Experimental exercise-induced ischemia: drug therapy can eliminate regional dysfunction and oxygen supply-demand imbalance.

The purpose of this study was to test the hypothesis that moderately severe exercise-induced regional myocardial ischemia can be prevented by combined pharmacologic intervention. Eight chronically instrumented dogs were studied using an ameroid constrictor to produce critical stenosis of the left circumflex coronary artery. The dogs were studied during steady state treadmill exercise that induced regional myocardial dysfunction (reduced systolic wall thickening; sonomicrometers) and ischemia (reduced subendocardial blood flow; microspheres). During a control exercise run, wall thickening in the ischemic posterior wall decreased from 21.4 to 13.3% whereas subendocardial blood flow failed to increase normally (36% of that in the normal zone). In the control anterior wall, both wall thickening and subendocardial blood flow increased significantly during the control run. Wall thickness-left ventricular pressure loop areas were calculated as an index of regional work; this index increased abruptly with the onset of exercise in both regions but became significantly depressed in the ischemic region during the steady state exercise. Therapy with a combination of atenolol (0.3 mg/kg body weight orally), diltiazem (0.3 mg/kg intravenously) and isosorbide dinitrate (2.0 mg/kg orally) effectively prevented regional myocardial ischemia and regional dysfunction. After drug therapy, wall thickening in the posterior wall increased from 17.3% at rest to 18.8% during exercise, and the regional transmural blood flow pattern was markedly improved. The initial overshoot of the regional work index during exercise was blunted by the drug therapy, and at steady state no differences between the ischemic and control regions were detected. Thus, combined drug therapy can eliminate exercise-induced regional myocardial ischemic dysfunction and appears to normalize the oxygen supply-demand imbalance.

Blood pressure response and renin release following 4 days of treatment with dihydralazine and urapidil in conscious dogs.

The magnitude and the persistence of blood pressure reduction by dihydralazine and urapidil were investigated following treatment over a period of 4 days. The experiments were performed on six normotensive dogs, trained to submit to puncture of the femoral artery and to stand quietly in a special frame. The first-dose effects of orally administered dihydralazine (1.42, 7.1 mg X kg-1) and urapidil (2.0, 10.0 mg X kg-1) on heart rate, arterial blood pressure and plasma renin activity (PRA) were compared with the effects of the substances after 4 days of treatment. Both compounds caused a dose-dependent decrease in blood pressure but in contrast to urapidil the effect of dihydralazine was accompanied by large increases in heart rate and PRA. Dose-dependent tolerance to dihydralazine but not to urapidil was observed after treatment over only 4 days. However, basal blood pressure was significantly lowered after 4 days of treatment with urapidil at the high dosage and no further reduction was achieved on the fifth day. The importance of persistent counterregulation in the development of tolerance to the antihypertensive effect of dihydralazine is discussed.

First experience with the new Sorin Crown PRT bioprosthetic aortic valve: early postoperative outcome and hemodynamic performance in 90 patients.

AIM: The Crown PRT (The Phospholipid Reduction Treatment) is a new stent bovine bioprosthesis for aortic valve replacement (AVR). Aim of this paper is to report the postoperative clinical and hemodynamic results after ninety consecutive implants. METHODS: After receiving CE mark in July 2014, two European university centers implanted the new Crown PRT (Sorin Group, Burnaby, Canada) for the first time. Up to now, ninety patients underwent aortic valve replacement, in isolated or combined procedures, for aortic stenosis or insufficiency. Intraoperative transesophageal echocardiogram was used to assess the prosthesis's function. In hospital outcomes and echocardiographic parameters were recorded. RESULTS: Age and Log Euroscore were 71.8±7.9 years and 10.2%±4.5 respectively. In-hospital mortality for isolated AVR was 0%; one patient died after a multiple procedure (overall 30-days mortality 1.1%). No adverse device effects were recorded. Intensive Care Unit stay was 2±5.8 days. At discharge, echocardiogram showed no paravalvular leaks and normal postoperative gradients. CONCLUSION: Our starting results showed that the Crown PRT is safe and reliable, with excellent hemodynamic performance. Further clinical results with a larger population and long term follow-up are needed to assess the versatility and the durability of this new device.

