Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 µg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Left ventricular reduction for idiopathic dilated cardiomyopathy as alternative to transplant--truth or dare?

BACKGROUND: Although the concept of reducing wall tension a treatment for advanced heart failure is convincing, clinical data from the Batista operation are conflicting. Despite a number of publications, it is not clear whether left ventricular reduction surgery truly benefits patients with idiopathic, dilated cardiomyopathy (DCM). Surgery may reduce wall tension, but the reason for dilation and contractile dysfunction remains. Thus, the potential benefit of the operation may be overshadowed by the natural course of the underlying disease. CASES: We report a series of five cases where left ventricular reduction was performed and physiological geometry was restored in patients with DCM by a modification of Dor's endoventricular patch plasty. All patients demonstrated an improvement in cardiac function immediately after the operation. This improvement was sustained in one of the patients after 18 months of follow-up. Another patient developed severe heart failure due to therapy-resistant ventricular arrhythmia (Lown IV b), and underwent successful transplantation 4 months after ventricular reduction surgery. Left ventricular dilation reoccurred in two patients 9 and 12 months after reduction surgery, and they were listed for transplant. One patient died after 9 weeks due to sepsis and respiratory dysfunction. CONCLUSIONS: Although the endoventricular patch plasty, as used in this study, is well tolerated by most patients with dilated cardiomyopathy, and results in immediate improvement of contractile function, the long-term benefits of this technique for DCM are uncertain. Thus, the technique is currently not an alternative for heart transplantation. However, the procedure may be an option in patients with contraindications for transplantation.

Microperfusion enhancement after TMLR in chronically ischemic porcine hearts.

OBJECTIVE: The purpose of this study was to determine the effect of transmyocardial laser revascularization (TMLR) on myocardial perfusion and function in chronically ischemic myocardium. METHODS: In the first operation a stenosis of the left anterior descending artery was created in 20 open-chest anesthetized pigs to implement this ischemic model. In contrast, four pigs served as controls (thoracotomy only). Seven days later (2nd operation), all animals were studied at baseline by analyzing different parameters of perfusion (radioactive microspheres), function, and intramyocardial pressure. Afterwards, pigs who received a left anterior descending artery stenosis were randomized into one of three groups: animals in laser group 1 (n=7) received one and in laser group 2 (n=7) two laser channels per cm(2) in the left anterior descending artery territory. Animals of the ischemic group (n=6) underwent the same procedures without transmyocardial laser revascularization. Three months later, the animals were re-studied (3rd operation) and additional analysis of histochemistry and myocardial water content was performed. RESULTS: Regional myocardial blood flow (RMBF) in laser group 2 revealed statistically higher RMBF values compared to the ischemic group (0.39+/-0.13 versus 0.14+/-0.12 ml/min/g; P=0.043), after 3 months, whereas the absolute RMBF had not increased compared to the 1-week baseline values. Left ventricular stroke work index (LVSWI) at rest and under stress did not show any improvement compared to the initial values in all study groups (P=ns). Nevertheless, laser group 1 demonstrated relatively higher LVSWI(max) values compared to the ischemic (1.33+/-0.19 versus 0.93+/-0.16 mJ/kg; P=0.03) and laser group 2 (1.33+/-0.19 versus 1.02+/-0.15; P=0.024). Regional contractility of laser groups 1 and 2 recovered after 3 months (which had deteriorated shortly after transmyocardial laser revascularization) and increased under stress (100% versus 144.33+/-46.42, P=0.029 and 100% versus 116.26+/-21.06, P=0.034; respectively). In contrast, the corresponding ischemic group values were not different from initial values (P=ns). CONCLUSIONS: This model of chronic regional ischemia demonstrates that CO(2)-laser revascularization significantly improves microperfusion and regional function, whereas the overall perfusion and global LV function is unchanged.

Investigations on the new free radical scavenger polynitroxyl-albumin to prevent ischemia and reperfusion injury after orthotopic heart transplantation in the pig model.

