The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort.

OBJECTIVE: The CC genotype of the C3435T polymorphism in ABCB1 is associated with increased P-glycoprotein expression, reduced low-density lipoprotein cholesterol (LDL-C) response to atorvastatin, and a reduced area-under-the-curve in pharmacokinetic studies. We sought to assess the relationship between 1) genotype and Atorvastatin efficacy, independently of variation in cholesterol metabolism and 2) genotype and myalgia. METHODS: High-risk vascular patients were genotyped and treated with atorvastatin 80 mg for 6 weeks. The lipid panel and percent LDL-C reduction with atorvastatin were related to C3435T genotype. Genotypes and allele frequency were assessed in patients with and without myalgia. RESULTS: A total of 117 patients were recruited and genotyped. Of these, 98 completed the study with adequate atorvastatin adherence, and 10 reported myalgia. T and C allele frequencies were 0.63 and 0.37, respectively. A 6-week course of atorvastatin (80 mg/day) reduced LDL-C by 58% ± 11% (mean ± SD). Patients with the CC genotype showed less LDL-C reduction with atorvastatin compared with the TT/TC genotype (53% vs 59%, respectively, P = .034), and this finding was independent of variation in cholesterol metabolism (P = .045 after correction for desmosterol and cholestanol/cholesterol ratio). The T allele was more frequent in patients with myalgia than those without (0.80 vs 0.62) and the C allele less frequent (0.20 vs 0.38, P = .043). CONCLUSION: In patients treated with atorvastatin, the CC genotype at the C3435T polymorphism in ABCB1 is associated with reduced atorvastatin efficacy independently of cholesterol metabolism. The T allele is more frequent and the C allele less frequent in patients with myalgia.

Low density lipoprotein cholesterol is inversely correlated with abdominal visceral fat area: a magnetic resonance imaging study.

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.

MRI sagittal abdominal diameter is a stronger predictor of metabolic syndrome than visceral fat area or waist circumference in a high-risk vascular cohort.

OBJECTIVE: To determine whether sagittal abdominal diameter (SAD) is associated with the metabolic syndrome independently of visceral fat area (VFA) and waist circumference (WC). METHODS: Forty-three high-risk vascular patients were evaluated for metabolic syndrome criteria and underwent magnetic resonance imaging (MRI) to quantify SAD and VFA at the L4-L5 disc. 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 SAD, VFA and WC as independents 3. Correlates of SAD. RESULTS: Patients with metabolic syndrome had greater SAD, VFA and WC than patients without the metabolic syndrome (P < 0.01). Of SAD, VFA and WC, only SAD was associated with metabolic syndrome on forward binary logistic regression; beta 0.68, Wald's statistic 10.8 (P = 0.001) and c-statistic 0.89 (P < 0.001). A > 22.7 cm SAD threshold identified metabolic syndrome with a 91% sensitivity and 80% specificity. SAD correlated with waist circumference (r = 0.918), high-density lipoprotein-cholesterol (r = -0.363), triglyceride (r = 0.401), fasting glucose (r = 0.428) and the QUICK index of insulin sensitivity (r = -0.667) (all P < 0.05). CONCLUSIONS: MRI-measured SAD is associated with the metabolic syndrome and renders the current gold standard of VFA redundant. This measure of obesity-related cardiovascular risk requires validation and evaluation in a prospective cohort.

Markers of cholesterol absorption and synthesis predict the low-density lipoprotein cholesterol response to atorvastatin.

OBJECTIVE: Genetic loci predict <5% of variation in low-density lipoprotein cholesterol (LDL-C) response to statins. Cholestanol and desmosterol are plasma markers of cholesterol absorption and synthesis, respectively. Because statins lower LDL-C by inhibiting cholesterol synthesis, we studied the relationship between cholestanol and desmosterol and LDL-C response to atorvastatin. METHODS: High-risk patients were treated with 80 mg of atorvastatin for 6 weeks. LDL-C response to atorvastatin was related to baseline cholestanol to cholesterol ratio (CCR) and desmosterol. The following comparisons were used: (1) correlates of percentage LDL-C response, (2) baseline characteristics of hyperresponders versus hyporesponders, and (3) binary logistic regression analysis for predictors of achieved LDL-C <70 mg/dL. RESULTS: One hundred fifty-four patients were enrolled of which 118 completed the study with adequate adherence. Average LDL-C reduction was 57% ± 13% (mean ± SD). On univariate analysis, desmosterol and CCR correlated with percentage LDL-C reduction and multivariate modeling explained approximately 16% of the variation in response. Atorvastatin hyperresponders had higher mean desmosterol (P = 0.046) and lower CCR (P = 0.035) than hyporesponders. On logistic regression analysis for the outcome of achieved LDL-C of <70 mg/dL, baseline LDL-C and CCR were significant predictors; odds ratios were 0.932 and 0.979, respectively. CONCLUSIONS: CCR and desmosterol explain more variation in LDL-C response to statin than that reported with pharmacogenomics. CCR and desmosterol may guide lipid-lowering therapy.

