	A 50-year-old man with no previous history of cardiac disease had symptoms of atypical chest discomfort while exercising. He was receiving medical therapy for hypertension and had a family history of early heart disease. He did not smoke and did not have a history of diabetes mellitus. A stress test showed age-appropriate exercise tolerance with no inducible chest discomfort or electrocardiographic abnormalities. Results of myocardial perfusion testing by nuclear single-photon emission computed tomography were normal. A fasting lipid profile showed the following values: total cholesterol, 216 mg/dL; triglycerides, 146 mg/dL; high-density lipoprotein (HDL) cholesterol, 32 mg/dL; and low-density lipoprotein (LDL) cholesterol, 155 mg/dL.

	Statin therapy was prescribed. Follow-up laboratory tests 3 months later showed improvement in the patient’s lipoprotein profile (total cholesterol, 181 mg/dL; triglycerides, 130 mg/dL; HDL cholesterol, 34 mg/dL; and LDL cholesterol, 121 mg/dL). Despite diet alterations, including the ingestion of red wine, and increased exercise, no further appreciable changes in his lipid profile were noted over the ensuing months. Niacin therapy was added to his medical regimen, and follow-up tests showed the following values: total cholesterol, 175 mg/dL; triglycerides, 106 mg/dL; HDL cholesterol, 43 mg/dL; and LDL cholesterol, 111 mg/dL. The combination of a statin and niacin was well tolerated.

	This case report represents a patient profile from the cohort examined in our study. Although there are limited outcome data regarding the treatment of such patients with elevated cardiovascular risk in the setting of low HDL cholesterol, the data presented in this study indicate that endothelial function—a marker of vascular health&mdash;correlates with HDL cholesterol levels. These findings suggest that increasing HDL cholesterol levels may improve endothelial function. Further research, including well-designed, randomized studies, is needed.

Articles

Cardiology Review Online

Case report: Improved HDL cholesterol levels with niacin and statin therapy

	Despite advances in the understanding of its pathophysiology and pharmacotherapy, the diagnosis of chronic heart failure remains profoundly morbid. Numerous prognostic markers that allow the prospective identification of clinical risk strata have been identified. Many of these, however, such as serum catecholamine levels, tumor necrosis factor-alpha, and formal metabolic testing, are not widely available.

	Only one prognostic stratification system has been prospectively validated, the seven-parameter heart failure survival score (HFSS); however, this multifactorial model is probably too complex for routine application. A simple parameter that predicts prognosis in chronic heart failure patients and is easily assessed would be valuable.

	Hyperuricemia is a common finding in patients with chronic heart failure and is independent of diuretic use and renal impairment.1 Uric acid (UA) levels rise in parallel with New York Heart Association (NYHA) functional class.2 They are independently associated with cardiovascular mortality both in the general population3 and in high-risk groups, including patients with hypertension, diabetes mellitus, and chronic heart failure.4 The relationship between serum UA levels and survival and its ease of measurement makes UA a potentially ideal prognostic variable.

	The study by Doehner and Anker (page 25) investigated the hypothesis that UA levels can be used as a prognostic marker in patients with chronic heart failure. They also hypothesized that UA levels provide a staging system for assessing prognosis in chronic heart failure when combined with measures of cardiac function (left ventricular ejection fraction) and patient functional status (maximal oxygen consumption [VO2] with exercise). To explore this, the authors assessed the relationship between survival and UA level in a derivation sample and a validation sample of patients with chronic heart failure. A post hoc calculation of the seven-parameter HFSS was performed in 194 patients, and its prognostic value was compared with that of UA level. Finally, the authors documented the survival of patients with chronic heart failure in relation to a three-risk-factor model that included a high UA level above 565 µmol/L

	(> 9.5 mg/dL) as a marker of metabolic status, a low peak VO2 (≤ 14 mL/kg per minute) as a marker of low functional capacity, and a low ejection fraction (≤ 25%) as a marker of poor cardiac function.

	Results from the derivation study showed that an elevated UA level predicted mortality. Receiver-operator curve analysis showed the best UA level for predicting survival status at 12 and 18 months was 565 µmol/L (9.5 mg/dL). This was confirmed in the validation study, and for every additional 1-mg/dL increase in UA level there was an increase in risk of approximately 30% during the 2 years of follow-

	565 µmol/L or higher, survival was 52% at 12 months and 36% at 24 months. In those with UA levels below 565 µmol/L, survival was 92% and 86% at 12 and 24 months, respectively. When considering all patients from both cohorts, a highly significant graded relationship was found between serum UA level

	and chronic heart failure mortality (chi-square test, 76.2; P < .001). In

	a multivariate Cox regression model with seven variables, only UA

	level (P < .001), left ventricular ejection fraction (P < .04), and peak VO2 (P < .005) predicted survival.

	The authors also showed that HFSS and UA level predicted prognosis independently of each other. Applying the best UA level cutoff

	(≥ 565 µmol/L) to the HFSS subgrouping improved the positive and negative discriminatory power for predicting survival in all HFSS

	strata. The cumulative metabolic, functional, and hemodynamic score (the triad of factors including high UA level, low VO2, and low left ventricular ejection fraction) was highly predictive of death or heart transplantation. Of 120 chronic heart failure patients with a score of 3, 81% were subsequently listed for transplantation. None of those with a score of 0 to 1 were listed.

	pothesis that UA level provides a strong, independent marker of impaired prognosis in patients with moderate to severe chronic heart failure, and that this relationship is graded. The study also showed that UA level predicts prognosis independently of the HFSS, and when added to this score, improves its prognostic power. For these reasons, and because of the ease with which UA levels can be determined in routine clinical practice, the study is important and timely and provides the astute clinician with a valuable disease marker.

	As in all studies of chronic heart failure patient cohorts, this study is limited by the clinical characteristics of the populations studied. Patients were mostly men and mostly ischemic, and only a minority (6%) were treated with beta blocking agents. Moreover, the patients tended to have a poor NYHA functional class (mean, 2.7) to begin with, and no information was provided about serial UA testing as a measure of treatment efficacy.

	Acknowledging these limitations, the study does raise some intriguing biological questions: Why is UA elevated in this context? Is it epiphenomenal or does the UA itself contribute to the progression of disease? Finally, does treatment targeted at UA or the pathways that lead to its production alter the natural progression of chronic heart failure? The answers to these questions are unclear, but there are interesting suggestions in the literature. UA is a byproduct of purine metabolism, and elevated serum levels reflect either increased generation, such as from tissue destruction, increased xanthine oxidase activity, or both, or decreased renal excretion. Because xanthine oxidase activity is up-regulated in the heart in both human and animal models of chronic heart failure, increased UA generation via xanthine oxidase is likely significant.5,6 Xanthine oxidase itself has potentially deleterious effects in chronic heart failure, both by mechanoenergetic uncoupling and via altered myofilament calcium sensitivity.5,7 Moreover, xanthine oxidase is a major contributor to the production of superoxide anions and thus oxidative stress, which has been linked to processes associated with endothelial dysfunction, the local release of inflammatory cytokines, and the activation of ectoproteases that might contribute to cardiac dilation and cell loss.8-11

	It is reasonable to postulate that the metabolic pathways leading

	to UA elevation in chronic heart failure are not epiphenomenal but

	may contribute to disease progression. The availability of pharmacologic agents that specifically target xanthine oxidase activity, such as allopurinol, raises the question of whether this potentially deleterious sequence of events could be targeted and interrupted. Several animal studies and a few clinical observations have suggested that allopurinol has beneficial structural and functional effects in heart failure patients.5,6,12,13 The present observational study would certainly encourage this line of investigation. 

