct interference with the function of the implanted device itself or as interference with the telemetric communication without compromising device function. RESULTS: Among all patients, there was no interference with the intrinsic function of their pacemakers or ICDs. A total of 120 episodes of telemetry interference occurred in 48% of the patients. Of those episodes, 112 of 404 (28%) were observed in transmit and eight of 404 (2%) in receive mode (P < 0.0001). The digital avalanche transceiver (Pieps DSP) was associated with significantly less telemetry interference (20/202; 10%) than the analog transceiver (Ortovox f1) (39/202; 19%) (P = 0.0108). CONCLUSIONS: Avalanche transceivers are safe for patients with pacemakers and ICDs. Despite the observed telemetry interferences, the intrinsic function of the implanted devices was never compromised.

Cost-effectiveness of paclitaxel-coated balloon angioplasty in patients with drug-eluting stent restenosis.

BACKGROUND: The economic impact of drug-eluting stent (DES) in-stent restenosis (ISR) is substantial, highlighting the need for cost-effective treatment strategies. HYPOTHESIS: Compared to plain old balloon angioplasty (POBA) or repeat DES implantation, drug-coated balloon (DCB) angioplasty is a cost-effective therapy for DES-ISR. METHODS: A Markov state-transition model was used to compare DCB angioplasty with POBA and repeat DES implantation. Model input parameters were obtained from the literature, and the cost analysis was conducted from a German healthcare payer's perspective. Extensive sensitivity analyses were performed. RESULTS: Initial procedure costs amounted to €3488 for DCB angioplasty and to €2782 for POBA. Over a 6-month time horizon, the DCB strategy was less costly (€4028 vs €4169) and more effective in terms of life-years (LYs) gained (0.497 versus 0.489) than POBA. The DES strategy incurred initial costs of €3167 and resulted in 0.494 LYs gained, at total costs of €4101 after a 6-month follow-up. Thus, DCB angioplasty was the least costly and most effective strategy. Base-case results were influenced mostly by initial procedure costs, target lesion revascularization rates, and the costs of dual antiplatelet therapy. CONCLUSIONS: DCB angioplasty is a cost-effective treatment option for coronary DES-ISR. The higher initial costs of the DCB strategy compared to POBA or repeat DES implantation are offset by later cost savings.

Cost-effectiveness of cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary artery disease in Germany.

BACKGROUND: Recent studies have demonstrated a superior diagnostic accuracy of cardiovascular magnetic resonance (CMR) for the detection of coronary artery disease (CAD). We aimed to determine the comparative cost-effectiveness of CMR versus single-photon emission computed tomography (SPECT). METHODS: Based on Bayes' theorem, a mathematical model was developed to compare the cost-effectiveness and utility of CMR with SPECT in patients with suspected CAD. Invasive coronary angiography served as the standard of reference. Effectiveness was defined as the accurate detection of CAD, and utility as the number of quality-adjusted life-years (QALYs) gained. Model input parameters were derived from the literature, and the cost analysis was conducted from a German health care payer's perspective. Extensive sensitivity analyses were performed. RESULTS: Reimbursement fees represented only a minor fraction of the total costs incurred by a diagnostic strategy. Increases in the prevalence of CAD were generally associated with improved cost-effectiveness and decreased costs per utility unit (ΔQALY). By comparison, CMR was consistently more cost-effective than SPECT, and showed lower costs per QALY gained. Given a CAD prevalence of 0.50, CMR was associated with total costs of €6,120 for one patient correctly diagnosed as having CAD and with €2,246 per ΔQALY gained versus €7,065 and €2,931 for SPECT, respectively. Above a threshold value of CAD prevalence of 0.60, proceeding directly to invasive angiography was the most cost-effective approach. CONCLUSIONS: In patients with low to intermediate CAD probabilities, CMR is more cost-effective than SPECT. Moreover, lower costs per utility unit indicate a superior clinical utility of CMR.

Pulmonary vein anatomy predicts freedom from atrial fibrillation using remote magnetic navigation for circumferential pulmonary vein ablation.

