Low-density lipoprotein 4: a novel predictor of coronary artery disease severity.

BACKGROUND: Hyperlipidemia is a well established risk factor for coronary artery disease (CAD). Severe CAD has been observed in patients with normal levels of total and low-density lipoprotein (LDL) cholesterol. Small dense LDL particle subtypes (LDL3 and LDL4) have been observed to be more oxidizable and atherogenic. We aimed to identify the role of cholesterol particle subtypes in predicting CAD severity. METHODS: Blood samples were obtained immediately before cardiac catheterization in 179 consecutive patients with suspected CAD. Detailed lipid profiling was performed using a VAP cholesterol test. CAD severity was categorized angiographically as no/minor CAD (<20% luminal diameter stenosis [LDS]), moderate CAD (20% to 74% LDS) and severe CAD (>75% LDS of any major coronary vessel). RESULTS: Patients with severe CAD had significantly higher LDL4 and triglycerides, and lower total HDL, HDL2, HDL3, LDL2 and LDL3 compared to patients with no/minor CAD (p < .05 for all). Multivariate analysis showed high LDL4 as an independent predictive of severe CAD. ROC analysis showed an area under the curve of 0.62 (p < .0001) with a cut-point of >16.9 mg/dL to predict severe CAD with a sensitivity of 53% and specificity of 79%. CONCLUSION: Elevated LDL4 levels are associated with severe CAD. Further large-scale investigations are required to evaluate the utility of LDL4 in predicting CAD severity.

Statin therapy and inflammation in patients with diabetes treated with high dose aspirin.

BACKGROUND: Statin and aspirin form the therapeutic cornerstone in patients with coronary artery disease (CAD) and diabetes. Little is known about relationship of statins with blood thrombogenicity and inflammation in these patients. METHODS: Two hundred nine consecutive patients with diabetes and suspected CAD undergoing elective cardiac catheterization were divided in groups based on statin treatment in the Multi-Analyte, Thrombogenic, and Genetic Markers Atherosclerosis study. Urinary 11-dehydrothromboxane B2 (11-dh-TxB2), lipid profile and oxLDL/ß2GPI were measured by AspirinWorks™ ELISA assay, vertical density gradient ultracentrifugation and immunoassay respectively. Thrombelastography, and ADP- and collagen-induced light transmittance aggregometry assessed thrombogenicity. CAD was classified as none/minor [<20% diameter stenosis (DS)], moderate (20-75% DS), or severe (>75% DS). RESULTS: Severe, moderate, and no CAD was observed in 66, 19, and 15% of patients respectively. Patients on statins had significantly lower 11-dh-TxB2, collagen-induced aggregation, total cholesterol, total LDL, LDL3, oxidized-LDL, Apo B100, and ApoB100/A1 ratio (p<0.01 for all). Statin therapy demonstrated a lower proportion of patients with high urinary 11-dh-TxB2 (>1500pg 11-dh-TxB2/mg creatinine) (25 vs. 57%, p=0.01). CONCLUSION: Statins along with aspirin, confers additional anti-inflammatory and antithrombotic effect in diabetics with CAD. Urinary 11-dh-TxB2 may be a useful biomarker for personalizing statin therapy.

Thrombin-Induced Platelet-Fibrin Clot Strength Identified by Thrombelastography: A Novel Prothrombotic Marker of Coronary Artery Stent Restenosis.

BACKGROUND AND OBJECTIVE: In-stent restenosis (ISR) is a limitation of percutaneous coronary intervention and has been linked to specific clinical and angiographic variables. We aimed to simultaneously assess thrombosis biomarkers and lipid levels in patients with and without ISR. METHODS: Consecutive patients (n = 170) with a history of coronary stenting undergoing elective angiography were studied. Blood samples for thrombelastography, light transmittance aggregometry, and lipid levels were obtained prior to cardiac catheterization. RESULTS: Sixty-nine patients (41%) had ISR (>50% luminal diameter stenosis). Among patients with ISR, 40 (58%) had ISR in more than one stent bed. Patients with ISR were more often female (37.7% vs. 21.8%, P = 0.04), had higher thrombin-induced platelet-fibrin clot strength (TIP-FCS) (69.9 mm vs. 65.6 mm, P < 0.001), and a higher ApoB/A1 ratio (0.65 vs. 0.59, P = 0.03). In patients on dual antiplatelet therapy (n = 86), there were no differences in ADP-, arachidonic acid-, and collagen-induced platelet aggregation between groups. The frequency of patients with ISR increased with TIP-FCS quartiles and by ROC analysis, TIP-FCS = 67.0 mm was the cutpoint for identification of ISR (AUC = 0.80 (95%CI 0.73-0.87, P < 0.0001). By multivariate analysis, TIP-FCS ≥67.0 mm strongly associated with ISR (OR = 7.3, P = 0.004). CONCLUSION: Patients with ISR identified at the time of cardiac catheterization have a prothrombotic phenotype indicated by high TIP-FCS, a novel marker. Studies to confirm the prognostic utility of high TIP-FCS for the development of ISR are ongoing.

