Atherosclerosis

Background

Atherosclerosis is really a part of the disease process known as arteriosclerosis. Arteriosclerosis means hardening of the arteries and is divided into three variants: atherosclerosis, Monckeberg's medial calcific sclerosis, and arteriolosclerosis (See below). The identification of risk factors is a significant advance to our understanding and prevention of the disease.

Major risk factors include:
Diet and hyperlipidemia
Hypertension
Cigarette smoking
Diabetes

Minor risk factors include:
Obesity
Physical inactivity
Male
Increased Age
Type A personality
Birth control pills
High carbohydrate intake
Hyperhomocysteinemia

Atherosclerotic Heart Disease
The importance of correctly and accurately identifying the disease in its early stages lies in preventing cardiovascular disease and its complications of heart attack (myocardial infarction), angina, aneurysms, and strokes. However, even with the current sophisticated testing, 30% of all deaths related to atherosclerosis occur in patients with no symptoms.

A myocardial infarction is best thought of as a series of events which begins with atheroscelerotic heart disease affecting the coronary arteries. The overall disease process has been called the acute coronary syndrome (ACS). As the disease progresses, the following stages occur:

Asymptomatic coronary artery disease
Stable angina
Unstable angina
Non-Q-wave myocardial infarction
Transmural myocardial infarction
Cardiac arrhythmia
Death

During this process, the coronary atherosclerotic plaque undergoes change and extension with erosion, rupture, and ulceration, leading to activation of platelets and thrombus development. This causes occlusion of the coronary artery leading to ischemia and finally necrosis or death of the heart tissue.

Until recently, the criteria for the diagnosis of a myocardial infarction included 2 of the 3 following changes: chest pain, serum markers, and ECG changes. Today, measurement of serum troponin is now the gold standard for the diagnosis of myocardial infarction. A consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) has redefined a myocardial infarction (MI) as any amount of myocardial necrosis as indicated by an elevation of troponin in the setting of clinical ischemia. It is a "maximal concentration of troponin T or I exceeding the decision limit (99th percentile of the values for a reference control group) on at least one occasion during the first 24 hours after the index clinical event" (see outline below for reference). The change in diagnostic criteria is the result of numerous studies that have documented the sensitivity and specificity of serum troponin which is the single best marker for myocardial infarction.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION

See above discussion

OMEGA-3 FATTY ACIDS

Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women

Frank B. Hu, MD; Leslie Bronner, MD; Walter C. Willett, MD; Meir J. Stampfer, MD; Kathryn M. Rexrode, MD; Christine M. Albert, MD; David Hunter, MD; JoAnn E. Manson, MD

JAMA. 2002;287:1815-1821 Abstract quote

Context
Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women.
Objective
To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women.

Design, Setting, and Participants
Dietary consumption and follow-up data from 84 688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994.

Main Outcome Measures
Incident nonfatal myocardial infarction and CHD deaths.

Results
During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend = .001). Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction.

Conclusion
Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths.

LIPOPROTEIN LIPASE GENE POLYMORPHISMS

Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population.

Abu-Amero KK, Wyngaard CA, Al-Boudari OM, Kambouris M, Dzimiri N.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Arch Pathol Lab Med 2003 May;127(5):597-600 Abstract quote
CONTEXT: Previous studies reported an association of certain polymorphisms in the lipoprotein lipase (LPL) gene with the risk of coronary artery disease (CAD); however, these studies were small and inconsistent. In addition, none of these studies attempted to establish such an association in the Arab population.

OBJECTIVE: To determine whether 2 LPL polymorphisms (LPL-HindIII and LPL-PvuII located on introns 8 and 6, respectively, of the LPL gene) can be considered as independent risk factors or as predictors for CAD in Arabs.

DESIGN: We used polymerase chain reaction and restriction enzyme digestion to determine the distribution of the LPL-HindIII and LPL-PvuII polymorphisms among healthy blood donors of Arabic origin (BD group) and angiographically confirmed CAD patients (CAD group) with identical ethnic backgrounds.

RESULTS: For the HindIII genotypes, within the BD group (n = 410), the +/+ genotype was found in 206 individuals (50.2%), 173 (42.2%) carried the +/- genotype, and 31 (7.6%) carried the -/- genotype. Within the CAD group (n = 352), the +/+ genotype was found in 189 individuals (53.7%), 138 (39.2%) carried the +/- genotype, and 25 (7.1%) carried the -/- genotype. P values of.38,.45, and.92 were obtained for the +/+, +/-, and -/- genotypes, respectively. For the PvuII genotypes, within the BD group (n = 511), the +/+ genotype was found in 182 individuals (35.6%), 248 (48.5%) carried the +/- genotype, and 81 (15.9%) carried the -/- genotype. Within the CAD group (n = 431), the +/+ genotype was found in 138 individuals (32%), 225 (52.2%) carried the +/- genotype, and 68 (15.8%) carried the -/- genotype. P values of.28,.29, and.98 were obtained for the +/+, +/-, and -/- genotypes, respectively. The distribution and the allele frequency of these 2 LPL variants were similar in CAD and BD study groups and followed the Hardy-Weinberg equilibrium.

