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Abstract Background Visceral Fat Area (VFA) is an independent predictor of coronary disease. While low density lipoprotein cholesterol (LDL-C) is used to determine risk and guide therapy, its accuracy fails in obese patients who may have low LDL-C despite high VFA. Objective We sought to describe the relationship between VFA, LDL-C and to describe shifting cholesterol metabolism with increasing VFA. Methods 42 High-risk vascular patients not on lipid-lowering therapy provided a fasting lipid profile and underwent magnetic resonance imaging (MRI) to quantify VFA and subcutaneous fat area (SFA) at the L4-L5 disc. Comparisons: 1. Correlation between VFA, SFA, LDL-C and the standard lipid panel 2. Correlation between VFA, SFA and markers of cholesterol synthesis (desmosterol, lathosterol) and cholesterol absorption (cholestanol, sitosterol). Results VFA was inversely correlated with LDL-C (r = -0.348) indicating potential discordance between cardiovascular risk and LDL-C. However, VFA was appropriately correlated with other markers of increased risk: r = -0.361 with HDL-C, r = 0.503 with VLDL-C, r = 0.499 with TG (all p < 0.05). VFA did not correlate significantly with non-HDL-C. VFA correlated positively with cholesterol synthesis markers (desmosterol, lathosterol) and negatively with an absorption marker (cholestanol). Conclusions LDL-C is inversely correlated with VFA and this may explain the loss of the relationship between LDL-C and cardiovascular events in the obese. While Non-HDL-C did not correlate positively with VFA, the absence of a negative correlation suggests that it may be a more appropriate lipid target in an increasingly obese world.

Abstract Objective To determine whether liver fat percent (LFP) is associated with the metabolic syndrome independently of visceral fat area (VFA). Methods 43 High-risk vascular patients not on lipid-lowering therapy were evaluated for the Adult Treatment Panel III (ATPIII) metabolic syndrome criteria and underwent magnetic resonance imaging (MRI) to quantify VFA and subcutaneous fat area (SFA) at the L4-L5 disc and liver magnetic resonance spectroscopy (MRS) to quantify LFP. Comparisons: 1. Baseline differences in patients with and without the metabolic syndrome 2. Forward binary logistic regression analysis of predictors of the metabolic syndrome with VFA, SFA and LFP as independents 3. Correlates of LFP. Results 43 patients were included in analysis. Patients with metabolic syndrome had greater VFA, SFA and LFP than patients without the metabolic syndrome (all p < 0.01). Of VFA, SFA and LFP, only LFP was associated with the diagnosis of the metabolic syndrome on forward binary logistic regression with an OR of 1.17 per 1% increase in LFP (p = 0.015). A 4% LFP threshold identified the metabolic syndrome with 84% sensitivity and 82% specificity. LFP correlated with waist circumference (r = 0.768), HDL-cholesterol (r = -0.342), triglyceride (r = 0.369), fasting glucose (r = 0.584) and the QUICK Index of insulin sensitivity (r = -0.679) (all p < 0.05) Conclusions LFP is associated with the metabolic syndrome and renders the current gold standard of VFA redundant in this analysis. This measure of obesity-related cardiovascular risk requires further validation and evaluation in a prospective cohort.

Ageing is associated with endothelial dysfunction, decreased endothelial progenitor cell (EPC) function and mobilization. These defects culminate in a decreased capacity for neovascularization in the aged. Multiple lines of evidence suggest that defective neovascularization with ageing is related to depressed signaling by hypoxia inducible factor-1 (HIF-1). HIF-1, the master regulator or neovascularization, regulates the expression of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1) and CXC chemokine Receptor-4 (CXCR4). Given that the SDF-1/CXCR4 axis is a crucial regulator of progenitor cell function and homing, the ramifications of depressed HIF-1 signaling with age include depressed vascular repair, neovascularization and wound healing. We review the literature showing the depression of these processes with age and discuss the relevance of these findings to several clinical contexts. Further, the effects of age on EPC number, function and mobilization are related to the age-related decline in HIF-1 signaling. We suggest that exercise, Cobalt compounds or hydralazine may reverse the age-related decline by up-regulating HIF-1-mediated signaling.

Recent studies revealed an exceedingly high mortality with diastolic heart failure that was previously regarded as relatively benign compared to systolic heart failure. Prominent risk factors for diastolic heart failure are increasing age, hypertension and diabetes. These risk factors are associated with coronary microvascular rarefaction and resultant decreased coronary flow reserve, thereby rendering the myocardium vulnerable to ischemia. We discuss the importance of angiogenic gene programming in preserving the coronary microvasculature, preserving cardiac function and altering disease course. Further, we discuss the possible utility of therapies that activate hypoxia inducible factor-1 in preventing rarefaction of the coronary microvasculature and maintaining cardiac diastolic function.

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.