The progression of mild acute cardiac rejection evaluated by risk factor analysis. The impact of maintenance steroids and serum creatinine.

The natural course of mild acute cardiac allograft rejection (MAR) under cyclosporine-based therapy is generally considered benign, and usually antirejection therapy is not instituted. The present study was undertaken to determine the frequency of and the risk factors for progression of MAR into a clinically significant (moderate or severe) rejection on subsequent endomyocardial biopsy (EMB). Among 167 cardiac recipients, transplanted from 3/1984 to 4/1990, MAR under cyclosporine-based therapy was diagnosed on 220 EMBs. Depending upon the outcome on the subsequent EMB, MAR was categorized as progressive or nonprogressive. This served as the dependent variable for a stepwise logistic regression analysis evaluating 11 covariates as potential risk factors: perioperative antibody prophylaxis (ATG vs. OKT3), maintenance therapy, underlying disease, HLA-mismatches for A- and B + DR-loci, serum creatinine (mg/dl) and cyclosporine HPLC blood level (ng/ml) at diagnosis of MAR and at subsequent biopsy, recipient age, donor age. 40 (18.2%) of 220 MARs became progressive as opposed to 37 (7.3%) of a control cohort of 507 negative EMBs (P less than 0.0001). Stepwise logistic regression yielded the type of maintenance therapy (P = 0.0019) and serum creatinine level at diagnosis of MAR (P = 0.0615) as independent predictors of progression of MAR. After adjustment for influence of maintenance therapy and serum creatinine none of the cyclosporine variables provided any additional information. MARs without maintenance steroids and low serum creatinine levels had the highest risk (37.2% observed incidence) to develop moderate or severe rejection on subsequent EMB. This analysis supports evidence that diagnosis of MAR on EMB is associated with a considerable high progression rate into clinically significant rejection when compared to negative EMBs. Progression particularly occurs in MAR under steroid-free maintenance therapy and suggests early augmentation of immunosuppression. In terms of progression of MAR serum creatinine values, obviously indicating cyclosporine nephrotoxicity, appear to reflect the extent of cyclosporine-mediated immunosuppressive activity more properly than parameters of its bioavailability by measuring cyclosporine HPLC blood levels.

Experimental use of a modified fibrin glue to induce site-directed angiogenesis 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.

Effects of diltiazem on perioperative ischemia, arrhythmias, and myocardial function in patients undergoing elective coronary bypass grafting.

A prospective, randomized study was performed on 120 patients undergoing elective coronary bypass grafting to define the effect of the calcium channel blocker diltiazem on perioperative ischemia, arrhythmias, and myocardial function. Patients received a continuous 24-hour perioperative infusion of either diltiazem (0.1 mg/kg per hour, n = 60) or nitroglycerin (1 micrograms/kg per minute, n = 60). Perioperative monitoring included hemodynamic measurements, three-channel Holter monitoring, repeated assessment of 12-lead electrocardiograms, and analysis of ischemia-specific laboratory parameters (creatine kinase, creatine kinase-MB, and creatine kinase-MB-mass and troponin-T). Global and regional systolic function and diastolic compliance were assessed by means of transesophageal echocardiography. The two groups did not differ with respect to preoperative and operative data. Except for a significant reduction in perioperative heart rate, diltiazem had no influence on hemodynamic parameters. The number (17 +/- 9 versus 25 +/- 5, p < 0.05) and the duration (69 +/- 47 versus 104 +/- 87 minutes, p < 0.05) of transient ischemic events were significantly reduced as compared with the nitroglycerin group. In addition, peak values of all assessed laboratory parameters except creatine kinase were significantly lower in the diltiazem group. Patients treated with diltiazem had a lower incidence of perioperative atrial fibrillation (5% versus 18%, p < 0.05) and lower numbers of ventricular premature beats per hour (10 +/- 8 versus 19 +/- 22, p < 0.05) and ventricular runs per hour (5 +/- 17 versus 32 +/- 38, p < 0.05). Postoperatively, the percent fractional area of contraction and percent systolic wall thickening of the anterior wall were significantly improved in the diltiazem group but not in the nitroglycerin group. In addition, the postoperative diastolic flow/velocity ratio was significantly lower in the nitroglycerin group than in the diltiazem group (0.949 +/- 0.391 versus 1.331 +/- 0.475, p < 0.001). It is concluded that perioperative infusion of the calcium antagonist diltiazem has no adverse effect on perioperative hemodynamics and systolic myocardial function and provides potent anti-ischemic and antiarrhythmic protection in patients undergoing coronary bypass grafting.