OBJECTIVE: Nitroxides have strong antioxidant capacity but their effectiveness is limited by their rapid intracellular inactivation. Polynitroxyl-Albumin (PNA) is capable of regenerating inactivated nitroxide. We tested the effect of PNA against reperfusion injury in heart transplantation. METHODS: Pig hearts were transplanted orthotopically. In the control group (n=9) reperfusion was performed without reperfusion modifications. In the experimental group (n=10) 1 ml/kg PNA was given before cross-clamp release. RESULTS: Hemodynamic performance was impaired after transplantation in both groups without significant intergroup differences. Plasma malonedialdehyde levels were significantly diminished in the PNA group as compared to the controls. CK-MB levels in both groups were increased within the first 2 h of reperfusion without significant intergroup differences. In contrast, there were found significant higher values of myocardial specific lactate dehydrogenase (LD1) in the controls versus PNA group. CONCLUSIONS: PNA was able to reduce lipid peroxidation and attenuate free radical activity. Contractile dysfunction could no be improved, indicating that (a) the radical scavenging effect was to weak or (b) other mechanisms than free oxygen radicals are responsible for myocardial damage in this experimental model.

[Endoventricular patch plasty in patients with idiopathic dilated cardiomyopathy: an alternative to heart transplantation?]. / Endoventrikuläre Patchplastik bei Patienten mit idiopathischer, dilatativer Kardiomyopathie--eine Alternative zur Herztransplantation?

BACKGROUND: Although the concept of reducing wall tension as a treatment for advanced heart failure is convincing, clinical data from the Batista operation are conflicting. Despite a number of publications, it is not clear whether left ventricular reduction surgery is truly of benefit for patients with idiopathic, dilated cardiomyopathy (DCM). Surgery may reduce wall tension but the reason for dilation and contractile dysfunction remains. Thus, the potential benefit of the operation may be overshadowed by the natural course of the underlying disease. CASES: We report a series of five cases where left ventricular reduction was performed and physiological geometry was restored in patients with DCM by a modification of Dor's endoventricular patch plasty. All patients demonstrated an improvement in cardiac function immediately after the operation. This improvement was sustained in one of the patients at 18 months follow-up. Another patient developed severe heart failure due to therapy resistant ventricular arrhythmia (Lown IVb), and underwent successful transplantation 4 months after ventricular reduction surgery. Left ventricular dilation reoccurred in two patients 9 and 12 months after reduction surgery, and they were listed for transplant. One patient died after 9 weeks due to sepsis and respiratory dysfunction. CONCLUSIONS: Although the endoventricular patch plasty as used in this study is well tolerated by most patients with dilated cardiomyopathy and results in immediate improvement of contractile function, the long-term benefits of this technique for DCM are uncertain. Thus, the technique is currently not an alternative for heart transplantation. However, the procedure may be an option in patients with contraindications for transplantation.

Evaluation of transmyocardial laser revascularization by following objective parameters of perfusion and ventricular function.

BACKGROUND: Does transmyocardial laser revascularization (TMLR), a new surgical technique for treating patients with otherwise intractable angina pectoris, improve myocardial perfusion, metabolism, and, consequently, function? METHODS: Patients referred for TMLR, alone or with coronary artery bypass grafting (CABG), were preoperatively evaluated clinically and by treadmill stress testing, echocardiography, ventriculography, radionuclide assessment of perfusion and metabolism, and hemodynamic assessment. Intraoperatively it was decided that some patients only required CABG. Follow-up evaluations were repeated after 6 (n = 40) and 12 months (n = 23) and compared with preoperative values. RESULTS: CABG only was performed in 35 cases, TMLR + CABG in 17, TMLR only in 45. 1-year mortality was 11% in the TMLR, zero in the TMLR + CABG, and 11% in the CABG groups. In all groups a significantly improved CCS angina- and NYHA class was observed immediately after operation and after 6 and 12 months. In all study groups treadmill tolerance (p<0.05) improved, but regional and global function, perfusion at rest, and metabolism were not significantly changed at 6 and 12-months follow-ups. Perfusion studies under stress demonstrated an improvement only in the CABG group after 12 months (p<0.05), whereas in both TMLR groups the lasered ischemic segments remained unchanged. CONCLUSIONS: TMLR significantly improves long-term clinical status and treadmill stress tolerance, but appears to have little if any effect upon regional and global function, perfusion, and metabolism.

Evaluation of the indirect revascularization method after 3 months chronic myocardial ischemia.

