Andreas Krack

Paclitaxel-eluting stents for the treatment of chronic total coronary occlusions: A strategy of extensive lesion coverage with drug-eluting stents

The recanalization of a chronic total coronary occlusion (CTO) is hampered by a high rate of lesion recurrence. The goal of the present study is to assess the effect of paclitaxel‐eluting stents in CTOs in a strategy of extensive stent coverage and the optional use of additional bare metal stents (BMSs). In 82 consecutive patients, a CTO (duration > 2 weeks) was successfully recanalized with implantation of one or more Taxus stents. These patients underwent a repeat angiography after 5.0 ± 1.5 months and were assessed by quantitative angiography. The patients were compared with 82 clinically and lesion‐matched patients from a consecutive series of 148 patients with CTOs treated by BMS in the preceding time period. In 21 of the 82 patients, additional lesions in the target artery not directly related to the original occlusion site were treated with BMSs (hybrid approach). The history of diabetes, extent of coronary artery disease, clinical symptoms, and angiographic features were similar in the Taxus and BMS group. Periprocedural adverse events were 3.3% with Taxus and 3.3% with BMS, but 12 months MACE was significantly lower in the group with exclusive use of Taxus (13.3% vs. 56.7%; P < 0.001), mainly due to a lower target lesion revascularization of 10.0% as compared to 53.4% (P < 0.001). There was only one late reocclusion with Taxus (1.7%) as compared to 21.7% with BMS (P < 0.05). However, in the hybrid group, the MACE rate was considerably higher, with 33.3%. Our data of a 80% reduction of target vessel failure as compared to BMS, with a lower risk of late reocclusions without increased acute adverse events, demonstrate the benefit of paclitaxel‐eluting stents in CTOs. However, diffuse atherosclerosis in CTOs should be covered completely by the drug‐eluting stents.

Reduced glucose transporter GLUT4 in skeletal muscle predicts insulin resistance in non-diabetic chronic heart failure patients independently of body composition.

BACKGROUND In chronic heart failure (CHF) skeletal muscle insulin resistance occurs independently of etiology and contributes to impaired energy metabolism. GLUT4, the predominant glucose transporter in the skeletal muscle promotes the rate-limiting step of glucose utilization in skeletal muscle. The significance of skeletal muscle GLUT4 in patients with CHF has not been studied in detail. METHODS In patients with CHF and free of diabetes mellitus (n=29; mean NYHA class 2.3+/-0.1, peak VO(2) 18.8+/-1.1 mL/kg/min) and healthy control subjects of similar age (n=7), GLUT4 protein was assessed from percutaneous skeletal muscle biopsies. Skeletal muscle insulin sensitivity was assessed by intravenous glucose tolerance testing using a minimal modeling technique. Body composition was analyzed by dual energy X-ray absorptiometry (DEXA) scanning. RESULTS Skeletal muscle GLUT4 was lower in CHF patients than in controls (0.75+/-0.07 vs 1.24+/-0.19 density units, P<0.01) and decreased in parallel to severity of CHF, being lowest in NYHA III/IV (0.596+/-0.08, ANOVA P<0.01 vs controls). GLUT4 was lower in patients with an ischemic etiology compared to dilated cardiomyopathy and controls (ANOVA P<0.01). Patients and controls were similar for global parameters of body composition (weight: 78+/-4 vs 76+/-4 kg, BMI 25.5+/-0.8 vs 25.8+/-1.5 kg/m(2)), and total tissue amount and regional distribution of fat and lean tissue (all P>0.2). Low GLUT4 predicted impaired insulin sensitivity, i.e. insulin resistance (r=0.55, P<0.01). In multivariate analysis, GLUT4 levels predicted insulin sensitivity independently of age and parameters of body composition (including weight, BMI, and total and regional fat and lean tissue distribution). CONCLUSION In non-diabetic patients with CHF, skeletal muscle GLUT4 transport protein is reduced in parallel to disease severity, independently of body composition. Low skeletal muscle GLUT4 contributes to insulin resistance in CHF.