CONCLUSION: There was no difference in the distribution of both LPL polymorphisms between the healthy group and the CAD group. Therefore, these 2 LPL polymorphisms cannot be considered as independent risk factors or as predictors for CAD in this population.

PROTHROMBIN VARIANT

Prevalence of the 20210 G-->A prothrombin variant and its association with coronary artery disease in a Middle Eastern Arab population.

Abu-Amero KK, Wyngaard CA, Kambouris M, Dzimiri N.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Arch Pathol Lab Med 2002 Sep;126(9):1087-90 Abstract quote
BACKGROUND: No reports are available on the distribution of the 20210 G-->A prothrombin variant among Middle Eastern Arabs. Additionally, to date, studies that attempt to establish this polymorphism as an independent risk factor or as a predictor for coronary artery disease (CAD) have yielded conflicting results.

OBJECTIVE: To determine the prevalence of the 20210 G-->A prothrombin variant among Middle Eastern Arabs and to evaluate the potential relevance of this variant to Arab patients with angiographically documented CAD.

METHODS AND RESULTS: We used the polymerase chain reaction and restriction enzyme digestion to determine the prevalence of this polymorphism in 613 individuals from Arabic ethnic origin with CAD and from 593 healthy blood donors (BDs) from an identical ethnic background. Within the BD group (n = 593), 10 individuals (1.7%) were heterozygous, 583 individuals (98.3%) were normal, and none were homozygous for the 20210 G-->A prothrombin variant. Within the CAD group (n = 613), 13 individuals (2.1%) were heterozygous, 600 individuals (97.9%) were normal, and none were homozygous for the 20210 G-->A prothrombin variant. A chi(2) analysis was used to evaluate any significance in the distribution of genotypes. A value of 1.23 was obtained. Values less than 3.84 indicate no statistically significant difference between the heterozygous carriers of the 20210A allele in both study groups.

CONCLUSIONS: In our population of Middle Eastern Arabs, the presence of the 20210 G-->A prothrombin variant is not associated with patients with angiographically documented CAD. Therefore, this variant cannot be considered as an independent risk factor or as a predictor for CAD in this population.

SMOKING

Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review.

Critchley JA, Capewell S.

Department of Public Health, University of Liverpool, Liverpool, England.
JAMA. 2003 Jul 2;290(1):86-97 Abstract quote
CONTEXT: As more interventions become available for the treatment of coronary heart disease (CHD), policy makers and health practitioners need to understand the benefits of each intervention, to better determine where to focus resources. This is particularly true when a patient with CHD quits smoking.

OBJECTIVE: To conduct a systematic review to determine the magnitude of risk reduction achieved by smoking cessation in patients with CHD.

DATA SOURCES: Nine electronic databases were searched from start of database to April 2003, supplemented by cross-checking references, contact with experts, and with large international cohort studies (identified by the Prospective Studies Collaboration).

STUDY SELECTION: Prospective cohort studies of patients who were diagnosed with CHD were included if they reported all-cause mortality and had at least 2 years of follow-up. Smoking status had to be measured after CHD diagnosis to ascertain quitting.

DATA EXTRACTION: Two reviewers independently assessed studies to determine eligibility, quality assessment of studies, and results, and independently carried out data extraction using a prepiloted, standardized form.

DATA SYNTHESIS: From the literature search, 665 publications were screened and 20 studies were included. Results showed a 36% reduction in crude relative risk (RR) of mortality for patients with CHD who quit compared with those who continued smoking (RR, 0.64; 95% confidence interval [CI], 0.58-0.71). Results from individual studies did not vary greatly despite many differences in patient characteristics, such as age, sex, type of CHD, and the years in which studies took place. Adjusted risk estimates did not differ substantially from crude estimates. Many studies did not adequately address quality issues, such as control of confounding, and misclassification of smoking status. However, restriction to 6 higher-quality studies had little effect on the estimate (RR, 0.71; 95% CI, 0.65-0.77). Few studies included large numbers of elderly persons, women, ethnic minorities, or patients from developing countries.

CONCLUSIONS: Quitting smoking is associated with a substantial reduction in risk of all-cause mortality among patients with CHD. This risk reduction appears to be consistent regardless of age, sex, index cardiac event, country, and year of study commencement.

DISEASE ASSOCIATIONS CHARACTERIZATION

See above discussion

ANDROGENIC ALOPECIA

Early onset of androgenetic alopecia associated with early severe coronary heart disease: a population-based, case-control study.

