Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). METHODS AND RESULTS: A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy. CONCLUSIONS: A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.

Triglycerides: risk factor or fellow traveler?

An unresolved issue in preventive cardiology is whether the serum triglyceride level is an independent risk factor for coronary heart disease and, as a direct practical consequence, whether it has value as a diagnostic test. Evidence published in the past year has contributed substantially to clarifying these issues. In this review, we discuss the data that bears upon the importance of triglycerides as a risk factor and the implications of recent clinical trials directed at lipid lowering. We then discuss the alternatives for triglyceride lowering therapy in the light of this new knowledge.

Lessons from the post coronary artery bypass graft study in evaluating and controlling technical variability in angiographic trials. Post CABG Investigators.

Although many investigators have evaluated the technical variability of quantitative angiographic techniques used to study atherosclerosis regression in native coronary arteries, few have studied the variability inherent in repeated studies of atherosclerotic saphenous vein grafts. This study describes 2 studies performed during the course of the Post Coronary Artery Bypass Graft (CABG) Clinical Trial that were designed to assess the reproducibility of: (1) repeated angiographic views within a short time period; and (2) reproducibility of the total process of quantitative analysis of saphenous vein graft angiograms. Statistical methods are described that provide a more meaningful assessment of the impact of measurement variability in the analytic process versus the variability related to changes induced by pharmacologic interventions. One such method, the increase in standard deviation (SD) among patients (ISDP), showed that repeated angiographic views increased the variability of calculation of lesion minimal diameter by 1.5%, whereas the ISDP for repetition of the entire process of quantitative angiographic readings increased variability 6.4%. These data from the Post CABG trial reveal that technical variability is small and has negligible impact on the conclusions of the study.

Usefulness of left ventricular mass in predicting recovery of left ventricular systolic function in patients with symptomatic idiopathic dilated cardiomyopathy.

Prognosis of idiopathic dilated cardiomyopathy (IDC) is variable. We determined the prognostic value of left ventricular (LV) mass and systolic and diastolic function in patients with IDC of <12 months duration. Clinical and echocardiographic assessment was performed at baseline and at 8+/-6 months follow-up in 25 patients (47+/-13 years) with IDC and an LV ejection fraction (LVEF1) of <40% (22+/-7%). Based on a follow-up LVEF (LVEF2) of < or >40%, patients were divided into unimproved (n = 13, LVEF2 = 21+/-9%) and improved groups (n = 12, LVEF2 = 51+/-11%). There was no difference in the LVEF1 (22+/-8% vs. 22+/-6%), LV end-systolic (5.7+/-0.8 vs. 5.8+/-0.9 cm) or end-diastolic (6.5+/-0.6 vs. 6.6+/-0.9 cm) dimension, wall stress (102+/-26 vs 99+/-28 g/cm2), end-systolic (1.7+/-0.3 vs. 1.8+/-0.2) or end-diastolic (1.7+/-0.3 vs. 1.6+/-0.1) sphericity, dp/dt (582+/-163 vs. 678+/-222 mm Hg/s), or right ventricular fractional shortening (20+/-9% vs. 27+/-7%, p = 0.06) in unimproved and improved groups. LV mass was lower (1.00+/-0.21 vs. 1.38+/-0.27 g/ml, p = 0007) and mitral inflow E-wave deceleration time shorter (97+/-42 vs. 164+/-58 ms, p = 0007) in the unimproved versus the improved group. On Pearson correlation analysis, LV mass (r = 0.62, p = 0.001), deceleration time (r = 0.68, p = 0.0002), wall motion score index (r = -0.47, p = 02), and dp/dt (r = 0.52, p = 03) were the significant predictors of LVEF2. There was correlation between LV mass (grams per milliliter) and deceleration time (r = 0.61, p = 0.001). During follow-up, death occurred in 1, and readmission for worsening heart failure in 4 patients in the unimproved group versus no hospitalization in the improved group. Thus, in patients with recent onset IDC, LV mass and diastolic function determine late outcome.

Role of plaque rupture in acute coronary syndromes.