OBJECTIVE: The long-term effectiveness of transmyocardial laser revascularization (TMLR) was evaluated in the setting of a severe left anterior descending artery (LAD) stenosis. METHODS: To employ the chronic ischemic model, pigs underwent three operative procedures over a 13-week period. In the first operation, an operative stenosis of the LAD was created. One week later, the animals were studied at baseline by analyzing different parameters of perfusion (microspheres), function and ECG changes. Afterwards, pigs were randomized into one of three different experimental groups: animals in laser group 1 received one laser channel (n=9) and laser group 2 two channels per cm(2) (n=6) in the LAD territory (using a CO(2)-laser). Animals of the ischemic group (n=12) underwent the same procedures without TMLR-treatment. Twelve weeks later, the animals were re-studied (third operation) and killed. Additional analysis of myocardial water content and histochemistry was performed. RESULTS: Chronic myocardial ischemia and regional myocardial blood flow (RMBF) in laser group 2 revealed relatively higher RMBF values compared with the ischemic group (P=0.015), after 3 months, but no absolute improvement of perfusion at rest compared with baseline was observed in all experimental groups. Left ventricular stroke work index (LVSWI) at rest and under stress did not show any improvement compared with initial values in all study groups (P not significant). However, laser group 1 demonstrated relatively higher LVSWI(max) values in comparison with the ischemic group (P=0.013) as did laser group 2 (P=0.017). Regional contractility of the laser groups recovered after 3 months (which was deteriorated shortly after TMLR, P<0.001) and increased under stress compared with baseline (laser 1: P=0.015, laser 2: P=0.017). In contrast, the ischemic group did not show any difference from initial values (P not significant). The lased pigs of group 2 were less prone to intractable ventricular fibrillation (P=0.036 vs. ischemic group), and showed a significant smaller area of necrosis in the area at risk (P=0.012 vs. ischemic group). CONCLUSIONS: This model of chronic regional ischemia demonstrates that CO(2)-laser revascularization significantly ameliorates microperfusion and regional contractility, and diminishes the incidence of ventricular fibrillation and necrosis in the area at risk. However, it does not change the overall perfusion and global LV function.

Successful orthotopic pig heart transplantation from non-heart-beating donors.

BACKGROUND: With the aim to expand the severely limited donor pool by use of non-heart-beating donors we developed a technique for successful transplantation of hearts after 30 minutes of normothermic ischemia without donor pretreatment. METHODS: In control groups hearts were transplanted in a conventional fashion using crystalloid cardioplegia (Group I, n = 6) or BCP (Group II, n = 8) for induction of cardiac arrest. In the ischemic groups hearts were harvested after 30 minutes of normothermic ischemia, perfused with blood cardioplegia (BCP) (Group III, n = 9) or BCP containing the Na(+)-H(+)-exchange inhibitor HOE 642 (Group IV, n = 8) and transplanted orthotopically. RESULTS: All animals could be weaned from cardiopulmonary bypass. Low dose inotropic support was necessary in the ischemic groups only. Recovery of the maximal left ventricular stroke work index (LVSWImax) in Groups I vs II was 62.6+/-19.6% vs 73.3+/-23.3% (NS), maximal right ventricular stroke work index (RVSWImax) averaged 61.1+/-18.8 vs 87.8+/-31.7% (NS) as compared to the preoperative level. In the ischemic groups (III vs IV) LVSWImax was 27.3+/-11.7 vs 59.5+/-32.4% (p = 0.038), RVSWImax was 27.4+/-20.9 vs 64.2+/-46.6% (NS). CONCLUSIONS: The results indicate that (a) successful pig heart transplantation after 30 minutes of normothermic ischemia is possible without donor pretreatment, and (b) that HOE 642 improves posttransplant LVSWImax significantly.

Diagnostic and surgical approach of innominate artery saddle embolus.

Patients with an acute arterial occlusion of the right upper extremity and absent axillary pulse should have a Doppler scan examination before a balloon catheter embolectomy is performed. If there is no arterial pulse detectable, an angiography should be performed afterwards to localize the embolus. In the case of a proximal arterial occlusion of the right arm, the authors recommend this procedure to prevent an embolus dislocation by catheter embolectomy and subsequent cerebral embolization. For direct surgical embolectomy the authors recommend a supraclavicular incision.

Transmyocardial laser-revascularization: experimental studies on prolonged acute regional ischemia.

