Rainald Seitelberger

Experimental use of a modified fibrin glue to induce site-directed angliogenesis from the aorta to the heart

From 10 cultures of manipulated Escherichia coli bacteria expressing the class I heparin-binding growth factor polypeptide alpha-endothelial cell growth factor, 11.2 +/- 0.7 mg alpha-endothelial cell growth factor was eluted by heparin-sepharose affinity chromatography. Analysis of molecular weight (17,000 kD) was done by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and purification of the growth factor was done by high-performance liquid chromatography. The harvested alpha-endothelial cell growth factor was proved by protein blotting. To assess the growth-promoting activity, we did an endothelial cell growth assay by comparing adult human endothelial cell control cultures, without adding growth factor to the culture medium, with adult human endothelial cell cultures with 0.02 to 20.0 ng/ml alpha-endothelial cell growth factor and 1.0 ng/ml heparin and with adult human endothelial cell cultures with alpha-endothelial cell growth factor but without heparin. Tritiated thymidine counts proved the significant growth-promoting activity of alpha-endothelial cell growth factor. In 10 experimental animals modified fibrin glue containing 1 microgram alpha-endothelial cell growth factor was implanted between the aorta and the myocardium of the left ventricle and results were compared with those in five control animals that received normal fibrin glue without growth factor. After 9 weeks of implantation, angiography and histologic investigation showed newly grown vascular structures between the aorta and the myocardium in all experimental animals, but none in the control animals. Our study proved the feasibility of initiating site-directed formation of new blood vessel structures to the heart by a modified fibrin glue implant containing angiogenic growth factor alpha-endothelial cell growth factor.

Epicardial branches of the coronary arteries and their distribution in the rabbit heart: The rabbit heart as a model of regional ischemia

The rabbit heart has been frequently used to study regional ischemia, but there is hardly any detailed information on the epicardial branching of the coronary arteries. Therefore, we wanted to determine whether there is a constant branching pattern and how comparable this pattern is with the human heart.

Nifedipine reduces the incidence of myocardial infarction and transient ischemia in patients undergoing coronary bypass grafting.

A randomized study was performed on 104 patients undergoing elective coronary artery bypass grafting to examine whether the infusion of nifedipine (n = 53) reduces the incidence of perioperative myocardial ischemia and necrosis in the early postoperative period. Continuous hemodynamic and three-channel Holter monitoring was performed for 24 hours and serial assessment of serum enzymes and 12-lead electrocardiography were performed for 36 hours postoperatively. Nifedipine (minimum dose, 10 micrograms/kg/hr for 24 hours) was applied from the onset of extracorporal circulation. The control group (n = 51) received nitroglycerin (minimum dose, 1 micrograms/kg/min for 24 hours). Using the combined analyses of electrocardiography and Holter recordings, myocardial ischemia was defined as being either a transient ischemic event (TIE), transient coronary spasm (TCS), or myocardial infarction (MI). The two groups did not differ with respect to preoperative New York Heart Association classification, age, history of myocardial infarction, extracorporal circulation and aortic cross-clamp time, number of distal anastomoses, or systemic and pulmonary hemodynamics. The incidence of perioperative myocardial ischemia was substantially lower in the nifedipine than in the nitroglycerin group [TIE: three of 53 patients (6%) versus nine of 50 patients (18%), p less than 0.001; MI: two of 53 patients (4%) versus six of 50 patients (12%), p less than 0.001; and TCS: none of 53 patients (0%) versus two of 50 patients (4%), p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of perioperative myocardial protection with nifedipine versus nifedipine and metoprolol in patients undergoing elective coronary artery bypass grafting

A randomized study was performed on 70 patients undergoing elective coronary bypass grafting to examine whether the combined infusion of the calcium channel blocker nifedipine (10 micrograms/kg per hour) and the beta 1-blocker metopropol (12 micrograms/kg per hour, n = 34) reduces the prevalence of perioperative myocardial ischemia and arrhythmias. The control group received nifedipine alone (n = 36). In both groups the infusion was started from the onset of extracorporal circulation and maintained over a period of 24 hours. Repeated 12-lead electrocardiographic and 3-channel Holter monitor recordings for 48 hours were used to define perioperative myocardial ischemia (transient ischemic event, myocardial infarction) and arrhythmias (sinus tachycardia, supraventricular tachycardia, atrial flutter/fibrillation, ventricular tachycardia). Hemodynamic parameters were repeatedly assessed for 24 hours and serum enzyme levels (creatine kinase, MB isoenzyme of creatine kinase) for up to 36 hours after the operation. The two groups did not differ significantly with respect to preoperative anamnestic and surgical data. No signs of perioperative myocardial infarction were detected in either group. However, a significantly lower incidence of transient ischemic episodes was observed in the nifedipine-metoprolol group than in the nifedipine group (3% vs 11%; p < 0.05). In addition, there was a tendency toward lower creatine kinase MB levels and peak values of creatine kinase and creatine kinase MB in the nifedipine-metoprolol group. With regard to perioperative arrhythmias, there was a significantly lower incidence of sinus tachycardia and atrial flutter/fibrillation in the nifedipine-metoprolol group (9% and 6%) than in the nifedipine group (33% and 27%, p < 0.05). In addition, postoperative heart rate was lower in the nifedipine-metoprolol group starting from the sixth hour after release of the aortic crossclamp (p < 0.05 and p < 0.01, respectively). No other hemodynamic parameters showed significant differences between the two groups and all returned to preoperative levels within 24 hours. In conclusion, perioperative application of nifedipine and metoprolol in patients undergoing elective coronary bypass grafting reduces the prevalence of perioperative myocardial ischemia and arrhythmias without significant negative inotropic effects. The combined infusion of the two drugs appears superior to nifedipine alone in preventing perioperative myocardial ischemia and reducing reperfusion-induced arrhythmias.