Uric acid as a prognostic marker  in chronic heart failure 

	The study by McLellan and colleagues (page 18) is a subanalysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, which randomly assigned more than 2,000 patients undergoing nonurgent coronary stent implantation to receive either placebo or the glycoprotein (GP) IIb/IIIa inhibitor eptifibatide.

	The primary end point of this trial was a composite of death, myocardial infarction, urgent target vessel revascularization, or bailout use of the drug for acute stent throm-bosis within 48 hours. Secondary end points included these same end points examined at 30 days, 6 months, and 1 year.

	Because previous trials with similar drugs have suggested a greater benefit for diabetic patients, this study evaluated the diabetic patients in the ESPRIT trial. Patients were selected based on the medical history and included diet-controlled diabetic patients.

	The diabetic patients were compared with the nondiabetic patients in baseline and procedural characteristics, and for differences in outcomes at 48 hours and 30 days. Of the 2,061 patients randomized, there were 466 (22.6%) patients classified as diabetic and 1,595 (77.4%) classified as nondiabetic.

	Diabetic patients were more likely to be women (37.6% versus 24.2%; P = .001), hypertensive (71.7% versus 55%; P = .001), heavier (89 kg versus 83.5 kg; P ≤ .001), and to have had a previous coronary procedure (26.8% versus 22.4%; P = .046). Diabetic patients tended to have longer procedure times.

	There was no difference in primary end points between the two groups (diabetic versus nondiabetic patients) at 48 hours or 30 days. At

	6 months, however, the diabetic patients fared worse, with a composite end point reached in 20.9% versus 15% in the nondiabetic patients (P = .008). This difference continued at 1 year with 24.5% of diabetic patients reaching an end point versus 18.4% in the non-

	diabetic patients (P = .008). This was mostly driven by target vessel re-vascularization, and one can only speculate whether results would have been better with drug-eluting stents. When the same analysis was carried out comparing eptifibatide with placebo, the drug did not confer any advantage to the diabetic patients as was seen in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT)1 in which the drug abciximab was used.

	This substudy showed how diabetic patients fare worse with coronary intervention. This was shown with percutaneous transluminal coronary angioplasty in the Bypass Angioplasty Revascularization Investigation (BARI),2 and now with stents in this trial. Eptifibatide did not seem to confer any additional protection for diabetic patients undergoing nonurgent stent deployment, especially with regard to restenosis.

Not all GP IIb/IIIa drugs are the same Stanley Katz, MD

	From the Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

	Many studies have shown that ST-segment depression on admission electrocardiograms (ECGs) provides timely and independent prognostic insights for patients with non—ST-segment elevation acute coronary syndromes (ACS).1-3 Recent evidence from the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON-A) study has extended this by demonstrating a quantitative relationship between the magnitude and distribution of ST-segment depression and short- and long-term outcomes.4 The admission ECG does not reflect the dynamic nature of myocardial ischemia, however, because it is limited to a single point assessment. Little is known about the prognostic utility of combining the discharge and admission ECGs to predict short- and long-term outcomes in patients with non–ST-segment elevation ACS. Therefore, we undertook the current study to (1) examine the prevalence of ST-segment depression on admission and discharge ECGs; (2) determine whether ST changes at discharge provide prognostic value for predicting death and recurrent myocardial infarction (MI) at 6 months in addition to admission ECGs; and (3) determine the prevalence and prognostic implications of Q-waves on admission and discharge ECGs.

	Our study included 918 patients from the PARAGON-B Troponin T substudy who had non—ST-segment elevation ACS and survived to hospital discharge free of confounding factors.5 All patients had evidence of cardiac ischemia, such as elevated creatine kinase-MB or troponin levels or electrocardiographic changes.

	ECG analysis. All 12-lead ECGs were evaluated centrally by two readers at the ECG core laboratory at the Canadian VIGOUR Centre who were blinded to outcomes. Four patient groups were identified according to the ST status of admission and discharge ECGs. Group 1 included patients who had no ST-segment depression on admission or discharge; group 2 included patients who had no ST-segment depression on admission but developed new ST-segment depression at discharge; group 3 included those

	who had ST-segment depression on admission with normalization by discharge; and group 4 included those with ST-segment depression on admission and discharge. The median interval between admission and discharge ECGs was 8 days (4 to 12 days for 25th and 75th percentiles, respectively).

	Statistical analysis. Data are presented as medians with 25th and 75th percentiles for continuous variables. The Kruskal-Wallis test was used for group comparisons, and a Fisher’s exact test or chi-square test was employed for categorical variables. Kaplan-Meier survival estimates were used to compare the time to the first occurrence of the end point among the groups. A multivariate logistic analysis and Cox proportional hazards regression model were performed to determine how baseline characteristics and ECG variables affected outcomes. All tests were two-sided and had a 5% level of significance.

	Of the 918 patients studied, 542 (59%) had ST-segment depression on admission and 376 (41%) did not (table 1). Their 6-month death rates were 4.4% and 0.8% (P = .002), respectively. By discharge, the 35 patients (9.3%) who did not have ST-segment depression on admission had developed ST-segment depression, whereas 320 (59%) of those with admission ST-segment depression had normalized ST segments.

	The patients’ key baseline characteristics, the in-hospital cardiac invasive procedures they were treated with, and their clinical outcomes according to the ST status of admission and discharge ECGs are shown in table 2. Patients who had new ST-segment depression by hospital discharge were more likely to have a history of congestive heart failure (CHF), a previous MI, and prior revascularization. Those with persistent ST-segment depression at discharge were older, had higher troponin T levels, and were more likely in Killip class II or higher on admission. The in-hospital coronary angiography rate for these patients was low (45.4%), yet they had a greater frequency of double and triple vessel disease compared with the other groups.

	At 6 months, patients who had new ST-segment depression at discharge had more recurrent MIs

	than those who never had ST-segment depression (20.6% versus 7.4%;

	P = .018) and higher rates of death and recurrent MI (20.6% versus 8.3%; P = .03). Patients with persistent ST-segment depression on discharge had higher rates of death

	(6% versus 0.9%; P = .001), recurrent MI (16.3% versus 7.4%; P = .002), and death and recurrent MI (20% versus 8.3%; P < .001) at 6 months compared with those who never had

	We also performed a Kaplan-Meier analysis to compare the rates of death and death and recurrent MI at 6 months according to the patients’ ST status at baseline and at discharge (figure). Patients with new ST-segment depression at

	discharge were not included in this survival analysis because of their small sample size. Mortality rates differed significantly at 6 months between patients with no ST-segment depression on either admission or discharge and those with persistent ST-segment depression (P = .001) and those with normalized ST-segment depression at discharge (P = .038). The adjusted relative risk of 6-month mortality among patients with normalized ST-segment depression compared with those without ST-segment depression was 3.38 (95% confidence interval [CI], 0.914—12.3); comparing those with persistent ST-segment depression at discharge with those with no ST-segment depression, the adjusted relative risk was 5.18 (95% CI, 1.45–18.5; P = .011). Patients with persistent ST-segment depression had significantly higher rates of death and recurrent MI compared with patients with no ST-segment depression on both admission and discharge ECGs and those with normalized ST-segment depression by discharge (all P ≤ .005). At 6 months, the adjusted relative risk of death and recurrent MI among patients with normalized ST-segment depression compared with those without ST-segment depression was 1.20 (95% CI, 0.72–2.14); among patients with persistent ST-segment depression at discharge compared with those without

