Günther Breithardt

Impact of late incomplete stent apposition after sirolimus-eluting stent implantation on 4-year clinical events: intravascular ultrasound analysis from the multicentre, randomised, RAVEL, E-SIRIUS and SIRIUS trials

Background: The impact of incomplete stent apposition (ISA) after drug-eluting stent implantation determined by intravascular ultrasound (IVUS) on late clinical events is not well defined. Objective: To evaluate the clinical impact of ISA after sirolimus-eluting stent (SES) placement during a follow-up period of 4 years. Design: Pooled analysis from the RAVEL, E-SIRIUS and SIRIUS trials, three randomised, multicentre studies comparing SES and bare-metal stents (BMS). Methods: IVUS at angiographic follow-up was available in 325 patients (SES: nu200a=u200a180, BMS: nu200a=u200a145). IVUS images were reviewed for the presence of ISA defined as one or more unapposed stent struts. Clinical follow-up was available for a 4-year period in all patients. Frequency, predictors and clinical sequel of ISA at follow-up after SES and BMS implantation were determined. Results: ISA at follow-up was more common after SES (nu200a=u200a45 (25%)) than after BMS (nu200a=u200a12 (8.3%), p<0.001). Canadian Cardiology Society class III or IV angina at stent implantation (odds ratio (OR)u200a=u200a4.69, 95% CI 2.15 to 10.23, p<0.001) and absence of diabetes (ORu200a=u200a3.42, 95% CI 1.05 to 11.1, pu200a=u200a0.041) were predictors of ISA at follow-up after SES placement. Rate of myocardial infarction tended to be slightly higher for ISA than for non-ISA patients. When SES patients only were considered, major adverse cardiac event free survival at 4 years was identical for those with and without ISA at follow-up (11.1% vs 16.3%, pu200a=u200a0.48). Conclusions: ISA at follow-up is more common after SES implantation than after BMS implantation. Considering the current very sensitive IVUS definition, ISA appears to be an IVUS finding without significant impact on the incidence of major adverse cardiac events even during long-term follow-up.

Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response

Intrauterine and neonatal manifestations of congenital long QT syndrome are associated with a high cardiac risk, particularly when atrioventricular block and excessive QT prolongation (> 600 ms1/2) are present. In a female newborn with these features, treatment with propranolol and mexiletine led to complete reduction of arrhythmia that was maintained 1.5 years later. High throughput genetic analysis found a sodium channel gene (LQT3) mutation. Disappearance of the 2:1 atrioventricular block and QTc shortening (from 740 ms1/2 to 480 ms1/2), however, was achieved when mexiletine was added to propranolol. This effect was considered to be possibly genotype related. Early onset forms of long QT syndrome may benefit from advanced genotyping.

Vascular response to sirolimus-eluting stents delivered with a nonaggressive implantation technique: Comparison of intravascular ultrasound results from the multicenter, randomized E-SIRIUS, and SIRIUS trials†

The effectiveness of SES to reduce the risk of restenosis was initially demonstrated in short lesions using stent implantation with routine pre‐dilatation and post‐dilatation. This intravascular ultrasound (IVUS) substudy of the E‐SIRIUS trial sought to evaluate local arterial responses to sirolimus‐eluting stents (SES) delivered with a stent implantation technique allowing direct stenting and only selectively applying high‐pressure post‐dilatation.

Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and future perspectives.

