Manfred Grisold

Clinical results after coronary stenting with the Genous™ Bio-engineered R stent™: 12-month outcomes of the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) worldwide registry.

AIMS e-HEALING is a worldwide, internet-based registry designed to capture post marketing clinical data on the use of the Genous™ EPC capturing R stent™. Rapid restoration of a healthy endothelial layer after stent placement by capturing circulating endothelial progenitor cells may reduce both stent thrombosis (ST) and in-stent-restenosis. METHODS AND RESULTS We planned a 5,000 patient registry with ≥1 lesion suitable for stenting. The 12-month primary outcome was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction (MI) and target vessel revascularisation. Secondary outcomes were the composite of cardiac death, MI or target lesion revascularisation (TLR), and individual outcomes including ST. A total of 4,939 patients received ≥1 Genous stent between 2005 and 2007. Baseline characteristics showed a median age of 63 years, 79% males, 25% diabetics, and 37% with prior MI. A total of 49% of lesions treated were ACC/AHA type B2 or C; 1.1 stents per lesion were used. At 12 months, TVF occurred in 8.4% and the composite of cardiac death, MI or TLR in 7.9%. Twelve-month TLR and ST were 5.7% and 1.1%, respectively. CONCLUSIONS Coronary stenting with the Genous results in good clinical outcomes, and low incidences of repeat revascularisation and ST.

Final results of the HEALING IIB trial to evaluate a bio-engineered CD34 antibody coated stent (Genous™Stent) designed to promote vascular healing by capture of circulating endothelial progenitor cells in CAD patients

OBJECTIVE To assess the safety and efficacy of the Genous™ endothelial progenitor cell (EPC) capturing stent in conjunction with HmG-CoA-reductase inhibitors (statins) to stimulate EPC recruitment, in the treatment of patients with de novo coronary artery lesions. METHODS AND RESULTS The HEALING IIB study was a multi-center, prospective trial, including 100 patients. The primary efficacy endpoint was late luminal loss by QCA at 6-month follow-up (FU). Although statin therapy increased relative EPC levels by 5.6-fold, the angiographic outcome at 6 month FU was not improved in patients with an overall in-stent late luminal loss of 0.76±0.50 mm. The composite major adverse cardiac events (MACE) rate was 9.4%, whereas 6.3% clinically justified target lesion revascularizations (TLRs) were observed. 2 Patients died within the first 30 days after stent implantation due to angiographically verified in-stent thrombosis. At 12 month FU, MACE and TLR increased to 15.6% and 11.5% respectively and stabilized until 24 month FU. 18 Month angiographic FU showed a significant decrease in late luminal loss (0.67±0.54, 11.8% reduction or 10% by matched serial analysis, P=0.001). CONCLUSION The HEALING IIB study suggests that statin therapy in combination with the EPC capture stent does not contribute to a reduction of in-stent restenosis formation for the treatment of de novo coronary artery disease. Although concomitant statin therapy was able to stimulate EPC recruitment, it did not improve the angiographic outcome of the bio-engineered EPC capture stent. Remarkably, angiographic late loss was significantly reduced between 6 and 18 months.

Roxithromycin in the treatment of Lyme disease--update and perspectives.