	ST-segment depression, the adjusted relative risk was 2.58 (95% CI,

	Q-wave status of admission and discharge ECGs. Table 3 shows the prevalence of Q-waves on admission

	and discharge ECGs.6 On admission, 662 patients (72%) did not have

	Q-waves, whereas 256 (28%) patients had Q-waves. Discharge ECGs demonstrated 320 patients (35%) had Q-waves and 53 (6%) lost their

	Q-waves. Of the 249 patients who had a previous MI, 136 (54.6%) did not have admission Q-waves. Compared with those without a Q-wave or with Q-waves that disappeared

	Q-waves or persisting Q-waves on discharge had more death (4.8% versus 1.9%; P = .021), recurrent MI (13.8% versus 8.3%; P =.011), and death and recurrent MI (16.4% versus 9.6%; P = .005) at 6 months. Patients with discharge Q-waves also had higher troponin T levels (0.081 ng/mL; range, 0—0.44 ng/mL) compared with those without discharge Q-waves (0.03 ng/mL; range, 0–0.21 ng/mL; P = .001). The presence of discharge Q-waves was highly significant in predicting

	6-month death (2.52; 95% CI, 1.14-5.56; P = .021) and death and recurrent MI (1.83; 95% CI, 1.22—2.75;

	P = .003) after adjusting for key baseline characteristics and status of ST-segment depression.

	Identifying patients with non—ST-segment elevation ACS who are at increased risk is crucial if we are to wisely allocate limited health resources toward appropriate intervention. The ECG remains a simple, noninvasive tool to detect evolutionary changes from admission to discharge.

	Prognostic value of admission and discharge ECGs. Our findings indicate an association between ST-segment depression on the admission ECG and adverse short- and long-term outcomes. Patients with persistent ST-segment depression on discharge were older with more

	prior MI and heart failure; their Killip class on admission and higher troponin T levels suggest a greater risk. Although there was a greater frequency of multivessel disease in this population, the frequency of angiography was lower. The poor prognosis of these patients suggests, but does not prove, that a more aggressive approach could be rewarding. This finding is consistent with previous studies showing the importance of ST-segment depression on the admission ECG, including our study.7-9

	Our study provides new insights into the evolutionary ST-segment changes that occurred in 39% of our patients between admission and discharge. Most patients (90%) had normalization of ST-segment depression at discharge. We provide novel in-formation on the relationship between the discharge ECG and long-term outcomes in non—ST-segment elevation ACS. Schechtman and colleagues showed that ST-segment depression on the discharge ECG was an independent predictor of poor prognosis in non–ST-segment elevation ACS patients.10 Our results support and extend these findings

	to a more comprehensive population. Important differences between the two studies include our larger sample and broader inclusion criteria. The mechanism by which persistent ST-segment depression relates to a worse prognosis is unclear. It could signal residual areas of ischemic myocardium, hibernating myocardium, or continuing silent myocardial ischemia.11-13

	Prognostic value of Q-waves on discharge ECGs. The study by Kleiger and colleagues showed that Q-waves could develop during hospitalization or at discharge in patients with non—ST-segment elevation MI, the majority (70%) developing within 3 days.14 Our study provides new information on the value of Q-waves on the discharge ECG for predicting outcomes. Even after exclusion of in-hospital recurrent MI, those with discharge Q-waves had higher 6-month mortality rates. Because this finding was present at discharge as opposed to early after admission, it is unlikely that it reflects a missed ST-segment elevation MI or a temporal ECG lag. Most of our patients who had a previous MI (54.6%) did not have Q-waves on the admission ECG. This finding is consistent with those of Marcus and colleagues, who found that 42% of patients who had a previous acute MI showed a regression of Q-waves.15

	Our study highlights the utility of adding a discharge ECG to the care plan of ACS patients to craft an appropriate follow-up strategy.

Prognostic value of  ECG changes in non-ST elevation ACS patients

	We will soon celebrate the 100th anniversary of the electrocardiogram (ECG). Although the equipment used has evolved, the fundamental principle of recording the net electrical activity of the heart from the surface of the chest remains the same. As such, the ECG is probably the most durable diagnostic test in modern medicine. As shown by Fu and Armstrong (page 34) in their article on the prognostic value of the ECG at discharge in patients with acute coronary syndromes (ACS), its value remains substantial in the prognosis of unstable coronary disease.

	ST-segment depression at any time (even, presumably, in the presence of left ventricular hypertrophy and other possible causes of altered repolarization) has long been recognized as a predictor of multivessel coronary artery disease and poor short-term outcomes in a variety of coronary disease populations. Suggesting that ST-segment depression indicates ischemia is probably a physiologic oversimplification. Nevertheless, the finding carries independent weight regarding diagnosis (multivessel disease) and prognosis (higher rates of death, myocardial infarction, and revascularization).

	As shown in the current study, there is a gradient of risk, with those who have persistent ST-segment depression being the most likely to have adverse events, those with transient ST-segment depression being at intermediate likelihood, and those with no ST-segment depression being the least likely. This would suggest that, in a population of patients treated at facilities where catheterization is not available, or in patients for whom catheterization may not be immediately suitable for reasons such as patient choice or concerns about complications, ST-segment depression could be the key factor that influences physicians to make a catheterization referral.

	Patients enrolled in the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON-B) study are at high risk by virtue of the entry criteria; all had either positive serum markers or ECG changes. In the present PARAGON-B substudy, a higher risk group was further selected by virtue of ST-segment depression. Yet, less than one half of patients with persistent ST-segment depression underwent diagnostic catheterization. This probably reflects the emotional response of caregivers to “be more aggressive” with younger, healthier patients (and possibly with more male patients). It may also reflect the higher rates of bleeding and other complications in older and sicker patients undergoing an invasive strategy. Yet, it is precisely these higher risk patients who have the greatest net clinical benefit from the invasive approach, the higher rates of bleeding and other complications notwithstanding.

	How should the findings of the study by Fu and Armstrong be incorporated into practice? In centers where ACS patients with one high-risk feature or more routinely undergo catheterization and anatomic revascularization, the study adds little. In centers where catheterization is not available, or in patients for whom a conservative strategy is initially selected, ST-segment depression early or late in the hospital course should be considered to mark a higher risk for adverse outcomes and a greater proportionate benefit from revascularization.

Role of ST-segment status in guiding treatment 

	From the Division of Applied Cachexia Research, Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany, and the Department of Clinical Cardiology, Imperial College, National Heart and Lung Institute (NHLI), London, United Kingdom

	Clinical parameters of prognostic significance are crucially important for risk stratification and treatment planning in chronic diseases such as heart failure. In recent years, numerous parameters have emerged that can predict prognosis in chronic heart failure patients. Problematically, however, many of these parameters are assessed only in research settings and with tests that are not suitable for routine clinical use. Simple parameters that can be measured anywhere and at low cost, but with sufficient prognostic power, are needed for improved clinical applicability in determining chronic heart failure prognoses.

	In chronic heart failure, hyperuricemia is a common finding (independent of kidney function and diuretic dose) that can be used as a marker of impaired oxidative metabolism and hyperinsulinemia,1,2 inflammatory cytokine activation,3 as well as impaired vascular function.4,5 It has been shown that in chronic heart failure, levels of uric acid (UA) reflect the activity of xanthine oxidase,6 an enzymatic system that is an important source of oxygen free radicals.7 Moreover, through the degradation of accumulated purines, UA is a general marker of cell death and hypoxia. We therefore hypothesized that UA might be a potent prognostic marker in chronic heart failure, and that high levels of this acid in combination with a low left ventricular ejection fraction and peak oxygen consumption (VO2) would indicate a particularly poor prognosis.