OBJECTIVE: This experimental study in pigs was undertaken to answer the question whether TMLR after acute myocardial infarction may improve regional myocardial perfusion, left ventricular function and diminish myocardial necrosis in the area at risk. METHODS: Thirty open-chest anesthetized pigs were observed for 6 h, six pigs served as controls. In 24 pigs, occlusion of the left anterior descending artery (LAD) beyond the first diagonal branch was performed: seven pigs had LAD occlusion only (ischemia group), and 17 pigs were treated by TMLR (using a CO2-laser, energy: 40 J) prior to coronary occlusion; nine pigs received one laser channel (1 mm diameter) per cm2 (laser group 1) and eight pigs two channels per cm2 in the LAD territory (laser group 2). Regional myocardial blood flow by microspheres, function (franc starling curves), histochemical assessment (triphenyl tetrazolium chloride, TTC and histology), were performed. RESULTS: The lased pigs were less prone to ventricular fibrillation (laser group 2, 38%; laser group 1, 56%; ischemic group, 100%; P < 0.05), and showed a significant smaller area of necrosis (TTC) in the area at risk (laser group 1, 23%; laser group 2, 14%; vs. ischemia group, 31%; P < 0.01). There was no significant difference between laser-treated and ischemia hearts regarding the amount of blood flow into the infarcted LAD region and the maximal left ventricular stroke work index after 6 h (P = n.s). Regional myocardial blood flow: ischemia group, 4 +/- 5 ml/100 g/min; laser group 1, 3 +/- 10 ml/100 g/min, and laser group 2, 2 +/- 10 ml/100 g/min; maximal left ventricular stroke work index: ischemia group, 1.8 mJ/g; laser group 1, 2.1 mJ/g and laser group 2, 2.1 mJ/g. CONCLUSIONS: This model of acute regional ischemia demonstrates that CO2-laser revascularization diminish significantly the incidence of ventricular fibrillation and necrosis in the area at risk, and does not change regional myocardial perfusion and global left ventricular function. This experiment indicates that TMLR may be an alternative in treating advanced ischemic heart disease.

Normoxic cardiopulmonary bypass reduces oxidative myocardial damage and nitric oxide during cardiac operations in the adult.

OBJECTIVE: Hyperoxic cardiopulmonary bypass is widely used during cardiac operations in the adult. This management may cause oxygenation injury induced by oxygen-derived free radicals and nitric oxide. Oxidative damage may be significantly limited by maintaining a more physiologic oxygen tension strategy (normoxic cardiopulmonary bypass). METHODS: During elective coronary artery bypass grafting, 40 consecutive patients underwent either hyperoxic (oxygen tension = 400 mm Hg) or normoxic (oxygen tension = 140 mm Hg) cardiopulmonary bypass. At the beginning and the end of bypass this study assessed polymorphonuclear leukocyte elastase, nitrate, creatine kinase, and lactic dehydrogenase, antioxidant levels, and malondialdehyde in coronary sinus blood. Cardiac index was measured before and after cardiopulmonary bypass. RESULTS: There was no difference between groups with regard to age, sex, severity of disease, ejection fraction, number of grafts, duration of cardiopulmonary bypass, or ischemic time. Hyperoxic bypass resulted in higher levels of polymorphonuclear leukocyte elastase (377 +/- 34 vs 171 +/- 32 ng/ml, p = 0.0001), creatine kinase 672 +/- 130 vs 293 +/- 21 U/L, p = 0.002), lactic dehydrogenase (553 +/- 48 vs 301 +/- 12 U/L, p = 0.003), antioxidants (1.97 +/- 0.10 vs 1.41 +/- 0.11 mmol/L, p = 0.01), malondialdehyde (1.36 +/- 0.1 micromol/L,p = 0.005), and nitrate (19.3 +/- 2.9 vs 10.1 +/- 2.1 micromol/L, p = 0.002), as well as reduction in lung vital capacity (66% +/- 2% vs 81% +/- 1%,p = 0.01) and forced 1-second expiratory volume (63% +/- 10% vs 93% +/- 4%, p = 0.005) compared with normoxic management. Cardiac index after cardiopulmonary bypass at low filling pressure was similar between groups (3.1 +/- 0.2 vs 3.3 +/- 0.3 L/min per square meter). [Data are mean +/- standard error (analysis of variance), with p values compared with an oxygen tension of 400 mm Hg.] CONCLUSIONS: Hyperoxic cardiopulmonary bypass during cardiac operations in adults results in oxidative myocardial damage related to oxygen-derived free radicals and nitric oxide. These adverse effects can be markedly limited by reduced oxygen tension management. The concept of normoxic cardiopulmonary bypass may be applied to surgical advantage during cardiac operations.

Orthotopic transplantation of pig hearts harvested after 30 min of normothermic ischemia: controlled reperfusion with blood cardioplegia containing the Na+-H+-exchange inhibitor HOE 642.

