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Objective: Niacin therapy fails to reduce cardiovascular events in statin-treated subjects even though it increases plasma HDL-C (HDL [high-density lipoprotein] cholesterol) and decreases LDL-C (LDL [low-density lipoprotein] cholesterol) and triglyceride levels. To investigate potential mechanisms for this lack of cardioprotection, we quantified the HDL proteome of subjects in 2 niacin clinical trials: the CPC study (Carotid Plaque Composition) and the HDL Proteomics substudy of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides). Approach and Results: Using targeted proteomics, we quantified levels of 31 HDL proteins from 124 CPC subjects and 120 AIM-HIGH subjects. The samples were obtained at baseline and after 1 year of statin monotherapy or niacin-statin combination therapy. Compared with statin monotherapy, niacin-statin combination therapy did not reduce HDL-associated apolipoproteins APOC1, APOC2, APOC3, and APOC4, despite significantly lowering triglycerides. In contrast, niacin markedly elevated HDL-associated PLTP (phospholipid transfer protein), CLU (clusterin), and HP/HPR (haptoglobin/haptoglobin-related proteins; P ≤0.0001 for each) in both the CPC and AIM-HIGH cohorts. Conclusions: The addition of niacin to statin therapy resulted in elevated levels of multiple HDL proteins linked to increased atherosclerotic risk, which might have compromised the cardioprotective effects associated with higher HDL-C levels and lower levels of LDL-C and triglycerides. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00715273; NCT00880178; NCT00120289.

Objective To investigate the relationship between admission SBP and subsequent cardiovascular and all-cause mortality in older patients hospitalized for acute coronary syndrome (ACS). Methods This is a retrospective observational study. Data from the CBD Bank (Cardiovascular Center Beijing Friendship Hospital Database Bank) were used to analyze the cardiovascular and all-cause mortality during hospitalization and over the follow-up period in relation to admission SBP among patients aged at least 65 years admitted for ACS from December 2012 through July 2019. Results were presented according to SBP quartiles: Q1, less than 120 mmHg; Q2, from 120 to 129 mmHg; Q3, from 130 to 143 mmHg; and Q4, at or above 144 mmHg. Results A total of 6785 patients were included in this cohort study. Mean (SD) patient age was 74.0 (6.5) years, and 47.6% were women. Mean (SD) follow-up time was 2.54 (1.82) years. A nonlinear relation was observed between SBP at admission and cardiovascular and all-cause mortality during hospitalization and over the follow-up period using restricted cubic splines. After adjustment for potential confounders, patients in Q1 had higher risk for 2-year cardiovascular death by Cox proportional hazard model compared with patients in Q2 [hazard ratio, 1.58; 95% confidence interval (CI), 1.12-2.21, P = 0.009], whereas patients in Q3 or Q4 exhibited a trend towards increased risk for 2-year cardiovascular death (hazard ratio, 1.33, 95% CI, 0.95-1.86, P = 0.094, for Q3 vs. Q2; and hazard ratio, 1.28, 95% CI, 0.91-1.82, P = 0.160, for Q4 vs. Q2). Meanwhile, when compared with patients in Q1, patients in Q2 had lower risk for 2-year cardiovascular death (hazard ratio, 0.64; 95% CI, 0.45-0.89, P = 0.009) whereas patients in Q3 or Q4 had similar risk for cardiovascular death (hazard ratio, 0.85, 95% CI, 0.63-1.14, P = 0.272, for Q3 vs. Q1; and hazard ratio, 0.82, 95% CI, 0.59-1.13, P = 0.221, for Q4 vs. Q1). However, low-admission SBP was not an independent predictor of 2-year all-cause mortality in this population. Conclusion Among patients aged at least 65 years admitted for ACS, there is a J-curve relationship between supine admission SBP and risk for 2-year cardiovascular death, with a nadir at 120-129 mmHg.