	To test our hypotheses, we assessed the relationship between survival and UA level in 112 chronic heart failure patients who had been extensively evaluated and prospectively recruited into a long-term metabolic study program from 1992 to 1997. To validate our results, we used a second patient sample, consisting of chronic heart failure patients (n = 182) who were treated on an outpatient basis at our hospital. We used this latter patient sample to test the principal results and best cutoff values in receiver-operator curve analyses for UA levels as prognostic markers as derived from the first,

	112-patient sample. All patients were clinically stable and were being treated with an individually optimized treatment regimen of standard heart failure medications, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta blocking agents, digitalis, nitrates, calcium antagonists, aspirin, and warfarin. As of September 2001, follow-up data for survival based on all-cause mortality was available from the United Kingdom’s Office of National Statistics.

	All parameters needed for calculating the seven-parameter heart failure survival score (HFSS)8 were available for 194 patients from both cohorts, and we compared this with the prognostic power of the UA

	level. We also assessed the survival of chronic heart failure patients with a three-risk-factor model including the three simple parameters of a high UA level as a marker of metabolic status, peak VO2 as a marker of low exercise capacity (peak VO2 ≤ 14 mL/kg per minute),9 and a low left ventricular ejection fraction (≤ 25%) as a marker of impaired hemodynamic and cardiac function.10 We accordingly defined this three-risk-factor model as a metabolic, functional, and hemodynamic (MFH) staging system.

	We then retrospectively analyzed data from 120 consecutive patients who underwent full assessment of eligibility for heart transplantation at the German Heart Institute in Berlin from January to June 1999. On the basis of the results of this assessment, we calculated the MFH score for each patient and compared it retrospectively with the decision of the responsible physicians in each case. The decision for or against listing a patient as eligible for heart transplantation was based solely on the clinical findings for the patient, because the responsible physicians were unaware of the patient’s MFH score or of our data on UA level and heart failure prognosis.

	In the 112-patient derivation sample, UA levels ranged from 187 to 930 µmol/L. A normal level was considered a concentration below 400 µmol/L, which was observed

	in 34 patients (30%). During a follow-up of 51 ± 39 months, 69 patients died (12-month mortality, 24%; 95% confidence interval [CI], 16%—32%). Survivors had significantly lower mean UA levels than did nonsurvivors at 438 ± 108 µmol/L versus 544 ± 163 µmol/L,

	Established prognostic markers, such as urea, age, peak VO2 (all

	P < .001), left ventricular ejection fraction (P = .003), creatinine, sodium, and furosemide equivalent dose (all P < .03), predicted mortality. UA as a continuous variable significantly predicted mortality (hazard ratio [HR], 1.00498; 95% CI, 1.00322-1.00674). Additionally, impaired survival was predicted by UA levels above the median (> 484.5 µmol/L; relative risk [RR], 2.6; 95% CI, 1.6—4.3; P < .0001), in the highest tertile (≥ 565 µmol/L; RR, 3.9; 95% CI, 2.4–6.4; P < .0001), and in the highest quartile (≥ 595 µmol/L; RR, 3.2; 95% CI, 1.9–5.4; P < .0001). In receiver-operator curve analyses, a UA level of 565 µmol/L was the best predictor of survival status at both 12 and 18 months.

	The 182 outpatients of the validation sample were older, on average, than the derivation study patients (63 ± 12 years versus 59 ± 12 years), and they had a somewhat better left ventricular ejection fraction (32% ± 15% versus 26% ± 15%; both P < .05). The two samples were similar in terms of New York Heart Association (NYHA) functional class, peak VO2, sex and etiology distribution, UA levels, and creatinine levels (all P > .05). Mean UA levels were 466 ± 155 µmol/L (range, 106—1,251 µmol/L). A UA level below 400 µmol/L was seen in 35% of patients (n = 64) in the validation sample. During a follow-up of 41 ± 23 months, 59 patients died (12-month mortality, 15%; 95% CI, 10%–20%). Survivors had significantly lower mean UA levels than nonsurvivors at 418 ± 102 µmol/L versus 565 ± 195 µmol/L, respectively (P < .0001). UA levels also predicted mortality in the validation sample (RR, 1.00532; 95% CI, 1.00400–1.00666; P < .0001). For every 100 µmol/L increase in UA, the risk of death increased by 53%.

	When we used the data from the derivation sample, we found that

	a UA level of 565 µmol/L or more (RR, 7.14; 95% CI, 4.20—12.15) was strongly related to increased mortality (P < .0001). For patients with

	In patients with a UA level below 565 µmol/L, survival at 12 and

	24 months was 92% (88%—96%) and 86% (80%–92%), respectively. In

	(P < .0001), left ventricular ejection fraction (P < .04), and peak VO2

	(P < .005) predicted prognosis. Creatinine, sodium, urea, and age were the variables that did not predict prognosis.

	When we evaluated all 294 chronic heart failure patients from both cohorts, we found a graded rela-tionship between serum UA and mortality in heart failure (P < .0001;

	figure 1). There was a stepwise increase in mortality risk paralleling higher UA levels (figure 2).

	UA, HFSS, and MFH score. Sufficient data were available for 194 patients to calculate the seven-pa-rameter HFSS. The mean HFSS in these patients was 8.56 ± 1.24. Both at its three risk levels (chi-square test, 39.1; P < .0001) and as a con-

	tinuous variable (chi-square test, 45.4; P < .0001), the HFSS had prognostic power that was similar to

	P < .0001). Both the HFSS and the UA level predicted prognosis independently of each other, regardless of whether the parameters were treated as continuous or categorical variables (all P < .0001).

	We were able to calculate the three-risk-factor MFH score for

	212 patients (figure 3). Survival was best for those patients without any risk factors (3-year survival, 91%; 95% CI, 85%—98%). With each additional risk factor, we observed a stepwise impairment in survival. Three-year survival with one and two risk factors was 67% (57%–77%) and 33% (19%–47%), respectively. Survival was lowest for patients with all three risk factors (3-year

	MFH staging and heart transplantation (German Heart Institute, Berlin). For the 120 chronic heart failure patients (105 men and 15 women) undergoing evaluation for heart transplantation (clinical characteristics: age, 53 ± 8 years; NYHA functional class, 2.5 ± 0.7; treadmill peak VO2, 14.3 ± 4.4 mL/kg per minute; left ventricular ejection fraction, 23% ± 8%; UA, 469 ± 145 µmol/L), we calculated the three-risk-factor MFH score retrospectively. Of these patients, 20 had an MFH score of 0 and another 35 had an MFH score of 1. None of these 55 patients was listed for heart transplantation. Of 47 patients with an MFH score of 2, there were 24 patients (51%) listed, whereas 16 of 18 patients with an MFH score of 3 (89%) were listed for heart transplantation. The positive predictive value of an MFH score of 0 or 1 for nonlisting for heart transplantation was 100%.

	Our study demonstrated that high serum UA levels are a strong independent marker of impaired prognosis in patients with moder-ate to severe heart failure. A stepwise, graded relationship exists between the serum UA level and survival in these patients. Assessing the UA level provides information that is independent of and prognostically stronger than that of other well-established parameters, such

	as clinical status, exercise capacity, and parameters of kidney function.

