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Objective. To investigate vascular endothelial function (VEF) responses to a single low-density lipoprotein (LDL) apheresis session in hypercholesterolemic patients undergoing chronic treatment. Methods. We measured brachial artery flow-mediated dilation (FMD), plasma lipids, vitamin E (α- and γ-tocopherol), markers of oxidative/nitrative stress (malondialdehyde (MDA) and nitro-γ-tocopherol (NGT)), and regulators of NO metabolism (arginine (ARG) and asymmetric dimethylarginine (ADMA)) prior to (Pre) and immediately following (Post) LDL apheresis and at 1, 3, 7, and 14 d Post in 5 hypercholesterolemic patients ( 52 ± 11 y). Results. Relative to Pre, total cholesterol ( 7.8 ± 1.5 mmol/L) and LDL-cholesterol ( 6.2 ± 1.2 mmol/L) were 61% and 70% lower ( P < 0.01 ), respectively, at Post and returned to Pre levels at 14 d. Brachial FMD responses ( 6.9 ± 3.6 %) and plasma MDA, ARG, and ADMA concentrations were unaffected by LDL apheresis. Plasma α-tocopherol, γ-tocopherol, and NGT concentrations were 52–69% lower at Post ( P < 0.01 ), and α-tocopherol remained 36% lower at 1 d whereas NGT remained 41% lower at d 3. Conclusions. Acute cholesterol reduction by LDL apheresis does not alter VEF, oxidative stress, or NO homeostasis in patients treated chronically for hypercholesterolemia.

BackgroundSeveral publications and guidelines designate diabetes mellitus (DM) as a coronary artery disease (CAD) risk equivalent. The aim of this investigation was to examine DM cardiac risk equivalence from the perspective of stress SPECT myocardial perfusion imaging (MPI).Methods and ResultsWe examined cardiovascular outcomes (cardiac death or nonfatal MI) of 17,499 patients referred for stress SPECT-MPI. Patients were stratified into four categories: non-DM without CAD, non-DM with CAD, DM without CAD, and DM with CAD, and normal or abnormal perfusion. Cardiac events occurred in 872 (5%), with event-free survival best among non-DM without CAD, worst in DM with CAD, and intermediate in DM without CAD, and non-DM with CAD. After multivariate adjustment, risk remained comparable between DM without CAD and non-DM with CAD [AHR 1.0 (95% CI 0.84–1.28), P =0.74]. Annualized event rates for normal subjects were 1.4% and 1.6% for non-DM with CAD and DM without CAD, respectively (P = 0.48) and 3.5% (P = 0.95) for both abnormal groups. After multivariate adjustment, outcomes were comparable within normal [AHR 1.4 (95% CI 0.98–1.96) P = 0.06] and abnormal [AHR 1.1 (95% CI 0.83–1.50) P = 0.49] MPI.ConclusionsDiabetic patients without CAD have comparable risk of cardiovascular events as non-diabetic patients with CAD after stratification by MPI results. These findings support diabetes as a CAD equivalent and suggest that MPI provides additional prognostic information in such patients.

Functional magnetic resonance imaging (fMRI) has not been used to assess the effects of statins on the brain. We assessed the effect of statins on cognition using standard neuropsychological assessments and brain neural activation with fMRI on two tasks. Healthy statin-naïve men and women (48±15 years) were randomized to 80 mg/day atorvastatin (n=66; 27 men) or placebo (n=84; 48 men) for 6 months. Participants completed cognitive testing while on study drug and 2 months after treatment cessation using alternative test and task versions. There were few changes in standard neuropsychological tests with drug treatment (all P>.56). Total and delayed recall from the Hopkins Verbal Learning Test-Revised increased in both groups (P<.05). The Stroop Color-Word score increased (P<.01) and the 18-Point Clock Test decreased in the placebo group (P=.02) after drug cessation. There were, however, small but significant group-time interactions for each fMRI task: participants on placebo had greater activation in the right putamen/dorsal striatum during the maintenance phase of the Sternberg task while on placebo but the effect was reversed after drug washout (P<.001). Participants on atorvastatin had greater activation in the bilateral precuneus during the encoding phase of the Figural Memory task while on-drug but the effect was reversed after drug washout (P<.001). Six months of high dose atorvastatin therapy is not associated with measurable changes in neuropsychological test scores, but did evoke transient differences in brain activation patterns. Larger, longer-term clinical trials are necessary to confirm these findings and evaluate their clinical implications.