Acute coronary syndromes are caused by plaque rupture. The conventional strategy of prevention of plaque rupture has been driven by the "lipid hypothesis"--if lipid levels are optimized to target levels, the risk of coronary events is decreased. Indeed, the hypothesis has been validated by the dramatic success of statin therapy. However, further major reductions in cardiac events is a realistic goal; various mechanistic and small clinical studies show that statins have beneficial effects in addition to their lipid-lowering properties. One of these beneficial effects is stabilization of plaque. Despite billions of dollars spent on randomized clinical trials, optimal therapy for coronary artery disease is yet to be tested. This therapy might include various combinations of the Mediterranean or low-fat diet, endothelial passivation, lipid-lowering drugs, antioxidants, antiplatelet agents and anti-inflammatory agents.

The aggressive low density lipoprotein lowering controversy.

Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.

Bradyarrhythmias, temporary and permanent pacing.

Bradycardia is common in critical care units. It may be transient, asymptomatic and of little consequence, or life-threatening. Bradycardia may result from abnormalities of the sinus node, atrioventricular node, or the His-Purkinje system. It may also be precipitated by drug effects or enhanced vagal tone. Proper diagnosis is pivotal to determining prognosis and management. Temporary and permanent pacing is now readily available, markedly improving the morbidity and mortality associated with bradyarrhythmias.

Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. METHODS AND RESULTS: Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P=0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P=0.008 and 0.003, respectively. CONCLUSIONS: -The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.

Bloody pericardial effusion in patients with cardiac tamponade: is the cause cancerous, tuberculous, or iatrogenic in the 1990s?

STUDY OBJECTIVES: The decrease in incidence of tuberculosis, along with the increase in invasive cardiovascular procedures, may have changed the frequency of causes of bloody pericardial effusion associated with cardiac tamponade, although this is not yet recognized by medical textbooks. We analyzed the causes of bloody pericardial effusion in the clinical setting of cardiac tamponade in the 1990s; patients' survival; the effect of laboratory results on discharge diagnosis; and how often bloody pericardial effusion is a presenting manifestation of a new malignancy or tuberculosis. DESIGN: Retrospective, observational, single-center study. SETTING: A community hospital. PATIENTS: The charts of all patients who underwent pericardiocentesis for cardiac tamponade and had bloody pericardial effusion were retrospectively reviewed. RESULTS: Of 150 patients who had pericardiocentesis for relieving cardiac tamponade, 96 patients (64%) had a bloody pericardial effusion. The most common cause of bloody pericardial effusion was iatrogenic disease (31%), namely, secondary to invasive cardiac procedures. The other common causes were malignancy (26%), complications of atherosclerotic heart disease (11%), and idiopathic disease (10%). Tuberculosis was detected as a cause of bloody pericardial effusion in one patient and presumed to be the cause in another patient. Bloody pericardial effusion was found to be a presenting manifestation of a newly diagnosed malignancy in two patients. The patients in the idiopathic and iatrogenic groups were all alive and had no recurrence of pericardial effusion at 24 +/- 27 and 33 +/- 21 months after hospital discharge, respectively, whereas 80% of patients with malignancy-related bloody effusions died within 8 +/- 6 months. CONCLUSIONS: In a patient population that is reasonably representative of that in most community hospitals in the United States, the most common cause of bloody pericardial effusion in patients with signs or symptoms of cardiac tamponade is now iatrogenic disease. Of the noniatrogenic causes, malignancy, complications of acute myocardial infarction, and idiopathic disease predominated. Hemorrhagic tuberculous pericardial effusions are uncommon and may likely reflect a low incidence of cardiac tuberculosis in community hospitals in the United States.