Die arrhythmogene rechtsventrikuläre Kardiomyopathie (ARVC) wird als eine primär myokardiale Erkrankung mitverantwortlich gemacht für das Entstehen ventrikulärer Tachyarrhythmien und den plötzlichen Herztod bei jungen, anscheinend herzgesunden Menschen. Obwohl verschiedene strukturelle, bildgebende und elektrokardiographische Charakteristika in einem Katalog von Diagnosekriterien zusammengefasst worden sind, erscheint die Beurteilung über das Vorliegen der Erkrankung bei Patienten oft schwierig. Die Rolle der Molekulargenetik für die Pathogenese der ARVC wird in der folgenden Übersicht dargestellt. Ausgehend von Kopplungsanalysen in betroffenen Familien erhärten sich die Hinweise für eine genetische Determinierung dieser Erkrankung, wobei in der Mehrzahl der bislang bekannten chromosomalen Loci ein autosomal-dominantes Vererbungsmuster mit variabler Penetranz und polymorphen Phänotyp beschrieben wird. Daneben wurden auch zwei autosomal-rezessive Formen identifiziert, die sich nicht nur hinsichtlich des Vererbungsmodus von den vorgenannten unterscheiden, sondern auch durch einen charakteristischen Phänotyp: Patienten mit der Naxos-Krankheit imponieren klinisch durch typische Haut- und Haarveränderungen in Kombination mit einem ausgeprägten Krankheitsverlauf. Dagegen liegen bei einer anderen autosomal-rezessiven Variante ophtalmologische Besonderheiten mit einem eher milderen Verlauf der ARVC vor. Bislang konnten zwei Mutationen in unterschiedlichen Genen identifiziert werden. Für die Genese der Naxos-Krankheit wird eine Mutation in dem für das zytoskelettäre Protein Plakoglobin kodierende Gen verantwortlich gemacht. Eine weitere Mutation, die den kardialen Ryanodin-Rezeptor betrifft, wurde bei Patienten mit ARVC-2 gefunden. u2002u2009u2009Eine molekulargenetische Diagnostik bei Patienten (oder deren Angehörigen) mit einer vermuteten ARVC steht für den Einsatz in der klinischen Routine aktuell noch nicht zur Verfügung. Sollte dieses Ziel erreicht werden, böten sich neue Aspekte für die Pathogenese und somit auch für eine optimierte individualisierte Therapie und Risikostratifizierung bei Patienten mit ARVC. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder of unknown origin. In recent years, the disease has been recognized as a major cause of ventricular tachyarrhythmias and sudden cardiac death in young patients with apparently normal hearts. Although characteristic structural, imaging and electrocardiographic features are included in a proposed catalogue of diagnostic criteria, the correct diagnosis of ARVC often remains difficult. Much effort has been undertaken to enlarge the knowledge on pathophysiological mechanisms of the disease. The role of molecular genetics for the pathogenesis of ARVC is discussed in the following review. On the basis of linkage analyses in large families affected by ARVC, there is growing evidence for genetic alterations in ARVC, which, in the majority of chromosomal loci (seven) reported so far, follow a Mendelian autosomal-dominant pattern of inheritance with variable penetrance and polymorphic phenotype. Besides this, two autosomal-recessive forms of ARVC are known. These can be differentiated from the autosomal-dominant forms not only in terms of the mode of inheritance but also as to their specific phenotype: patients with Naxos disease exhibit characteristic hair and skin abnormalities and experience a more severe course of disease. Patients with another autosomal-recessive form display the typical but milder signs of ARVC together with opacifications of the crystalline lens. So far, two mutations in cardiac genes responsible for the development of ARVC have been reported. A homozygous two base pair deletion in the gene encoding for the cytoskeletal protein plakoglobin seems to account for the evolution of Naxos disease. The second mutation affecting the cardiac ryanodine receptor gene was found in patients with ARVC-2. u2002u2009u2009Routine genetic testing of patients or relatives with a suspected diagnosis of ARVC is not available at present but may become the future gold standard with potential implications for a better understanding of the pathogenesis and management of the disease.