Background. Blocking nitric oxide (NO) and vasodilator prostanoids (PN) does not consistently reduce flow-mediated dilation (FMD) in young adults. The impact of aging on the contribution of NO and PG to FMD is unknown. Methods. FMD was measured in older adults (n=10, 65±3 y) after arterial infusion of saline, N(G)-monomethyl-L-arginine (L-NMMA), and ketorolac + L-NMMA. Data were compared to published data in young adults. Results. L-NMMA reduced FMD in older adults (8.9±3.6 to 5.9±3.7%) although this was not statistically significant (P=0.08) and did not differ (P=0.74) from the reduction observed in young adults (10.0±3.8 to 7.6±4.7%; P=0.03). Blocking PN did not affect FMD in young or older adults. In older adults, L-NMMA reduced (n=6; range = 36–123% decrease), augmented (n=3; 10–122% increase), or did not change FMD (n=1; 0.4% increase). After PN blockade, FMD responses were reduced (n=2), augmented (n=6), or unaffected (n=1). Conclusions. NO or PN blockade did not consistently reduce FMD in healthy older adults, suggesting the existence of redundant vasodilator phenotypes as observed previously in young adults.

Previous studies have demonstrated that diabetic patients undergoing exercise stress single-photon emission-computed tomography (SPECT) myocardial perfusion imaging (MPI) have significantly lower cardiac events when compared to the diabetic patients undergoing pharmacologic stress SPECT MPI across all perfusion categories. However, there are limited data on the level of exercise achieved during exercise SPECT MPI among diabetic patients and its impact on cardiovascular outcomes. We retrospectively analyzed 14,849 consecutive patients (3,654 diabetics and 11,195 non-diabetics) undergoing exercise stress, combined exercise and pharmacologic stress, and pharmacologic stress SPECT MPI from 1996 to 2005 at a single tertiary care center. Diabetic and non-diabetic patients were categorized into 3 groups based on the metabolic equivalents (METs) achieved: ≥5 METs, <5 METs, and pharmacologic stress groups. All studies were interpreted using the 17-segment ASNC model. The presence, extent, severity of perfusion defects were calculated using the summed stress score (SSS), and patients were classified into normal (SSS < 4), mildly abnormal (SSS 4-8), and moderate-severely abnormal (SSS > 8) categories. Annualized event rates (AER) for the composite end point of non-fatal myocardial infarction and cardiac death were calculated over a mean follow-up period of 2.4 ± 1.4 years with a maximum of 6 years. In moderate-severe perfusion abnormality (SSS > 8) category, diabetic patients who were able to achieve ≥5 METs had significantly lower AER compared to diabetic patients who were unable to achieve ≥5 METs (3% vs 5.5%, P = .04), and non-diabetic patients unable to achieve ≥5 METs (3% vs 4.8%, P < .001). Diabetic patients who achieved a high workload of ≥10 METs had a very low AER of 0.9%. Diabetic patients, who attempted exercise but were unable to achieve ≥5 METs, still had significantly lower AER than diabetics undergoing pharmacologic stress MPI across all perfusion categories [1.5% vs 3.2%, P = .006 (SSS < 4); 2.5% vs 4.9%, P = .032 (SSS 4-8); 5.5% vs 10.3%, P = .003 (SSS > 8)]. After adjustment for cardiovascular risk factors, the percentage decrease in cardiac event rate for every 1-MET increment in exercise capacity was 10% in the overall cohort, 12% in diabetic group, and 8% in non-diabetic group. Despite significant perfusion defects, diabetic patients who achieve ≥5 METs during stress SPECT MPI have significantly reduced risk for future cardiac events. Diabetic patients who achieve ≥10 METs have a very low annualized event rate. These findings support that exercise capacity obtained during SPECT MPI is a surrogate for outcomes among diabetic patients undergoing nuclear stress testing.

