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Dennis L Sprecher

Publications and source records attributed to Dennis L Sprecher.

At least 19 recordsLinked to original sources
PubMed2006

Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist.

OBJECTIVE: Exercise increases fatty acid oxidation (FAO), improves serum high density lipoprotein cholesterol (HDLc) and triglycerides (TG), and upregulates skeletal muscle peroxisome proliferator activated receptor (PPAR)delta expression. In parallel, PPARdelta agonist-upregulated FAO would induce fatty-acid uptake (via peripheral lipolysis), and influence HDLc and TG-rich lipoprotein particle metabolism, as suggested in preclinical models. METHODS AND RESULTS: Healthy volunteers were allocated placebo (n=6) or PPARdelta agonist (GW501516) at 2.5 mg (n=9) or 10 mg (n=9), orally, once-daily for 2 weeks while hospitalized and sedentary. Standard lipid/lipoproteins were measured and in vivo fat feeding studies were conducted. Human skeletal muscle cells were treated with GW501516 in vitro and evaluated for lipid-related gene expression and FAO. Serum TG trended downwards (P=0.08, 10 mg), whereas TG clearance post fat-feeding improved with drug (P=0.02). HDLc was enhanced in both treatment groups (2.5 mg P=0.004, 10 mg P<0.001) when compared with the decrease in the placebo group (-11.5+/-1.6%, P=0.002). These findings complimented in vitro cell culture results whereby GW501516 induced FAO and upregulated CPT1 and CD36 expression, in addition to a 2-fold increase in ABCA1 (P=0.002). However, LpL expression remained unchanged. CONCLUSIONS: This is the first report of a PPARdelta agonist administered to man. In this small study, GW501516 significantly influenced HDLc and TGs in healthy volunteers. Enhanced in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression, suggests peripheral fat utilization and lipidation as potential mechanisms toward these HDL:TG effects.

ATP Binding Cassette Transporter 1↗
PubMed2006

The independent correlation between high-density lipoprotein cholesterol and subsequent major adverse coronary events.

BACKGROUND: There is substantial evidence from clinical trials that lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk. There is less evidence for the salutatory effects of raising high-density lipoprotein cholesterol (HDL-C). The predictive strength of an initial HDL-C measurement and its change over time for major adverse coronary events is not well understood. METHODS: We identified a cohort of all 6928 patients in an urban primary care practice who had two or more lipid measurements between January 1985 and December 1997. We used bivariable and multivariable (Cox proportional hazards) techniques to identify independent predictors of subsequent major adverse coronary events (hospitalization for myocardial infarction or acute coronary syndrome) after the second set of lipid measurements. RESULTS: The time between first and second lipid measurements averaged 2.6 years. During a mean of 5.1 +/- 3.2 years of observation after their second lipid measurements, 2167 (31%) patients had an acute coronary event. Patients having events were significantly older, more often white, male, and smokers and more often had antecedent diabetes, hypertension, coronary heart disease, and myocardial infarctions. Adjusting for covariates, a 10-mg/dL higher initial HDL-C was associated with an 11% (95% CI 7%-14%) lower risk of coronary events. A 10-mg/dL increase in HDL-C between lipid measurements was associated with a 7% (95% CI 3%-10%) lower risk of events. Neither initial or change in triglycerides nor LDL-C predicted subsequent coronary events. CONCLUSION: High-density lipoprotein cholesterol measurements and change in HDL-C predicted major adverse coronary events in this urban practice, which provides support studying interventions targeting HDL-C for cardiovascular risk reduction.

Adult↗
PubMed2006

Skin cholesterol adds to Framingham risk assessment.