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.

Monitoring of mononuclear cell subsets isolated from the coronary sinus and the right atrium in patients after heart allograft transplantation.

The rejection of a transplanted heart leads to an accumulation of mononuclear cells in the cardiac tissue and to reactions of the antigen-recognizing cells with the foreign tissue. Consequently, during rejections immunologic changes, such as the number of mononuclear cells and the patterns of mononuclear cell subpopulations, should be detectable by analysis of mononuclear cells from the coronary sinus of transplanted hearts. Seventy-nine endomyocardial biopsies were performed in 37 patients. Severity of graft rejection was classified by the Billingham scheme. Thirty-two biopsy specimens showed no rejection, 33 mild, and 14 moderate rejection. After endomyocardial biopsy the coronary sinus was catheterized under x-ray guidance. Heparinized blood samples were obtained from the coronary sinus and the right atrium, and mononuclear cell counts and subpopulation pattern were compared. Patients without rejection and patients with mild rejection showed no significant differences in the patterns of mononuclear cell subpopulation identified in right atrium blood. However, a significant (1.56-fold) increase of mononuclear cells was assessed in the CS blood (p less than 0.01). Moderate rejections showed a 4.2-fold augmentation of mononuclear cells in the coronary sinus (p less than 0.005) compared with nonrejections. In addition, the T-helper/inducer (CD4) percentage increased from 27.1% in the right atrium to 41.2% in the coronary sinus (p less than 0.005), natural killer cells (CD16) from 17.7% to 31.8% (p less than 0.005), and the interleukin 2 receptor-bearing cells from 6.6% to 15.3% (p less than 0.005). Percentage of pan-T cells (CD3), T-cytotoxic/suppressor cells (CD8), and monocytes (CD14) showed no statistically significant changes. These findings correlated with grading according to endomyocardial biopsy. Using the ratio of values obtained from cells of the coronary sinus and the right atrium rendered the coronary sinus immunologic monitoring independent of changes in the administered immunosuppressive regimen. The specificity of the described method was as good as that of endomyocardial biopsy. It is concluded that the discrimination of the patterns of mononuclear cell subpopulations from right atrium versus coronary sinus blood samples is highly sensitive and allows the correct diagnosis of graft rejection within 1 to 2 hours.

Shed blood autotransfusion influences ischemia-sensitive laboratory parameters after coronary operations.

The diagnostic significance of ischemia-sensitive laboratory parameters in respect to possible interference with shed blood autotransfusion was assessed in a prospective study with 100 patients undergoing elective coronary artery bypass grafting. Serum levels of creatine kinase, creatine kinase MB activity, creatine kinase MB mass concentration, 2-hydroxybutyrate dehydrogenase, lactate dehydrogenase-1, troponin-T, myoglobin, and glutamicoxaloacetic transaminase were repeatedly assessed up to the sixth postoperative day. Thirty-seven patients were excluded from the study due to postoperative development of myocardial infarction (n = 4), transient ischemic events (n = 25), and left bundle-branch blocks (n = 8). In the remaining group of 63, 37 patients were retransfused with 580 +/- 370 mL shed blood up to the twelfth postoperative hour, and 26 patients did not receive autotransfusion due to minimal mediastinal blood loss. The results of our study show that the ischemia-sensitive laboratory parameters were significantly influenced by shed blood autotransfusion: 8 hours postoperatively, creatine kinase (272%), creatine kinase MB fraction (151%), 2-hydroxybutyrate dehydrogenase (130%), lactate dehydrogenase-1 (133%), troponin-T (200%), myoglobin (159%) and glutamic-oxaloacetic transaminase levels (153%) were significantly elevated (p < 0.05) in patients with postoperative autotransfusion, although there were no electrocardiographic signs of myocardial ischemia in this group of patients. Our study shows that postoperative autotransfusion of mediastinal shed blood may interfere with the diagnosis of perioperative myocardial ischemia by laboratory parameters in coronary bypass patients.

