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Biomedical subjects

G Breithardt

Publications and source records attributed to G Breithardt.

At least 145 records · Page 8Linked to original sources
PubMed1999

Expression of type VIII collagen after cholesterol diet and injury in the rabbit model of atherosclerosis.

This study presents an analysis of the expression of type VIII collagen mRNA in response to cholesterol diet and balloon injury in the rabbit iliac artery. The design of the animal experiments was as follows: 28 male New Zealand White rabbits were divided into the 3 different treatment groups. Group 1 received regular chow; group 2 was fed with a 1% cholesterol diet for 6 weeks and normal chow for 5 weeks; and group 3 underwent balloon injury, then 6 weeks of a 1% cholesterol diet, which was followed by 5 weeks of normal chow. The expression pattern of type VIII collagen mRNA was compared with that of the fibrillar collagen types I and III, transforming growth factor-beta1, a factor known to exert the most potent stimulatory effect on collagen synthesis in vitro, and matrix metalloproteinase 1, a collagen-degrading enzyme. The cholesterol diet resulted in an upregulation of type VIII collagen, fibrillar collagens, transforming growth factor-beta1, and matrix metalloproteinase I in the adventitia. Although the number of type VIII collagen mRNA-expressing cells in the media increased, no significant difference in overall expression levels was detectable by northern blot analysis. The ratio of medial smooth muscle cells expressing type VIII collagen mRNA to those expressing type I and type III collagen mRNA (CVIII:CI:CIII) changed from 1:1.88:0.03 in the normal media to 1:0.78:0.29. When cholesterol feeding was preceded by balloon injury, type VIII collagen mRNA expression concomitant with the fibrillar collagens was further upregulated over and above that level reported after cholesterol diet alone. In general, low levels of transforming growth factor-beta1 mRNA correlated with high expression of matrix metalloproteinase I. Our study indicates that a cholesterol diet resulted in a balanced reorganization of the collagen composition but did not result in marked collagen accumulation. This may provide an extracellular environment that favors migration and proliferation processes during early atherogenesis. It also demonstrates that type VIII collagen is highly expressed and deposited at later stages, and this may be linked to processes such as tissue reorganization during vascular repair and plaque stabilization.

Animals↗
PubMed1999

Protein kinase C mediates basic fibroblast growth factor-induced proliferation through mitogen-activated protein kinase in coronary smooth muscle cells.

Proliferation of coronary smooth muscle cells (cSMCs) contributes to the pathogenesis of arteriosclerosis and restenosis after angioplasty, and basic fibroblast growth factor (bFGF) is a powerful mitogen for cSMCs. In this study, we investigated the involvement of mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and the transcription factor c-myc in bFGF-stimulated mitogenesis, as well as the functional relationship between these factors. cSMC stimulation with bFGF resulted in phosphorylation of p42 MAPK, as well as the phosphorylation and increased expression of c-myc. The MAPK kinase (MEK) inhibitor PD98059 blocked bFGF-stimulated MAPK phosphorylation and resulted in both a decrease of c-myc expression and inhibition of bFGF-stimulated DNA synthesis in cSMCs. bFGF also increased PKC activity in cSMCs in a time-dependent manner. The inhibition of PKC by chelerythrine or its downregulation by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis and blocked the phosphorylation of MAPK and c-myc expression in response to bFGF. This indicates an involvement of phorbol ester-sensitive PKC isoforms in MAPK activation and mitogenic signaling by bFGF. Western blot analysis revealed the presence of the phorbol ester-sensitive isoforms PKC alpha, epsilon, and gamma as well as the PKC isoforms iota, lambda, micro, and zeta in cSMCs. In this study, we show that the MAPK cascade is required for bFGF-induced proliferation and that phorbol ester-sensitive PKC isoforms contribute to the bFGF-induced cSMC mitogenesis in cSMCs.

Animals↗
PubMed1999

Cardiac 123I-MIBG uptake in idiopathic ventricular tachycardia and fibrillation.

