Direct costs and cost-effectiveness of dual-source computed tomography and invasive coronary angiography in patients with an intermediate pretest likelihood for coronary artery disease

The study aims to determine the direct costs and comparative cost-effectiveness of latest-generation dual-source computed tomography (DSCT) and invasive coronary angiography for diagnosing coronary artery disease (CAD) in patients suspected of having this disease

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

Clinical utility and cost-effectiveness of innovative technologies in cardiovascular medicine

Begrenzte Ressourcen und steigende Gesundheitsausgaben haben zu einer zunehmenden Bedeutung von Nutzen- und Wirtschaftlichkeitsaspekten geführt. Ziel der vorliegenden kumulativen Habilitationsschrift war es, den klinischen Nutzen oder die Kosteneffektivität ausgewählter innovativer Verfahren in der kardiovaskulären Medizin zu evaluieren. Hinsichtlich des klinischen Nutzens konnte gezeigt werden, dass bei Patienten mit Vorhofflimmern eine kontrastmittelverstärkte 64-Zeilen-Computertomographie (CT)-Untersuchung im Vergleich zum Goldstandard der transösophagealen Echokardiographie eine unterlegene diagnostische Genauigkeit zur Detektion von Vorhofthromben aufweist. Weiterhin hatte die Bestimmung des Mikrovolt-T-Wellen-Alternans (TWA) bei Herzschrittmacher-Patienten mit struktureller Herzerkrankung und erhaltener linksventrikulärer (LV)-Pumpfunktion einen prognostischen Wert für das Gesamtüberleben. Allerdings erwiesen sich nur die während atrialer, aber nicht die während ventrikulärer Stimulation gemessenen TWA-Testergebnisse als prädiktiv. Ferner besaß die invasiv bestimmte maximale Steigung der elektrischen Restitutionskurve bei Patienten mit ischämischer oder dilatativer Kardiomyopathie und hochgradig eingeschränkter LV-Pumpfunktion keine langfristige prognostische Aussagekraft hinsichtlich des Auftretens eines kombinierten Endpunktes aus Mortalität und/oder adäquater Schockabgabe eines implantierten Kardioverter-Defibrillators. In den durchgeführten gesundheitsökonomischen Analysen war die nicht-invasive Koronarangiographie mittels Dual-Source-CT bis zu einer 55%-igen Prätestwahrscheinlichkeit kosteneffektiver als die invasive Koronarangiographie zur Detektion einer signifikanten koronaren Herzkrankheit. Weiterhin erwies sich die Angioplastie mit einem Paclitaxel-beschichteten Ballon im Vergleich zur Implantation eines Paclitaxel-beschichteten Stents als kostensparende Therapieoption von In- Stent-Restenosen. Außerdem zeigte sich die kathetergestützte renale Sympathikusdenervation im Vergleich zu einer bestmöglichen medikamentösen Therapie als potenziell kosteneffektive Behandlungsoption für die resistente Hypertonie. Zusammenfassend lässt sich sagen, dass eine valide Innovationsbewertung in der kardiovaskulären Medizin differenzierte Nutzen- und Kosteneffektivitätsanalysen einbeziehen muss. Auf diese Weise kann ein wichtiger Beitrag zu einer effizienteren Ressourcenallokation im Gesundheitswesen geleistet werden.Limited resources and rising health care expenditures have led to a growing importance of utility and cost considerations. The objective of this habilitation treatise was to evaluate the clinical utility or cost- effectiveness of selected innovative technologies in the field of cardiovascular medicine. Regarding the results of the utility analyses, contrast-enhanced 64-slice computed tomography (CT) demonstrated an inferior diagnostic accuracy to detect atrial thrombi in patients with atrial fibrillation when compared to the gold standard of transesophageal echocardiography. Furthermore, the measurement of microvolt T-wave alternans (TWA) was of prognostic value in pacemaker patients with structural heart disease and preserved left ventricular (LV) function. However, only TWA test results obtained during atrial but not during ventricular pacing were predictive of outcome. Moreover, the invasively determined maximum slope of the electrical restitution curve could not predict long-term outcome in terms of mortality and/or appropriate shocks from an implantable cardioverter- defibrillator in patients with severely impaired LV function due to ischemic or dilated cardiomyopathy. The results of the health economic analyses showed that non-invasive dual-source CT coronary angiography was more cost-effective than invasive coronary angiography for diagnosing significant coronary artery disease in patients with a pre-test disease probability of up to 55%. Furthermore, angioplasty with a paclitaxel-coated balloon was found to be a cost-saving treatment option for coronary in-stent restenosis when compared to paclitaxel-eluting stent implantation. In comparison to optimal medical management, catheter-based renal sympathetic denervation appeared to be a potentially cost-effective treatment option for patients with resistant arterial hypertension. In conclusion, the assessment of innovative technologies in cardiovascular medicine has to take into consideration differentiated analyses of clinical utility and cost-effectiveness. In this way, an important contribution to a more efficient allocation of health care resources can be made

Effects of endothelin ETA receptor blocker LU 135252 on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure

To investigate whether the endothelin ETA receptor blocker provides similar benefit on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure (CHF). Male stroke-prone spontaneously hypertensive (SHR-SP) rats were subjected to permanent ligation of the left coronary artery and were treated for 6 weeks with the endothelin ETA receptor blocker LU 135252 (30 mg.kg(-1).d(-1)) starting 24 h after ligation or untreatment. Sham-operated rats served as normal controls. The mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular contractility (LV dp/dt(max)), left ventricular inner diameter (LVD) and circumference (LVC), septal thickness, left ventricular interstitial collagen content (ICC) and heart weight (HW) were measured at the end of the treatment. Compared with the untreated group, LU 135252 tended to increase HW (1.43 +/-0.03 vs 1.38 +/-0.04 g; P> 0.05), increased LVD (7.65+/-0.24 mm vs 6.58+/-0.14 mm; P 0.05), reduced LVEDP (14 4 mmHg vs 27+/-4 mmHg; P <0.05) and improved LV dp/dtmax (4230+/-450 mmHg/s vs 1950+/-400 mmHg/s; P <0.05); survival was not prolonged significantly (13% vs 11%; P=NS). In this hypertensive rat model of CHF, chronic endothelin ETA receptor blockade with LU 135252 improves cardiac hemodynamics, however, it does not affect long-term survival and worsens cardiac remodeling. Thus, endothelin ETA receptor antagonists are unlikely to have an important role in the management of patients with CH

Pharmacological Targeting of the RAGE-NF&kappa;B 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 TNF&alpha; signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNF&alpha; 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 NF&kappa;B 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-NF&kappa;B signalling in regulating SHP-2 expression, the elevated binding of NF&kappa;B to the SHP-2 promoter&mdash;induced by MG or AGE-BSA&mdash;was reversed by RAGE and NF&kappa;B 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-NF&kappa;B-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation

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

Abstract 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

APD₉₀ restitution slope characteristics.

<p>RVA  =  right ventricular apex, RVOT  =  right ventricular outflow tract.</p