Introduction: Compared to coronary and carotid arteries, there is much less knowledge on atherosclerotic plaque characteristics and their clinical relevance in lower-extremity arteries. Magnetic resonance (MR) vessel wall imaging allows for in vivo detection of intraplaque hemorrhage (IPH), which has been consistently associated with increased risks for clinical events in coronary and carotid artery disease. Objective: In a pilot study, we sought to estimate the prevalence of IPH in peripheral artery disease and examine plaque progression in the presence of IPH. Methods: Ten patients with ankle brachial index 3 ) was used to scan bilateral legs in the coronal plane from the common femoral artery bifurcation to the popliteal artery at baseline and 6 months later. Images were reformatted into axial slices for detailed visualization of vessel wall. Following previous publications on carotid MRI, IPH was detected as hyperintense signals on heavily T1-weighted images. Superficial femoral artery (SFA) segments (3 cm in length) with IPH were identified, of which lumen and outer wall were segmented on black-blood images (motion-sensitized flow suppression for improved vessel wall delineation) to measure plaque progression and remodeling. Image analysis was performed in a blinded fashion without knowing time relationship between serial images. Results: Twenty SFAs were analyzed. After excluding 4 arteries with total occlusion, 5 out of the 16 arteries (31%) or 50% of the subjects showed IPH in 1 or more SFA segments. After 6 months, there was significant progression in vessel wall area in SFA segments with IPH (mean ± standard deviation: 43.5 ± 13.9 mm 2 versus 47.3 ± 17.3 mm 2 , p=0.045), which resulted in outer wall expansion (mean [95% confidence intervals]: +3.9 mm 2 [+0.4, +7.4], p=0.035) rather than lumen reduction (-0.02 mm 2 [-2.6, +2.5], p=0.99). Conclusions: MR vessel wall imaging revealed that IPH is likely a common feature in femoral atherosclerosis. SFA segments with IPH showed expansive remodeling in 6 months, of which the clinical significance needs to be further studied.

In the mammalian brain, neurogenesis persists throughout the embryonic period and adulthood in the subventricular zone of the lateral ventricle and the granular zone (dentate gyrus) of the hippocampus. Newborn neural progenitor cells (NPCs) in the two regions play a critical role in structural and functional plasticity and neural regeneration after brain injury. Previous studies have reported that extremely low-frequency electromagnetic fields (ELF-EMF) could promote osteogenesis, angiogenesis, and cardiac stem cells' differentiation, which indicates that ELF-EMF might be an effective tool for regenerative therapy. The present studies were carried out to examine the effects of ELF-EMF on hippocampal NPCs cultured from embryonic and adult ischemic brains. We found that exposure to ELF-EMF (50 Hz, 0.4 mT) significantly enhanced the proliferation capability both in embryonic NPCs and in ischemic NPCs. Neuronal differentiation was also enhanced after 7 days of cumulative ELF-EMF exposure, whereas glial differentiation was not influenced markedly. The expression of phosphorylated Akt increased during the proliferation process when ischemic NPCs were exposed to ELF-EMF. However, blockage of the Akt pathway abolished the ELF-EMF-induced proliferation of ischemic NPCs. These data show that ELF-EMF promotes neurogenesis of ischemic NPCs and suggest that this effect may occur through the Akt pathway.Video abstract, Supplemental Digital Content 1, http://links.lww.com/WNR/A347.

Background— Boosting low high-density lipoprotein (HDL) levels is a current strategy for preventing clinical events that result from cardiovascular disease. We previously showed that HDL 3 of subjects with coronary artery disease is enriched in apolipoprotein E and that the lipoprotein carries a distinct protein cargo. This observation suggests that altered protein composition might affect the antiatherogenic and antiinflammatory properties of HDL. We hypothesized that an intervention that increases HDL levels—combined statin and niacin therapy—might reverse these changes. Methods and Results— HDL 3 isolated from 6 coronary artery disease subjects before and 1 year after combination therapy was analyzed by liquid chromatography–Fourier transform–mass spectrometry. Alterations in protein composition were detected by spectral counting and confirmed with extracted ion chromatograms. We found that combination therapy decreased the abundance of apolipoprotein E in HDL 3 while increasing the abundance of other macrophage proteins implicated in reverse cholesterol transport. Treatment-induced decreases in apolipoprotein E levels of HDL 3 were validated biochemically in a second group of 18 coronary artery disease subjects. Interestingly, the changes in HDL 3 proteome with niacin/statin treatment resulted in a protein composition that more closely resembled that of HDL 3 in healthy control subjects. Conclusions— Combined statin and niacin therapy partially reverses the changes in the protein composition seen in HDL 3 in coronary artery disease subjects. Our observations raise the possibility that quantifying the HDL proteome could provide insights into the therapeutic efficacy of antiatherosclerotic interventions.

Matrix metalloproteinases (MMPs) mediate tissue injury during acute stroke. Clinical data show that elevated MMPs in plasma of stroke patients may correlate with outcomes, suggesting its use as a biomarker. MMP-9 signal has also been detected in clinical stroke brain tissue samples. Because tissue plasminogen activator can upregulate MMPs via lipoprotein receptor signaling, these neurovascular proteolytic events may underlie some of the complications of edema and hemorrhage that plague thrombolytic therapy. However, in contrast to its deleterious actions in acute stroke, MMPs and other neurovascular proteases may play beneficial roles during stroke recovery. MMPs are increased in the subventricular zone weeks after focal stroke, and inhibition of MMPs suppress neurogenic migration from subventricular zone into damaged tissue. In peri-infarct cortex, MMPs may mediate neurovascular remodeling. Delayed inhibition of MMPs decrease markers of remodeling, and these phenomena may be related to reductions in bioavailable growth factors. Acute versus chronic protease profiles within the neurovascular unit are likely to underlie critical responses to stroke, therapy, and recovery.

Objective: Changes in carotid plaque lipid-rich necrotic core (LRNC) as assessed by magnetic resonance imaging (MRI) were investigated in subjects who continued and discontinued statin therapy for 2 years after a prospective study. Methods: The Rosuvastatin Evaluation of Atherosclerotic Chinese Patients (REACH) study in 32 lipid treatment naïve subjects with LRNC showed a significant reduction in LRNC during 24 months (M) of rosuvastatin therapy. All subjects received a clinical follow-up (F/U) visit and a repeat carotid MRI scan at 48 M as planned REACH-F/U. Despite receiving a strong recommendation to continue the statin therapy at 24 M when REACH was completed, only 15 subjects continued taking statins (rosuva.=9, simva.=4 and atorva.=2) in REACH-F/U and 17 discontinued. Lipids and LRNC, both in volume (V) and % (LRNC-V/Wall Vх100%), were compared between the statin-continued and -discontinued groups at 48 M. Results: There were no significant differences in demographic, clinical characteristics, lipids and plaque changes during 24 M in REACH between the statin-continued and -discontinued groups in REACH-F/U. Not surprisingly, at 48 M, total-Cholesterol (C), LDL-C and triglycerides were significantly lower in subjects who continued statin than those discontinued (163±43 vs. 207±30 mg/dl, p=0.002), (93±36 vs. 131±22 mg/dl, p=0.001) and (85±27 vs. 143±65 mg/dl, p=0.003), while HDL-C levels were similar. LRNC-V and %LRNC decreased significantly from 24 M in the statin-continued group (101±76 mm 3 at 24 M vs. 76±65 mm 3 at 48 M, p=0.001) and (17.3±11.9% at 24 M vs. 12.6±7.6% at 48 M, p=0.04). By contrast, subjects who discontinued statin showed non-statistically significant increase in LRNC-V and %LRNC (103±93 mm 3 at 24 M vs. 112±106 mm 3 at 48 M, p=0.4) and (15.4±11.3% at 24 M vs. 16.7±11.4% at 48 M, p=0.07). Furthermore, the changes in LRNC-V and %LRNC from 24 to 48 M were significantly different between the statin-continued and -discontinued groups in REACH-F/U (-25±18 vs. 9±14 mm 3 , p Conclusion: Continued statin therapy in REACH-F/U resulted in continued decrease in LRNC, which indicates improved plaque stability. These findings provided vascular biological evidence supporting long-term statin therapy.

High density lipoprotein (HDL) plays a key role in reverse cholesterol transport from arteries and protects against development of atherosclerosis by removing cholesterol from lipid loaded macrophages in atherosclerotic lesions. Low levels of HDL-cholesterol (HDL-C) strongly associate with increased risk of cardiovascular disease (CVD) in clinical and epidemiological studies. However, recent trials with drugs that elevate HDL-C failed to reduce CVD events. In contrast recent studies strongly suggested that HDL sterol efflux capacity-its ability to remove cholesterol from macrophages-predict incident cardiovascular disease risk. Moreover, CVD risk strongly associates with low levels of HDL particle concentration (HDL-P). However, the relations between HDL efflux capacity, HDL particle concentration and HDL composition are not well understood. Using proteomics analysis, we have previously identified over 50 proteins on HDL. Here we investigated the relationship of HDL composition, and HDL-P in two independent populations of people with and without CVD (Study 1, n=40, and Study 2, n=65). Using quantitative targeted multiplex MS/MS analysis quantifying majority (40) of HDL associated proteins, we found that phospholipid transfer protein (PLTP) and clusterin (CLU or ApoJ) strongly correlated in HDL (r = 0.9, P < 0.001) indicating that the two proteins likely coexist in a single population of HDL particles. Furthermore, abundance of these two proteins correlated strongly with the concentration of large HDL particles (PLTP r = 0.58; CLU r = 0.61, both P < 0.001) and negatively with the concentration of small HDL particles (both PLTP and CLU r = -0.49, P < 0.001) as determined by calibrated ion mobility analysis. Moreover, both PLTP and CLU were significantly decreased in CVD subjects, and both predicted CVD status after adjustment for age and sex (PLTP, OR 0.53, 95% CI, 0.28-0.94, P = 0.02). Collectively, this data supports the hypothesis that PLTP and CLU play important roles in determining HDL-P and that these are interrelated factors determining HDL’s anti-atherogenic properties.

Introduction: Postmortem coronary artery histopathology and post-surgical carotid endarterectomy studies demonstrate that women have less calcification and inflammatory cells, but more smooth muscle cells than men. Gender differences in atherosclerotic plaque composition are not well known. Yet, the age-adjusted incidence of stroke and myocardial infarction are higher in men than women. Hypothesis: We hypothesized that gender differences exist in carotid plaque composition (CPC), % lipid rich necrotic core (LRNC) and % wall volume (PWV), comparing living women and men. Methods: The CPC study is a prospective, randomized study evaluating the effect of 1) atorvastatin + placebo + placebo vs 2) atorvastatin + niacin ER + placebo 3) atorvastatin + niacin ER + colsevelam on CPC. Participants had coronary or carotid artery disease and ApoB levels ≥120 mg/dL. CPC was evaluated using MRI. Baseline PWV [(wall volume/total vessel volume) х 100%], a measure of plaque burden that adjusts for variation in artery size, and % LRNC volume (among slices with LRNC present) were evaluated. Statistical analysis used Wilcoxon rank sum test, chi-square, and multivariate linear regression. Results: There were 82 women and 118 men. Women vs. men were older, mean±SD age 58±8 vs. 55±8 yrs. (p=0.008), had higher HDL-C, 48±13 vs. 40±10 mg/dL (p Conclusions: Gender differences exist in CPC in that there is a higher volume of LRNC in men compared to women. Further studies are needed which delineate the mechanisms underlying the differences in prevalence of LRNC comparing men to women.

Our analysis presents an alternative hypothesis to the prevailing view that low-density lipoprotein-C is the only important target of lipid therapy.Two recently published studies showed surprising results. In the Armed Forces Regression Study, low-density lipoprotein-C was lowered only 22% with cholystyramine, niacin and gemfibrozil. Coronary stenosis regressed, however, and the primary clinical event rate was reduced by 54%. Conversely, in the FIELD trial, the primary event rate reduction was only 11% (P = NS). These differences appeared to be explained largely by the difference in high-density lipoprotein response to these regimens (38 vs. 3%). This meta-analysis of 23 trials strongly supports the notion that the sum of percent reduction in low-density lipoprotein-C plus percent increase in high-density lipoprotein-C predicts benefits much more effectively than either lipoprotein component.Epidemiology suggests that the cardiovascular event rate is reduced by nearly 1% for each 1% reduction in low-density lipoprotein-C and by at least 1% for each 1% increase in high-density lipoprotein. These effects are statistically independent; thus, for moderate lipid changes, they are additive. If this simple algorithm is proven accurate, a 30% high-density lipoprotein-C increase and a 40% low-density lipoprotein-C reduction would result in a nearly 70% CHD risk reduction - and a revolution in cardiovascular prevention.

During the past decade, the perception flourished that lipid and antioxidant therapy were 2 independent avenues for cardiovascular protection. However, studies have shown that commonly used antioxidant vitamin regimens do not prevent cardiovascular events. We found that the addition of antioxidant vitamins to simvastatin-niacin therapy substantially blunts the expected rise in the protective high density lipoprotein (HDL)2 cholesterol and lipoprotein(A-I) subfractions of HDL, with apparent adverse effects on the progression of coronary artery disease. To better understand this effect, 12 apolipoproteins, receptors, or enzymes that contribute to reverse cholesterol transport have been examined in terms of their relationship to HDL2 and lipoprotein(A-I) levels and the potential for antioxidant modulation of their gene expression. Three plausible candidate mechanisms are identified: (1) antioxidant stimulation of cholesteryl ester transfer protein expression/activity, (2) antioxidant suppression of macrophage ATP binding cassette transmembrane transporter A1 expression, and/or (3) antioxidant suppression of hepatic or intestinal apolipoprotein A-I synthesis or increase in apolipoprotein A-I catabolism. In summary, antioxidant vitamins E and C and β-carotene, alone or in combination, do not protect against cardiovascular disease. Their use for this purpose may create a diversion away from proven therapies. Because these vitamins blunt the protective HDL2 cholesterol response to HDL cholesterol–targeted therapy, they are potentially harmful in this setting. We conclude that they should rarely, if ever, be recommended for cardiovascular protection.

Background: Although vulnerable plaques are considered the pathological substrate for acute cardiovascular events, the pursuit of imaging surrogate markers for systemic atherothrombotic risk is currently focused on plaque burden. The prognostic value of vulnerable plaque characteristics as novel markers for systemic cardiovascular outcomes remains elusive. Advances in magnetic resonance imaging (MRI) have enabled characterization of the vulnerable carotid plaque. In a prospective study, we tested whether MRI-detected carotid plaque characteristics predict subsequent cardiovascular events. Methods: As part of an event-driven clinical trial, subjects with clinically established atherosclerotic disease were recruited. A multi-sequence protocol was used to measure the volumes of calcification and necrotic core (NC), and to identify the presence of intraplaque hemorrhage (IPH) and thin/ruptured fibrous cap (FC) using published criteria. The primary endpoint included fatal and non-fatal myocardial infarction or ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization. Cox regression analysis was used to present results as hazard ratio (HR) with 95% confidence interval (CI). Results: Of 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (mean age: 61±9 years; male: 82%; statin use: 94%). Calcification, NC, IPH, and thin/ruptured FC were detected in 48%, 52%, 8% and 14% of subjects, respectively. During a median follow-up of 35.1 months, 18 (8.4%) subjects reached the primary endpoint. MRI-detected plaque characteristics associated with the primary endpoint included larger NC (HR per 1 standard deviation increase in volume [1-SD]: 1.43 [1.16, 1.75], p Conclusions: Vulnerable plaque characteristics are prevalent in carotid arteries of patients with established atherosclerosis and are predictive of systemic cardiovascular outcomes.

Objective: Changes in carotid wall morphology (MORPH) and plaque composition (COMP) over 2 years (yrs) of intensive lipid therapy by plaque types were investigated in AIM-HIGH. Methods: Qualified baseline and 2-yr follow-up scans were obtained in 156 AIM-HIGH subjects. MR images were analyzed by independent Core Lab reviewers using published criteria for quantifications of MORPH and COMP. MORPH included volumes of total vessel (TVV), lumen (LV), wall (WV=TVV-LV) and fibrous tissue (FTV) in mm3 and %WV was calculated using the formula: (WV/TVV) X 100% in all available slices. COMP focused on percentages of lipid-rich necrotic core (%LRNC), FT (%FT) and calcium (%CA) calculated using the formula: (LRNC, FT or CA V/WV) x 100% using the slices containing LRNC. Of 156, 89 were in statin+placebo for extended-release niacin (ERN) and 67 in statin+ERN groups. Changes in MORPH and COMP were compared between the 2 treatment groups and between plaque types: w/o LRNC (n=76), w/ LRNC but w/o intraplaque hemorrhage (IPH) (n=62), w/ LRNC & IPH (n=18). Results: In the 76 subjects w/o LRNC, there were significant increases in TVV (24±52 mm3/yr, p Conclusions: Intensive lipid therapy with statin or statin plus ERN significantly associated with positive MORPH remodeling in plaques w/o LRNC. Plaques w/ LRNC experienced COMP improvement without significant MORPH changes. However, the COMP improvement was not seen in plaques w/ IPH. These results indicate that plaques in different disease stages respond to lipid therapy differently.

Background: Previously we demonstrated plaque lipid depletion by carotid MRI during lipid lowering. Effect of different lipid therapy on plaque lipid content was investigated. Methods: Subjects (n=182) with coronary or carotid artery disease, apoB ≥120 mg/dl, and lipid treatment history Results: Overall, the 46 subjects with measurable LRNC at baseline had a significant plaque lipid content reduction. LRNC-V decreased from 58.8±9.0 to 39.7±10.2 mm3 (p Conclusions: Intensive combination lipid therapy of atorvastatin plus niacin or atorvastatin, niacin and colesevelam significantly depletes carotid plaque lipid content as assessed by MRI over 2 years.

Background and Purpose — We sought to investigate the effects of EPC-K1, a free radical scavenger, on reducing heparin-produced cerebral hemorrhage in a rabbit model of middle cerebral artery (MCA) photothrombosis and to investigate whether the combination of EPC-K1 and heparin enhances neuroprotection from cerebral ischemic damage. Methods — In the heparin-alone group (n=8), heparin was administered intravenously for 24 hours, starting from 3 hours after MCA occlusion. In the EPC-K1-alone group (n=8), EPC-K1 was administered as a bolus injection (10 mg/kg) twice at 3 and 6 hours after MCA occlusion. In the combination group (n=8), EPC-K1 and heparin both were administered as in the single-drug procedures. In the vehicle group (n=10), saline were infused for 24 hours. Results — Heparin prolonged activated partial thromboplastin time by ≈3 times that of control animals. In the heparin-treated animals, the hemorrhage size was significantly increased ( P P P P P Conclusions — These data indicate that free radical formation may play a key role in intracerebral hemorrhage exacerbated by heparin treatment and that the combination of a free radical scavenger and heparin augmented neuroprotection from acute brain ischemia. The results of the present study may suggest a potential clinical approach for the treatment of acute stroke.

3-Chlorotyrosine is a specific product of myeloperoxidase (MPO), a heme protein expressed by macrophages in human atherosclerotic lesions. We have previously shown in vitro that chlorination of Tyr192 (3-chloroTyr192) together with methionine oxidation of lipid-free apoA-I impairs the apolipoprotein’s ability to promote cholesterol efflux from macrophages by the ABCA1 pathway. Using a sensitive and quantitative LC-MS/MS approach with selected reaction monitoring (SRM), we have recently demonstrated that Tyr192 is the major site of chlorination in apoA-I of HDL isolated from human atherosclerotic lesions. In a prospective study, we determined if: i) MPO contributes to the chlorination of apoA-I in circulating HDL; and ii) 3-chloroTyr192 serves as a marker for clinically significant cardiovascular disease. We quantified HDL oxidation and sterol efflux in three groups: i) stable CAD subjects, ii) acute coronary syndrome (ACS) subjects, and iii) healthy control subjects (N=20 per group). SRM analysis demonstrated that levels of 3-chloroTyr192 were markedly elevated in HDL isolated from subjects with CAD or ACS (p=0.009 and p=0.01 vs. control subjects, respectively). A key cardioprotective effect of HDL is its ability to promote cholesterol efflux from macrophages by the ABCA1 pathway. We found that the ABCA1-dependent sterol efflux capacity of HDL isolated from CAD and ACS subjects was significantly impaired. Importantly, sterol efflux capacity associated inversely with levels of 3-chloroTyr192 (R=-0.30, p=0.02), suggesting that oxidation of HDL by MPO contributes to the impaired cholesterol efflux capacity of HDL. Receiver operating characteristic curve analysis revealed that levels of 3-chloroTyr192 distinguished between CAD or ACS subjects and control subjects (AUC 0.76, p=0.0008 and AUC 0.73, p=0.004, respectively). These observations strongly suggest that MPO contributes to the generation of dysfunctional HDL in subjects with clinically significant atherosclerosis. They further indicate that quantification of 3-chloroTyr192 levels in HDL may provide a new approach to the diagnosis and treatment of CAD and ACS.

BACKGROUND Do the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms? METHODS AND RESULTS Of 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B > or = 125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P < .001). Among the 91 symptomatic patients, those in the intensive group experienced definite (> or = 10%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P = .009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0% of conventional, regression (P = .04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P < .01); no asymptomatic patient had an event. CONCLUSIONS Asymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.