UNLABELLED: Patients with idiopathic ventricular tachycardia or fibrillation have no additional structural or functional myocardial abnormalities. However, the inducibility of typical tachyarrhythmias by physical or mental stress or by catecholamine infusion suggests the involvement of the adrenergic system in the pathogenesis of these potentially life-threatening diseases. METHODS: 45 patients with idiopathic right ventricular outflow tract tachycardia (RVO-VT), 25 patients with idiopathic left ventricular tachycardia (ILVT), 15 patients with idiopathic ventricular fibrillation (IVF) and 10 age-matched control patients were investigated in this study. Diagnoses were made on the basis of detailed evaluation of the results of two-dimensional echocardiography, left and right ventricular angiography, coronary angiography and endomyocardial biopsy. Local presynaptic norepinephrine re-uptake was assessed using the norepinephrine analog 1231-metaiodobenzylguanidine (MIBG), SPECT and semiquantitative 33-segment bull's-eye analysis. RESULTS: Locally reduced 123I-MIBG uptake was found in 27 of 45 RVO-VT patients (60%), 5 of 15 ILVT patients (33%) and 17 of 25 IVF patients (68%). Unlike ILVT patients, RVO-VT and IVF patients had significantly reduced segmental 123I-MIBG uptake of the posterior wall compared with control patients. CONCLUSION: Patients with idiopathic tachycardia and fibrillation show abnormal 1231-MIBG uptake, which indicates presynaptic sympathetic dysfunction. RVO-VT and IVF patients exhibit significantly reduced 123I-MIBG uptake in the posterior left ventricular wall, whereas ILVT patients do not.

3-Iodobenzylguanidine↗
PubMed1998

Potential benefit from implantable cardioverter-defibrillator therapy in patients with and without heart failure.

BACKGROUND: Whether patients with heart failure derive a benefit from therapy with implantable cardioverter-defibrillators (ICDs) has been questioned. The purpose of this study was to investigate whether New York Heart Association (NYHA) functional class had an impact on the potential benefit from ICD therapy as assessed from data stored in the memory of ICDs. METHODS AND RESULTS: Between 1989 and 1996, 603 patients (77% men; 59% with coronary artery disease and 16% with dilated cardiomyopathy; age, 57+/-13 years; ejection fraction, 44+/-18%) were treated with an ICD with extended memory function (storage of electrograms and/or RR intervals from treated episodes) in combination with endocardial lead systems. The stages of heart failure (NYHA functional class I through III) at implantation were correlated with overall mortality and the recurrence of fast ventricular tachyarrhythmias (>240 bpm) during follow-up. The potential benefit of the device was estimated as the difference between overall mortality and the hypothetical death rate had the device not been implanted. The latter was based on the recurrence of fast and, without termination by the devices, presumably fatal ventricular tachyarrhythmias. In the overall group, a significant difference between hypothetical death rate and overall mortality was observed (13.9%, 23.5%, and 26.6% at 1, 3, and 5 years, respectively) that suggested a benefit from ICD implantation. In patients in NYHA class I, the estimated benefit, which increased over time, was 15.2%, 29.2%, and 35.6% after 1, 3, and 5 years, respectively. In patients in NYHA class II or III, the estimated benefit increased until the third year (21.8% and 21.9%, respectively) and then remained constant until the fifth year (22.9% and 23.8%, respectively). Even those patients in NYHA class III with a history of decompensated heart failure benefited from ICD implantation. CONCLUSIONS: Analysis of stored ECG data suggests that in patients with a history of ventricular tachycardia or ventricular fibrillation, ICD therapy may lead to a prolongation of life in NYHA classes I through III. The initial benefit is greatest in patients in NYHA class II and class III, but the estimated benefit might persist longest for patients in NYHA class I.

Adolescent↗
PubMed1998

External beam irradiation inhibits neointimal hyperplasia after injury-induced arterial smooth muscle cell proliferation.