Upregulation of connexin43 gap junctions between neointimal smooth muscle cells

Increased expression of connexin43 gap junctions in smooth muscle cells (SMC) is implicated in the response to primary arterial injury and in the early stages of human coronary atherosclerosis, but the relevance of these findings to restenosis is unknown. Here we investigated the expression of connexin43 gap junctions in restenotic aortas of cholesterol-fed double injured rabbits. Immunofluorescence confocal microscopy was used to evaluate temporal and spatial expression patterns and to characterize the major expressing cell type. Parallel studies were conducted by electron microscopy, in situ hybridization and Northern blot analysis. Connexin43 gap junctions- and connexin43 mRNA-expressing cells were abundant in the media of non-injured control aorta. Following primary injury and 6 weeks cholesterol diet, connexin43 gap junctions were found distributed throughout the primary intimal layer; although medial expression was reduced, the overall mRNA expression level remained similar to that of non-injured controls. After secondary injury, no major change in distribution pattern of connexin43 gap junctions occurred up to day 10, when marked neointimal labeling was observed. This overall pattern persisted, though with some diminution, at later stages. On the mRNA level total connexin43 mRNA expression declined to about 40% of control values within 4 days after secondary injury (P < 0.05), but subsequently increased four-fold, attaining levels double that of non-injured controls in the 10-day group (P < 0.005 versus control and 4 days). At later stages mRNA expression levels returned to values similar to those of non-injured controls. At all stages, connexin43 gap junctions were localized to the SMC, not to macrophages. We conclude that the enhanced gap junction formation may contribute to the coordination of the response of SMC after secondary injury, particularly in the early phase of restenosis.

QT interval prolongation and risk for cardiac events in genotyped LQTS-index children

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder with a disturbance in repolarization characterized by a prolonged QT interval on the surface electrocardiogram and life-threatening ventricular tachycardia. Publications from the International LQTS Registry have provided information that the cardiac risk may be influenced by gender, genotype, exposure to arrhythmia triggers, and previous cardiac events. In children, early-onset of disease, changes in life style, and medical treatment is a sensitive issue and significant, gender-related differences of a first life-threatening event were reported. Thus, we investigated the clinical features of a large genotyped population of LQTS-index children (age ≤16xa0years) upon a single-center experience and determined risk factors for symptoms. Of 83 children [mean corrected QT interval (QTc) 510u2009±u200974xa0ms], 89% had LQT1, -2, or -3. Nine patients (11%) were identified as having Jervell and Lange-Nielsen syndrome. Among symptomatic children (nu2009=u200951, 61%), syncope was the most prevalent symptom at initial presentation (49%); however, aborted cardiac arrest (ACA) occurred in 33% and sudden cardiac death (SCD) in 18%, respectively, as the initial manifestation. During a mean follow-up period of 5.9u2009±u20094.7xa0years, 31% of the children developed symptoms while on therapy (86% syncope, 9% ACA, 5% SCD). Statistical analyses of risk factors for cardiac events showed that the QTc >500xa0ms was a strong and significant predictor for cardiac events during follow-up (pu2009=u20090.02). Furthermore, a prior syncope [hazard ratio (HR), 4.05; 95% confidence interval (CI), 1.1 to 15.0; pu2009=u20090.03] or an ACA (HR, 11.7; 95% CI, 3.1 to 43.4; pu2009=u2009<0.001) identified children with an increased risk for recurrent cardiac events compared to asymptomatic LQT children. LQTS-index children manifest with a high percentage of severe symptoms. Among presently validated risk factors for LQTS, a QTc interval >500xa0ms and a history of prior syncope or ACA were strong predictors for recurrent cardiac events.

Stroke volume and mitral annular velocities. Insights from tissue Doppler imaging.