SummarySpirochaetal infections have been successfully treated with penicillin; more recently, erythromycin has been used in cases with known penicillin allergy. The discovery of the spirochaeteBorrelia burgdorferi and the elaboration of a new generation of macrolides with properties that differ from older macrolides have led to new ways of treating spirochaetal disease with these compounds. This paper presents data on thein vitro andin vivo efficacy of a combination of roxithromycin and co-trimoxazole againstB. burgdorferi. In vitro (checkerboard technique;B. burgdorferi strain B31; modified BSK II medium) it was found that while roxithromycin showed excellent efficacy againstB. burgdoferi (MIC 0.031 mg/l), co-trimoxazole had no effect. However, the combination of both chemotherapeutics led to a minor synergistic effect, decreasing the MIC for roxithromycin by one dilution step at concentrations of co-trimoxazole from 256 to 8 mg/l. In addition, a clearly reduced growth of microorganisms was seen at concentrations of roxithromycin as low as 0.015 mg/l in combination with 256 to 4 mg/l co-trimoxazole, when compared to the positive controls. Most interestingly, however, the motility ofB. burgdorferi was markedly reduced even when the two drugs were combined at very low concentrations. In anin vivo, non-randomised, open, prospective pilot study it was found that of 17 patients, with confirmed late Lyme borreliosis (stage II/III), treated with combined roxithromycin (300 mg b.i.d.) and co-trimoxazole for 5 weeks, 13 (76%) recovered completely by the end of treatment, and four continued to have symptoms on follow-up at 6 and 12 months. This success rate is similar to that seen with i.v. penicillin and ceftriaxone. It appears that the reduced motility ofB. burgdorferi makes the pathogen mor accessibile to the immune system.ZusammenfassungEs wird über diein vitro- undin vivo- Wirksamkeit einer Kombination von Roxithromycin und Co-trimoxazol gegenBorrelia burgdorferi berichtet.In vitro zeigte sich, daß Roxithromycin über eine ausgezeichnete Wirksamkeit gegenüberB. burgdorferi verfügt, Co-trimoxazol war jedoch unwirksam. Die Kombination beider Chemotherapeutika führt zu einem geringen synergistischen Effekt u.z., um eine Verdünnungsstufe bei einer Co-trimoxazol-Konzentration von 256/8mg/1. Bei einer 0.015 mg/l Roxithromycin-Konzentration in Kombination mit 256/4 mg/l zeigte sich in Vergleich zu positiven Kontrollen ein eindeutig reduziertes Wachstum der Mikroorganismen. Die Motilität war sogar eindeutig reduziert, wenn beide Substanzen nur sehr niedrige Konzentrationen aufwiesen. Bei einer offenen prospektiven Pilot-Studie, bei 17 Patienten mit einer gesicherten Borreliose in Stadium II/III, die mit einer Kombination von Roxithromycin (300 mg b.i.d.) 5 Wochen behandelt wurden, waren danach 13 ausgeheilt, vier hatten weiterhin Symptome nach 6 bis 12 Monaten. Das Ergebnis entspricht der einer i.v. Penizillin-oder Ceftriaxon-Behandlung.

EDRF does not mediate coronary vasodilation secondary to simulated ischemia : A study on KATP channels and Nω-nitro-L-arginine on coronary perfusion pressure in isolated Langendorff-perfused guinea-pig hearts

Several authors have alluded to the possible involvement of EDRF (NO) in ischemia-induced coronary artery dilation. Alternatively, it has been suggested that opening of ATP-dependent K channels could play a key role in this context. We studied the effects of sulfonylureas and NG-nitro-L-arginine (LNNA), a specific inhibitor of endothelial NO (EDRF) synthesis, on ischemia-induced coronary vasodilation in isolated Langendorff-perfused guinea pig hearts arrested with 15 mM KCl in normal Tyrode, and isolated pig coronary arteries precontracted with 43 mM KCl. In Isolated Langerdorff-perfused guinea pig heart, when hypoxia was simulated by switching 100% O2 in the perfusate to 100% N2, coronary perfusion pressure (CPP) fell from 90 cm H2O by 45 ± 5 cm H2O. In the presence of LNNA, a specific inhibitor of NO synthetase in endothelial cells, CPP dropped by 44 ± 6 cm H2O (n = 6; ± SEM, no statistically significant). On biochemical simulation of ischemia (addition of iodoacetate [IAA]), CPP dropped 40 ± 6 cm H2O, and in experiments performed under the same conditions but in the presence of LNNA, CPP dropped by 38 ± 5 cm H2O (n = 6; ± SEM; not statistically significant). When ischemia was simulated metabolically by equimolar replacement of 10 mM glucose with 2-deoxyglucose (DOG), an inhibitor of glycolysis CPP decreased by 24 ± 1 cm H2O (n = 6; ± SEM) after 15 minutes. This fall in CPP was almost prevented by 20 μM glibenclamide, whereas in the presence of 20 μM LNNA the DOG-induced decrease in CPP was not significantly inhibited, and CPP decreased by 22 ± 2.6 cm H2O (n = 6; ± SEM). In isolated pig coronary artery rings, maximal tension, achieved by depolarizing the smooth muscle cells by 43 mM KCl, decreased by 37 ± 7% upon simulated hypoxia by replacing 100% O2 with 100% N2 in the perfusate (n = 6; ± SEM) in arteries with intact endothelium. In arteries without endothelium, maximal tension also dropped by 35 ± 6% (not statistically significant). In the same experiments the decrease in tension could be largerly inhibited in the presence of 50 μM glibenclamide. Our results clearly show that in isolated perfused guinea pig hearts, as well as in isolated pig coronary arteries, EDRF does not play a decisive role in the coronary dilatory response to hypoxia and ischemia.

