Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway.

Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of ß-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased ß-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, ß-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.

Clinical outcomes following IVUS-guided stent deployment in a community hospital.

OBJECTIVES: A discrepancy exists in the medical literature as to what effect intravascular ultrasound (IVUS)-guided stent deployment has on target vessel revascularization (TVR) at 6 months. The major endpoints of this study are the need for TVR, defined as clinically driven repeat interventional or surgical therapy of the index vessel at 6 months and major adverse cardiac events. METHODS: One hundred interventional stent cases (50 IVUS-guided, 50 non-IVUS guided) were randomly selected in a 6-month period (January to June 2001) for review by measurement of minimal luminal diameter (MLD) pre- and post-intervention. Seventy males and 30 females were distributed among the 2 groups. There were a total of 135 lesions (70 IVUS-guided, 65 non-IVUS guided) in the 2 groups. A 6-month follow-up chart review was performed following the initial stenting. RESULTS: At 6-month follow-up, there were 2 deaths in the IVUS-guided group and 3 deaths in the non-IVUS guided group (p=NS). All deaths were cardiovascular in nature. Post-procedure MLD was 3.58+/-0.08 mm for the IVUS-guided group and 2.88+/-0.09 mm for the non-IVUS guided group [t=5.7 (df, 133); p<0.001]. Ten of 70 IVUS-guided lesions (14.3%) and 3 of 65 non-IVUS guided lesions (4.2%) underwent TVR within the 6-month study period (Chi square=3.62; p=0.057). CONCLUSION: In this population, IVUS-guided stent deployment does not appear to reduce either the need for TVR or overall cardiovascular mortality at 6 months. The added expense of IVUS does not appear to be warranted.

Obesity and the risk for cardiovascular disease.

Coronary heart disease (CHD) is the leading cause of mortality in the United States. Hypertension, diabetes mellitus, hypercholesterolemia, and smoking have all been directly related to CHD. Obesity is on the rise in the United States and has also been associated with CHD. This review clearly establishes obesity as an independent risk factor for CHD as demonstrated by the Framingham Heart Study, Nurses Health Study, Buffalo Health Study, and the Cancer Prevention Study II. Morbid obesity was found to correlate with a significant risk of mortality from CHD, especially in young men. Prevention of obesity, and therefore reduction in risk from cardiovascular disease, is paramount in the management of obesity. New approaches to behavioral, medical, and surgical management of obesity are reviewed, including thalidomide, an antiangiogenic agent. A primary and secondary prevention model details a multidisciplinary approach to reducing risk in obesity.

Increased sensitivity of the obese Zucker rat to deoxycorticosterone-salt-induced hypertension.

OBJECTIVE: The objective of this study was to test the hypothesis that obesity increases the sensitivity of rats to experimentally induced hypertension. DESIGN AND METHODS: To induce hypertension, unilaterally nephrectomized lean and obese Zucker rats were injected with 25 mg/kg of deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks and given water containing 1% NaCl to drink. Unilaterally nephrectomized control rats were injected with vehicle and drank tap water. Systolic blood pressure (SBP) was measured by the tail cuff method. Renal histology and urinary albumin excretion were used to assess the effects of the experimental treatment on the kidney. RESULTS: Obese rats exhibited a significant rise in SBP at 4 days after the start of DOCA-salt treatment. In contrast, SBP of DOCA-treated lean rats was not significantly elevated from pretreatment measurements until day 22. Moreover, SBP was significantly higher during the plateau phase of blood pressure development in obese DOCA-salt treated rats (196 mmHg) than in correspondingly treated lean rats (150 mmHg). Both obesity and DOCA-salt treatment promoted glomerulosclerosis and mild tubulointerstitial damage in the kidney with DOCA-salt treatment exacerbating the effect of obesity. Urinary albumin excretion was significantly greater in obese control rats compared with lean controls and in DOCA-treated obese rats relative to vehicle-treated obese rats. CONCLUSION: Results of this study indicate that obese Zucker rats are more sensitive to mineralocorticoid-induced hypertension than lean rats. This study provides experimental evidence supporting the epidemiological findings that obesity is a risk factor for the development of hypertension.