Improvement of the primary success rate of recanalization of chronic total coronary occlusions with the Safe-Cross system after failed conventional wire attempts

BackgroundIn view of the improved long-term patency with drug-eluting stents, the challenge with chronic total coronary occlusion (CTO) remains the low primary success rate. Improved guide wires have increased this rate, but alternative devices may be of additional value. The goal of the present study was to determine the additional benefit of a new penetration device in CTOs after an extensive conventional wire approach.Methods and ResultsIn 148 consecutive patients the recanalization of a CTO of >3 months was attempted. A conventional wire approach was used with recent dedicated recanalization wires, which was successful in 104 patients (70%). If after at least 20 min of fluoroscopic time no crossing of the wire was achieved, the Safe-Cross wire (SC) (Intralumina) was used which enables verification of the intraluminal wire position via optical reflectometry, and crossing of resistent occlusion caps by radiofrequency ablation. Due to severe dissections after the conventional approach, the SC was not used in 10 patients. In 34 patients the SC wire was applied, leading to successful lesion crossing in 14 patients (41%). Thus, the primary success rate was improved from 70.2% to 79.7%. No periprocedural major adverse events were observed with the SC wire. The successful attempts with the SC wire were predominantly in blunt occlusions. All patients with successful wire passage could be treated with one or more stents.ConclusionsIn a real world cohort of patients with CTO, the SC wire could increase the primary success rate after failed extensive conventional wire attempt. In these worst case patients the SC success rate was 41%. This new wire appears to have additional potential in failures of a conventional wire approach.

Sirolimus-eluting stents for the prevention of restenosis in a worst-case scenario of diffuse and recurrent in-stent restenosis

For recurrent in‐stent restenosis (ISR), surgical revascularization or brachytherapy is still the principal therapeutic options. The present investigation explores the efficacy of a sirolimus‐eluting stent to prevent restenosis in these lesions with a high risk of recurrence. In 22 consecutive patients with a recurrent and diffuse ISR, a sirolimus‐eluting stent was implanted to cover the restenotic lesion. All patients were followed clinically for at least 1 year and underwent a repeat angiography after 7 months. A quantitative coronary angiographic analysis was done. The target vessel failure was 14% in the sirolimus‐eluting stent group, with an angiographic late loss of only 0.39 ± 0.54. No subacute stent thrombosis was observed, and the 1‐year event‐free survival was 86%. The three cases with restenosis were all focal and could be successfully treated by additional drug‐eluting stent implantation. This study showed the efficacy of a sirolimus‐eluting stent for the prevention of restenosis in a worst‐case scenario of recurrent and diffuse ISR. The observed restenosis rate is lower than that reported after brachytherapy and suggests that sirolimus‐eluting stents are a promising treatment option for ISR. Catheter Cardiovasc Interv 2004;63:259–264.

Carvedilol inhibits platelet-derived growth factor-induced signal transduction in human cardiac fibroblasts.

In the current study, first the platelet-derived growth factor (PDGF)-induced stimulation of the PDGF-&bgr; receptor kinase in human cardiac fibroblasts was examined, and then the possibility of counterbalancing this signal transduction by carvedilol, a &bgr;-blocker with &agr;1-blocking properties, was investigated. Human cardiac fibroblasts were cultured from myocardial biopsy samples taken from patients with idiopathic dilated cardiomyopathy. The stimulation of the PDGF-&bgr; receptor kinase by recombinant human PDGF (BB) in the cells and the inhibitory effect of carvedilol (1, 5, 10, and 20 &mgr;M) were investigated by analyzing PDGF-induced PDGF receptor tyrosine phosphorylation using Western blotting and by measuring DNA synthesis with a colorimetric assay. In human cardiac fibroblasts, the PDGF receptor kinase could be stimulated with PDGF (100 ng/ml) and inhibited with carvedilol (5 &mgr;M). In addition, carvedilol at a concentration of 5 &mgr;M significantly decreased DNA synthesis by approximately 50%. The inhibition of PDGF-stimulated mitogenesis by carvedilol at concentrations of 10 and 20 &mgr;M was 64 or 75%, respectively. Other &bgr;-adrenoceptor antagonists such as propranolol (10 &mgr;M) and metoprolol (10 &mgr;M) did not significantly affect the PDGF-induced &bgr;-receptor autophosphorylation. These findings provide novel experimental support for the known beneficial clinical effects of carvedilol in the treatment of chronic heart failure associated with myocardial fibrosis.