Ziel der vorliegenden Studie war es, den Einfluss des Schlagvolumens (SV) auf die mittels Gewebedoppler (Tissue Doppler Imaging=TDI) abgeleiteten Mitralringgeschwindigkeiten zu untersuchen. Zu diesem Zweck wurden konventionelle echokardiographische Parameter und Mitralringgeschwindigkeiten (S′, E′, A′) bei 14 Patienten mit erhöhtem SV (bei primärer Mitralinsuffizienz (ESV-Gruppe)), bei 41 Patienten mit reduziertem SV (bei ischämischer (n=27) oder dilatativer Kardiomyopathie (n=9) oder hypertensiver Herzerkrankung (n=5) (RSV-Gruppe) und bei 29 asymptomatischen Kontrollprobanden erfasst. Systolische (S′) und frühdiastolische (E′) Mitralringgeschwindigkeiten waren in der ESV-Gruppe im Vergleich zur Kontrollgruppe erhöht, in der RSV-Gruppe erniedrigt. In der linearen Regressionsanalyse bestanden signifikante Beziehungen zwischen SV und systolischer Mitralannulusgeschwindigkeit S′ (r=0,74, p<0,001), SV und frühdiastolischer Mitralannulusgeschwindigkeit E′ (r=0,74, p<0,001) sowie SV und spätdiastolischer Mitralannulusgeschwindigkeit A′ (r=0,41, p<0,01). In der multivariaten Regressionsanalyse war SV ein stärkerer unabhängiger Prädiktor von S′ und E′ als konventionelle systolische oder diastolische echokardiographische Indices. Somit besitzt das Schlagvolumen einen bedeutsamen Einfluss auf systolische (S′) und frühdiastolische (E′) Mitralringgeschwindigkeiten. Dies sollte berücksichtigt werden, wenn Mitralringgeschwindigkeiten zur Beurteilung von systolischer/diastolischer Ventrikelfunktion oder zur Abschätzung von Füllungsdrücken eingesetzt werden. The aim of this study was to assess the impact of stroke volume (SV) on mitral annular velocities derived from tissue Doppler imaging (TDI). To this end, conventional echocardiographic variables and TDI derived mitral annular velocities (S′, E′, A′) were obtained in 14 patients (pts) with increased SV (due to primary mitral (n=12) (ISV group)), in 41 pts with reduced SV (due to ischemic (n=27) or dilated cardiomyopathy (n=9) or hypertensive heart disease (n=5) (RSV group)) and 29 asymptomatic controls with normal SV (CON group). Systolic (S′) and early diastolic (E′) mitral annular velocities were elevated in the ISV group in the comparison to the CON group, but were significantly reduced in the RSV group. Late diastolic annular velocities (A′) did not differ between the ISV and the CON group, but were lowest in the RSV group. On simple linear regression analysis, SV was significantly related to S′ (r=0.74, p<0.001), to E′ (r=0.74, p<0.001) and to A′ (r=0.43, p<0.01). On multiple regression analysis, SV was a stronger independent predictor of S′ and E′ than conventional systolic or diastolic echocardiographic variables. Thus, stroke volume has a significant impact on TDI derived systolic (S′) and early diastolic (E′) mitral annular velocities. This should be considered, when TDI is used in the evaluation of LV performance or in the estimation of filling pressures.

Undersulfation of Proteoheparan Sulfate Stimulates the Expression of Basic Fibroblast Growth Factor and Protein Synthesis but Suppresses Replication of Coronary Smooth Muscle Cells

Heparan sulfate proteoglycans are obligatory for receptor binding and mitogenic activity of the basic fibroblast growth factor (bFGF). In the present study the influence of undersulfated heparan sulfate on the expression of basic fibroblast growth factor and coronary smooth muscle cell (cSMC) proliferation was investigated. Chlorate, known to be an inhibitor of ATP-sulfurylase, was used as a tool to suppress sulfation of heparan sulfate. When cultured cSMC were treated with 10 mM sodium chlorate in sulfate-depleted medium, the cell number and [3H]thymidine incorporation decreased by 76% and 66% respectively, while the protein content per cell was doubled. At the same time the [35S]sulfate incorporation into cell-associated proteoglycans was reduced by 90%. The remaining minimal amount of available [35S]radioactivity was preferably incorporated into heparan sulfate. Under the same conditions the [6-(3)H]glucosamine incorporation into glycosaminoglycans was not impaired. The chlorate-induced increase of cell protein content includes an overexpression of bFGF, which increased from 6-8 ng to 18-22 ng/mg cell protein. However, no changes in the distribution of bFGF between the intracellular and pericellular compartment could be observed. Cell cycle analysis by FACS revealed a G1 arrest of the cell cycle with increase of the G1/S ratio from 2.9 (control) to 6.1 (chlorate) but the DNA content per cell corresponded to normal diploid cells both in control and chlorate-treated cells. The chlorate effect can be abolished by addition of 5 mM sodium sulfate to the cultures. Our results demonstrate an inverse association between the sulfation of heparan sulfate and the expression of bFGF. They suggest that chlorate blocks the cell cycle in the late G1-phage and that mitogenesis of cSMC requires fully sulfated cell-associated proteoheparan sulfate.