Matilainen VA, Makinen PK, Keinanen-Kiukaanniemi SM.

Department of Public Health Science and General Practice, University of Oulu, Finland.

J Cardiovasc Risk 2001 Jun;8(3):147-51 Abstract quote

CONTEXT: The relationship of ischaemic heart disease (IHD) with androgenic alopecia (AGA) has been demonstrated, but no differentiation between early and late onsets of alopecia with regard to the risk and severity of IHD has been made.

OBJECTIVE: To test if the early onset of alopecia is a risk factor for early severe, coronary artery disease (CAD) requiring surgery and to test if the early onset of AGA differs in this respect from the late onset of AGA.

DESIGN: Population-based case-control study.

SETTING AND PARTICIPANTS: All the 85 male persons living on 31 December 1999 in a Finnish town with total population of 7200, who had had a coronary revascularization procedure between March 1987 and January 1999, were drawn from the discharge register. For each case, an individually selected age-matched control person living in the same town was drawn from the official census register.

MAIN OUTCOME MEASURE: Alopecia defined as grade 3 vertex or more on the alopecia classification scale of Hamilton, modified by Norwood South Med J, 68:1359-1365, 1975.

RESULTS: The unadjusted odds ratio (OR) for coronary revascularization under the age of 60 years was 3.57 (95% confidence interval (CI) 1.19-10.72) in men with an early onset of AGA compared with men with normal hair status or late AGA. After multivariate adjustment for the traditional CAD risk factors, the corresponding OR was 3.18 (95% CI, 1.01-10.03). The unadjusted OR for the coronary revascularization procedure at any age was 2.14 (95% CI, 1.08-4.23) in the subgroup of the men with early AGA compared to those with late AGA or normal hair status. After adjustment for traditional risk factors this OR was 1.84, being nearly significant (95% CI, 0.90-3.77).

CONCLUSION: Our results support the hypothesis that the early onset of AGA is a risk factor for an early onset of severe coronary heart disease.

Baldness and Coronary Artery Disease The Dermatologic Point of View of a Controversial Issue

Alfredo Rebora, MD

Arch Dermatol. 2001;137:943-947 Abstract quote

Objective Several articles, most of them written by nondermatologists, have stressed that bald men have a higher risk for coronary artery disease than men who are not bald. This study was performed to evaluate the validity of such conclusions from a dermatologic point of view.

Design A review of the 24 articles in literature from 1954 to 1999 as provided by MEDLINE and a previous review.

Results Five articles contained simple comments; 1 was a review of the previous literature; and 3 dealt only with the lipid profile. The remaining 15 articles dealt with coronary artery disease and baldness, and 9 of these concluded that there is a relationship between the 2 conditions, especially in younger subjects with severe early-onset androgenetic alopecia.

Conclusions Baldness did not coincide with androgenetic alopecia in some of the articles examined, which makes it difficult to settle the issue. Subjects who develop baldness before their 30s may have a higher risk for coronary artery disease than other men, and they may be individuals with early-onset androgenetic alopecia who also present with particularly elevated dihydrotestosterone-testosterone ratios. The baldness theory should be included as a secondary hypothesis in large epidemiological studies of coronary artery disease. Such studies should include dermatologic expertise for accurate, cost-effective evaluation of baldness.

HORMONE REPLACMENT THERAPY

Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).

Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N.

University of California, San Francisco, 74 New Montgomery St, Suite 600, San Francisco, CA 94105.

JAMA 2002 Jul 3;288(1):49-57 Abstract quote
CONTEXT: The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5.

OBJECTIVE: To determine if the risk reduction observed in the later years of HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-up.

DESIGN AND SETTING: Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers.

PARTICIPANTS: A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II.

INTERVENTION: Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group.

MAIN OUTCOME MEASURES: The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease.

RESULTS: There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19).

CONCLUSIONS: Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.

Noncardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).

Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake D.

University of California, San Francisco, San Francisco, CA 94143-0560.
JAMA 2002 Jul 3;288(1):58-64 Abstract quote
CONTEXT: The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen plus progestin therapy after menopause.

OBJECTIVE: To examine the effect of long-term postmenopausal hormone therapy on common noncardiovascular disease outcomes.

DESIGN AND SETTING: Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent open-label observational follow-up for 2.7 years (HERS II), carried out between 1993 and 2000 in outpatient and community settings at 20 US clinical centers.

PARTICIPANTS: A total of 2763 postmenopausal women with coronary disease and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II.

INTERVENTION: Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group and increased from 0% (year 1) to 8% (year 6) in the placebo group.

MAIN OUTCOME MEASURES: Thromboembolic events, biliary tract surgery, cancer, fracture, and total mortality.