PURPOSE: Restenosis after catheter-based revascularization has been demonstrated to be primarily caused by smooth muscle cell proliferation. This study examines the effects of external beam irradiation on neointimal proliferation after external injury to the central artery of the rabbit ear. METHODS AND MATERIALS: Thirty male New Zealand White rabbits were used in this study. Crush lesions were performed on each ear under general anesthesia and bilateral auricular nerve blockade. A single dose of 1200 cGy (n = 10), 1600 cGy (n = 10), or 2000 cGy (n = 10) gamma radiation was delivered to the left or right central artery of the ear 24 hours after injury; the contralateral central artery served as control. All rabbits were sacrificed after 21 days and the central arteries of both ears were fixed for morphometric measurements. RESULTS: Mean (+/-SD) neointimal area was 0.062 +/- 0.005 mm2 (1200 cGy), 0.022 +/- 0.005 mm2 (1600 cGy), and 0.028 +/- 0.006 mm2 in irradiated arteries compared with 0.081 +/- 0.009 mm2 in the control group. Mean (+/-SD) luminal area was 0.049 +/- 0.004 mm2 (1200 cGy), 0.059 +/- 0.002 mm2 (1600 cGy), and 0.072 +/- 0.006 mm2 (2000 cGy) in irradiated arteries compared with 0.043 +/- 0.008 mm2 in the control group. The differences in neointimal and luminal area between control and irradiated arteries were significant (p < 0.05) for the 1600 and 2000 cGy group only. CONCLUSION: We conclude that in this model, external beam X-ray irradiation was successful in reducing neointimal proliferation after injury of the central artery of the rabbit ear. Marked reductions in neointimal proliferation were demonstrated in vessels subject to 1600 and 2000 cGy radiation; a less prominent effect was noted for 1200 cGy. Whether this approach can be used successfully to inhibit restenosis in the clinical setting requires further investigation.

Animals↗
PubMed1998

T-cell and monocyte subsets, inflammatory molecules, rejection, and hemodynamics early after cardiac transplantation.

BACKGROUND: In the early period after cardiac transplantation, differential diagnosis of graft failure due to rejection, infection, and other causes is important but difficult. METHODS: In 22 consecutive patients undergoing heart transplantation, we prospectively determined levels of interleukin-6 as well as T-cell and monocyte subsets at eight points in time during biopsy and right heart catheterization and within 12 hr of echocardiography during the first 3 months after transplantation. RESULTS: Worse hemodynamic parameters, as characterized by dichotomization according to median values (pulmonary capillary wedge pressure >10 mmHg, mean pulmonary arterial pressure > 18 mmHg, pulmonary vascular resistance > 115 dyn x sec x cm(-5), right atrial pressure > 5 mmHg, cardiac index <3 L/min/m2, early mitral deceleration time < 135 msec, and isovolumic relaxation time <80 msec), were associated with higher levels of interleukin-6, C-reactive protein, polymorphonuclear cells, CD71+/CD14+ monocytes, and IgM levels and, in contrast, with lower levels of immunocompetence markers such as CD3+ T cells, CD4+ T cells, CD8+ T cells, CD3+/CD25+ T cells, CD4+/ CD45RO+ T cells, NK cells, and lower biopsy scores. CONCLUSION: Early after cardiac transplantation, elevated levels of inflammatory cells and soluble inflammatory molecules and lower levels of immunocompetence markers are associated with impaired allograft function in the absence of cellular rejection.

Adult↗
PubMed1998

[Arrhythmogenic right ventricular cardiomyopathy. Etiology, diagnosis and therapy].

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by regional atrophy of right ventricular myocardium and subsequent replacement by fatty and fibrous tissue. The disease manifests in young adulthood with a predominance of males. Hallmarks of ARVC are ventricular tachyarrhythmias of left bundle branch block pattern which frequently occur during exercise. However, sudden death may also be the first manifestation of the disease. Characteristic findings are repolarization abnormalities and QRS prolongation in the right precordial leads of the surface ECG and regional abnormalities of right ventricular structure and wall motion. Left ventricular involvement may occur in later stages of the disease but rarely leads to progressive biventricular heart failure. Therapeutic efforts are mainly directed to the treatment of ventricular tachyarrhythmias and the prevention of sudden death. A tailored treatment strategy including antiarrhythmic drug therapy, catheter ablation and implantation of cardioverter-defibrillators may be used to improve the long-term prognosis of patients with ARVC.