Although line source attenuation correction (AC) in SPECT MPI studies improves diagnostic accuracy, its prognostic value is less understood. Consecutive patients (n = 6,513) who underwent rest/stress AC ECG-gated SPECT MPI were followed for cardiac death or non-fatal myocardial infarction (MI). A 17-segment model and AC summed stress score (SSS) were used to classify images. Of the 6,513 patients, cardiac death or non-fatal MI occurred in 267 (4.1%), over 2.0 ± 1.4 years. The AC-SSS in patients with a cardiac event (5.6 ± 7.8) was significantly higher than in those without (1.9 ± 4.6, P < .001). The annualized cardiac event rate in patients with an AC-SSS 1-3 (3.6%) was significantly higher than in those with an AC-SSS = 0 (1.1%, P < .001) but similar to that in those with an AC-SSS 4-8 (2.9%, P = .4). Accordingly, patients were classified to AC-SSS = 0, 1-8, and >8 with annualized cardiac event rates of 1.1%, 3.2%, and 8.5%, respectively (P < .0001). In multivariate analysis, an AC-SSS 1-8 and >8 emerged as independent predictors of cardiac events (P < .02 and P < .0001, respectively). Rest/stress ECG-gated SPECT MPI with line source AC provides highly effective and incremental risk stratification for future cardiac events.

Previous studies have suggested that diabetic patients undergoing single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) are at greater risk for cardiac events than non-diabetic patients with both normal and abnormal imaging results. However, the impact of stress modality on outcomes in this patient group has not been examined. The data on all patients undergoing exercise stress or vasodilator stress SPECT MPI from 1996 to 2005 were reviewed. After excluding patients based on our predefined criteria, we subcategorized the study population into diabetic patients and non-diabetic patients. Among the diabetic patients, we identified patients with known coronary artery disease (CAD) and no known CAD. All studies were interpreted using the 17-segment ASNC model. The presence, extent, and severity of perfusion defects were calculated using the summed stress score (SSS), and patients were classified into normal (SSS < 4), mildly abnormal (SSS 4-8), and moderate-severely abnormal (SSS > 8) categories. The annualized cardiac event rate including cardiac death and non-fatal myocardial infarction was calculated over a mean follow-up period of 2.4 ± 1.4 years with a maximum of 6 years. The cardiac event rate was statistically significantly lower in diabetic patients undergoing exercise stress MPI when compared to the diabetic patients undergoing pharmacological stress MPI across all three perfusion categories (1.3% vs 3.4%, 2.3% vs 5.7%, 4.2% vs 10.7%, respectively). Diabetic patients with no known CAD, who underwent exercise stress MPI had significantly lower cardiac events across all three perfusion categories as compared to the remainder of the diabetic population. Ability to perform exercise stress test was the strongest multivariate predictor of favorable outcome, whereas ejection fraction < 50%, abnormal perfusion imaging on SPECT MPI, and increasing age stood out as independent predictors of adverse outcome in the diabetic patients. Within the abnormal perfusion category, the annualized cardiac event rate among patients undergoing exercise stress SPECT MPI was not statistically different between the diabetic and non-diabetic cohorts. Diabetic patients undergoing exercise SPECT MPI have a significantly better prognosis than those undergoing pharmacological stress, more similar to patients without diabetes. In patients with diabetes exercise stress test MPI identifies low risk patients and provides precise risk stratification.