RESULTS: Comparing women assigned to hormone therapy with those assigned to placebo, the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04) during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend =.08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of the 73 women with thromboembolism died within 30 days due to pulmonary embolism. The overall RH for biliary tract surgery was 1.48 (95% CI, 1.12-1.95); for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture, 1.04 (95% CI, 0.87-1.25). There were 261 deaths among those assigned to hormone therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjusted and as-treated analyses did not alter our conclusions.

CONCLUSIONS: Treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery. Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations.

Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.

Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI.

Division of Cardiology, Room 5G1, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110.
JAMA 2002 Nov 20;288(19):2432-40 Abstract quote
CONTEXT: Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.

OBJECTIVE: To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.

DESIGN, SETTING, AND PATIENTS: The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.

INTERVENTIONS: Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.

MAIN OUTCOME MEASURE: Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.

RESULTS: The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P =.17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P =.32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P =.045), and suggested an increased risk in the active vitamin group (P =.09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.

CONCLUSION: In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.

PATHOGENESIS CHARACTERIZATION

FATTY STREAK This may be the earliest stage of the disease found in late teens and young adults

ATHEROSCLEROTIC PLAQUE

Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: Morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors

Vaiva Lesauskaite, MD, PhD
Piero Tanganelli, MD
Carlo Sassi, MD
Eugenio Neri, MD
Francesco Diciolla, MD
Laima Ivanoviene, PhD
Maria Carmela Epistolato, PhD
Anna Vittoria Lalinga, MD
Carlo Alessandrini, PhD
Donatella Spina, MD

Hum Pathol 32:1003-1011 Abstract quote

The etiopathogenesis of thoracic aortic aneurysms is currently an issue of debate.

The present study investigated ultrastructural, morphometric, and immunohistochemical aspects of smooth muscle cells (SMCs) in chronic aneurysm of the thoracic aorta (aneurysm group), aortic dilatation associated with valvular disease (valvular group), and dissection of the thoracic aorta (dissection group).

Fragments of the ascending aorta that had been taken from the patients during coronary bypass surgery were used as controls. No significant difference was observed in the density of SMCs between the 3 pathologic groups put together and the controls. Only separate analysis of SMC density in each of the pathologic groups showed that the valvular group samples had significantly smaller amounts of SMCs in the internal layer of the media than the dissection group samples and controls. Ultrastructural analysis, in situ end labeling, propidium iodide assay, and DNA laddering did not show apoptosis of SMCs in the samples investigated. Ultrastructure of SMCs characteristic of the synthetic phenotype, together with increased expression of osteopontin in the media of pathologic thoracic aortas indicated the transition of SMCs from the contractile to the synthetic phenotype. Immunohistochemical investigation showed that medial SMCs in the samples taken from aortas of all 3 pathologic groups expressed stronger immunoreactivity for matrix metalloproteinase 1, 2, and 9 and tissue inhibitor of metalloproteinase 1 and 2 than the controls.

The present study shows that during the formation of aneurysms, dissection of the thoracic aorta, or aortic dilatation associated with valvular disease, loss of SMCs was not of great importance with respect to their transition from the contractile to the synthetic type in leading to increased production of matrix metalloproteinases.

GRANZYME B

Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity.

Choy JC, McDonald PC, Suarez AC, Hung VH, Wilson JE, McManus BM, Granville DJ.

The iCAPTUR E Centre/UBC McDonald Research Laboratories, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada.
Mod Pathol 2003 May;16(5):460-70 Abstract quote
Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD). Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD.

Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle alpha-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0-5+/5+ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle alpha-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells.

Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.

INSULIN RESISTANCE

Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthase Inhibitor

Markus C. Stühlinger, MD; Fahim Abbasi, MD; James W. Chu, MD; Cindy Lamendola, MSN, ANP; Tracey L. McLaughlin, MD; John P. Cooke, MD, PhD; Gerald M. Reaven, MD; Philip S. Tsao, PhD

JAMA. 2002;287:1420-1426 Abstract quote

Context
Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of cardiovascular disease. Several cardiovascular risk factors are associated with reduced sensitivity to insulin, but elevated ADMA concentrations have not been fully linked to the metabolic syndrome.

Objective
To evaluate the relationship between insulin sensitivity and plasma ADMA concentrations, and to determine whether a pharmacological treatment that increases insulin sensitivity would also modulate ADMA concentrations.

Design, Setting, and Subjects
Cross-sectional study, containing a nonrandomized controlled trial component, of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal blood pressure and 16 with hypertension), which was conducted at a university medical center between October 2000 and July 2001.

Intervention
Rosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks), an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with hypertension. These subjects were studied before and after 12-week treatment.

Main Outcome Measures
Insulin sensitivity measured by the insulin suppression test, and fasting plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and ADMA concentrations.