Leptin: ein Parameter für metabolische Veränderungen der Herzinsuffizienz

Objective Advanced chronic heart failure is a hypercatabolic state with an imbalance between anabolic and catabolic metabolism and finally progressive loss of both muscle mass and adipose tissue. Leptin, the product of the obesity gene, is a hormone secreted by adipocytes. Therfore, we tested the hypothesis that plasma leptin concentrations are reduced in advanced chronic heart failure. Methods In 20 patients with chronic congestive heart failure (LVEF 23±6%) and 20 healthy controls (LVEF 65±8%) matched for gender, age, and body mass index, fasting plasma leptin (ELISA) and TNFα (ELISA) were measured. Follow-up examination was performed after 1 year. Results The fasting plasma leptin concentrations of patients with NYHA grade III (8.4±3.8 ng/ml*) and NYHA grade IV (4.6±2.4 ng/ml†) were significantly lower as compared with the controls (11.2±3.1 ng/ml; *p<0.05, †p<0.01). In patients with NYHA grade II plasma leptin levels were significantly elevated as compared with the healthy controls (14.9±4.2 ng/ml). TNFα was higher in heart failure patients than in healthy controls (8.6±3.6 pg/ml; 5.9±2.1 pg/ml; respectively; p<0.05), but did not correlate with the NYHA functional class. Mortality of the controls was 0%, whereas 15% (n=3) in the congestive heart failure group; one patient (5%) needs an urgent heart transplantation. All of those patients had leptin concentrations below 5 ng/ml. Conclusions Plasma leptin concentrations correlate with the NYHA functional class suggesting anabolic metabolism in NYHA class II and catabolic metabolism in advanced heart failure which might be of prognostic relevance. Hintergrund Die terminale Herzinsuffizienz ist ein hyperkataboler Status der durch ein Ungleichgewicht zwischen anabolem und katabolem Stoffwechsel gekennzeichnet ist und mit einem progredienten Verlust sowohl von Muskel- als auch Fettmasse einhergeht. Leptin, ist ein Hormon, das von dem obese-Gen kodiert und überwiegend von Adipozyten sezerniert wird. Wir stellten deshalb die Hypothese auf, dass die Plasmaleptinkonzentration bei der chronischen, fortgeschrittenen Herzinsuffizienz vermindert ist. Methoden 20 Patienten mit chronischer Herzinsuffizienz (LVEF 25±6%) wurden mit 20 Patienten ohne kardiovaskuläre Erkrankung (LVEF 65±8%) in einer „matched-pair” Analyse (Alter, Geschlecht und body mass index [BMI]) hinsichtlich ihrer Leptin- (ELISA) und TNFα- (ELISA) Plasmakonzentrationen untersucht. Eine Follow-up-Untersuchung erfolgte nach einem Jahr. Ergebnisse Die Leptinkonzentration von Patienten im NYHA-Stadium III (8,4±3,8 ng/ml*) und IV (4,6±2,4 ng/ml†) waren im Vergleich zu dem Kontrollkollektiv (11,2±3,1 pg/ml) signifikant erniedrigt (*p<0,05, †p<0,01). Patienten im NYHA-Stadium II (14,9±4,2 ng/ml) zeigten die höchsten Leptinspiegel. Die TNFα-Konzentrationen waren bei den herzinsuffizienten Patienten höher als bei dem herzgesunden Kontrollkollektiv (8,6±3,6 pg/ml vs. 5,9±2,1 pg/ml; p<0,05), korrelierten aber nicht mit dem NYHA-Stadium. Die Mortalität des Kontrollkollektives lag bei 0%, hingegen waren aus der Gruppe der herzinsuffizienten Patienten 15% (n=3) verstorben, ein Patient (5%) bedurfte einer dringlichen Herztransplantation. Alle vier Patienten zeigten Plasmaleptinspiegel unter 5 ng/ml. Schlussfolgerung Die Plasmaleptinkonzentration korreliert invers mit dem klinischen Stadium der Herzinsuffizienz und charakterisiert den anabolen Stoffwechsel im Frühstadium und den katabolen Stoffwechsel im Spätstadium der Herzinsuffizienz und besitzt möglicherweise prognostische Relevanz.