	Several factors support the concept that serum UA is a valid metabolic marker in chronic heart failure. First, chronic heart failure is a condition of several abnormally activated metabolic and hormonal regulatory feedback loops. In this context, several pathways, such as those of hypoxia, cell death, immune activation, and insulin resistance, may contribute to increased concentrations of purine metabolites, leading to the activation of xanthine oxidase and increased production of UA. Hyperuricemia has been found to reflect increased xanthine oxidase activity in chronic heart failure.6 Second, this enzymatic system is an important source of oxygen free radicals,7 which provide the pathophysiologic link between high UA levels and a wide variety of detrimental processes including increased cytokine production, cell apoptosis, and endothelial dysfunction, all of which occur in patients with chronic heart failure. In a prospective series of studies of chronic heart failure patients, we have previously shown that hyperuricemia relates to many of these abnormalities independently of diuretic treatment and of markers of kidney function.2-5

	In heart failure patients, treatment must be individualized to achieve an optimal outcome. This tailoring of treatment requires a re-liable assessment of individual

	patient prognosis. One prognostic stratification system, the seven-pa-rameter HFSS,8 has been previously validated for this purpose, but is computer-based and may not be simple enough for routine use. We have now shown that the UA level predicts prognosis as well as the HFSS and independently of it.

	Three main areas of relatively independent prognostic importance in heart failure have emerged: (1) hemodynamic factors, such as the left ventricular ejection fraction; (2) the patient’s functional status, such as peak VO2; and (3) metabolic aspects including neuroendocrine and immunologic processes. The MFH score appears to be a helpful and easy-to-use tool for improving clinical and prognostic assessment in chronic heart failure. We therefore recommend the use of MFH assessment for predicting prognosis in these patients.11 In such MFH staging, we suggest that measurement of UA as a straightforward and easily assessable metabolic marker should become a routine procedure in the evaluation and follow-up of heart failure patients.

	Peak VO2 at maximum exercise is widely accepted as an ideal parameter for objectively assessing the functional capacity of chronic heart

	failure patients. Combining a threshold for this latter parameter (peak VO2 < 14 mL/kg per minute) with the functional cardiac assessment (left ventricular ejection fraction

	≤ 25%) and UA as a metabolic pa-rameter (UA ≥ 565 µmol/L) permits four risk groups to be distinguished, with mortality ranging from very low (MFH score, 0; mortality at

	3 years, 9%) to extremely high (MFH score, 3; mortality at 18 months, 87.5%). In that it involves an easily applicable method with wide availability at very low cost, the MFH score appears to be a meaningful tool for improving the stage-related, tailored treatment of chronic heart failure. Besides benefiting patients with moderate, compensated chronic heart failure, use of the MFH score may also benefit patients with severe heart failure by providing additional information for determining their eligibility for heart transplantation.

	To extend its use beyond chronic heart failure to the general medical community, the MFH score needs to be tested in further studies to validate its prognostic power and possibly to simplify it to a greater extent. The assessment of peak VO2, for example, may be replaceable by simpler measures, such as the 6-minute walk test. Similarly, some clinicians may want to use higher left ventricular ejection fraction cutoff levels or to replace these levels with brain natriuretic peptide levels.

	in therapy for chronic heart failure may affect the prognostic value

	of parameters used for its assessment.12 Consequently, the studies that we report here may have had

	a limitation in that relatively few patients (6%) were receiving beta blockers. Preliminary analyses also indicate that in the population of

	the Second Evaluation of Losartan in the Elderly (ELITE II), UA was a strong, independent prognostic factor that was independent of concomitant beta blocker therapy. Whether therapeutically targeting UA may have beneficial effects in chronic heart failure has not been assessed in detail; however, emerging data suggest that inhibiting the production of UA through blockade of xanthine oxidase with allopuri-

	Elevated serum UA levels are common in chronic heart failure and are a strong, independent marker

	of impaired prognosis in patients with moderate to severe heart failure. As an easily measurable parameter with wide availability, the UA level may be useful for providing ad-ditional prognostic information. Whether UA predicts the development of chronic heart failure or the mode of death in any given individual is unknown. Fang and Alderman15 showed that increased serum UA levels in the general population are independently associated with all-cause, total cardiovascular, and ischemic heart disease mortality. Therefore, the assessment of UA may be of general value in both healthy and unhealthy individuals. The MFH score also appears to be a helpful, easy-to-use tool to improve clinical and prognostic assessment in chronic heart failure. 

Uric acid and  survival in chronic  heart failure

	From the University of Ottawa Heart Institute, Ottawa, Ontario, Canada, and Duke Clinical Research Institute, Durham, North Carolina

	Glycoprotein (GP) IIb/IIIa platelet receptor blockade reduces ischemic complications of percutaneous coronary intervention (PCI) with stenting.1-4 Several studies have suggested abnormal platelet activity and reactivity in the presence of diabetes.5,6 Clinically, a greater degree of benefit in patients with diabetes than in those without diabetes has been reported in one analysis of the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial of abciximab (ReoPro®), a monoclonal antibody that blocks the GP IIb/IIIa receptor.7 Analysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial2 regarding the outcomes of patients with diabetes treated with eptifibatide, a small molecule GP IIb/IIIa inhibitor, is reported herein.

	The ESPRIT trial2 randomly assigned 2,061 patients undergoing nonurgent coronary stent implantation to treatment with either eptifibatide or placebo. Eptifibatide was administered as two 180-µg/kg boluses given 10 minutes apart followed by a 2.0-µg/kg per minute infusion for 18 to 24 hours. All patients were treated with aspirin and a thienopyridine, and heparin was given during the procedure to achieve an activated clotting time of 200 to 300 seconds. The primary end point was a composite of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), or bailout GP IIb/IIIa treatment for thrombosis at 48 hours. Secondary end points included the individual and combined occurrences of death, MI, and TVR at 30 days, 6 months, and 1 year. Definitions of these end points have been previously published.1 All sites were blind to treatment for the 1-year follow-up period.

	For this report, patients were classified as having diabetes based on their medical history and included diet-controlled patients as well as patients receiving oral hypoglycemic agents or insulin. This definition is the same one used in the report of outcomes by diabetes status by Labinaz and colleagues8; the definition of diabetes as reported in the primary outcome paper did not include diet-controlled patients.1 These definitions were as specified in the long-term follow-up and primary trial protocols, respectively. Diabetic and nondiabetic patients were then analyzed for differences in baseline and procedural characteristics, and for differences in outcomes at 48 hours and 30 days with either a Pearson chi-square test or Wilcoxon rank-sum test, depending on the type of variable. A P value of .05 or below was considered statistically significant. A log-rank chi-square test was used to compare event rates at 6 months and 1 year by diabetes status.

	To determine if treatment effects were different by the presence or absence of diabetes, the covariates of treatment assignment, diabetes, and the interaction of the two were entered into a logistic regression model for events at 48 hours and 30 days. The covariates were then entered into a Cox proportional hazards model to determine the interaction at 6 months and 1 year.

	In the ESPRIT trial, 2,061 patients were randomly assigned to either eptifibatide or placebo as an adjunct to stent PCI. Of these, 466 (22.6%) had diabetes and 1,595 (77.4%) were classified as not having diabetes. There was complete follow-up in 95.6% of nondiabetic patients and 94.4% of diabetic patients. One-year mortality status was available in 98.5% of nondiabetic patients and 98.3% of diabetic patients.

	In the overall ESPRIT trial, and also the subgroups by presence or absence of diabetes, there were no significant differences in baseline clinical characteristics between patients assigned to eptifibatide treatment or placebo. The comparison

	of baseline characteristics between patients by diabetes status showed several differences. Diabetic patients were more likely to be women (37.6% versus 24.2%; P = .001), to have hypertension (71.7% versus 55.0%; P = .001), to have a higher weight (89.0 kg versus 83.5 kg;

	P < .001), and to have undergone a previous PCI procedure (26.8% versus 22.4%; P = .046). Angiographic and procedural characteristics were similar between diabetic and nondiabetic patients, except that the diabetic patients tended to have longer procedure times.