Liver fat percent is associated with metabolic risk factors and the metabolic syndrome in a high-risk vascular cohort.

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.

Insulin resistance is associated with increased cholesterol synthesis, decreased cholesterol absorption and enhanced lipid response to statin therapy.

OBJECTIVE: Increasing insulin resistance is associated with a shift in cholesterol metabolism to increased synthesis and decreased absorption. Since statins inhibit cholesterol synthesis, we hypothesized that insulin-resistant patients will have greater LDL cholesterol (LDL-C) response to statins than insulin-sensitive patients. METHODS: High-risk vascular patients not on lipid-lowering therapy were recruited and treated with Atorvastatin 80 mg for 6 weeks. Percent LDL-C response to Atorvastatin was related to insulin sensitivity using the quantitative insulin sensitivity check index (QUICKI). Comparisons: (1) correlation between %LDL-C response and QUICKI. (2) Differences in cholesterol metabolism markers in insulin-resistant (lowest tertile QUICKI) vs insulin-sensitive patients (highest tertile of QUICKI). (3) Correlation of QUICKI with percent LDL-C response after correction for cholesterol metabolism markers. RESULTS: 154 patients were enrolled of which 66 were suitable for this sub-study. Average LDL-C reduction was 57+/-12% (mean+/-SD). QUICKI correlated negatively with percent LDL-C reduction (Pearson's r=-0.258, p=0.037) and on regression analysis explained approximately 7% (R2=0.067) of the variation in percent LDL-C response which approximates that reported by pharmacogenomics. Insulin-resistant patients had higher levels of cholesterol synthesis markers (desmosterol, lathosterol) and lower levels of absorption markers (cholestanol, sitosterol) and the correlation between QUICKI and percent LDL-C response ceased to be significant when these factors were controlled for. CONCLUSIONS: Insulin-resistant patients have superior LDL-C responses to statin therapy and that this may be related to increased cholesterol synthesis. BACKGROUND: Patients with features of the metabolic syndrome, e.g. high triglycerides (TG) and low high density lipoprotein cholesterol (HDL-C) may have an enhanced benefit from statin therapy. A retrospective analysis from the 4S investigators where the study population was stratified by HDL-C and TG quartiles revealed variations in statin efficacy. Patients who fell into both the lowest quartile of HDL-C (<39 mg/dl) and highest quartile of TG (>159 mg/dl) had a greater frequency of features of the metabolic syndrome (high BMI, hypertension, diabetes) than the patients in the highest quartile of HDL-C (>52 mg/dl) and lowest quartile of TG (<98 mg/dl). The 4S investigators suggested that patients with low HDL-C and high TG achieved an enhanced clinical benefit from statins compared to patients with high HDL-C and low TG with hazard ratios of 0.48 and 0.86 respectively and a treatment-by-subgroup interaction p value of 0.03 [1]. Since the clinical benefit of statin therapy is directly proportional to achieved percent reduction in low density lipoprotein cholesterol (LDL-C) [2], we hypothesized that insulin-resistant patients would have greater percent decreases in LDL-C with statin therapy.

Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era.

BACKGROUND: In patients with unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI) two strategies are possible, either a routine invasive strategy where all patients undergo coronary angiography shortly after admission and, if indicated, coronary revascularization; or a conservative strategy where medical therapy alone is used initially, with selection of patients for angiography based on clinical symptoms or investigational evidence of persistent myocardial ischemia. OBJECTIVES: To determine the benefits of an invasive compared to conservative strategy for treating UA/NSTEMI in the stent era. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE and EMBASE were searched (1996 to February 2008) with no language restrictions. SELECTION CRITERIA: Included studies were prospective trials comparing invasive with conservative strategies in UA/NSTEMI. DATA COLLECTION AND ANALYSIS: We identified five studies (7818 participants). Using intention-to-treat analysis with random-effects models, summary estimates of relative risk (RR) with 95% confidence interval (CI) were determined for primary end-points of all-cause death, fatal and non-fatal myocardial infarction, all-cause death or non-fatal myocardial infarction, and refractory angina. Further analysis of included studies was undertaken based on whether glycoprotein IIb/IIIa receptor antagonists were used routinely. Heterogeneity was assessed using Chi(2) and variance (I(2) statistic) methods. MAIN RESULTS: In the all-study analysis, mortality during initial hospitalization showed a trend to hazard with an invasive strategy (RR 1.59, 95% CI 0.96 to 2.64). The invasive strategy did not reduce death on longer-term follow up. Myocardial infarction rates assessed at 6 to 12 months (5 trials) and 3 to 5 years (3 trials) were significantly decreased by an invasive strategy (RR 0.73, 95% CI 0.62 to 0.86; and RR 0.78, 95% CI 0.67 to 0.92 respectively). The incidence of early (< 4 month) and intermediate (6 to 12 month) refractory angina were both significantly decreased by an invasive strategy (RR 0.47, 95% CI 0.32 to 0.68; and RR 0.67, 95% CI 0.55 to 0.83 respectively), as were early and intermediate rehospitalization rates (RR 0.60, 95% CI 0.41to 0.88; and RR 0.67, 95% CI 0.61 to 0.74 respectively). The invasive strategy was associated with a two-fold increase in the RR of peri-procedural myocardial infarction (as variably defined) and a 1.7-fold increase in the RR of (minor) bleeding with no hazard of stroke. AUTHORS' CONCLUSIONS: Compared to a conservative strategy for UA/NSTEMI, an invasive strategy is associated with reduced rates of refractory angina and rehospitalization in the shorter term and myocardial infarction in the longer term. However, the invasive strategy is associated with a doubled risk of procedure-related heart attack and increased risk of bleeding and procedural biomarker leaks. Available data suggest that an invasive strategy may be particularly useful in those at high risk for recurrent events.

Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1.

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.

The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure.

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.

Implications of the obesity epidemic for lipid-lowering therapy: non-HDL cholesterol should replace LDL cholesterol as the primary therapeutic target.

Obesity, metabolic syndrome and diabetes are conditions with increasing prevalence around the world. Cardiovascular risk in diabetics is often so high as to overlap with event rates observed in those with established coronary disease and this has lead to diabetes being classified as a coronary risk equivalent. However, despite the elevated risk of cardiovascular events associated with diabetes and the metabolic syndrome, these patients often have normal low density lipoprotein (LDL) cholesterol despite frequent increases in apolipoprotein B, triglycerides and nonhigh density lipoprotein (HDL) cholesterol. In contrast to LDL cholesterol, non-HDL cholesterol represents cardiovascular risk across all patient populations but is currently only recommended as a secondary target of therapy by the ATP III report for patients with hypertriglyceridemia. This article provides an overview of the studies that shown non-HDL cholesterol to be superior to LDL cholesterol in predicting cardiovascular events and presents the case for non-HDL cholesterol being the more appropriate primary target of therapy in the context of the obesity pandemic. Adopting non-HDL cholesterol as the primary therapeutic target for all patients will conceivably lead to an appropriate intensification of therapy for high risk patients with low LDL cholesterol.

Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis.

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.

Hypothesis: myostatin is a mediator of cardiac cachexia.

Myostatin is a recently described negative regulator of skeletal muscle mass. This paper hypothesizes a role for this system in cardiac cachexia and insulin resistance and osteoporosis associated with advanced heart failure.

Implications of the obesity epidemic for statin therapy: shifting cholesterol metabolism to a high synthesis and low dietary absorption state.

Obesity and the metabolic syndrome are becoming one of the biggest health challenges of the 21(st) century. Cholesterol metabolism is significantly altered in both obesity and metabolic syndrome in that cholesterol synthesis is increased and absorption reduced and this has important implications for the treatment of lipid disorders in both obesity and the metabolic syndrome. In the present review we discuss these changes in detail especially in the context of a more standardized approach for cholesterol reduction like the TARGET LDL trial. Customized care is topical in lipidology as we strive to achieve LDL cholesterol and non-HDL cholesterol targets in every patient.

Vascular grafts and the endothelium.

This article discusses the importance of the endothelium for successful vascular grafts derived from both native arteries and synthetic materials. It also discusses the fundamental strategies to endothelialize synthetic grafts in animal experiments and in the clinic, as well as the use of endothelial progenitor cells (EPCs), bone marrow-derived cells, and mesothelium as endothelial substitutes.

Cholestanol: a serum marker to guide LDL cholesterol-lowering therapy.

Statins have been the mainstay of lipid-lowering therapy since their introduction. However, as lower LDL cholesterol targets are sought, adjunct therapies are becoming increasingly important. Few patients reach new targets with statin monotherapy. We propose that the cholestanol:cholesterol ratio can be used to guide lipid-lowering therapy and result in greater numbers of patients reaching target LDL cholesterol. By determining whether a patient is mainly a synthesizer or absorber of cholesterol, customized regimens can be used and are expected to improve patient outcomes and minimize costs of treatment.

Tissue-engineered blood vessels: alternative to autologous grafts?

Although vascular bypass grafting remains the mainstay for revascularization for ischemic heart disease and peripheral vascular disease, many patients do not have healthy vessels suitable for harvest. Thus, prosthetic grafts made of synthetic polymers were developed, but their use is limited to high-flow/low-resistance conditions because of poor elasticity, low compliance, and thrombogenicity of their synthetic surfaces. To fill this need, several laboratories have produced in vivo or in vitro tissue-engineered blood vessels using molds or prosthetic or biodegradable scaffolds, but each artificial graft has significant problems. Recently, conduits have been grown in the peritoneal cavity of the same animals in which they will be grafted, ensuring no rejection, in the short time of 2 to 3 weeks. Remodeling occurs after grafting such that the tissue is almost indistinguishable from native vessels. This conduit is derived from cells of bone marrow origin, opening new possibilities in vascular modeling and remodeling.