Lovastatin controls signal transduction in vascular smooth muscle cells by modulating phosphorylation levels of mevalonate-independent pathways

Abstract Lovastatin has been proven to effectively lower circulating LDL cholesterol and to exert antiproliferative effects on various cell lines, the latter effect being only incompletely understood. We found that lovastatin modulates the signal transducing phosphorylation cascade in vascular smooth muscle cells in a mevalonate-independent manner. Lovastatin was found to distinctively increase total phosphotyrosine levels in smooth muscle cells, an effect which could not be restored by mevalonate. At a concentration of 5 μmol/L lovastatin had a highly specific effect on the mitogen-activated protein kinase pathway. The expression of p42/44 mitogen-activated protein kinase (MAPK) was clearly reduced, but could be restored by addition of mevalonate, while the phosphorylation of p44 was mildly suppressed and the phosphorylation of p42 MAPK was reduced to non-detectable levels. While the phosphorylation of p44 MAPK could partially be restored by addition of mevalonate, the reduced phosphorylation of p42 MAPK could not be restored by addition of excessive doses of mevalonate or stimulation of the cells with basic fibroblast growth factor. Concurrently the expression of the GTP-binding Ras protein was significantly elevated at 5 and 20 μmol/L lovastatin, this effect being attenuated by addition of mevalonate to cell cultures.The data indicate that lovastatin is capable of modulating cellular signaling independently of the cholesterol synthesis pathway.

Pulmonary β adrenoceptor density in arrhythmogenic right ventricular cardiomyopathy and idiopathic tachycardia

Objective. In recent in vivo studies using positron emission tomography (PET) our group demonstrated that the myocardial β adrenoceptor (βMAR) density is reduced in arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow tract tachycardia (RVO-VT) associated with an increased presynaptic catecholamine washout. It was hypothesised that the reduction of myocardial βAR density is secondary to an increase of local catecholamines in the myocardium resulting from the presynaptic dysfunction since circulating plasma catecholamines were demonstrated to be unchanged in these conditions. To further prove this hypothesis of an organ-limited adrenergic nervous dysfunction of the heart, this study aimed to investigate βAR density in another thoracic organ, the lung. Methods. Pulmonary and myocardial βAR density was measured in 7 ARVC patients, 8 RVO-VT patients and in a group of healthy controls (n = 13) using the non-selective β-blocker [11C]-CGP 12177 and PET. Results. Pulmonary βAR density was similar in controls (12.4 ± 1.7 pmol/g tissue), ARVC (11.6 ± 1.7 pmol/g tissue, p = ns) and RVO-VT (12.8 ± 2.0 pmol/g tissue, p = ns), whereas myocardial βAR density was significantly reduced in ARVC (6.3 ± 1.1 pmol/g tissue, p = 0.006) and RVO-VT (6.8 ± 1.2 pmol/g tissue, p = 0.02) as compared to controls (8.8 ± 1.5 pmol/g tissue). Conclusion. The unchanged pulmonary βAR density in the presence of a previously described significant reduction in myocardial βAR density in the same patient principally supports our pathophysiological hypothesis that the myocardial βAR density may be reduced in ARVC and RVO-VT because of an increase in local synaptic catecholamine levels due to an organ-limited presynaptic adrenergic dysfunction of the heart. Since in the present study only pulmonary βAR density was measured, future functional studies excluding pulmonary βAR desensitisation are required to finally prove the unchanged pulmonary sympathetic innervation in ARVC and RVO-VT.