AIMS: Multidetector computed tomography (MDCT) is frequently used to guide circumferential pulmonary vein ablation (PVA) for treatment of atrial fibrillation (AF) as it offers accurate visualization of the left atrial (LA) and pulmonary vein (PV) anatomy. This study aimed to identify if PV anatomy is associated with outcomes following PVA using remote magnetic navigation (RMN). METHODS AND RESULTS: We analysed data from 138 consecutive patients and 146 ablation procedures referred for PVA due to drug-refractory symptomatic AF (age 63 ± 11 years; 57% men; 69% paroxysmal AF). The RMN using the stereotaxis system and open-irrigated 3.5 mm ablation catheters was used in all procedures. Prior to PVA, all patients underwent electrocardiogram-gated 64-MDCT for assessment of LA dimensions, PV anatomy, and electro-anatomical image integration during the procedure. Regular PV anatomy was found in 68%, a common left PV ostium was detected in 26%, and variant anatomy of the right PVs was detected in 6%. After a mean follow-up of 337 ± 102 days, 63% of the patients maintained sinus rhythm after the initial ablation, and 83% when including repeat PVA. Although acutely successful PV isolation did not differ between anatomical subgroups (regular 3.5 ± 0.8 vs. variant 3.2 ± 1.3; P = 0.31), AF recurrence was significantly higher in patients with non-regular PV anatomy (P = 0.04, hazard ratio 1.72). Pulmonary vein anatomy did not influence complication rates. CONCLUSION: Pulmonary vein anatomy assessed by MDCT is a good predictor of AF recurrence after PVA using RMN.

Left atrial volumetry from routine diagnostic work up prior to pulmonary vein ablation is a good predictor of freedom from atrial fibrillation.

AIMS: This study aimed to identify whether left atrial (LA) volume assessed by multidetector computed tomography (MDCT) is related to the long-term success of pulmonary vein ablation (PVA). MDCT is used to guide PVA for the treatment of atrial fibrillation (AF). MDCT permits accurate sizing of LA dimensions. METHODS AND RESULTS: We analysed data from 368 ablation procedures of 279 consecutive patients referred for PVA due to drug-refractory symptomatic AF (age 62 ± 10; 58% men; 71% paroxysmal AF). Prior to the procedure, all patients underwent ECG-gated 64-MDCT scan for assessment of LA and PV anatomy, LA thrombus evaluation, LA volume estimation, and electroanatomical mapping integration. Within a mean follow-up of 356 ± 128 days, 64% of the patients maintained sinus rhythm after the initial ablation, and 84% when including repeat PVA. LA diameter (P = 0.004), LA volume (P = 0.002), and type of AF (P = 0.001) were independent predictors of AF recurrence in univariate analysis. There was a relatively low correlation between the echocardiographic LA diameter and LA volume from MDCT (P = 0.01, r = 0.5). In multivariate analysis, paroxysmal AF (P < 0.006) and LA volume below the median value of 106 mL (P = 0.042) were significantly associated with the success of PVA, whereas LA diameter was not (P = 0.245). Analysing receiver-operator characteristics, the area under the curve for LA volume was 0.73 (P = 0.001) compared with 0.60 (P = 0.09) for LA diameter from echocardiography. CONCLUSION: LA volume assessed by MDCT is a better predictor of AF recurrence after PVA than echocardiograpic LA diameter and can be derived from the pre-procedural imaging data set.

Long-term prognostic value of restitution slope in patients with ischemic and dilated cardiomyopathies.

BACKGROUND: An action potential duration (APD) restitution curve with a steep slope ≥1 has been associated with increased susceptibility for malignant ventricular arrhythmias. We aimed to evaluate the "restitution hypothesis" and tested ventricular APD restitution slope as well as effective refractory period (ERP)/APD ratio for long-term prognostic value in patients with ischemic (ICM) or dilated cardiomyopathy (DCM). METHODOLOGY/PRINCIPAL FINDINGS: Monophasic action potentials were recorded in patients with ICM (n = 32) and DCM (n = 42) undergoing routine programmed ventricular stimulation (PVS). Left ventricular ejection fraction was 32±7% and 28±9%, respectively. APD and ERP were measured at baseline stimulation (S(1)) and upon introduction of one to three extrastimuli (S(2)-S(4)). ERP/APD ratios and the APD restitution curve were calculated and the maximum restitution slope was determined. After a mean follow-up of 6.1±3.0 years, the combined end-point of mortality and and/or implantable cardioverter-defibrillator shock was not predicted by restitution slope or ERP/APD ratios. Comparing S(2) vs. S(3) vs. S(4) extrastimuli for restitution slope (1.5±0.6 vs. 1.4±0.4 vs. 1.3±0.5; p = NS), additional extrastimuli did not lead to a steepening restitution slope. ERP/APD ratio decreased with additional extrastimuli (0.98±0.09 [S(1)] vs. 0.97±0.10 [S(2)] vs. 0.93±0.11 [S(3)]; p = 0.03 S(1) vs. S(3)). Positive PVS was strongly predictive of outcome (p = 0.006). CONCLUSIONS/SIGNIFICANCE: Neither ventricular APD restitution slope nor ERP/APD ratios predict outcome in patients with ICM or DCM.