Results
Plasma ADMA concentrations were positively correlated with impairment of insulin-mediated glucose disposal in nondiabetic, normotensive subjects (r = 0.73; P<.001). Consistent with the metabolic syndrome, ADMA levels were also positively correlated with fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels (r = 0.19; P = .20). Plasma ADMA concentrations increased in insulin-resistant subjects independent of hypertension. Pharmacological treatment improved insulin sensitivity and reduced mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) µmol/L (P = .001).

Conclusion
A significant relationship exists between insulin resistance and plasma concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations may contribute to the endothelial dysfunction observed in insulin-resistant patients.

LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION

CT-ELECTRON BEAM

The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study.

Oei HH, Vliegenthart R, Hak AE, Iglesias del Sol A, Hofman A, Oudkerk M, Witteman JC.

Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, 3000 DR Rotterdam, the Netherlands.
J Am Coll Cardiol 2002 Jun 5;39(11):1745-51 Abstract quote
OBJECTIVES: The present study was designed to examine the associations of coronary calcification assessed by electron beam computed tomography (CT) with measures of extracoronary atherosclerosis.

BACKGROUND: Although measures of extracoronary atherosclerosis have been used to predict coronary events, it is not yet known to what extent those measures reflect coronary atherosclerosis.

METHODS: The Rotterdam Coronary Calcification Study is a population-based study in subjects age 55 years and over. Participants of the study underwent an electron beam CT scan. Coronary calcification was quantified according to the Agatston calcium score. Measures of extracoronary atherosclerosis included common carotid intima media thickness (IMT), carotid plaques, ankle-arm index (AAI) and aortic calcification. We used the first 2,013 participants for the present analyses. Age-adjusted geometric mean calcium scores were computed for categories of extracoronary measures using analyses of variance.

RESULTS: Graded associations with coronary calcification were found for the carotid and aortic measures. Associations were strongest for carotid plaques and aortic calcification; coronary calcification increased from the lowest category (no plaques) to the highest category 9-fold and 11-fold in men and 10-fold and 20-fold in women, respectively. A nonlinear association was found for AAI with an increase in coronary calcification only at lower levels of AAI.

CONCLUSIONS: In this population-based study, graded associations were found between coronary calcification and common carotid IMT, carotid plaques and aortic calcification. A nonlinear association was found between coronary calcification and the AAI.

Laboratory Markers

CARDIAC ENZYME PANEL

LIPID PANEL

Gold Standard for the diagnosis of acute myocardial infarction Eur Heart J 2000;21:1502
J Am Coll Cardiol 2000;36:959
Consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

VARIANTS

ACUTE CORONARY SYNDROME

CHOLESTEROL EMBOLI SYNDROME

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL Plaque has cholesterol clefts, foamy histiocytes, and calcifications depending upon stage of plaque formation

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Arteriolosclerosis-This is characterized by proliferation and thickening of the inner lining of the small arteries and arterioles. It is most commonly seen in with hypertension in the kidney, intestines, and pancreas.

Atherosclerosis-This is the most common type of arteriosclerosis affecting all arteries but preferentially affecting the coronaries, aorta, and cerebral arteries. It is characterized by deposits of lipid within the wall of the artery with thickening of the inner lining called the intima.

Cardiac Enzymes

Electrocardiogram (ECG or EKG)-This is an electrical measurement of the heart's electrical discharges, measured from multiple axis. It is a useful tool in examining electrical conduction disturbances which may be secondary to severl disease processes, including a myocardial infarction. Example of normal ECG.

Fatty Streak-This is universally present in children and may represent the earliest precursor to anatheromatous plaque.

Lipid Profile Testing

Monckeberg's medial calcific sclerosis-This is characterized by calcification of the media or muscular portions of the artery wall. It occurs in medium sized vessels and in some organs such as the uterus.

Plaque-This is the pathologic hallmark of atherosclerosis. It is present as firm yellow-white nodules that cling to the vessel lining and lead to occlusion. It is composed of inflammatory cells, fat, and connective tissue.