Ventricular thrombus and subarachnoid bleeding during support with ventricular assist devices.

We report the case of a 23-year-old man with acute aortic valve insufficiency caused by endocarditis, who after emergency aortic valve replacement developed biventricular heart failure. The heart failure was treated with temporary assist devices. Subarachnoid bleeding and thrombus obstruction of the left ventricular outflow tract was detected. The postoperative course is presented with special emphasis on management of subarachnoid bleeding and the simultaneous use of anticoagulation necessary for ventricular assist devices.

Initial experience with two sequential anterolateral thoracotomies for bilateral lung transplantation.

BACKGROUND: Bilateral transsternal thoracotomy (clamshell incision) is the standard approach used for bilateral sequential lung transplantation (BLTX). The morbidity of this large incision can be considerable. Two separate sequential anterolateral thoracotomies represent a less invasive approach. METHODS: The value of this approach was investigated in a prospective series of 13 consecutive patients with the underlying diagnosis of COPD or cystic fibrosis (group A). Results were compared to 8 consecutive patients with similar indications who had undergone BLTX via clamshell incision during the last year prior to this new technique (group B). RESULTS: No intraoperative complications occurred in either group. The difference between the cold ischemic time of the 1st and 2nd transplanted lung was comparable between the 2 groups (81 min+/-17 min in group A vs 79 min+/-14 min in group B, p = 0.783). Postoperative restriction was significantly less in the group operated through 2 separate thoracotomies, as proven by the vital capacity in the first spirometry performed during the 3rd postoperative week (VC group A 55%+/-16% predicted vs 41%+/-11% predicted in group B; p = 0.043). CONCLUSION: The bilateral sequential anterolateral thoracotomy represents a safe and less invasive approach for BLTX in patients with large chest volumes. It minimizes the operative trauma, improves postoperative functional recovery and prevents the potential spread of unilateral complications to the other pleural cavity.

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.

Effects of indomethacin on changes in renal blood flow induced by adenosine and its analogues in conscious dogs.

The effects of indomethacin on changes in renal blood flow induced by adenosine, NECA (adenosine-5'-N-ethyl-carboxamide) and 2',3'-dinitro-NECA were investigated in 6 chronically instrumented conscious dogs. Adenosine (187.5, 375 and 750 nmol/kg, i.v.) induced a dose-dependent initial decrease, followed by a reactive increase in renal blood flow. NECA (1.5 nmol/kg, i.v.) also induced an initial decrease, which was, however, followed by a prolonged reactive increase in renal blood flow. 2',3'-dinitro-NECA (50 nmol/kg, orally) induced only an increase in renal blood flow. Indomethacin (27.9 mumol/kg, i.v.) caused no relevant change of the initial decrease and a significant attenuation of the reactive increase in renal blood flow induced by adenosine. NECA-induced changes in blood flow were affected by indomethacin in the same direction but to a greater extent than were adenosine-induced changes in blood flow. Indomethacin reversed the increase to a decrease in renal blood flow induced by 2',3'-dinitro-NECA. Thus, prostaglandins seem to be involved in mediating the response of renal blood flow to adenosine, NECA and 2',3'-dinitro-NECA.

Evidence against the adenosine-catecholamine antagonism under in vivo conditions.