Current views on mechanisms of vasodilation in response to ischemia and hypoxia

Myocardial function (and thus life) is entirely dependent on sufficient O2 supply. Therefore, this supply is extremely well regulated via a refined system of interacting mechanisms. These have been subject to extensive research for more than 100 years. Surprisingly, remarkable dispute still arises among scientists concerning the factors and mechanisms involved in this regulatory system.During ischemia, myocardial cells have been shown to release vasoactive metabolites (eg, H+ and K+ ions, lactic acid, adenosine, and others), which cause spontaneous coronary dilation. On the other hand claims have been made that the endothelium itself could play a key role in hypoxic/ischemic vasodilation by releasing endothelium-derived relaxant factor (EDRF) (NO = nitric oxide) and other still partially unspecified vasoactive substances (eg, prostaglandins). Furthermore, it has been discussed that intravascular O2 tension (pO2) itself would exert a direct effect upon endothelial and/or vascular smooth muscle cells and thus produce per se a local reflectory vasodilation. In contrast, the intravascular CO2 tension has also been shown to act upon coronary vascular resistance during myocardial ischemia. Recently, hints have been made about the membrane potential of arterial smooth muscle cells as a key factor in hypoxia/ischemia vasodilation. However, during hypoxia and metabolic inhibition, the membrane potential seems to be modulated primarily by the action of adenosinetriphosphate-dependent (ATP) potassium channels (KATP+ channels).In conclusion, a number of factors contribute to ischemia/hypoxia-induced vasodilation. The present review contrasts recent findings on ATP-dependent K+ channels with other experimental evidence concerning other mechanisms involved in hypoxic/ischemic vasodilation.

Frequency of magnetic resonance signal abnormalities of the brain in patients aged <50 years with idiopathic dilated cardiomyopathy

Twenty patients with idiopathic dilated cardiomyopathy (IDC) aged <50 years (mean 41) and an age-matched group of 20 healthy volunteers were studied. All subjects were free of cerebrovascular symptoms and risk factors for stroke. Magnetic resonance imaging of the brain, extracranial Doppler ultrasonography, heart catheterization and echocardiography were performed. In patients with IDC, a higher frequency of ventricular enlargement (p < 0.02), cortical atrophy (p < 0.01) and white matter lesions (p <0.05) was observed. Cerebral infarcts were found in 4 patients (p < 0.05) who showed clinically severe limitation of functional capacity (New York Heart Association class III or IV). The extent of cortical atrophy, and the duration of clinical evidence of IDC showed a significant correlation (p < 0.04). The data indicate a high incidence of parenchymal abnormalities of the brain in young, neurologically asymptomatic patients with IDC.

Blockade of ATP-dependent K+ channels in myocardium and coronary artery smooth muscle: a possible cause of increased cardiovascular mortality in sulfonylurea-treated patients.

