Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome.

Clinical metabolic syndrome conveys a poor prognosis in patients with acute coronary syndrome, not fully accounted for by the extent of coronary atherosclerosis. To explain this observation, we determined whether postischemic myocardial contractile and metabolic function are impaired in a porcine dietary model of metabolic syndrome without atherosclerosis. Micropigs (n = 28) were assigned to a control diet (low fat, no added sugars) or an intervention diet (high saturated fat and simple sugars, no added cholesterol) for 7 mo. The intervention diet produced obesity, hypertension, dyslipidemia, and impaired glucose tolerance, but not atherosclerosis. Under open-chest, anesthetized conditions, pigs underwent 45 min of low-flow myocardial ischemia and 120 min of reperfusion. In both diet groups, contractile function was similar at baseline and declined similarly during ischemia. However, after 120 min of reperfusion, regional work recovered to 21 ± 12% of baseline in metabolic syndrome pigs compared with 61 ± 13% in control pigs (P = 0.01). Ischemia-reperfusion caused a progressive decline in mechanical/metabolic efficiency (regional work/O2 consumption) in metabolic syndrome hearts, but not in control hearts. Metabolic syndrome hearts demonstrated altered fatty acyl composition of cardiolipin and increased Akt phosphorylation in both ischemic and nonischemic regions, suggesting tonic activation. Metabolic syndrome hearts used more fatty acid than control hearts (P = 0.03). When fatty acid availability was restricted by prior insulin exposure, differences between groups in postischemic contractile recovery and mechanical/metabolic efficiency were eliminated. In conclusion, pigs with characteristics of metabolic syndrome demonstrate impaired contractile and metabolic recovery after low-flow myocardial ischemia. Contributory mechanisms may include remodeling of cardiolipin, abnormal activation of Akt, and excessive utilization of fatty acid substrates.

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty.

Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.

Prescription-filling rates for key medications in Veterans Affairs patients after coronary artery bypass grafting.

PURPOSE: The six-month prescription-filling rates for key secondary-prevention drugs in Department of Veterans Affairs (VA) patients who had undergone coronary artery bypass grafting (CABG) were studied. METHODS: Patient records for elective CABG from April 2000 through March 2002 (divided into four six-month periods) were analyzed. The study population included 8925 CABG-only patients surviving to hospital discharge. For each six-month period and in aggregate, the primary study endpoint was the six-month prescription-filling rate. RESULTS: Across the four six-month periods, prescription-filling rates increased for all categories of medications studied. There were modest progressive increases for lipid-lowering agents, statins, -blockers, angiotensin-converting-enzyme Inhibitors, and angiotensin-receptor blockers. The antithrombotic-filling rate averaged 88.5%. Filling rates for aspirin were much higher than for aspirin alternatives. CONCLUSION: Prescription-filling rates for post-CABG medications in VA facilities were generally high and suggested compliance with guidelines for the prevention of cardiovascular events.

An investigation of the cytotoxicity and histocompatibility of in situ forming lactic acid based orthopedic biomaterials.

The cytotoxicity and biocompatibility of polymer networks prefabricated from multifunctional lactic acid based oligomers that are being developed for orthopedic applications were assessed through in vitro cytotoxicity analysis and subcutaneous implantation. After 7 and 14 days, no significant difference was observed in the relative viability or alkaline phosphatase activity of primary rat calvarial osteoblasts cultured in the presence or absence of degrading polymer networks, indicating that the degradation products had no detrimental effect on the function or activity of the cultured cells. The tissue response to preformed lactic acid networks implanted in rats consisted of a mild inflammatory response with an increase in fibrous capsule thickness and inflammation correlating with faster degrading polymer compositions. This relatively neutral response is indicative of a biocompatible, degradable polymer that has potential medical applications. Finally, porous scaffolds were implanted subcutaneously in rats, and vascularized fibrous tissue infiltration was highly dependent on the scaffold porosity and architecture. This finding indicates that an in situ forming porous scaffold of this composition may support the infiltration of surrounding vascularized tissue, and thus be applicable to orthopedic treatments of large bone defects.