Experiments were carried out in anaesthetized, thoracotomized dogs. The dose dependent positive inotropic and chronotropic effects of intracoronary (i.cor.) infusions or bolus injections of isoproterenol (ISO) were neither antagonized by adenosine (0.46, 1.0, and 2.91 x 10(-5) mol/l) nor by the adenosine analogue N6-phenylisopropyl-adenosine (PIA, 3.23 x 10(-7) mol/l). The results indicate, that adenosine and PIA do not have any antagonistic effects on isoproterenol induced positive inotropy and chronotropy in the intact dog heart. Consequently it can be assumed that an adenosine-catecholamine antagonism is of no physiological relevance.

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.

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.

Growth of "new" coronary vascular structures by angiogenetic growth factors.

The efficacy of the human angiogenetic heparin-binding growth factor I (HBGF-I) to initiate site-directed growth of new blood vessels from the aorta into the myocardium was studied. First, manipulated Escherichia coli bacteria, which had received the human mRNA-transcript for HBGF I into their genetic material, were cultivated. The growth factor derived was purified using heparin-Sepharose affinity chromatography. The separation and characterization of biologically active alpha- and beta-chains was carried out using high pressure liquid chromatography (HPLC) of dialyzed and lyophilized samples from the heparin-Sepharose column. One microgram HBGF I (alpha-ECGF) was bound to polytetrafluoroethylene (PTFE) sponges, precoated with collagen type I, and implanted between the aorta and the myocardium of the left ventricle in experimental rats. Twelve growth factor implants in the experimental group were compared to six controls receiving uncoated PTFE sponges for 9 weeks. Digitized computed angiography showed new blood vessels between the aorta and the myocardium in 11 of the 12 experimental animals, and retrograde coronary perfusion by these "new" vascular structures could be seen. Histology showed no specific structures in the control group (without HBGF I). In the experimental group (with HBGF I) individual vessels with highly differentiated endothelial and smooth muscle cell layers were evident. Our experiments proved the feasibility of induced, site-directed angiogenesis. It is possible to initiate in vivo growth of new "coronary" vascular structures between the aorta and the myocardium.

Significance of right bundle branch block in the diagnosis of myocardial ischemia in patients undergoing coronary artery bypass grafting.

BACKGROUND: Perioperative diagnosis of myocardial ischemia following cardiac surgical procedures remains a challenging problem. Particularly, the role of new conduction disturbances as markers of postoperative ischemia is still questionable. The goal of this study was to elucidate the diagnostic significance of new postoperative right bundle branch block (RBBB) for the detection of perioperative myocardial ischemia in patients undergoing elective coronary artery bypass grafting (CABG). METHODS: In 169 consecutive patients, three-channel Holter monitoring and serial assessment of serum enzymes were performed for 48 h, and 12-lead ECG repeated for up to 5 days postoperatively. Postoperative events were classified as either myocardial infarction (MI), transient ischemic events (TIE) or various conduction disturbances. RESULTS: Transient (n=9) or permanent (n=4) RBBB occurred in 13 patients (8%); 14 patients (8%) showed signs of perioperative MI and 18 patients (11%) evidence of TIE. Peak activity of creatine-kinase (CK, 561+/-135 vs. 316+/-19, P<0.05) and CK-MB (22.7+/-3.2 vs. 13.4+/-0.8, P<0.01) were higher in patients with RBBB than in patients without perioperative ischemic events. Peak CK-MB levels were significantly higher in patients with MI as compared to those with RBBB (33.4+/-7.6 vs. 22.7+/-3.2, P<0. 05). Patients with TIE had similar perioperative enzyme levels as patients with no events. CONCLUSION: It is concluded that the combined assessment of repeated 12-lead ECG, continuous Holter monitoring and enzyme analysis allows a reliable diagnosis of perioperative myocardial ischemia and conduction disturbances. The occurrence of new RBBB following elective CABG is indicative of perioperative myocardial necrosis and thus serves as a valuable tool for the diagnosis of new, perioperative ischemic events.

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.

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.