	Patient outcomes by diabetes. The primary end point (composite of death, MI, urgent TVR, or thrombotic bailout) between diabetic and nondiabetic patients was not statistically different at 48 hours (6.7% versus 9.1%) or at 30 days (7.5% versus 8.9%). At 6 months, the incidence of the composite end point of death, MI, and any TVR was higher in patients with diabetes, having been reached in 20.9% of diabetic patients compared with 15.0% of patients without diabetes (P = .008). At 1 year, patients with diabetes continued to have an excess of composite end point events (24.5% versus 18.4%;

	P = .008), resulting mostly from a higher incidence of TVR in diabetic patients (figure 1).

	Effect of eptifibatide on patient outcomes by diabetes. The primary end point for patients assigned to eptifibatide compared with placebo occurred at 48 hours in 4.7% versus 8.6% in diabetic patients and 7.2% versus 11.0% in nondiabetic patients. The effect of eptifibatide on diabet-

	benefit of eptifibatide treatment was approximately the same with respect to diabetes status (and by definition of diabetes). All analyses at all time points for an interaction

	of eptifibatide treatment with diabetes documented no additional specific benefit (or lack thereof) in diabetic versus nondiabetic patients (table).

	The effect of a small molecule GP IIb/IIIa inhibitor on outcomes according to diabetes status for patients undergoing nonurgent coronary stent implantation has not previously been studied. Treatment with eptifibatide was associated with a reduction in the primary composite end point of death, MI, urgent TVR, or thrombotic bailout at 48 hours that was similar in both diabetic and nondiabetic patients. The benefit of eptifibatide on outcomes continued during the 1-year follow-up period and was similar between diabetic and nondiabetic patients.

	Outcomes in diabetic versus nondiabetic patients. The incidence of adverse events in the diabetic group was relatively low, and actually was lower for diabetic patients than for those without diabetes at 48 hours. By 1 year, however, there were significantly more events in the diabetic patients. The incidence of death or MI was similar for all points during the 1-year follow-up. The difference between diabetic and nondiabetic patients was due to an increase in TVR for diabetic patients. This is consistent with the fact that restenosis is known to occur more often with diabetes.9,10

	In a previous analysis of the ESPRIT study, there were 419 diabetic patients receiving oral hypoglycemic agents or insulin.2 In performing the 1-year analysis of the ESPRIT study we elected to obtain greater detail on the type of diabetes. As a result, we identified an additional 47 patients who were controlled by diet and were not included in the original analysis. Therefore, in order to provide a comprehensive analysis of all diabetic patients in the ESPRIT study, we included these diet-controlled patients in the current analysis, resulting in a total of 466 patients with diabetes. Statistical testing showed no interaction between the definition of diabetes and outcomes.

	Other studies. The EPISTENT investigators studied outcomes in diabetic patients according to the use

	of abciximab, a monoclonal antibody that binds to the GP IIb/IIIa receptor and to other integrins.7 Patients with diabetes undergoing stent implantation were found to have a statistically significant reduction in adverse outcomes with abciximab; as in ESPRIT, the overall degree of benefit was similar to that seen in patients without diabetes. The composite end point of death, MI, or TVR at 6 months was significantly lower in diabetic patients undergoing stenting if they received abciximab compared with stenting alone (13.0% versus 25.2%; P = .005). At 6 months, both the incidence

	P = .041). At 1 year, there was a trend toward reduced mortality in patients with diabetes (4.1% versus 1.2%).

	Subsequently, tirofiban, another small molecule GP IIb/IIIa inhibitor, was compared with abciximab as an adjunct to stent PCI in the Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET).11 The 6-month composite end point of death, MI, or TVR was similar with abciximab compared with tirofiban in diabet-

	ic patients undergoing coronary stent implantation (16.7% versus 15.2%, respectively), suggesting similar long-term outcomes regardless of the GP IIb/IIIa inhibitor chosen.

	Target vessel revascularization. The significant effects of eptifibatide

	in the reduction of death and MI. The effects on reducing TVR appear to be much less important. Studies

	of the effects of GP IIb/IIIa inhibi-tors on TVR according to diabetes status have reported conflicting results. In EPISTENT, the subgroup of patients having diabetes and undergoing coronary stenting had a 51% reduction in the rate of TVR with treatment (16.6% versus 8.1%;

	P = .021). Conversely, there was no effect on reducing TVR among patients without diabetes (8.8% versus 9.0%). The earlier Evaluation in PTCA to Improve Long-term Outcome with Abciximab Glycoprotein IIb/IIIa Blockade (EPILOG) trial

	of abciximab suggested a trend toward increased rates of TVR after abciximab treatment in patients with diabetes treated with balloon an-

	gioplasty.12 Perhaps the most relevant trial is the TARGET trial11; in this study, rates of TVR at 6 months in patients with diabetes were

	10.8% after abciximab treatment and 8.8% in those treated with tirofiban, suggesting no specific interaction between diabetes and abciximab treatment with regard to the TVR end point.

	In this study of eptifibatide, patients with diabetes assigned to eptifibatide or placebo had almost identical rates of TVR at 6 months (13.8% versus 13.0%), which continued to be no different at 1 year. The reason for the reported differences between studies of the effects of platelet GP IIb/IIIa inhibition vis á vis TVR is unclear, but is most likely related to the small sample sizes inherent to subgroup analyses, the differences in trial designs or populations, or both.

	This study analyzed the outcomes of patients with diabetes compared with those without diabetes in the ESPRIT trial. Eptifibatide treatment during nonurgent coronary stent implantation conferred similar degrees of benefits to both cohorts of patients in reducing ischemic complications associated with stent PCI.

Coronary artery  stenting and eptifibatide treatment in diabetes

	From the Department of Medicine, Division of Cardiology, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

	Endothelial cells perform crucial functions within the vascular system. Abnormal vasoactivity largely results from decreased nitric oxide production by the endothelium.1 Endothelial dysfunction can be detected in coronary and peripheral arteries before the development of atherosclerotic plaque,2 and its presence has been shown to predict future cardiac events.3 High-resolution ultrasonography of the brachial artery during reactive hyperemia is a noninvasive method of assessing endothelium-dependent vasomotion. Abnormalities in peripheral vasomotor function correlate with the presence of coronary arterial endothelial dysfunction.4 In some studies, maximal ability of the artery to vasodilate via an endothelium-independent pathway also appears to correlate with the presence of coronary artery disease (CAD).5 Abnormalities in low-density lipoprotein (LDL) cholesterol, along with other risk factors for atherosclerosis, correlate with impaired vasorelaxation of coronary and peripheral arteries.

	The beneficial effects of high-density lipoprotein (HDL) cholesterol on the vasculature are numerous. HDL cholesterol inhibits oxidation of LDL cholesterol, up-regulates prostacyclin formation, and exerts direct anti-inflammatory effects.6 HDL cholesterol also has direct beneficial effects on the vascular endothelium, including rapid activation of endothelial nitric oxide synthase (eNOS)7 and reversal of oxidized LDL-mediated inhibition of eNOS activity.8 Based on these observations, we sought to determine whether HDL levels correlate with peripheral endothelial function in a population of adults with CAD.

	The study population consisted of consecutive adult subjects under-going nuclear stress testing for evaluation of CAD. Subjects with a recent myocardial infarction or unstable angina, congestive heart failure, or valvular heart disease were excluded. The presence or absence of cardiovascular risk factors was assessed in each subject. All subjects underwent clinically indicated, symptom-limited nuclear stress testing with intravenous technetium-99m sestamibi using a standard Bruce exercise protocol. Single-

	photon emission computed tomography (SPECT) scans were analyzed in

	a blind fashion and considered positive for CAD if perfusion abnormalities were found and negative for CAD if no perfusion abnormalities were noted.