Relation of fish oil supplementation to markers of atherothrombotic risk in patients with cardiovascular disease not receiving lipid-lowering therapy.

Fish oil supplementation (FOS) is known to have cardiovascular benefits. However, the effects of FOS on thrombosis are incompletely understood. We sought to determine if the use of FOS is associated with lower indices of atherothrombotic risk in patients with suspected coronary artery disease (sCAD). This is a subgroup analysis of consecutive patients with sCAD (n=600) enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis study. Patients on FOS were compared with patients not on FOS. Lipid profile was determined by vertical density gradient ultracentrifugation (n=520), eicosapentaenoic acid+docosahexaenoic acid was measured by gas chromatography (n=437), and AtherOx testing was performed by immunoassay (n=343). Thromboelastography (n=419), ADP- and collagen-induced platelet aggregation (n=137), and urinary 11-dehydrothromboxane B2 levels (n=259) were performed immediately before elective coronary angiography. In the total population, FOS was associated with higher eicosapentaenoic acid+docosahexaenoic acid content (p<0.001), lower triglycerides (p=0.04), total very low-density lipoprotein cholesterol (p=0.002), intermediate-density lipoprotein cholesterol (p=0.02), and AtherOx levels (p=0.02) but not in patients on lipid-lowering therapy. Patients not on lipid-lowering therapy taking FOS had lower very low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, remnant lipoproteins, triglycerides, low-density lipoprotein cholesterol, AtherOx levels, collagen-induced platelet aggregation, thrombin-induced platelet-fibrin clot strength, and shear elasticity (p<0.03 for all). In clopidogrel-treated patients, there was no difference in ADP-induced aggregation between FOS groups. Patients on FOS had lower urinary 11-dehydrothromboxane B2 levels regardless of lipid-lowering therapy (p<0.04). In conclusion, the findings of this study support the potential benefit of FOS for atherothrombotic risk reduction in sCAD with the greatest benefit in patients not receiving lipid-lowering therapy. Future prospective studies to compare FOS with lipid-lowering therapy and to assess the independent effects of FOS on thrombogenicity are needed.

Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients.

BACKGROUND: It is uncertain whether sex and race affect thrombogenicity in patients with coronary artery disease. We evaluated the effects of sex and race on thrombogenicity in patients with coronary artery disease treated with aspirin. METHODS AND RESULTS: Patients on aspirin therapy for 1 week or longer with known or suspected coronary artery disease undergoing nonurgent cardiac catheterization (n=1172), of whom 924 were on aspirin and clopidogrel therapy, were studied. The primary end point was thrombin-induced platelet-fibrin clot strength (MAKH) measured by thrombelastography. Secondary end points included coagulation index, a measure of overall coagulation; G, another measure of clot strength; and maximal platelet aggregation. Women had greater MAKH, G, and coagulation index than men, both with and without clopidogrel therapy (with clopidogrel: 68.3±6 versus 65.8±6 mm, P<0.0001; 11.4±3 versus 9.5±4 dyne/cm(2), P<0.0001; and 0.12±3 versus -0.7±3, P=0.003, respectively). Platelet aggregation (induced by ADP, thrombin receptor activating peptide, or collagen) did not differ between sexes. Black patients had greater MAKH and G than white patients (with clopidogrel: 67.8±7 versus 66.4±6 mm, P=0.005; 11±4 versus 10±3 dyne/cm(2), P=0.02, respectively). Black women had the highest MAKH levels. By multivariate analysis, sex, race, diabetes, platelet count, and hemoglobin level were independently associated with MAKH . Sex, but not race, was also associated with the frequency of MAKH ≥72 mm (a threshold related to ischemic event occurrence in patients undergoing coronary intervention). CONCLUSIONS: Sex and race independently influence platelet-fibrin clot strength. Black women appear to have the highest thrombogenicity profile, potentially conferring a high-risk phenotype for thrombotic event occurrence.

Pharmacology of antiplatelet agents.

Pharmacotherapies with agents that inhibit platelet function have proven to be effective in the treatment of acute coronary syndromes, and in the prevention of complications during and after percutaneous coronary intervention. Because of multiple synergetic pathways of platelet activation and their close interplay with coagulation, current treatment strategies are based not only on platelet inhibition, but also on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current strategies can be broadly categorized as anticoagulants, antiplatelet agents, and fibrinolytics. This review focuses on the pharmacology of current antiplatelet therapy primarily targeting the inhibition of the enzyme cyclooxygenase 1, the P2Y12 receptor, the glycoprotein IIb/IIIa receptor, and protease-activated receptor 1.