Anti-Arrhythmia Agents↗
PubMed1998

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.

Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

Action Potentials↗
PubMed1998

Syncope in patients with an implantable cardioverter-defibrillator: incidence, prediction and implications for driving restrictions.

OBJECTIVES: This retrospective study was undertaken to provide information on occurrence, risk prediction and prevention of syncope in patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: ICDs effectively terminate ventricular tachycardia and fibrillation (VT/VF). Incapacitating symptoms, such as syncope, may still occur. METHODS: We performed a retrospective analysis of data from 421 patients (clinical history, outpatient chart reviews and episode data) with mean (+/-SD) follow-up of 26 +/- 18 months. RESULTS: Of 421 patients, 229 (54.4%) had recurrent VT/VF, and 62 (14.7%) had syncope. The actuarial survival rate free of VT/VF was 58%, 45% and 37% and that for survival free of syncope was 90%, 85% and 81% at 12, 24 and 36 months after implantation, respectively. Once VT/VF had occurred, 76%, 68% and 62% of patients remained free of syncope during the following 12, 24 and 36 months, and 68%, 64% and 56% remained free of second syncope 12, 24 and 36 months after first syncope, respectively. In cases of syncope, the mean cycle length (CL) of VT was 251 +/- 56 ms. A low baseline left ventricular ejection fraction (LVEF), induction of fast VT (CL <300 ms) during programmed ventricular stimulation and chronic atrial fibrillation (AF) were associated with an increased risk of syncope. If the LVEF was >40%, fast VT had not been induced, and patients had no chronic AF; 96%, 92% and 92% of patients remained free of syncope after 12, 24 and 36 months, respectively. Once patients had a VT recurrence, syncope during the first VT and a high VT rate were the strongest risk predictors of future syncope. CONCLUSIONS: Identification of patients with an ICD with a low and high risk of syncope seems to be feasible and might help as a guide to driving restrictions in such patients.

Adolescent↗
PubMed1998

Torsade de pointes secondary to d,l-sotalol after catheter ablation of incessant atrioventricular reentrant tachycardia--evidence for a significant contribution of the "cardiac memory".

Radiofrequency catheter ablation of a right septal accessory pathway was performed in a 66-year-old patient with incessant orthodromic atrioventricular reentrant tachycardia. Intravenous administration of flecainide, ajmaline, verapamil, and d,l-sotalol had been ineffective in controlling the tachycardia. After the ablation procedure, precordial T-wave inversion was observed during sinus rhythm. These repolarization abnormalities persisted and were suggested to represent "cardiac memory." Three days later, atrial fibrillation with a fast ventricular response developed and oral d,l-sotalol, which had been well tolerated previously on a long-term basis, was started again. However, at this time, and in the presence of the persisting repolarization abnormalities, the T waves became deeper and broader within a few hours after the introduction of d,l-sotalol. Marked QT prolongation that was paralleled by the occurrence of repeated episodes of torsade de pointes developed. Serum electrolytes were normal. Direct current cardioversion was necessary due to the degeneration of torsade de pointes into ventricular fibrillation. Further sustained arrhythmia episodes were suppressed by temporary endocardial ventricular pacing. The patient recovered without any sequela. This case demonstrates that repolarization abnormalities after catheter ablation, which may be due, at least in part, to the "cardiac memory," are not always benign but may contribute significantly to proarrhythmia.

Administration, Oral↗
PubMed1998

[High frequency current catheter ablation of accessory conduction pathways].