	Brachial artery ultrasonography testing was performed to evaluate peripheral endothelial function as previously described by us and others.9 Longitudinal brachial artery images of subjects were obtained with a high-resolution (10 MHz)

	linear array vascular transducer during the morning hours after

	at least a 6-hour fast. After an equilibrium period of 10-minutes, base-

	line 2-dimensional images of the brachial artery were obtained 2 cm above the antecubital fossa. A blood pressure cuff placed on the upper arm was inflated to suprasystolic pressure for 5 minutes. After cuff release, the vessel was imaged continuously, and peak hyperemia brachial artery diameter was obtained after 60 seconds. After a return to the baseline brachial artery diameter, peak nitroglycerin brachial artery diameter was determined

	5 minutes after administration of sublingual nitroglycerin.

	Percent flow-mediated dilation was defined as the difference between the maximal brachial artery diameter during reactive hyperemia and the baseline brachial artery diameter divided by the baseline brachial ar-

	tery diameter. Percent nitroglycerin-mediated dilation was defined as the difference between the maximal brachial artery diameter after nitroglycerin administration and the baseline brachial artery diameter divided by the baseline brachial artery diameter. Fasting serum samples were drawn for analysis.

	One hundred fifty-one subjects (87 men, 64 women) were enrolled in the study. The average age (± SD) was 58 ± 11 years. Forty-three percent had hypertension, and 25% had diabetes mellitus. Approximately one fourth of the subjects were taking aspirin, one third were taking angiotensin-converting enzyme inhibitors, and nearly one half were receiving statin therapy. The average values for lipid levels were: total cholesterol, 188 ± 48 mg/dL; HDL cholesterol, 47 ± 13 mg/dL; LDL cholesterol, 108 ± 37 mg/dL; triglycerides, 154 ± 88 mg/dL; and non-HDL cholesterol, 141 ± 43 mg/dL. CAD was diagnosed in 66 subjects by SPECT imaging.

	There was a significant correlation between flow-mediated dilation and the HDL level (r = 0.3; P < .001). The average flow-mediated dilation for the group was 9.9 ± 5.2%, and the mean baseline brachial artery diameter was 3.8 ± 0.7 mm. Subjects with an HDL level below 40 mg/dL had lower flow-mediated dilation (n = 39; 7.4 ± 3.6%) compared with those with an HDL level 40 mg/dL or above (n = 112; 11.0 ± 5.5%; P < .001). The baseline brachial artery dimension was also different between the two groups (4.2 ± 0.7 mm for those with HDL cholesterol < 40 mg/dL compared with 3.7 ± 0.7 mm for those with HDL cholesterol ≥ 40 mg/dL; P < .001). The absolute difference between the brachial artery diameter during hyperemia and baseline in subjects with HDL cholesterol below 40 mg/dL was significantly less than for those with an HDL cholesterol level 40 mg/dL or above (P = .014). As expected, subjects with CAD (n = 66) had lower HDL cholesterol (40 ± 9 mg/dL) and flow-mediated dilation (7.4 ± 4.2%), whereas subjects without CAD

	(n = 85) had higher HDL cholesterol (53 ± 13 mg/dL) and flow-mediated dilation (11.7 ± 5.2%; P < .001). Multivariate analysis showed that HDL cholesterol was an independent

	predictor of flow-mediated dilation (P = .015). Endothelium-independent vasodilation was decreased in subjects with HDL cholesterol below 40 mg/dL (16.0 ± 6.3%) compared with those with HDL cholesterol 40 mg/dL or above (19.9 ± 9.6%; P = .02).

	This study shows that HDL cholesterol levels directly correlate with peripheral endothelial function in a population of patients undergoing evaluation for atherosclerosis. Interestingly, other lipid parameters, including total cholesterol and LDL cholesterol along with hyperten-sion and diabetes mellitus, did not correlate independently with flow-mediated dilation in this popula-tion. On average, brachial artery vasomotion during reactive hyperemia was blunted in subjects with low HDL cholesterol levels and well preserved in those with HDL cholesterol levels 40 mg/dL or above.

	In addition, the relationship between flow-mediated dilation and HDL cholesterol was stronger in men compared with women in this study, although this may be because of the small sample size of women.

	Atherosclerosis results in remodeling of the arterial wall and may lead to arterial expansion.10 Thus, arterial size alone may be an indicator of atherosclerosis. In our study, baseline brachial artery size was larger in subjects with HDL cholesterol below 40 mg/dL compared with those who had higher levels of this lipoprotein. Absolute changes in vessel diameter (reactive hyperemia minus baseline diameter) correlated with HDL levels. Endothelial-independent vasomotion was also decreased in subjects with low HDL levels compared with those with high levels.

	The data presented in this study are consistent with previous studies relating HDL cholesterol to endothelial function. Kuhn and colleagues studied subjects undergoing elective angiography and performed intracoronary acetylcholine injections to evaluate vasomotor responsiveness.11 In their study, subjects with a normal vasodilatory response to acetylcholine had higher levels of HDL cholesterol compared with those with paradoxical vasoconstriction. In a study by Toikka and colleagues, a similar correlation between HDL cholesterol levels and peripheral vasomotor function was noted. Low HDL levels in young healthy subjects were related to brachial artery endothelial dysfunction and increased oxidative stress.12 HDL cholesterol has also been shown to correlate with peripheral endothelial function in hyperlipidemic subjects.13 In another analysis, reconstituted HDL cholesterol infused into patients with hyperlipidemia resulted in a transient increase in HDL levels and improvement in acetylcholine-induced brachial artery blood flow.14 Infusion of an eNOS inhibitor in this population prevented the HDL-induced improvement in blood flow, indicating that a likely interaction between HDL cholesterol and eNOS was responsible for the vessel dilation. Finally, we have recently shown that brachial artery flow-mediated dilation improves after administration of HDL-raising therapy,9 thus supporting the importance not only of basal levels of HDL cholesterol, but also of approaches to raise these levels.

	HDL cholesterol levels independently predicted peripheral vasomotor function in a population

	undergoing evaluation for atherosclerosis. These findings may indicate a significant effect of HDL levels on endothelial function and help to unmask previously unrecognized mechanisms for the beneficial effects of HDL cholesterol. HDL levels may provide mechanistic insight into vasomotor dysfunction and perhaps offer a therapeutic target to improve cardiovascular risk. Further studies focusing on the effects of HDL-raising therapies on endothelial function are warranted.

Peripheral vascular  function and HDL  cholesterol

	A 73-year-old man presented with a history of crescendo angina during the preceding week. This culminated in a 20-minute bout of chest pain that awoke him from sleep and prompted him to go to a small community hospital without interventional capabilities. His clinical examination revealed a normal blood pressure and pulse and an S4 gallop at the apex. No other abnormalities were found. An electrocardiogram (ECG) showed diffuse ST and T-wave changes with up to 2 mm of ST-segment depression maximal in lead V5 (figure A). Cardiac troponin and creatine kinase-MB were negative.

	The patient was treated with anti-ischemic and antithrombotic medicines with a good clinical response. He was ambulated without return of discomfort and discharged on hospital day 4 with follow-up arrangements to see a cardiologist in a tertiary care center. His ECG at discharge

	(figure B) showed persisting, but less marked, ST and T-wave changes. The patient had recurrent pain associated with a non—ST-segment elevation myocardial infarction that occurred

	5 days after discharge. He again went to the community hospital and was triaged to a tertiary care center. Invasive studies showed severe proximal triple vessel disease. The patient underwent successful coronary bypass surgery 48 hours later.