Myocardial contractile reserve on dobutamine echocardiography predicts late spontaneous improvement in cardiac function in patients with recent onset idiopathic dilated cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine whether identification of contractile reserve with dobutamine would predict recovery of myocardial function during follow-up in patients with recent onset idiopathic dilated cardiomyopathy (IDC). BACKGROUND: The prognosis of patients presenting with new onset IDC is variable and difficult to predict. METHODS: Twenty-two patients (17 men, 5 women, 46 +/- 14 years) with recently diagnosed IDC (4 +/- 3 months) underwent dobutamine echocardiography. Left ventricular ejection fraction (LVEF) and LV sphericity before and at peak dobutamine infusion (30 +/- 11 microg/kg/min) were determined. A follow-up echocardiographic assessment was done at 6 +/- 4 months. RESULTS: The LVEF on dobutamine was directly related to baseline LV mass expressed as g/ml (Pearson r = 0.65, p = 0.0003). Baseline variables that were significantly predictive of follow-up LVEF were deceleration time (r = 0.69, p = 0.0006), wall motion score index (WMSI) (r = -0.63, p = 0.002), LV mass (r = 0.56, p = 0.008) and LVEF on dobutamine (r = 0.84, p = 0.0001). When either deceleration time or WMSI or LV mass was entered into a regression equation to predict follow-up LVEF, the LVEF on dobutamine added significantly to predictive power. However, if LVEF on dobutamine was entered first, none of the other three variables added significantly to prediction. Baseline LV sphericity at end diastole (ED) (r = 0.13, p = 0.6) did not correlate with follow-up LV sphericity in ED, whereas LV sphericity in ED on dobutamine (ED [r = 0.70, p = 0.0004]) correlated with LV sphericity in ED on follow up. CONCLUSIONS: This study demonstrates that dobutamine-induced improvement in baseline LVEF and LV sphericity identifies patients with IDC who exhibit substantial improvement in LV function and geometry over time.

Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.

BACKGROUND: The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). METHODS AND RESULTS: The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. CONCLUSIONS: Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.

Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque.

BACKGROUND: Tenascin is a large extracellular matrix glycoprotein generally found in adult tissues undergoing active remodeling such as healing wounds and tumors. To determine the potential role of tenascin-C (TN-C) in the pathophysiology of atherosclerosis, we investigated the pattern of expression of TN-C in human coronary atherosclerotic plaques. METHODS AND RESULTS: Immunohistochemical staining and in situ hybridization demonstrated minimal and random expression of TN-C in fibrotic but lipid-poor atherosclerotic plaques. In contrast, all plaques with an organized lipid core or ruptured intimal surface strongly expressed TN-C, which was preferentially concentrated around the lipid core, shoulder regions, and ruptured area of the plaques but not in the fibrous cap. TN-C was not detected in normal arterial tissue. To identify the cellular source of TN-C, the plaques were stained with smooth muscle cell- and macrophage-specific antibodies. TN-C expression correlated with the infiltration of macrophages. Northern blot and immunoprecipitation analysis showed that macrophages expressed 7. 0-kb TN-C mRNA and 220-kDa protein. Reverse transcription-polymerase chain reaction of total RNA derived from macrophages showed that they express the small isoform of TN-C. Zymogram analysis revealed that macrophages markedly increased MMP-9 expression. CONCLUSIONS: This study demonstrates that the level of TN-C expression correlates with the degree of inflammation present, not with plaque size. In addition, cultured macrophages have the capacity to express the TN-C gene. These findings suggest the significance of macrophages in the remodeling of atherosclerotic plaque matrix composition.

Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis.

AIMS: Use of ticlopidine in coronary stenting is limited by delayed onset of action. We studied the effects of clopidogrel, a rapidly acting analog of ticlopidine alone, and in combination with aspirin, in inhibiting stent thrombosis. METHODS: Unpolished nitinol stents were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood at a shear rate of approximately 1500. s-1. Stent thrombus, platelet aggregation and bleeding times were measured at baseline and after treatment. RESULTS: Intravenous clopidogrel produced a rapid (within 30 min) and dose-dependent inhibition of stent thrombosis, with 87% reduction at a dose of 10 mg.kg-1 (P < 0.001). Aspirin alone (10 mg.kg-1) was minimally effective (20% inhibition P > 0.05) in inhibiting stent thrombosis. Combined treatment with clopidogrel and aspirin produced 95-98% inhibition of stent thrombosis, even at low doses of clopidogrel (2.5-5.0 mg.kg-1) (P < 0.0001). At effective doses both clopidogrel and combined therapy produced significant prolongation of bleeding time (P < 0.05) and inhibition of platelet aggregation (P < 0.05). CONCLUSION: Clopidogrel, either alone or combined with aspirin, may have a potential role in preventing stent thrombosis in high-risk clinical situations.