Stroke

Internet Links

Last Updated 7/8/2003

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EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
See above discussion
OMEGA-3 FATTY ACIDS
Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women Frank B. Hu, MD; Leslie Bronner, MD; Walter C. Willett, MD; Meir J. Stampfer, MD; Kathryn M. Rexrode, MD; Christine M. Albert, MD; David Hunter, MD; JoAnn E. Manson, MD	JAMA. 2002;287:1815-1821 Abstract quote Context Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women. Objective To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women. Design, Setting, and Participants Dietary consumption and follow-up data from 84 688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994. Main Outcome Measures Incident nonfatal myocardial infarction and CHD deaths. Results During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend = .001). Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction. Conclusion Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths.
LIPOPROTEIN LIPASE GENE POLYMORPHISMS
Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population. Abu-Amero KK, Wyngaard CA, Al-Boudari OM, Kambouris M, Dzimiri N. Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia	Arch Pathol Lab Med 2003 May;127(5):597-600 Abstract quote CONTEXT: Previous studies reported an association of certain polymorphisms in the lipoprotein lipase (LPL) gene with the risk of coronary artery disease (CAD); however, these studies were small and inconsistent. In addition, none of these studies attempted to establish such an association in the Arab population. OBJECTIVE: To determine whether 2 LPL polymorphisms (LPL-HindIII and LPL-PvuII located on introns 8 and 6, respectively, of the LPL gene) can be considered as independent risk factors or as predictors for CAD in Arabs. DESIGN: We used polymerase chain reaction and restriction enzyme digestion to determine the distribution of the LPL-HindIII and LPL-PvuII polymorphisms among healthy blood donors of Arabic origin (BD group) and angiographically confirmed CAD patients (CAD group) with identical ethnic backgrounds. RESULTS: For the HindIII genotypes, within the BD group (n = 410), the +/+ genotype was found in 206 individuals (50.2%), 173 (42.2%) carried the +/- genotype, and 31 (7.6%) carried the -/- genotype. Within the CAD group (n = 352), the +/+ genotype was found in 189 individuals (53.7%), 138 (39.2%) carried the +/- genotype, and 25 (7.1%) carried the -/- genotype. P values of.38,.45, and.92 were obtained for the +/+, +/-, and -/- genotypes, respectively. For the PvuII genotypes, within the BD group (n = 511), the +/+ genotype was found in 182 individuals (35.6%), 248 (48.5%) carried the +/- genotype, and 81 (15.9%) carried the -/- genotype. Within the CAD group (n = 431), the +/+ genotype was found in 138 individuals (32%), 225 (52.2%) carried the +/- genotype, and 68 (15.8%) carried the -/- genotype. P values of.28,.29, and.98 were obtained for the +/+, +/-, and -/- genotypes, respectively. The distribution and the allele frequency of these 2 LPL variants were similar in CAD and BD study groups and followed the Hardy-Weinberg equilibrium. CONCLUSION: There was no difference in the distribution of both LPL polymorphisms between the healthy group and the CAD group. Therefore, these 2 LPL polymorphisms cannot be considered as independent risk factors or as predictors for CAD in this population.
PROTHROMBIN VARIANT
Prevalence of the 20210 G-->A prothrombin variant and its association with coronary artery disease in a Middle Eastern Arab population. Abu-Amero KK, Wyngaard CA, Kambouris M, Dzimiri N. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.	Arch Pathol Lab Med 2002 Sep;126(9):1087-90 Abstract quote BACKGROUND: No reports are available on the distribution of the 20210 G-->A prothrombin variant among Middle Eastern Arabs. Additionally, to date, studies that attempt to establish this polymorphism as an independent risk factor or as a predictor for coronary artery disease (CAD) have yielded conflicting results. OBJECTIVE: To determine the prevalence of the 20210 G-->A prothrombin variant among Middle Eastern Arabs and to evaluate the potential relevance of this variant to Arab patients with angiographically documented CAD. METHODS AND RESULTS: We used the polymerase chain reaction and restriction enzyme digestion to determine the prevalence of this polymorphism in 613 individuals from Arabic ethnic origin with CAD and from 593 healthy blood donors (BDs) from an identical ethnic background. Within the BD group (n = 593), 10 individuals (1.7%) were heterozygous, 583 individuals (98.3%) were normal, and none were homozygous for the 20210 G-->A prothrombin variant. Within the CAD group (n = 613), 13 individuals (2.1%) were heterozygous, 600 individuals (97.9%) were normal, and none were homozygous for the 20210 G-->A prothrombin variant. A chi(2) analysis was used to evaluate any significance in the distribution of genotypes. A value of 1.23 was obtained. Values less than 3.84 indicate no statistically significant difference between the heterozygous carriers of the 20210A allele in both study groups. CONCLUSIONS: In our population of Middle Eastern Arabs, the presence of the 20210 G-->A prothrombin variant is not associated with patients with angiographically documented CAD. Therefore, this variant cannot be considered as an independent risk factor or as a predictor for CAD in this population.
SMOKING
Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. Critchley JA, Capewell S. Department of Public Health, University of Liverpool, Liverpool, England.	JAMA. 2003 Jul 2;290(1):86-97 Abstract quote CONTEXT: As more interventions become available for the treatment of coronary heart disease (CHD), policy makers and health practitioners need to understand the benefits of each intervention, to better determine where to focus resources. This is particularly true when a patient with CHD quits smoking. OBJECTIVE: To conduct a systematic review to determine the magnitude of risk reduction achieved by smoking cessation in patients with CHD. DATA SOURCES: Nine electronic databases were searched from start of database to April 2003, supplemented by cross-checking references, contact with experts, and with large international cohort studies (identified by the Prospective Studies Collaboration). STUDY SELECTION: Prospective cohort studies of patients who were diagnosed with CHD were included if they reported all-cause mortality and had at least 2 years of follow-up. Smoking status had to be measured after CHD diagnosis to ascertain quitting. DATA EXTRACTION: Two reviewers independently assessed studies to determine eligibility, quality assessment of studies, and results, and independently carried out data extraction using a prepiloted, standardized form. DATA SYNTHESIS: From the literature search, 665 publications were screened and 20 studies were included. Results showed a 36% reduction in crude relative risk (RR) of mortality for patients with CHD who quit compared with those who continued smoking (RR, 0.64; 95% confidence interval [CI], 0.58-0.71). Results from individual studies did not vary greatly despite many differences in patient characteristics, such as age, sex, type of CHD, and the years in which studies took place. Adjusted risk estimates did not differ substantially from crude estimates. Many studies did not adequately address quality issues, such as control of confounding, and misclassification of smoking status. However, restriction to 6 higher-quality studies had little effect on the estimate (RR, 0.71; 95% CI, 0.65-0.77). Few studies included large numbers of elderly persons, women, ethnic minorities, or patients from developing countries. CONCLUSIONS: Quitting smoking is associated with a substantial reduction in risk of all-cause mortality among patients with CHD. This risk reduction appears to be consistent regardless of age, sex, index cardiac event, country, and year of study commencement.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
