Effects of local delivery of tetradecylthioacetic acid within the injured coronary vessel wall.

OBJECTIVES: Inflammation is involved in cell proliferation and collagen deposition causing vessel wall remodeling and restenosis after plain balloon angioplasty. Local drug delivery of bioactive agents that reduce the incidence of adverse wall remodeling is of considerable interest concerning treatment strategies for coronary vessel disease and could alter the need of repeated revascularization. DESIGN: In this study, 34 domestic pigs undergoing coronary balloon injury were randomly assigned to Tetradecylthioacetic acid (TTA) or placebo delivered locally. After four weeks, vessel wall collagen density, inflammatory markers and lipid fractions were assessed as well as cell proliferation. RESULTS: Collagen particle count was lower after TTA compared to placebo, 177 ± 11 n/area versus 225 ± 13 n/area (p = 0.007). Interleukin-2 (IL-2) concentration was reduced, 1.6 ± 0.02 pg/ml versus 2.6 ± 0.5 pg/ml, (p = 0.01). The anti-inflammatory index was increased after TTA, 46.28 ± 12.1 versus 34.66 ± 4.5, (p = 0.025). There were no differences between TTA and placebo with regard to cell proliferation. CONCLUSIONS: Local delivery of TTA reduced the local inflammatory response and collagen accumulation. Local balloon delivery of TTA into the vessel wall may represent an alternative antiproliferative strategy for preventing restenosis, in particular for vessels with obstructive disease not available for stent implantation.

Percutaneous left ventricular assist in ischemic cardiac arrest.

BACKGROUND: Ischemic cardiac arrest represents a challenge for optimal emergency revascularization therapy. A percutaneous left ventricular assist device (LVAD) may be beneficial. OBJECTIVE: To determine the effect of a percutaneous LVAD during cardiac arrest without chest compressions and to assess the effect of fluid loading. DESIGN: Totally, 16 pigs randomized to either conventional or intensive fluid with LVAD support during ventricular fibrillation (VF). SETTING: Acute experimental trial with pigs under general anesthesia. SUBJECTS: Farm pigs of both sexes. INTERVENTIONS: After randomization for fluid infusion, VF was induced by balloon occlusion of the proximal left anterior descending artery. LVAD and fluid were started after VF had been induced. MEASUREMENTS: Brain, kidney, myocardial tissue perfusion, and cardiac index were measured with the microsphere injection technique at baseline, 3, and 15 minutes. Additional hemodynamic monitoring continued until 30 minutes. MAIN RESULTS: At 15 minutes, vital organ perfusion was maintained without significant differences between the two groups. Mean cardiac index at 3 minutes of VF was 1.2 L x min(-1) x m2 (29% of baseline, p < 0.05). Mean perfusion at 3 minutes was 65% in the brain and 74% in the myocardium compared with baseline (p < 0.05), then remained unchanged during the initial 15 minutes. At 30 minutes, LVAD function was sustained in 11 of 16 animals (8 of 8 intensified fluid vs. 3 of 8 conventional fluid) and was associated with intensified fluid loading (p < 0.001). CONCLUSIONS: During VF, a percutaneous LVAD may sustain vital organ perfusion. A potential clinical role of the device during cardiac arrest has yet to be established.

Tetradecylselenoacetic acid, a PPAR ligand with antioxidant, antiinflammatory, and hypolipidemic properties.

OBJECTIVE: Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Here we present a selenium-substituted fatty acid, tetradecylselenoacetic acid (TSA), which is hypothesized to have antioxidant, antiinflammatory, and hypolipidemic properties. METHODS AND RESULTS: We show that TSA exerts antioxidant properties by delaying the onset of oxidation of human low density lipoprotein (LDL), by reducing the uptake of oxidized LDL in murine macrophages, and by increasing the mRNA level of superoxide dismutase in rat liver. TSA also showed antiinflammatory effects by suppressing the release of interleukin (IL)-2 and -4, and by increasing the release of IL-10 in human blood leukocytes. In addition, TSA decreased the plasma triacylglycerol level and increased the mitochondrial fatty acid beta-oxidation in rat liver. In pigs, TSA seemed to reduce coronary artery intimal thickening after percutaneous coronary intervention. In HepG2 cells TSA activated all peroxisome proliferator-activated receptors (PPARs) in a dose-dependent manner. CONCLUSIONS: Our data suggest that TSA exert potent antioxidant, antiinflammatory, and hypolipidemic properties, potentially involving PPAR-related mechanisms. Based on these effects, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders.

Release of cardiac biochemical markers after percutaneous myocardial laser or sham procedures.