Diltiazem provides anti-ischemic and anti-arrhythmic protection in patients undergoing coronary bypass grafting.

In 91 patients undergoing elective coronary bypass grafting, the anti-ischemic and anti-arrhythmic efficacy of a 24-hour infusion of either the calcium antagonist diltiazem (0.1 mg/kg per h, n = 44) or nitroglycerin (1 micrograms/kg per min, n = 47) were compared. Myocardial ischemia was diagnosed by Holter monitoring and the repeated assessment of 12-lead ECG and serum enzyme levels and defined as a transient ischemic event, transient coronary spasm or myocardial infarction. The two groups did not differ with respect to preoperative and operative data. Postoperatively, the average heart rate and pulse pressure rate were significantly lower in the diltiazem group. The incidence of postoperative atrial fibrillation (4.5 vs 19.1%, P < 0.01), transient coronary spasm (2.3 vs 11.4%, P < 0.05) and myocardial infarction (4.5 vs 8.5%, not significant) and the frequency of ventricular premature couplets/h (12.1 +/- 4.5 vs 18.1 +/- 5.1, P < 0.05) and ventricular runs/h (2.5 +/- 0.8 vs 6.5 +/- 2.8, P < 0.05) were lower in the diltiazem as compared to the nitroglycerin group. In addition, diltiazem-treated patients had significantly lower postoperative peak values of creatine kinase-MB (19.3 +/- 11.6 vs 29.3 +/- 20.6, P < 0.05). In conclusion, perioperative infusion of diltiazem is effective in reducing the incidence and extent of arrhythmias and myocardial ischemia in patients undergoing elective coronary bypass grafting as compared to patients receiving nitroglycerin.

Tezosentan and Right Ventricular Failure in Patients with Pulmonary Hypertension Undergoing Cardiac Surgery: The TACTICS Trial

OBJECTIVE To evaluate the efficacy of tezosentan in reducing the incidence of right ventricular (RV) failure and associated mortality in patients with pre-existing pulmonary hypertension. The primary endpoint was the proportion of patients with RV failure during weaning from cardiopulmonary bypass (CPB), assessed 30 minutes after the end of CPB. DESIGN Multicenter, double-blind, randomized, placebo-controlled trial. SETTING Thirty-one cardiac surgical centers in 14 countries. PARTICIPANTS Two hundred seventy-four patients with pulmonary hypertension aged ≥ 18 years scheduled to undergo cardiac surgery. INTERVENTION Intravenous tezosentan (5 mg/h) during surgery and up to 24 hours afterwards (1 mg/h), or matched placebo. MEASUREMENTS AND MAIN RESULTS One-hundred thirty-three patients received tezosentan and 141 placebo. RV failure occurred in 30 patients (10.9%), 37% of whom died. There was no difference in the incidence of RV failure between the two treatment groups (relative risk reduction: 0.07 [95% CI-0.83, 0.53; P = 0.8278]). CONCLUSION A reduction in RV failure with tezosentan was not observed in this study.(Current Controlled Trials, identifier NCT00458276).

Infusion of nifedipine after coronary artery bypass grafting decreases the incidence of early postoperative myocardial ischemia

We performed a randomized study on patients undergoing elective coronary bypass grafting to examine whether postoperative infusion of nifedipine (n = 25) could reduce the incidence of isolated transient myocardial ischemia, myocardial infarction, or both. The control group (n = 25) received nitroglycerin. Hemodynamic and Holter monitoring and serial assessment of enzymatic and electrocardiographic changes were performed for all patients. Both groups showed comparable preoperative and operative data. The incidence of myocardial infarction was significantly lower in the nifedipine group (n = 1) as compared with the control group (n = 4), whereas the number of patients with isolated transient myocardial ischemia was similar in both groups (nifedipine, 3; control, 4). At the time of peak activity, levels of creatine kinase (350 +/- 129 versus 511 +/- 287 IU/mL), creatine kinase-MB (8.4 +/- 5.4 versus 17.1 +/- 11.0 IU/mL), and glutamate-oxaloacetate-transaminase (30.4 +/- 4.4 versus 41.0 +/- 7.9 IU/mL) were markedly lower in the nifedipine group (p less than 0.05). We conclude that infusion of nifedipine after elective coronary artery bypass grafting effectively decreases the incidence of myocardial infarction and the extent of myocardial necrosis during the early postoperative period.