INTRODUCTION: It has been demonstrated that skin tissue cholesterol (SkinTc) is associated with angiographic disease. Now, we further delineate the relative risk of multivessel disease (>50% stenosis in at least two vessels) in the conjoint presence of high SkinTc and high traditional risk burden. METHODS: Patients scheduled for angiography (N = 649) had SkinTc measured immediately prior to the procedure. Patients were classified according to the presence of high (>110) SkinTc and high (>10) Framingham global risk scores. Multivariable logistic regression models were used to estimate relative risk of multivessel disease for patients with isolated high skin tissue cholesterol, isolated high Framingham risk or conjoint high skin tissue cholesterol and high Framingham risk (each compared to neither factor elevated). RESULTS: The mean age was 63 +/- 12 years and 33% (n = 214) were women. Thirty seven percent (n = 237) had angiographically determined multivessel disease. Patients with isolated high SkinTc showed a relative risk of multivessel disease of 1.6 (95% CI = 1.0-2.4), while patients with isolated high Framingham risk had an odds ratio of 1.8 (CI = 1.0-3.4). However, when both scores were elevated, risk of multivessel disease was increased 4.3 times (CI = 2.6-7.2) compared to neither elevated. CONCLUSIONS: We see an independent, additive risk of concurrent multivessel disease when Framingham risk and skin cholesterol are both elevated. Skin tissue cholesterol may have value in further stratifying subjects with Framingham scores >10.

Aged↗
PubMed2006

The association between fibrate use, change in high-density lipoprotein cholesterol, and the risk of cardiovascular disease: a retrospective chart review involving up to 8 years of follow-up.

BACKGROUND: Clinical trials have indicated that the use of fibric acid derivatives confers a benefit against cardiovascular disease (CVD) in selected populations. However, whether fibrates provide a CVD risk reduction independent of changes in the traditional lipoprotein fractions and other known CVD risk factors is not clear. OBJECTIVE: This study examined whether the use of fibrate therapy in a general clinical setting provided cardiovascular benefits independent of changes in the traditional lipoprotein fractions. METHODS: This was a matched, retrospective cohort study. From the electronic records of a large health maintenance organization in the northwestern United States, we identified a population that had newly initiated fibrate pharmacotherapy between January 1, 1996, and December 31, 2000. We then identified a comparator group of patients not using fibrates, matching them to fibrate users based on high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels, age, sex, and year of HDL-C and TG measurement. Subjects were followed until a CVD hospitalization, termination from the health plan, or December 31, 2003, whichever came first. We then used multivariate analysis accounting for differences in followup to identify predictors of CVD incidence. RESULTS: The study population included 1722 matched pairs (56.6% male; mean [SD] age, 57.3 [11.1] years). The patients who had newly initiated fibrate pharmacotherapy had low baseline HDL-C levels (mean, 37.4 mg/dL) and very high TG levels (617 mg/dL). The 2 groups were similar overall, with the only significant differences between fibrate users and nonfibrate controls being a greater prevalence of diabetes (37.7% vs 34.3%, respectively; P=0.040) and greater use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (56.6% vs 51.6%, respectively; P=0.003), beta-blockers (53.7% vs 49.0%; P=0.006), calcium channel blockers (25.1% vs 20.9%; P=0.004), and niacin (11.7% vs 7.4%; P<0.001). Overall, CVD risk was 26% lower for every 5-mg/dL increment in HDL-C. After adjustment for age, sex, smoking history, diabetes, existing diagnosis of CVD, weight, systolic blood pressure, baseline HDL-C, change in HDL-C, total cholesterol, TG, and use of statins, niacin, and other CVD drugs, fibrate use did not confer an additional CVD risk reduction. CONCLUSIONS: In this cohort with low baseline HDL-C levels and very high TG levels, fibrate use did not confer an independent CVD risk reduction after adjustment for CVD risk factors. Given the current obesity epidemic in the United States and the corresponding rise in the number of patients with the metabolic syndrome, the apparent risk reduction observed in association with higher HDL-C levels should not be ignored.

Age Factors↗
PubMed2006

Sensitivity and specificity of pediatric lipid determinations for adult lipid status: findings from the Princeton Lipid Research Clinics Prevalence Program Follow-up Study.

OBJECTIVE: The goal was to determine the diagnostic utility of the National Cholesterol Education Program pediatric guidelines. METHODS: With the use of pediatric lipid data from the Cincinnati Clinic of the Lipid Research Clinics Prevalence Study and lipid and cardiovascular disease data collected for the same subjects as adults in the Princeton Follow-up Study, the sensitivity and specificity of the National Cholesterol Education Program pediatric guidelines were calculated overall and according to age. Furthermore, whether use of parental cardiovascular disease history during childhood influenced the sensitivity and specificity was assessed. RESULTS: Overall sensitivities were 43% to 46% and specificities were 82% to 86% for total and low-density lipoprotein cholesterol levels. There was considerable variation in sensitivities according to age, with the lowest sensitivities at ages 14 to 16 years and the highest sensitivities at ages 5 to 10 years and 17 to 19 years. Results were similar whether or not the population was restricted to children with a positive parental history of cardiovascular disease. CONCLUSIONS: Results of our analyses suggest that the sensitivity and specificity for evaluating total cholesterol or low-density lipoprotein cholesterol levels that are elevated in adulthood are not improved by selecting children with a positive parental history. These data also show the strong role that age (particularly the pubertal years between 10 and 15 years of age) plays in lipid measurements for children and adolescents. Continued prospective and longitudinal studies designed with age as well as other risk parameters are needed to determine the best guidelines for clinical screening in the future.