BACKGROUND: Percutaneous myocardial laser (PML) reduces symptoms in patients with intractable angina. PML leads to a certain loss of viable myocardium, we therefore assessed if troponin or cardiac markers release may explain the clinical effect, and furthermore assessed the markers release during percutaneous sham procedures. METHODS: Eighty-two patients with chronic refractory angina were randomized to either percutaneous myocardial laser or a true sham procedure. Cardiac markers were assessed before the procedure, and (1/2), 2, 4, 6, and 10-12 h postprocedure. RESULTS: Troponin I increased to median peak levels (range) of 4 (0.6-43) microg/L in the laser group vs. 1.5 (0.1-5.9) microg/L, p=0.001, and creatine kinase MB to 14 (6-357) microg/L vs. 11 (3-40) microg/L, p<0.05, within and between-group comparison, the rise of CK-MB occurred significantly earlier in the sham group, 3.8 vs. 2.5 h. A time-dependent between-group difference was only detected for troponin. 88% of sham and 100% of laser patients had marker levels above reference limits. There was no correlation between the number of laser/sham created channels, biomarker levels postprocedure, and changes in left ventricular ejection fraction or angina improvement during 12 months of follow-up. CONCLUSIONS: The release of cardiac markers is not related to relief of angina after myocardial laser. The use of intracardiac catheters induces a considerable marker release, which is not caused by acute ischemia.

Only transient increase of vascular growth factors and microvascular density after percutaneous myocardial laser.

OBJECTIVE: We tested the hypothesis that percutaneous myocardial laser may stimulate microvascular growth in areas surrounding the laser channels. METHODS: We conducted a study of 24 domestic pigs, which underwent percutaneous myocardial laser to left ventricular myocardium using holmium:YAG laser. The pigs were sacrificed in groups of four after one day, 3-4 days, one week, three weeks and six weeks. Frozen sections from both normal and treated myocardium were prepared for immunofluorescence microscopy and stained with antibodies against von Willebrand factor, vascular endothelial growth factor (VEGF) and Extra Domain-A cellular fibronectin (ED-AcFN). Microvascular density (MVD) and vascular area (VA) were determined in sections stained with antibodies against von Willebrand factor VIII using a digitised image analysis system. When determined in laser treated areas, channel core remnants were excluded from analysis. RESULTS: Within the laser channel remnants and in the tissue closely surrounding these, expression of VEGF and ED-AcFN increased significantly after treatment at one, 3-4, and seven days and decreased to normal at three and six weeks. Expression of ED-AcFN was detected adjacent to endothelial cells of microvessels. The original laser channels were rapidly invaded by granulation tissue. There was no sign of recanalization at any stage during the six weeks. Morphometric analysis showed no increase in MVD and VA in the myocardium surrounding the laser channels. CONCLUSION: An increase of VEGF and ED-AcFN after myocardial laser is transient and is not associated with increase of MVD or VA in myocardium not involving laser channel remnants.

Percutaneous catheter-based intracoronary infusion of insulin--a dose finding study in the porcine model.

Insulin given at immediate reperfusion reduces myocardial infarct size in the in vitro and the ex vivo rat heart. In vivo, insulin may cause hypoglycaemia, hypokalaemia and elevation of catecholamines, potentially harmful during an acute myocardial infarction. The purpose of this study was to evaluate tolerance and safety of intracoronary insulin infusions in a porcine model applying percutaneous intervention techniques.

Treatment of cardiogenic shock with left ventricular assist device combined with cardiac resynchronization therapy: a case report.

Cardiogenic shock has a poor prognosis with established treatment strategies. We report a 62 years old man with heart failure exacerbating into refractory cardiogenic shock successfully treated with the combination of a percutaneous left ventricular assist device (LVAD) and subacute cardiac resynchronization therapy (CRT) implantable cardioverter-defibrillator device (CRT-D).

Pharmacology and safety of tetradecylthioacetic acid (TTA): phase-1 study.

This study describes the clinical, hematological, and biochemical safety of tetradecylthioacetic acid (TTA). A total of 18 healthy volunteers were included. Subjects were randomly assigned into 3 groups according to the daily given dose of TTA: group 1 (200 mg), group 2 (600 mg), and group 3 (1000 mg). TTA was given as a single oral dose for 7 consecutive days. Safety was evaluated by following the adverse events, vital signs, and hematological and biochemical parameters in blood and urine samples. Efficacy was estimated through its effects on plasma lipids profile. Few adverse events of mild severity were reported. No clinically significant changes were observed in the hematological or clinical chemical parameters in blood/urine. TTA did not induce significant changes in the blood lipids or free fatty acids, but it did result in an increase in plasma concentration of Delta9 desaturated TTA (TTA: 1n-8). Serum concentration pattern of TTA at day 1 showed a 1.5-hour lag time followed by a rapid absorption and a slower elimination phase. The median peak values were 2.9 mg/L (range, 1.1 to 5.4 mg/L), 11.5 mg/L (range, 4 to 35 mg/L), and 11 mg/L (range, 5 to 25 mg/L), in groups 1, 2, and 3, respectively (P = 0.006). The time to peak levels were 3.5 hours (range, 2.5 to 6.5 hours), 2.5 hours (range, 2.5 to 4.5 hours), and 4.5 hours (range, 2.5 to 12 hours), respectively (P = 0.2). TTA is safe and well tolerated.