Diltiazem during reperfusion preserves high energy phosphates by protection of mitochondrial integrity

OBJECTIVE This study evaluates the effects of diltiazem administered during reperfusion on hemodynamic, metabolic, and ultrastructural postischemic outcome. METHODS Hearts of 38 adult White New Zealand rabbits underwent 60 min of global cold ischemia followed by 40 min of reperfusion in an erythrocyte perfused isolated working heart model. Hearts were randomly assigned to four groups and received diltiazem (0.1, 0.25, and 0.5 micromol/l) during reperfusion only, or served as control. RESULTS The postischemic time courses of heart rate, aortic flow, and external stroke work clearly reflected the dose-dependent negative chronotropic and inotropic efficacy of diltiazem in the two higher concentrations. High energy phosphates (HEP) determined from myocardial biopsies taken after 40 min of reperfusion were significantly better preserved in all treatment groups compared to control hearts. Similarly ultrastructural grading of mitochondria and myofilaments revealed a significant reduction of reperfusion injury in hearts that received diltiazem compared to control. CONCLUSIONS Diltiazem protects mitochondrial integrity and function, thereby preserving myocardial HEP levels. Only low dose diltiazem (0.1 micromol/l) during reperfusion combines both, optimal mitochondrial preservation with minimal changes in hemodynamics.

Experimental development of an electrically stimulated biological skeletal muscle ventricle for chronic aortic counterpulsation

OBJECTIVE The chronic shortage of donor organs for cardiac transplantation and the high costs for mechanical assist devices demand the development of alternative cardiac assist devices for the treatment of severe heart failure. Cardiac assistance by stimulated skeletal muscles is currently investigated as such a possible alternative. The goal of the presented study was to construct a newly designed biological skeletal muscle ventricle and to evaluate its possible hemodynamic efficacy in an acute sheep model. METHODS A total of 14 adult sheep were used for acute experiments. The entire thoracic aorta including the aortic root was excised from a donor sheep. An aorto-pericardial pouch conduit (APPC) was created by enlarging the aortic circumference in its middle section with two strips of pericardium. This biological conduit was anastomosed in parallel to the descending aorta of a recipient sheep, using the aortic root as an inflow valve to the conduit. Stimulation electrodes were applicated to the thoracodorsal nerve and the latissimus dorsi muscle was detached from the trunk and wrapped around the pouch. ECG-triggered functional electrical stimulation was applied during cardiac diastole to simulate aortic counterpulsation. Stimulation was performed during various hemodynamic conditions. RESULTS A standardised surgical procedure suitable for long term studies was established during six experiments. An APPC, with 70-80 mm filling volume, was found to be of optimal size. In another eight experiments, hemodynamic measurements were performed. Under stable hemodynamic conditions the stimulation of the biological skeletal muscle ventricle induced a significant increase of mean arterial pressure by 14% and mean diastolic pressure by 26%. During pharmacologically induced periods of cardiac failure, the stimulation of the APPC increased mean arterial pressure by 13% and mean diastolic pressure by 19%. In all eight experiments, the diastolic peak pressure reached supra-systolic values during stimulation. CONCLUSIONS The results demonstrate the hemodynamic efficacy of this newly designed biological skeletal muscle ventricle as an aortic counterpulsation device. Chronic experiments using a preconditioned fatigue-resistant muscle will further help to evaluate its possible clinical significance.

New developments in the isolated working heart : a comparison of neonatal, immature, and adult rabbits after sixty minutes of ischemia in respect to hemodynamic and biochemical parameters

Hemodynamic and biochemical changes were studied on 36 white ELCO-rabbits, seven adult older than 150 days, seven immatures between 21 and 27 days, and seven neonatals between 7 and 14 days. Five supplementary hearts of each age group served for preischemic biochemical values. Protection during 60 min of global ischemia was provided by topical cooling and selective coronary perfusion with Bretschneider cardioplegia (8 degrees C). A comparison between pre- and postischemic results showed decreases in coronary flow in the adult (p < 0.004), aortic flow (p < 0.04), cardiac output (p < 0.02), and stroke volume (p < 0.02) in the neonate. The preservation of ATP and CP was sufficient in the adult and immature myocardium, whereas a significant decrease in neonatal ATP was found (p < 0.01). According to these findings we consider immature myocardium to be more resistant against ischemia than the two other age groups. The apparatus used is a development of the conventional working heart, but combines a physiological flow-pressure relation, with instruments guaranteeing high accuracy, devices for drug application, and fits for different sizes of hearts. Therefore, this new approach promises to be of clinical relevance for investigations on the improvement of myocardial protection in both adults and children.