Adolescent↗
PubMed2005

Elevated skin tissue cholesterol levels and myocardial infarction.

BACKGROUND: Skin cholesterol has been associated with coronary artery disease, extent of angiographic disease and inflammatory markers such as hs-CRP. Based on these findings we sought to determine whether skin cholesterol was associated with myocardial infarction (MI). METHODS: Patients (N = 649) underwent diagnostic catheterization and concurrent skin cholesterol measurement. History of MI was determined at the time of hospitalization. RESULTS: Patients with a history of MI (n = 225, 35%) had significantly higher skin cholesterol than those without MI (127+/-29 versus 120+/-20, p = 0.002). The odds ratio for high skin cholesterol (for MI) was 1.6 (95% CI = 1.1, 2.6; p = 0.01) after adjustment for traditional risk and extent of angiographic disease. CONCLUSION: Skin cholesterol may indicate increased risk of coronary-related events rather than simply the presence of angiographic narrowing.

Aged↗
PubMed2004

Impact of nonprescriptive factors on low-density lipoprotein cholesterol reduction with statins.

Nonprescriptive factors, including patient adherence, can affect the fluctuations in low-density lipoprotein (LDL) cholesterol observed in the clinical setting. In 241 statin-treated patients, although drugs and doses remained fixed, 57% of patients initially successful in reaching LDL cholesterol targets showed subsequent increases in LDL cholesterol. Conversely, 60% of patients who initially failed to reach targets had subsequent reductions in LDL cholesterol, with nearly 1/3 eventually attaining their LDL cholesterol goals.

Anticholesteremic Agents↗
PubMed2004

Relation of homocysteine and C-reactive protein to urinary albumin loss.

This study shows that elevated high-sensitivity C-reactive protein and plasma total homocysteine contribute independently to the likelihood of an increased urinary albumin:creatinine ratio. This result suggests that total homocysteine and C-reactive protein may be acting by separate mechanistic pathways.

Adult↗
PubMed2003

Association between apolipoprotein E alleles and calcific valvular heart disease.

BACKGROUND: Studies on apolipoprotein E (apoE) alleles have reported an increased risk of coronary heart disease in patients with the apoE4 allele. Given the risk factor and histological similarities between coronary and calcific valvular heart disease (aortic stenosis [AS] and mitral annular calcification [MAC]), we postulated that apoE alleles might be associated with the development of these valvular lesions. METHODS AND RESULTS: We evaluated the association between apoE alleles and calcific valvular lesions in 802 patients undergoing transthoracic echocardiography using logistic regression analyses. No difference was noted in genotype distribution (P=0.59) or prevalence of apoE4 between those with or without MAC (30% versus 27%, respectively; P=0.57). Compared with patients without AS, the genotype distribution of patients with AS differed significantly (P=0.03), with increasing prevalences of the apoE 4 allele (27% in those without versus 40% in those with AS; P=0.01). In multivariate analyses adjusting for age, gender, low-density lipoprotein cholesterol levels, and coronary artery disease, increasing age and the apoE4 allele were significant independent predictors of AS (odds ratio, 1.94; 95% confidence interval, 1.01 to 3.71; P=0.046), whereas the apoE4 allele was not predictive of MAC. CONCLUSIONS: These findings support extension of the importance of the apoE4 allele beyond atherosclerosis and Alzheimer's disease to calcific AS.

Aged↗
PubMed2003

Relation of albumin/creatinine ratio to C-reactive protein and to the metabolic syndrome.