OBJECTIVES: The aim of our study was to develop a surgical technique for a successful transplantation of hearts harvested after 30 min of normothermic ischemia without donor pretreatment. Successful transplantation of ischemic compromised hearts could help to expand the severely limited donor pool. We used the pig model because this species is very susceptible to myocardial ischemia. Na+-H+-exchange (NHE) inhibitors have shown excellent protective properties in several in vitro and in vivo models of myocardial ischemia and reperfusion. METHODS: In group I (n=12) hearts were harvested after 30 min of normothermic ischemia following cardiac arrest induced by exsanguination. Hearts were perfused with warm blood cardioplegia and transplanted orthotopically. In group II (n=9) controlled reperfusion with cold leucocyte-depleted blood cardioplegia was performed after 30 min of normothermic ischemia. In group III (n=8) the same procedure was performed as in group II but blood cardioplegia contained 1 mmol/l HOE 642. RESULTS: In group I massive myocardial oedema was observed and none of the animals could be weaned from cardiopulmonary bypass (CPB). In contrast, all animals in groups II and III could be weaned from CPB with low dose inotropic support. In groups II and III the contractility of the hearts, expressed as maximal left and right ventricular stroke work index was significantly impaired after transplantation as compared with the preoperative value. Supplementation of blood cardioplegia with HOE 642 resulted in a significantly better recovery of the LVSWImax (Group II vs. III). CONCLUSIONS: Successful transplantation of pig hearts is possible after 30 min of normothermic ischemia without donor pretreatment if a controlled reperfusion with cold leucocyte-depleted blood cardioplegia is performed. HOE 642 given during reperfusion only improves posttransplant left ventricular function.

Transcatheter closure of atrial septal defects by the "buttoned" device: complications and need for surgical revision.

Immediate and medium-term experience with transcatheter closure of a secundum atrial septal defect by the "buttoned" device in seven patients is reported. Complications occurred in two patients during the procedure. In one patient with complications, the occluder was partly released in the right atrium. All efforts to correct its position were unsuccessful and caused considerable deformation of the device, which had to be removed surgically. In the other patient with complications, disconnection of the occluder and counteroccluder occurred immediately after removal of the loading wire. Both parts were retrieved by catheter. Five patients had uneventful closure of the atrial septal defect. On follow-up, however, displacement of the device towards the mitral valve was observed in two patients, which caused mitral regurgitation. Surgical removal of the device and repair of the mitral valve was necessary in both patients. Two years after the procedure, the atrial septal defect was closed completely in two of the remaining three patients and a small residual defect persisted in one patient.

MEDOS HIA-VAD biventricular assist device for bridge to recovery in fulminant myocarditis.

Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the MEDOS HIA-VAD ventricular assist device. The device worked for 17 days and provided adequate hemodynamics. Despite anticoagulation therapy, we had to change both ventricles because of clot formation on the surface of the outflow tract. After 17 days the myocardial function had recovered and we could remove the assist system.

[Successful treatment of fulminant myocarditis with the biventricular MEDOS Assist System (MEDOS HIA-VAD)]. / Erfolgreiche Behandlung einer fulminanten Myokarditis mit dem biventrikulären MEDOS Assist-System (MEDOS HIA-VAD).

BACKGROUND: Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the new MEDOS HIA ventricular assist device. METHODS AND RESULTS: We used the MEDOS assist system to support a 30-year-old woman with profound circulatory impairment caused by acute myocarditis. The device provided adequate hemodynamics and recovery of myocardial function. Despite anticoagulation therapy we had to change either the left or right ventricular pump chamber because of clot formation on the surface of the outflow tract. On the 14th postoperative day a surgical reintervention was necessary for bleeding from the cannulation site of the pulmonary artery. After 17 days the myocardial function had recovered and we could remove the assist system. The following parameters were measured before implantation of the MEDOS assist system and after weaning from circulatory support: ejection fraction 15 vs. 45%, cardiac index 0.7 vs. 2.6 L/min/m2, arterial pressure (systolic/diastolic/mean) 81/55/66 vs. 113/66/82 mm Hg, pulmonary artery pressure 33/25/29 vs. 34/20/28 mm Hg, pulmonary capillary wedge pressure 24 vs. 19 mm Hg. CONCLUSIONS: Despite severe cardiac failure in fulminant myocarditis requiring biventricular mechanical support full recovery of the myocardium is possible.