	This case emphasizes the prognostic utility of a repeat ECG obtained close to the time of discharge in patients with acute coronary syndromes, and the need for increased suspicion in such instances.

Case report: Anticipating outcomes based on ECG status

	NEW ORLEANS—Compliance with lipid-lowering therapy and other cardiac risk factor-modifying behaviors improves when patients know that they have high coronary calcification scores, said Matthew J. Budoff, MD, associate professor of medicine, division of cardiology, Harbor-UCLA Research and Education Institute, Torrance, Calif.

	“Electron beam tomography appears to be very useful in addressing our most important issue in preventive medicine today: compliance,” he said. “Coronary artery calcification score may add motivation to asymptomatic patients recommended for lifestyle modifications and drug therapy.”

	About 50% of patients who are prescribed lipid-lowering therapy discontinue their drugs within 1 year; this percentage jumps to 75% by year 2. Guidelines for modifying risk in patients with hypertension or dyslipidemia stress a need for long-term compliance among patients at risk for coronary artery disease.

	“Successful systems for increasing compliance with exercise, diet, or medical therapy are badly needed,” said Dr. Budoff. He and his colleagues sought to measure whether showing coronary artery calcium results to patients had any effect on behavioral lifestyle changes.

	In the study, 1,215 consecutive asymptomatic patients referred for electron beam tomography (EBT) risk assessment by their primary care physicians were sent a survey questioning them about health behaviors. At the time of the original EBT scan, the results were discussed with patients, describing coronary artery calcification as identifying underlying coronary atherosclerosis and being predictive of heart disease risk. Follow-up survey information was obtained from 981 of the patients, a mean of 3.6 years after the baseline scan.

	Patients were divided into quartiles based on their coronary artery calcification score: those in the first quartile had a score of 0 to 2, while those in the fourth quartile had scores greater than 285. Patients in the first quartile had the lowest utilization of lifestyle modifications between scans; utilization improved with higher calcium scores, said Dr. Budoff. For example, statin use improved significantly, from 24% among patients with the lowest calcium scores to 74% among those with the highest scores (P < .001).  Likewise, dietary modification improved from 34% to 57% (P < .001), and an increase in aerobic activity was reported by 46% of those with the lowest calcium scores compared with 67% of those with the highest scores (P < .001). There was also a trend toward a higher incidence of smoking cessation among patients with higher calcium scores (P = .08).

	Persistence with statin therapy was 90% at 3.6 years in patients with coronary artery calcium scores in excess of 400 at baseline, compared with only 44% among those who did not have an EBT scan and 63% who had one but had scores less than 100. A calcium score greater than 100 is a significant risk factor for future cardiovascular events and mortality, noted Dr. Budoff. “Using this cutoff, we found an adherence rate of 83%, and these patients were 5.8-fold more likely to remain on statins than patients with lower scores,” he said.

Knowledge of calcium score improves compliance with risk-reducing behavior

	NEW ORLEANS—Several studies presented at the 53rd annual scientific sessions of the American College of Cardiology provide new insight into the harmful relationship between high blood glucose levels, metabolic syndrome, inflammation, and increased cardiovascular risk.

	The likelihood of developing cardiovascular disease increases with metabolic syndrome or diabetes, and is greatest in these populations who also have high levels of C-reactive protein (CRP), said Shaista Malik, MD, MPH, cardiology fellow, University of California, Irvine. Her study used data from 6,497 adults who participated in the Third National Health and Nutrition Examination Survey.

	The risk of cardiovascular disease climbed with each additional risk factor for metabolic syndrome, and was greatest in patients with diabetes. In examining whether CRP levels could help to further stratify risk in subjects with a diagnosis of metabolic syndrome or diabetes, she found a correspondingly higher risk of cardiovascular disease in those with higher CRP compared with lower CRP levels. Compared with persons without metabolic syndrome or diabetes and a low CRP level (≤ 3 mg/L), persons with metabolic syndrome and high CRP levels (> 3 mg/L) had an odds ratio of cardiovascular disease of 2.35

	(P < .001); those with diabetes and high CRP had an odds ratio of 5.60 (P < .001). “CRP levels help to further stratify risk in those with metabolic syndrome or diabetes mellitus, possibly identifying higher risk subsets that warrant more aggressive intervention,” said Dr. Malik.

	In the Framingham Offspring Study, CRP was found to be related to all components of the metabolic syndrome, and this relationship was stronger in women than in men, said Martin K. Rutter, MD, professor, department of medicine, Uni-

	versity of Manchester, United Kingdom. His analysis included 3,037 subjects, 24% of whom had metabolic syndrome, who were followed up for more than 8 years. The CRP level increased with each additional component of the metabolic syndrome: those with no traits of this syndrome had a mean CRP level of

	five traits had a mean CRP level of 4.1 mg/L. Furthermore, participants with the greatest number of metabolic syndrome characteristics were 1.8 times as likely to have a cardiovascular disease event compared with subjects with the fewest number of metabolic syndrome characteristics. Similarly, in participants with the highest CRP levels, the risk of cardiovascular disease was almost twice as high as in those with the lowest CRP levels.

	Patients who develop high fasting blood glucose levels after myocardial infarction (MI) have an increased risk of death within 30 days, according to Mahmoud Suleiman, MD, professor at Rambam Medical Center in Haifa, Israel. In

	a study of 577 nondiabetic patients admitted to their intensive care

	unit with MI, blood glucose levels were measured after 8 hours of fasting within 24 hours of admission. The 30-day death rate was 3% among patients with fasting glucose levels in the lowest tertile (< 97 mg/dL) compared with 19% among patients with fasting glucose above 118 mg/dL. After adjusting for other risk predictors, patients with fast-ing glucose levels in the high-est tertile were 3.5 times as likely to die compared with patients whose glucose levels were in the lowest tertile (P = .002). This finding suggests that fasting glucose concentration should be measured during hospitalization in nondiabetic patients with MI.

Features of metabolic syndrome are tied to inflammation, cardiovascular disease, and mortality

	The study by Kuvin and Karas (page 42) showed a significant correlation between vascular endo-

	thelial function and high-density lipoprotein (HDL) cholesterol level, which was detected by flow-mediated dilation of the brachial artery using ultrasonography. A multivariate analysis revealed HDL cholesterol was an independent predictor of flow-mediated dilation. This finding adds to the increasing literature about the importance of modulating HDL cholesterol. It also shows the role of this lipoprotein in the development of atherosclerosis, a diffuse disease characterized by anatomic and physiologic abnormalities of the blood vessels.

	The vascular endothelium plays a significant role in atherosclerosis by affecting vasomotor tone, thrombosis, and platelet function. HDL cholesterol consists of a heterogeneous class of lipoproteins, including apolipoprotein (apo) A-I as a major component, apo A-II, apo C, apo E, lecithin-cholesterol acyltransferase, paraoxonase, and platelet-activating factor, all of which impart significant physiologic functions.1

April 2004

Case report: Improved HDL cholesterol levels with niacin and statin therapy

Uric acid as a prognostic marker in chronic heart failure

Not all GP IIb/IIIa drugs are the same Stanley Katz, MD

Prognostic value of ECG changes in non-ST elevation ACS patients

Role of ST-segment status in guiding treatment

Uric acid and survival in chronic heart failure

Coronary artery stenting and eptifibatide treatment in diabetes

Peripheral vascular function and HDL cholesterol

Case report: Anticipating outcomes based on ECG status

Knowledge of calcium score improves compliance with risk-reducing behavior

Features of metabolic syndrome are tied to inflammation, cardiovascular disease, and mortality

High-density lipoprotein cholesterol and endothelial function

Mortality rate from MI is declining in women with diabetes

Research on prognostic indicators