Objective
Although a large variety of animal models for acute ischemia and acute heart failure exist, valuable models for studies on the effect of ventricular assist devices in chronic heart failure are scarce. We aimed to establish a stable and reproducible animal model of chronic heart failure in sheep.
Methods
Sheep (n=8, 77 ± 4 kg) were anesthesized and a 5F sheath was implanted into the left carotid artery. The left main coronary artery was catheterized under flouroscopic guidance and bolus injection of polysterol microspheres (90 μm, n=25.000) was performed. Microembolization (ME) was repeated up to three times in two to three week intervals until animals started to develop stable clinical signs of heart failure. Clinical and echocardiographic data were analyzed at baseline (base) and at three months (3 mo) after first ME. All animals were followed for 3 months after first microembolization and then sacrificed for histological examination. Another four healthy sheep (79±6 kg) served as control animals.
Results
All animals developed clinical signs of heart failure as indicated by increased heart rate at rest (68±4 bpm (base) to 93 ± 5 bpm (3 mo) (p<0.05)), increased respiratory rate at rest (28±5 (base) to 38 ± 7 (3 mo) (p<0.05)) and increased body weight 77 ± 2 kg to 81 ± 2 kg (p<0.05) due to pleural effusion, peripheral edema and ascites. Echocardiographic evaluation revealed significantly an increase of left ventricular enddiastolic diameter from 46 ± 3 mm (base) to 61 ± 4 mm (3 mo) (p<0.05). Clinically and echocardiographically no significant changes were revealed in healthy control animals.
Conclusions
We conclude that multiple sequential intracoronary microembolization can effectively induce myocardial dysfunction with clinical and echocardiographical signs of chronic ischemic cardiomyopathy. The present model may be suitable in experimental work on heart failure and left ventricular assist devices, e.g. for studying the impact of mechanical unloading, mechanisms of recovery and reverse remodeling.
Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP-binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI-H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy.
We evaluated the newly developed miniaturized HIA microdiagonal blood pump (MDP) as a continuous flow left ventricular assist device. In a sheep model (n = 6), the MDP was implanted through left lateral thoracotomy and placed paracorporeally with inflow conduit to left atrium and outflow conduit to descending aorta. The sheep were pumped at a mean flow rate of 2.5 L/min for 7 days. Anticoagulation was applied by intravenous heparin administration. Postoperatively, activated clotting time was held stable with values of 200 seconds. During follow-up, blood samples (creatinine kinase, creatinine, glutamic-oxaloacetic transaminase (aspartate aminotransferase) (GOT), glutamate dehydrogenase (GLDH), gamma-GT, plasma-free hemoglobin, and hemoglobine) were taken daily. After 7 days, the sheep were killed for macroscopic examination. Systemic artery pressures remained stable during the whole test period. Because of operative reasons, the hemoglobin value (7.5 +/- 0.61 g/dl) decreased perioperatively, but recovered within the test period, whereas creatinine kinase increased initially after thoracotomy, but decreased to normal within days. Renal and liver functions were slightly impaired perioperatively, indicated by temporarily enhanced values of GOT, gamma-GT, GLDH, and creatinine. The MDP did not produce significant hemolysis as measured by plasma-free hemoglobin levels. Wound infections did not occur. We conclude that the MDP ran successfully as an left ventricular assist device for 7 days in sheep has potential for long-term support, and may serve as an alternative to current technologies. Presented data were not obtained in a clinical trial; however, the results are promising enough to proceed with longer duration animal studies.
Our results demonstrate the presence of oral bacterial DNA in human cardiac tissue, as well as inflammatory markers potentially indicating connection of PD and VHD. Further investigation is necessary to confirm these preliminary data.
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