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.

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.

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.

Potential lifetime cost-effectiveness of catheter-based renal sympathetic denervation in patients with resistant hypertension.

AIMS: Recent studies have demonstrated the safety and efficacy of catheter-based renal sympathetic denervation (RDN) for the treatment of resistant hypertension. We aimed to determine the cost-effectiveness of this approach separately for men and women of different ages. METHODS AND RESULTS: A Markov state-transition model accounting for costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness was developed to compare RDN with best medical therapy (BMT) in patients with resistant hypertension. The model ran from age 30 to 100 years or death, with a cycle length of 1 year. The efficacy of RDN was modelled as a reduction in the risk of hypertension-related disease events and death. Analyses were conducted from a payer's perspective. Costs and QALYs were discounted at 3% annually. Both deterministic and probabilistic sensitivity analyses were performed. When compared with BMT, RDN gained 0.98 QALYs in men and 0.88 QALYs in women 60 years of age at an additional cost of €2589 and €2044, respectively. As the incremental cost-effectiveness ratios increased with patient age, RDN consistently yielded more QALYs at lower costs in lower age groups. Considering a willingness-to-pay threshold of €35 000/QALY, there was a 95% probability that RDN would remain cost-effective up to an age of 78 and 76 years in men and women, respectively. Cost-effectiveness was influenced mostly by the magnitude of effect of RDN on systolic blood pressure, the rate of RDN non-responders, and the procedure costs of RDN. CONCLUSION: Renal sympathetic denervation is a cost-effective intervention for patients with resistant hypertension. Earlier treatment produces better cost-effectiveness ratios.

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.

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.

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.

T-wave alternans testing in pacemaker patients: comparison of pacing modes and long-term prognostic relevance.

BACKGROUND: T-wave alternans (TWA) is a useful method for identifying patients who are at risk for sudden cardiac death. We aimed to determine the effects of different pacing modes on test results and long-term prognostic relevance of TWA in patients following a dual-chamber (DDD) pacemaker implantation. METHODS: Sixty-three patients (mean age 68 ± 13 years) with structural heart disease and recently implanted DDD pacemakers were enrolled. Left ventricular (LV) function was normal or moderately impaired (mean LV ejection fraction 61 ± 13%). All patients underwent sequential TWA testing using atrial and ventricular pacing. RESULTS: During atrial pacing requiring physiologic conduction to the ventricles, 21% of TWA tests were positive, 43% negative, and 36% indeterminate. When using right ventricular (RV) pacing in the same patients, 19% of tests were positive, 40% negative, and 41% indeterminate. When positive and indeterminate tests were grouped as nonnegative, the concordance between atrial and ventricular pacing was 62% (κ= 0.22). After a mean follow-up of 5.9 ± 1.9 years, 18 (29%) patients had died. Improved survival was predicted by a negative TWA test using atrial pacing (P = 0.028), but not with ventricular pacing (P = 0.722). CONCLUSIONS: In patients with dual-chamber pacemakers, there is a low concordance of TWA test results between atrial pacing with intrinsic conduction to the ventricles and apical RV pacing via pacemaker electrode. However, TWA during atrial pacing clearly exerts long-term prognostic relevance in a patient group with preserved LV function and structural heart disease.

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.

Chronic inhibition of p38MAPK improves cardiac and endothelial function in experimental diabetes mellitus.

To investigate the influence of p38 mitogen activated kinase (p38MAPK) on the development of diabetic cardiac and endothelial dysfunction, we assessed left ventricular and vascular function as well as inflammatory markers in diabetic rats after chronic pharmacological inhibition of p38MAPK. Diabetes mellitus was induced in rats by a single injection of streptozotocin. Rats were treated with the p38MAPK inhibitor SB 239063 (40 mg/kg/day, p.o.) or vehicle. 48 days after diabetes mellitus-induction, left ventricular function and vascular function were assessed in vivo by TIP-catheter and the autoperfused hindlimb, respectively. Cell adhesion molecules staining was quantified immunohistochemically in the heart and quadriceps muscle, respectively, as well as cardiac phosphorylation of p38MAPK by Western blot analysis. Treated and untreated diabetic groups displayed similar severe hyperglycemia. Left ventricular and endothelial function were impaired in the untreated diabetic group compared to controls (dp/dtmax: -40%, dp/dtmin: +49%, maximal vasodilatation: -57%; P < 0.05) associated with significantly increased cardiac (3-fold) and peripheral cell adhesion molecules staining, respectively. Treatment of diabetic rats with SB 239063 led to a significant reduction of diabetes-induced enhancement of p38MAPK phosphorylation associated with improved left ventricular function (dp/dtmax: +39%, dp/dtmin: +47%; P < 0.05) and peripheral endothelial function (maximal vasodilatation: +71%; P < 0.05) under diabetic conditions. This was associated with reduced cardiac and peripheral inflammation indexed by reduced adhesion molecules content. Pharmacological inhibition of p38MAPK is sufficient to mitigate the development of diabetic cardiac and endothelial dysfunction despite of hyperglycemia. Our data suggest that the anti-inflammatory properties due to p38MAPK inhibition contribute to these beneficial cardiovascular effects.

Role of coronary angiography before radiofrequency ablation in patients presenting with paroxysmal supraventricular tachycardia.

During episodes of paroxysmal supraventricular tachycardia (PSVT), electrocardiograms frequently show ST-segment depressions, and patients may experience typical chest pain prompting invasive coronary angiography. We evaluated 114 patients presenting with PSVT for concomitant coronary artery disease (CAD). Patients were classified as to the type of PSVT, symptoms during PSVT, and cardiovascular risk factors. Maximum heart rate, extent of ST-segment depression, and cardiac troponin levels during PSVT were recorded. Patients were subjected to exercise testing and/or coronary angiography. During PSVT, symptoms suggestive of myocardial ischemia, including chest pain (31%), ST-segment depression (61%), and elevated troponin levels (12%), were common. Sixty-seven patients (59%) underwent coronary angiography. The overall prevalence of significant CAD was found to be low (4%) and did not correlate to symptoms during tachycardia. Routine coronary angiography cannot be recommended in patients with PSVT unless routine evaluation outside episodes of tachycardia suggests the presence of significant CAD.

Protection against oxidative stress in diabetic rats: role of angiotensin AT(1) receptor and beta 1-adrenoceptor antagonism.

Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT(1)) receptor antagonist candesartan and the selective beta(1)-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague-Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22(phox) and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22(phox) and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+46.3% vs. placebo treatment; P<0.05). Angiotensin AT(1) receptor antagonism, but not beta(1)-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin-angiotensin system in the development of diabetic complications.

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.