FATTY STREAK	This may be the earliest stage of the disease found in late teens and young adults
ATHEROSCLEROTIC PLAQUE
Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: Morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors Vaiva Lesauskaite, MD, PhD Piero Tanganelli, MD Carlo Sassi, MD Eugenio Neri, MD Francesco Diciolla, MD Laima Ivanoviene, PhD Maria Carmela Epistolato, PhD Anna Vittoria Lalinga, MD Carlo Alessandrini, PhD Donatella Spina, MD	Hum Pathol 32:1003-1011 Abstract quote The etiopathogenesis of thoracic aortic aneurysms is currently an issue of debate. The present study investigated ultrastructural, morphometric, and immunohistochemical aspects of smooth muscle cells (SMCs) in chronic aneurysm of the thoracic aorta (aneurysm group), aortic dilatation associated with valvular disease (valvular group), and dissection of the thoracic aorta (dissection group). Fragments of the ascending aorta that had been taken from the patients during coronary bypass surgery were used as controls. No significant difference was observed in the density of SMCs between the 3 pathologic groups put together and the controls. Only separate analysis of SMC density in each of the pathologic groups showed that the valvular group samples had significantly smaller amounts of SMCs in the internal layer of the media than the dissection group samples and controls. Ultrastructural analysis, in situ end labeling, propidium iodide assay, and DNA laddering did not show apoptosis of SMCs in the samples investigated. Ultrastructure of SMCs characteristic of the synthetic phenotype, together with increased expression of osteopontin in the media of pathologic thoracic aortas indicated the transition of SMCs from the contractile to the synthetic phenotype. Immunohistochemical investigation showed that medial SMCs in the samples taken from aortas of all 3 pathologic groups expressed stronger immunoreactivity for matrix metalloproteinase 1, 2, and 9 and tissue inhibitor of metalloproteinase 1 and 2 than the controls. The present study shows that during the formation of aneurysms, dissection of the thoracic aorta, or aortic dilatation associated with valvular disease, loss of SMCs was not of great importance with respect to their transition from the contractile to the synthetic type in leading to increased production of matrix metalloproteinases.
GRANZYME B
Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity. Choy JC, McDonald PC, Suarez AC, Hung VH, Wilson JE, McManus BM, Granville DJ. The iCAPTUR E Centre/UBC McDonald Research Laboratories, Department of Pathology and Laboratory Medicine, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada.	Mod Pathol 2003 May;16(5):460-70 Abstract quote Apoptosis of intimal cells is an important contributor to the pathogenesis of atherosclerosis and transplant vascular disease (TVD). Since the activated immune response may be a key regulator of apoptosis in these lesions, we used immunohistochemistry to characterize the presence and localization of granzyme B, a major mediator of the cytotoxic immune response, in advanced atherosclerosis and TVD. Formalin-fixed, paraffin-embedded transverse sections from human left anterior descending coronary arteries were cut serially and stained with antibodies specific for granzyme B, smooth muscle alpha-actin, CD68, and CD3. The amount of granzyme B staining was semi-quantitated on a 0-5+/5+ scale. Also, TUNEL staining and in situ hybridization was performed to visualize cells undergoing cellular damage suggestive of apoptosis, and to localize granzyme B mRNA, respectively. Granzyme B localization was similar in both diseases. This protease was absent in arteries with mild atherosclerosis, but was abundant in the intima and media of vessels with advanced atherosclerosis and TVD. Within the intima, granzyme B localized to TUNEL-positive foam cells surrounding lipid-rich atheromas. Staining of serial sections with granzyme B and either smooth muscle alpha-actin, anti-CD68, or anti-CD3 showed that granzyme B localized to smooth muscle cells, macrophages, and T-cells. Further, in situ hybridization for granzyme B mRNA in TVD cases localized its expression to infiltrating leukocytes and not foam cells. In conclusion, the presence of granzyme B in advanced atherosclerotic lesions and TVD is associated with increasing disease severity and cell death. These observations suggest that granzyme B-mediated apoptosis may contribute to the pathogenesis of these diseases.
INSULIN RESISTANCE
Relationship Between Insulin Resistance and an Endogenous Nitric Oxide Synthase Inhibitor Markus C. Stühlinger, MD; Fahim Abbasi, MD; James W. Chu, MD; Cindy Lamendola, MSN, ANP; Tracey L. McLaughlin, MD; John P. Cooke, MD, PhD; Gerald M. Reaven, MD; Philip S. Tsao, PhD	JAMA. 2002;287:1420-1426 Abstract quote Context Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of cardiovascular disease. Several cardiovascular risk factors are associated with reduced sensitivity to insulin, but elevated ADMA concentrations have not been fully linked to the metabolic syndrome. Objective To evaluate the relationship between insulin sensitivity and plasma ADMA concentrations, and to determine whether a pharmacological treatment that increases insulin sensitivity would also modulate ADMA concentrations. Design, Setting, and Subjects Cross-sectional study, containing a nonrandomized controlled trial component, of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal blood pressure and 16 with hypertension), which was conducted at a university medical center between October 2000 and July 2001. Intervention Rosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks), an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with hypertension. These subjects were studied before and after 12-week treatment. Main Outcome Measures Insulin sensitivity measured by the insulin suppression test, and fasting plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and ADMA concentrations. Results Plasma ADMA concentrations were positively correlated with impairment of insulin-mediated glucose disposal in nondiabetic, normotensive subjects (r = 0.73; P<.001). Consistent with the metabolic syndrome, ADMA levels were also positively correlated with fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels (r = 0.19; P = .20). Plasma ADMA concentrations increased in insulin-resistant subjects independent of hypertension. Pharmacological treatment improved insulin sensitivity and reduced mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) µmol/L (P = .001). Conclusion A significant relationship exists between insulin resistance and plasma concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations may contribute to the endothelial dysfunction observed in insulin-resistant patients.