Dear Sir, It has been known for over 20 years that patients treated with sulfonylurea compounds are subject to increased cardiovascular mortality [1]. However, the mechanisms underlying this phenomenon have not been elucidated far. We have studied the effects of glibenclamide and tolbutamide on ischemia-induced coronary vasodilation in isolated Langendorff-perfused guinea pig hearts perfused and arrested with K-rich Norma Tyrode solution (in mM: NaCl 129.5, KCl 15, MgCl2 0.8, CaCl2 1.0, glucose 10.0) buffered with 10 mM HEPES to pH 7.4, at 378 C, equilibrated with 100% O2. Coronary perfusion pressure (CPP) fell from 90 cm H2O by 18.6 6 0.9 cm H2O (n 5 7, 6 SEM) when ischemia was simulated metabolically by equimolar replacement of 10 mM glucose with 2-deoxyglucose, an antimetabolite that has been widely used to simulate ischemia metabolically [2–4]. Figure 1A shows that this fall in CPP was prevented by 0.5 mM tolbutamide or 2 lM glibenclamide (therapeutic range). The fall in CPP was then reduced to 1.4 6 1.3 cm H2O and 2.1 6 2.4 cm H2O, respectively (in the glibenclamide group a slight increase in CPP even occurred during ischemia in two experiments). We have seen similar results in isolated guinea-pig aortas (Fig. 1B) and pig coronary artery rings and without endothelium. Both types of vessels showed instantaneous dilation upon both simulated ischemia (dog) and hypoxia (100% O2 replaced by 100% N2 in the superfusate). This vasodilation could be completely prevented by 2 lM glibenclamide and 1 mM tolbutamide. These results suggest that sulfonylureas may prevent a vital coronary response to ischemia — local vasodilation and mobilization of coronary reserve. Secondly, as we have shown earlier [4], sulfonylureas prevent ischemia-induced myocardial K ef_ux and action potential shortening. The latter leads to a reduction in the contractile force of the ischemic myocardium (shortening of the plateau phase of the action potential leads to decreased Ca in_ux through voltage-gated Ca channels, and hence to reduced contractility and decreased myocardial O2 consumption), another vital mechanism in the heart’s attempt to thwart ischemia. Furthermore, extracellular K accumulation is one of the known stimuli of pain during angina pectoris (depolarization of pain receptors) [5]. However, other mechanisms responsible for the development of anginal pain have also been discussed and the extent of the impact of K accumulation is still a matter of discussion [6–8]. The physiological mechanisms involved in the defeat of myocardial ischemia are shown in Figure 2. We hypothesize that prevention of the coronary dilatory response to ischemia, inhibition of ischemic K ef_ux (a possible cause of silent ischemia and overexertion?), and reduction of action-potential shortening (no local reduction in O2 consumption of the ischemic myocardium) by K ATP channel blockade may constitute potential causes for the increased cardiovascular mortality in sulfonylurea patients [9].

A Most Unusual Case of a Whole Family Suffering from Late Lyme Borreliosis for Over 20 Years

trian family (Bb is endemic in the area of Graz, Austria) who have suffered from Lyme disease for a period of more than twenty years. The wife is forty-three years of age and acquired Bb in 1968 with a most typical history of tick bite, erythema chronicum migrans, flu-like symptoms (stage I), and subsequent classical symptoms of Bb-associated disorders (arthritis, cranial neuritis, meningitis, and later, chronic arthritis, chronic radiculitis, depression-stages II and III). Her husband, fifty years of age, had no memory of a primary infection with classical stage I symptoms but remembers recurrent episodes of flu-like symptoms a year after the infection of his wife. These episodes were soon followed by stage II and III symptoms. Later he was treated several times for ventricular arrhythmias (Lown VIb), whereupon electrophysiological stimulation of the His bundle was performed. A son was born in 1969, who, at his birth, suffered from several minor abnormalities like a

Observations on the Effect of Glibenclamide on Noninvasive Clinical Parameters of Myocardial Ischemia

Dear Sir, Recently, the use of sulphonylurea compounds in the treatment of type II diabetes has been questioned in patients with coronary heart disease because of unfavorable actions of these compounds on the cardiovascular system [1–3]. Over 20 years ago, the UGDP study [4] showed that patients treated with such drugs are subject to increased cardiovascular mortality. Growing understanding of the function of KATP channels in the cardiovascular system has further corroborated the above-mentioned observations [5]. In order to investigate particular features of clinical ischemia under the effect of sulphonylurea drugs, we designed the following study. The objective of the study was to compare the in_uence of sulphonylurea and insulin therapy on myocardial ischemia in non–insulin-dependent diabetes mellitus patients (NIDDM) with coronary heart disease (CHD). The aim of the study was to demonstrate an improvement in subjective symptoms and clinical parameters of cardiac perfusion under insulin treatment in order to verify the experimental observation that sulphonylureas prevent reactive vasodilation in the ischemic myocardium. The study design was open, controlled, and randomized. Fourteen patients were included who suffered from NIDDM and angiographically con~rmed coronary heart disease. They were treated with sulphonylureas (glibenclamide, minimum dose of 2 3 5 mg) for more than 6 months, and Hba1c was less than 9%. Patients were subjected to bicycle ergometry, and subjective symptoms, blood pressure, heart rate, and ECG were monitored. In a ~rst run we noticed that a minor percentage of patients were eligible for this study. Major reasons for non eligibility were as follows: