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Background: Treating known risk factors for coronary artery disease (CAD) has substantially reduced CAD morbidity and mortality. However, a significant burden of CAD remains unexplained. Immunoglobulin E sensitization to mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal) was recently associated with CAD in a small observational study. We sought to confirm that α-Gal sensitization is associated with CAD burden, in particular noncalcified plaque. Additionally, we sort to assess whether that α-Gal sensitization is associated with ST-segment–elevated myocardial infarction (STEMI) Methods: We performed a cross-sectional analysis of participants enrolled in the BioHEART cohort study. We measured α-Gal specific-immunoglobulin E antibodies in serum of 1056 patients referred for CT coronary angiography for suspected CAD and 100 selected patients presenting with STEMI, enriched for patients without standard modifiable risk factors. CT coronary angiograms were assessed using coronary artery calcium scores and segmental plaque scores. Results: α-Gal sensitization was associated with presence of noncalcified plaque (odds ratio, 1.62 [95% CI, 1.04–2.53], P =0.03) and obstructive CAD (odds ratio, 2.05 [95% CI, 1.29-3.25], P =0.002), independent of age, sex, and traditional risk factors. The α-Gal sensitization rate was 12.8-fold higher in patients with STEMI compared with matched healthy controls and 2.2-fold higher in the patients with STEMI compared with matched stable CAD patients (17% versus 1.3%, P =0.01 and 20% versus 9%, P =0.03, respectively). Conclusions: α-Gal sensitization is independently associated with noncalcified plaque burden and obstructive CAD and occurs at higher frequency in patients with STEMI than those with stable or no CAD. These findings may have implications for individuals exposed to ticks, as well as public health policy. Registration: URL: https://www.anzctr.org.au ; Unique identifier: ACTRN12618001322224.

Supplemental Digital Content is available in the text., Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Revascularization because of coronary artery disease is commonly achieved by percutaneous coronary intervention with stent deployment. Refinement in interventional techniques, major improvements in stent design (particularly drug-eluting stents), and adjunctive pharmacotherapy with dual antiplatelet regimens have led to marked reductions in the overall rates of stent failure. However, even with the advancements made in the latest generation of drug-eluting stents, unresolved biological problems persist including delayed re-endothelialization and neoatherosclerosis, which can promote late expansion of the neointima and late stent thrombosis. Novel strategies are still needed beyond what is currently available to specifically address the pathobiological processes that underpin the residual risk for adverse clinical events. This review focuses on the emerging evidence that HDL (high-density lipoproteins) and its main apo (apolipoprotein), apoA-I, exhibit multiple vascular biological functions that are associated with an improvement in stent biocompatibility. HDL/apoA-I have recently been shown to inhibit in-stent restenosis in animal models of stenting and suppress smooth muscle cell proliferation in in vitro studies. Reconstituted HDL also promotes endothelial cell migration, endothelial progenitor cell mobilization, and re-endothelialization. Furthermore, reconstituted HDL decreases platelet activation and HDL cholesterol is inversely associated with the risk of thrombosis. Finally, reconstituted HDL/apoA-I suppresses key inflammatory mechanisms that initiate in-stent neoatherosclerosis and can efflux cholesterol from plaque macrophages, an important function of HDLs that prevents plaque progression. These unique multifunctional effects of HDL/apoA-I suggest that, if translated appropriately, have the potential to improve stent biocompatibility. This may provide an alternate and more efficacious therapeutic pathway for the translation of HDL.

Considerable evidence from preclinical and population studies suggests that HDLs (high-density lipoproteins) possess atheroprotective properties. Reports from HDL infusion studies in animals and early clinical imaging trials reported evidence of plaque regression. These findings have stimulated further interest in developing new agents targeting HDL. However, the results of more recent imaging studies in the setting of high-intensity statin use have been disappointing. As the concept of plaque changes with HDL therapeutics evolves and imaging technology to evaluate these effects advances, there will become increasing opportunity to determine the effects of HDL agents on atherosclerotic plaque (Graphic Abstract).

Revascularization because of coronary artery disease is commonly achieved by percutaneous coronary intervention with stent deployment. Refinement in interventional techniques, major improvements in stent design (particularly drug-eluting stents), and adjunctive pharmacotherapy with dual antiplatelet regimens have led to marked reductions in the overall rates of stent failure. However, even with the advancements made in the latest generation of drug-eluting stents, unresolved biological problems persist including delayed re-endothelialization and neoatherosclerosis, which can promote late expansion of the neointima and late stent thrombosis. Novel strategies are still needed beyond what is currently available to specifically address the pathobiological processes that underpin the residual risk for adverse clinical events. This review focuses on the emerging evidence that HDL (high-density lipoproteins) and its main apo (apolipoprotein), apoA-I, exhibit multiple vascular biological functions that are associated with an improvement in stent biocompatibility. HDL/apoA-I have recently been shown to inhibit in-stent restenosis in animal models of stenting and suppress smooth muscle cell proliferation in in vitro studies. Reconstituted HDL also promotes endothelial cell migration, endothelial progenitor cell mobilization, and re-endothelialization. Furthermore, reconstituted HDL decreases platelet activation and HDL cholesterol is inversely associated with the risk of thrombosis. Finally, reconstituted HDL/apoA-I suppresses key inflammatory mechanisms that initiate in-stent neoatherosclerosis and can efflux cholesterol from plaque macrophages, an important function of HDLs that prevents plaque progression. These unique multifunctional effects of HDL/apoA-I suggest that, if translated appropriately, have the potential to improve stent biocompatibility. This may provide an alternate and more efficacious therapeutic pathway for the translation of HDL.

Background: Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis, both of which can influence cardiovascular clinical outcomes. Studies implicate calcification as a driver of PAD, however, the mechanisms by which calcification modulates angiogenesis remain poorly understood. This study assessed the effect of high calcium on angiogenesis both in vitro and in vivo . Methods: Human Coronary Artery Endothelial Cells (EC) were cultured and treated with calcification medium (CM) (CaCl 2 2.7mM, Na 2 PO 4 2.0mM) for 24 h. Angiogenic assays of proliferation, migration and tubulogenesis were conducted, and immunoblotting assessed angiogenic regulatory proteins. In vivo studies employed a calcification model with 8-12-week-old male OPG -/- and wildtype (C57BL6/J, control) mice which underwent hind-limb ischaemia (HLI) surgery. Blood flow reperfusion was assessed by Laser Doppler Perfusion Imaging (LDPI). Calcium assay assessed calcium levels in blood serum of the C57BL6/J and OPG -/- mice. Results: CM significantly reduced EC tubulogenesis and viability (34% and 58% p-/- mice at days 6 (0.03±0.01 vs 0.32±0.05 p Conclusion: This is the first demonstration that high-levels of calcium impair ischaemia-driven angiogenesis in vivo and cause inflammation in ECs that suppresses tubule formation in vitro , despite upregulation of key angiogenic regulators VEGFA and HIF-1α. These findings have implications for the development of therapies that can suppress calcification in PAD.

Background: Vascular calcification (VC), alongside atherogenic lipoprotein profiles, have been correlated with poor cardiovascular outcome, however there is a paucity of literature exploring the relationship between the two regarding VC progression. We therefore aim to examine the roles of lipoprotein species and their oxidised forms on both medial and intimal VC. Methods: Human aortic smooth muscle cells (HAoSMC) were pre-treated with 200 μg/ml high (HDL), low (LDL) and very low (VLDL) density lipoproteins for 24 hours before treating cells with a calcification medium (CM; Ca 2.7mM, PO 4 2.0 mM). Cells were harvested using an alizarin red (ARS) calcification assay, or at various time points for qPCR analysis. In parallel, in vivo studies using apolipoprotein E knock-out mice were fed an atherogenic diet for 40 weeks and received reconstituted HDL (rHDL) infusions containing apoA-I (20mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine during the final 4 weeks of the study. Tissues were harvested and stained for plaque assessment (H&E) and calcium deposits (ARS). Results: Pre-treatment of HAoSMC with rHDL inhibited calcification (43.9%, p Conclusions: This study is the first to demonstrate the effects of lipoproteins on VC in vitro and the effects of rHDL on in vivo VC. Somewhat in accordance to the roles of lipoproteins in atherosclerosis, HDL and ox-VLDL show a reduction of calcification, where-as ox-LDL enhances calcification of HAoSMC.

Background: Peripheral artery disease (PAD) is a progressive occlusive disease of the arteries and a vascular complication in diabetes. Vascular calcification (VC) is implicated as a potential driver of PAD, and although the exact mechanisms are unclear, the site and location of calcification within the arterial wall contributes greatly. Long considered a passive process, VC is now recognised as a tightly regulated active process balancing the promotion and inhibition of calcification in the arterial wall. There is little evidence however, to demonstrate the effect of calcification on endothelial cell angiogenesis. This study sought to investigate the effects of calcium as a known inducer of calcification on in vitro angiogenesis. Methods: Human Coronary Artery Endothelial Cells were cultured and treated with increasing calcium concentrations (CaCl 2 2.45-3.3 mM) for 24h. Proliferation, migration and tubule formation assays were conducted and real-time PCR assessed angiogenic and osteogenic genes. Alkaline phosphotase (ALP) activity was measured in supernatants following treatment. Results: High concentrations of calcium reduced cell proliferation with a corresponding increase in ALP production suggesting release of osteogenic stimuli adversely affects cell viability. Mid-range concentrations of calcium induced a significant increase in cell migration (1.0 vs 2.4±0.3, p500 fold), and fibroblast growth factor-2 (>150 fold). This increase corresponded with a decrease (1.0 vs 15.02±4.24; p Conclusion: This is the first demonstration investigating the effects of calcium on endothelial cell angiogenesis. These findings suggest that calcium can directly affect genes involved in regulating angiogenesis, and could therefore provide an opportunity to develop potential treatments.

Background: Macrophages are integral to vascular biology and disease. Although traditional paradigms assert that vascular macrophages originate from circulating monocytes, recent data suggest that some are seeded in utero from CX 3 CR1 + progenitors, and are maintained postnatally by local self-renewal. We previously identified a novel population of locally-maintained adventitial macrophage progenitor cells (AMPCs) as a source of self-renewing macrophages in adult mouse arteries. Hypothesis: AMPCs express CX 3 CR1 and do not derive from definitive hematopoiesis. Methods: Single-cell disaggregates were prepared from postnatal murine aortas. AMPC content was assessed by macrophage colony-forming unit (CFU-M) assays. Flow cytometry together with fluorescence activated cell sorting (FACS) were used to investigate the immunophenotypic profile of AMPCs and fate-mapping to assess their origins. Results: CFU-M prevalence in C57BL/6J aortic cells was highest in neonatal mice (~100 per 10 5 cells), and diminished progressively with age (~55/10 5 at 3w, ~15/10 5 at 12w, ~5/10 5 at 52w, n>4, P95% expression of the stem cell markers Sca-1 and c-Kit, and high levels of CX 3 CR1, but did not acquire the monocyte/macrophage markers CD11b or F4/80 until treated with macrophage-colony stimulating factor (n=6). Mice deficient in CX 3 CR1 (Cx 3 cr1 GFP/GFP ) produced fewer CFU-M than heterozygous (Cx 3 cr1 +/GFP ) littermates (8.7±0.7 vs 15.3±0.7 per 10 5 , P7). FACS selection confirmed that CFU-M forming AMPCs were exclusively contained within a CX 3 CR1 + subpopulation that did not express either CD11b or F4/80 (n=3). Finally, CFU-M analysis from Flt3 Cre xRosa mT/mG mice demonstrated that AMPCs arise from a FLT3 -ve source, indicating that their origins are independent of definitive hematopoiesis (n=4). Conclusion: Clonogenic, self-renewing murine AMPCs express CX 3 CR1 but not the monocyte/macrophage markers CD11b and F4/80. The high prevalence of AMPCs in neonatal aorta is consistent with prenatal seeding from CX 3 CR1 + progenitors, independent of definitive hematopoiesis.

Objectives— Patients with acute coronary syndromes (ACS) display diffuse coronary atheroma instability and heightened risk of early and late recurrent coronary events. We compared the long-term antiatherosclerotic efficacy of high-intensity statins in patients with ACS when compared with stable disease. Approach and Results— Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The overall effect of high-intensity statins on the change in coronary percent atheroma volume and major adverse cardiovascular events (death/nonfatal myocardial infarction/coronary revascularization) were evaluated in this post hoc analysis. When compared with non-ACS patients (n=678), patients with ACS (n=361) were younger, actively smoking, and have had a previous myocardial infarction (all P P =0.002), a higher apolipoprotein B: apolipoprotein A-1 ratio (0.90±0.24 versus 0.83±0.24; P P =0.01) when compared with non-ACS patients. Despite similar achieved levels of lipid and inflammatory markers after high-intensity statin therapy, patients with ACS demonstrated greater percent atheroma volume regression than non-ACS patients (−1.46±0.14 versus −0.89±0.13; P =0.003). After propensity-weighted multivariable adjustment, baseline percent atheroma volume ( P P =0.02) independently associated with plaque regression. The 24-month major adverse cardiovascular events–free survival was similar between patients with ACS and non-ACS (90.6 versus 92.9%; P =0.25). Conclusions— Long-term high-intensity statin therapy caused greater plaque regression and comparable major adverse cardiovascular events rates in ACS when compared with non-ACS patients. Despite a higher clinical risk profile, patients with ACS harbor a more modifiable disease substrate and seem to benefit the most from potent statin therapy.

Aim: Statin therapy can slow the progression of coronary atherosclerosis. However, the clinical factors underlying the beneficial effects of statin therapy on disease progression remain poorly understood. We examined the relationship of circulating HDL subfractions with measures of coronary atheroma following long-term high-intensity statin therapy. Methods: Serial coronary intravascular ultrasound (IVUS) was utilized in SATURN to monitor changes in atheroma burden [percent atheroma volume (PAV)] in 915 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Results: Baseline levels of total HDL-C, apo E-containing HDL-C (apoE HDL-C), HDL 3 -C and HDL 2 -C did not differ significantly between treatment groups. Compared with the atorvastatin-treated group, rosuvastatin-treated patients demonstrated greater increases in levels of total HDL-C (4.4% vs. -1.8%, p3 -C (3.3% vs. -2.7%, p2 -C (7.0% vs. -0.7%, p3 -C levels were associated with PAV regression in rosuvastatin-treated patients (β=-0.84, p=0.018 and β=-1.10, p=0.056, respectively) but not in the atorvastatin-treated group (β=0.41, p=0.22 and β=0.71, p=0.22 for apo E HDL-C and HDL 3 -C, respectively). Conclusions: Rosuvastatin therapy resulted in favorable changes in HDL subfractions and on-treatment levels of apoE HDL-C and HDL 3 -C were associated with greater disease regression.

Objectives— Non–high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Approach and Results— Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status ( P P P Conclusions— Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDLC (and possibly TG) lowering in combating residual cardiovascular risk.

Objective— In a previous exploratory analysis, intracoronary near-infrared spectroscopy (NIRS) found the majority of culprit lesions in ST-segment–elevation myocardial infarction (STEMI) to contain a maximum lipid core burden index in 4 mm (maxLCBI 4mm ) of >400. This initial study was limited by a small sample size, enrollment at a single center, and post hoc selection of the maxLCBI 4mm ≥400 threshold. This study was designed a priori to substantiate the ability of NIRS to discriminate STEMI culprit from nonculprit segments and to confirm the performance of the maxLCBI 4mm ≥400 threshold. Approach and Results— At 2 centers in the United States and Sweden, 75 STEMI patients underwent intracoronary NIRS imaging after establishing thrombolysis in myocardial infarction 3 flow, but before stenting. Blinded core laboratory analysis defined the culprit segment as the 10-mm segment distal to the proximal angiographic culprit margin. The remaining vessel was divided into contiguous 10-mm nonculprit segments. The maxLCBI 4mm of culprit segments (median [interquartile range]: 543 [273–756]) was 4.4-fold greater than nonculprit segments (median [interquartile range]: 123 [0–307]; P 4mm differentiated culprit from nonculprit segments with high accuracy (c-statistic=0.83; P 4mm ≥400 identified STEMI culprit segments with a sensitivity of 64% and specificity of 85%. Conclusions— This study substantiates the ability of NIRS to accurately differentiate STEMI culprit from nonculprit segments and confirms that a threshold maxLCBI 4mm ≥400 is detected by NIRS in the majority of STEMI culprits.

Objectives— Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)–derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)–derived lipid content in ex vivo and in vivo human coronary arteries. Approach and Results— Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma ( P trend P trend c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy ( c index 0.77, P =0.028 versus PB; net-reclassification index 43%, P =0.003), whereas further adding remodeling index did not ( c index 0.80, P =0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. Conclusions— Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

Objective—This study investigates effects of short-term administration of high-density lipoproteins (HDL) and a statin on atherosclerosis in cholesterol-fed rabbits. Effects of HDL apolipoprotein and phospholipid composition have also been investigated.Methods and Results—Aortic atherosclerosis was established over 17 weeks in 46 rabbits by balloon denudation and cholesterol feeding. During the past 5 days of the cholesterol-feeding period, animals received: (1) no treatment; (2) oral atorvastatin 5 mg/kg on each of the 5 days; or (3) infusions of HDL (8 mg/kg apolipoprotein A-I) on days 1 and 3 of the treatment phase. After euthanization, lesion size and composition were assessed by histological and immunohistochemical analysis. HDL (but not atorvastatin) reduced lesion size by 36% (PPPPPPConclusion—Infusing small amounts of HDL rapidly reduces lesion size and is comparable to atorvastatin in promoting a stable plaque phenotype.

Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species. In addition to being an integral component of the innate immune response, evidence has emerged that MPO-derived oxidants contribute to tissue damage during inflammation. MPO-catalyzed reactions have been attributed to potentially proatherogenic biological activities throughout the evolution of cardiovascular disease, including during initiation, propagation, and acute complication phases of the atherosclerotic process. As a result, MPO and its downstream inflammatory pathways represent attractive targets for both prognostication and therapeutic intervention in the prophylaxis of atherosclerotic cardiovascular disease.

Objective— To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol, The Evaluation of Choline Fenofibrate (ABT-335) on Carotid Intima-Media Thickness (cIMT) in Subjects with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy (FIRST) trial evaluated the effects of fenofibric acid (FA) treatment on cIMT in patients with mixed dyslipidemia on atorvastatin. Approach and Results— This multicenter, double-blind, placebo-controlled study was performed in patients with mixed dyslipidemia (fasting triglycerides, ≥150 mg/dL; high-density lipoprotein cholesterol, ≤45 [men] or 55 mg/dL [women]; low-density lipoprotein cholesterol, ≤100 mg/dL once and averaging ≤105 mg/dL) and a history of coronary heart disease or risk equivalent. Patients on background atorvastatin (continued on starting dose or titrated to 40 mg, if needed) were randomized to FA 135 mg or placebo. The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT, measured by ultrasound. In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy, rate of change in posterior-wall cIMT was similar with FA plus atorvastatin (−0.006 mm/y) versus atorvastatin monotherapy (0.000 mm/y; P =0.22). FA plus atorvastatin was favored ( P 0.795 mm, triglycerides 170 to 235 mg/dL, and statin use at entry. Adverse events were consistent with the known safety profiles of both drugs; however, FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy (6.5% versus 0.9%). Conclusions— Compared with atorvastatin monotherapy, FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia.

Objective— The presence of subclinical myocardial necrosis as a prodrome to longer-term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than on the clinical significance of the presence of subclinical myocardial necrosis (ie, “troponin leak”) within stable cardiac patients. Herein, we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function. Methods and Results— Sequential consenting patients (N=3828; median creatinine clearance, 100 mL/min/1.73m 2 ) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (P P Conclusion— In stable cardiology patients, prodromal subclinical myocardial necrosis is associated with substantially higher long-term risk for major adverse cardiovascular events. The underlying mechanisms contributing to this minimal troponin leak phenomenon warrants further investigation.