Radiofrequency catheter ablation has established as the first line therapy for the curative treatment of patients with accessory pathway. Atrioventricular accessory pathways irrespective of the exact localisation can be successfully ablated in more than 90% of all cases. Severe complications associated with the ablation procedure are rare and occur in approximately 2% of patients treated. The recurrence rate after successful ablation is approximately 8 to 10%. Recurrence of accessory pathway conduction occurs almost exclusively within the first 3 months following successful ablation, late recurrences are rare. Patients with variants of accessory pathways such as atriofascicular pathways or retrogradely conducting accessory pathways with decremental conduction properties can also be cured with a high success rate. Because of its well balanced efficacy-risk profile radiofrequency catheter ablation should be recommended as the first line therapy to all symptomatic patients with accessory pathway.

Atrioventricular Node↗
PubMed1998

Clofilium in the isolated perfused rabbit heart: a new model to study proarrhythmia induced by class III antiarrhythmic drugs.

OBJECTIVE: The clinical usefulness of class III antiarrhythmic drugs for the treatment of tachyarrhythmias is limited by their potential proarrhythmic effects, mainly torsades-depointes (TdP). The goal of this experimental study was to develop an isolated whole-heart model exhibiting typical characteristics of class III drug-induced ventricular arrhythmias. METHODS: Isolated rabbit hearts were perfused with a Krebs-Henseleit buffer containing 10 microM clofilium and then exposed to a modified Krebs-Henseleit buffer with 2.0 mM K+ and 0.5 mM Mg2+. Hearts subjected to either clofilium alone or modified buffer alone were used as controls. RESULTS: Under clofilium the QT interval increased from 187 +/- 16 to 282 +/- 33 ms. Within 8 to 25 s after the change of the perfusate, ventricular arrhythmias developed in all hearts associated with a further QT prolongation to 380 +/- 73 ms when the first ventricular extrasystole occurred. Simultaneously, the monophasic action potential durations increased relatively more during late repolarization; from 99 +/- 21 to 110 +/- 25 ms (+11%) at 50% repolarization, from 143 +/- 24 to 178 +/- 40 ms (+24%) at 70%, and from 200 +/- 30 to 275 +/- 53 ms (+38%) at 90%. The predominant rhythm was polymorphic with either two alternating or multiple QRS morphologies exhibiting the characteristic features of torsades-depointes. All control hearts stayed in normal sinus rhythm. CONCLUSION: Under the conditions selected, the isolated perfused rabbit heart represents a useful experimental approach to study the proarrhythmic effects of class III agents. This model provides a convenient way to manipulate the ionic and pharmacologic milieu in a preparation conserving the functional anatomy of the whole organ without interference by cardiovascular reflexes. It might be useful for analyzing the conditions favoring and preventing drug-induced torsades-depointes.

Animals↗
PubMed1998

Experimental models of torsade de pointes.

Torsade de pointes is a potentially life threatening form of polymorphic ventricular tachycardia typically seen in the setting of congenital and acquired abnormal QT-prolongation. Numerous in vitro studies have investigated basic ionic mechanisms underlying delayed repolarization. The role of different ion channels and the induction of early afterdepolarizations have been studied in various cardiac cells including M cells. In addition, isolated heart models with and without electrical stimulation and/or the use of drugs which prolong repolarization have been developed in recent years. Some of these models have simulated conditions likely to exist in the clinical setting of torsade de pointes, such as bradycardia and hypokalemia. In in vivo canine and rabbit models, torsade-like polymorphic ventricular tachyarrhythmias have been induced by the administration of different agents such as cesium, neurotoxins, e.g., anthopleurin or various class III drugs under conditions designed to mimic the clinical situation. In the context of recent advances in the molecular genetics of long QT syndrome, those models which have used sodium or potassium channel blockers have gained particular interest. Based on all experimental studies it seems probable that the first beats of torsade occur due to early afterdepolarizations and triggered activity. The development of subsequent beats is less clear. Reentry based on inhomogeneity of refractoriness has been suggested as the underlying mechanism.

Animals↗