We hypothesized that the association of high sensitivity C-reactive protein (CRP) with urinary albumin excretion (UAE) is predominately mediated through its correlation with the metabolic syndrome. Serum CRP and urine albumin:creatinine ratios (ACR) from 720 preventive cardiology patients were analyzed to estimate age- and gender-adjusted relative risk of high CRP and metabolic syndrome for high ACR. These data demonstrate that CRP independently predicts the presence of UAE, a marker of endothelial dysfunction.

Age Factors↗
PubMed2003

Statins promote potent systemic antioxidant effects through specific inflammatory pathways.

BACKGROUND: The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. METHODS AND RESULTS: As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. CONCLUSIONS: Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Antioxidants↗
PubMed2003

Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy.

CONTEXT: Formation of nitric oxide-derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide-derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma. OBJECTIVES: To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy. DESIGN, SETTING, AND PATIENTS: A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For the case-control study, 100 case-patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol > or =130 mg/dL [> or =3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy. MAIN OUTCOME MEASURES: In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels. RESULTS: Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 micromol/mol [interquartile range, 4.8-13.8 micromol/mol] tyrosine vs 5.2 micromol/mol [interquartile range, 2.2-8.4 micromol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP. CONCLUSIONS: The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide-derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.

Adult↗
PubMed2003

Skin tissue cholesterol (SkinTc) is related to angiographically-defined cardiovascular disease.

UNLABELLED: Parallel changes associated with aging found in the vasculature and skin at necropsy, have prompted small preliminary studies to assess the relation between skin tissue cholesterol (SkinTc) and cardiovascular disease. While these studies have been suggestive, no formal investigation is available to test this association. It would, therefore, be valuable to determine whether a relation between SkinTc and angiographic narrowing actually exists, the latter representing one accepted measurement of coronary atherosclerosis. METHODS: Patients at three hospitals undergoing coronary angiography and not on lipid altering agents (n = 649) were examined for skinTc using a non-invasive method. Vessels were evaluated manually (number with stenosis > or = 50%). Clinical characteristics, current medication use, and Framingham global risk score were recorded. RESULTS: SkinTc was significantly higher in patients with angiographic disease (124 +/- 30 vs. 118 +/- 30, P = 0.02). After adjustment for traditional coronary artery disease risk factors, SkinTc provided 7% additional risk (per 10 SkinTc units) for angiographic disease. CONCLUSION: SkinTc, measured with a non-invasive method, is associated with the presence of coronary artery disease as determined by catheterization. Such an assay may eventually help stratify patient risk and target prevention efforts.

Aged↗
PubMed2003

Sex hormones and the changes in adolescent male lipids: longitudinal studies in a biracial cohort.

OBJECTIVE: To determine the role of increasing free testosterone and estradiol in pubertal changes in male lipids. METHODS: We conducted a 3-year, longitudinal, observation study with biannual visits of 251 black and 285 white boys who were 10 to 15 years of age at enrollment. Sex hormones, lipid parameters, and body composition measures were obtained according to a standard protocol. The body mass index (kg/m(2)) was used to characterize obesity. RESULTS: White boys had higher triglycerides, lower high-density lipoprotein cholesterol (HDL-C), lower apolipoprotein (apo)AI, and higher apoB than black boys. In boys of both races, increased body mass index was associated with increases in triglycerides, low-density lipoprotein cholesterol, apoB and decreases in HDL-C and apoAII. Within this framework, increased free testosterone was associated with increased apoB and decreased HDL-C and apoAI, whereas increased estradiol was associated with increased HDL-C and decreased triglycerides, low-density lipoprotein cholesterol, and apoB. CONCLUSION: Changes in sex steroid hormones have significant effects on changes in lipid parameters-increasing free testosterone levels has atherogenic effects and increasing estradiol has antiatherogenic effects.

Adolescent↗
PubMed2003

The Lescol Intervention Prevention Study (LIPS): start all patients on statins early after PCI.

The Lescol Intervention Prevention Study (LIPS) was the first randomized trial to show a significant reduction in the risk of cardiac events in patients started on fluvastatin immediately after a successful percutaneous coronary intervention. The benefit was independent of baseline cholesterol levels. The results suggest that all patients should be discharged on lipid-lowering therapy after a percutaneous coronary intervention. Currently, this is seldom done.

Angioplasty, Balloon, Coronary↗
PubMed2002

Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.

BACKGROUND: Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice. METHODS: Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug. RESULTS: The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39). CONCLUSIONS: The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting.

Aged↗