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
CT-ELECTRON BEAM
The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study. Oei HH, Vliegenthart R, Hak AE, Iglesias del Sol A, Hofman A, Oudkerk M, Witteman JC. Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, 3000 DR Rotterdam, the Netherlands.	J Am Coll Cardiol 2002 Jun 5;39(11):1745-51 Abstract quote OBJECTIVES: The present study was designed to examine the associations of coronary calcification assessed by electron beam computed tomography (CT) with measures of extracoronary atherosclerosis. BACKGROUND: Although measures of extracoronary atherosclerosis have been used to predict coronary events, it is not yet known to what extent those measures reflect coronary atherosclerosis. METHODS: The Rotterdam Coronary Calcification Study is a population-based study in subjects age 55 years and over. Participants of the study underwent an electron beam CT scan. Coronary calcification was quantified according to the Agatston calcium score. Measures of extracoronary atherosclerosis included common carotid intima media thickness (IMT), carotid plaques, ankle-arm index (AAI) and aortic calcification. We used the first 2,013 participants for the present analyses. Age-adjusted geometric mean calcium scores were computed for categories of extracoronary measures using analyses of variance. RESULTS: Graded associations with coronary calcification were found for the carotid and aortic measures. Associations were strongest for carotid plaques and aortic calcification; coronary calcification increased from the lowest category (no plaques) to the highest category 9-fold and 11-fold in men and 10-fold and 20-fold in women, respectively. A nonlinear association was found for AAI with an increase in coronary calcification only at lower levels of AAI. CONCLUSIONS: In this population-based study, graded associations were found between coronary calcification and common carotid IMT, carotid plaques and aortic calcification. A nonlinear association was found between coronary calcification and the AAI.
Laboratory Markers
CARDIAC ENZYME PANEL
LIPID PANEL
Gold Standard for the diagnosis of acute myocardial infarction	Eur Heart J 2000;21:1502 J Am Coll Cardiol 2000;36:959 Consensus document authored by a joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC)

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
VARIANTS
ACUTE CORONARY SYNDROME
CHOLESTEROL EMBOLI SYNDROME

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Plaque has cholesterol clefts, foamy histiocytes, and calcifications depending upon stage of plaque formation