Oscar C. Marroquin

Clinical Importance of Obesity Versus the Metabolic Syndrome in Cardiovascular Risk in Women: A Report From the Women’s Ischemia Syndrome Evaluation (WISE) Study

Background—Obesity and the metabolic syndrome frequently coexist. Both are associated with cardiovascular disease (CVD). However, the contribution of obesity to cardiovascular risk, independent of the presence of the metabolic syndrome, remains controversial. Methods and Results—From the WISE study, 780 women referred for coronary angiography to evaluate suspected myocardial ischemia were classified by body mass index (BMI; <24.9=normal, n=184; ≥25.0 to ≤29.9=overweight, n=269; ≥30.0=obese, n=327) and presence (n=451) or absence (n=329) of the metabolic syndrome, further classified by diabetes status. Prevalence of significant angiographic coronary artery disease (CAD; ≥50% stenosis) and 3-year risk of CVD were compared by BMI and metabolic status. The metabolic syndrome and BMI were strongly associated, but only metabolic syndrome was associated with significant CAD. Similarly, unit increases in BMI (normal to overweight to obese) were not associated with 3-year risk of death (adjusted hazard ratio [HR] 0.92, 95% CI 0.59 to 1.51) or major adverse cardiovascular event (MACE: death, nonfatal myocardial infarction, stroke, congestive heart failure; adjusted HR 0.95, 95% CI 0.71 to 1.27), whereas metabolic status (normal to metabolic syndrome to diabetes) conferred an approximate 2-fold adjusted risk of death (HR 2.01, 95% CI 1.26 to 3.20) and MACE (HR 1.88, 95% CI 1.38 to 2.57). Levels of C-reactive protein (hs-CRP) were more strongly associated with metabolic syndrome than BMI but were not independently associated with 3-year risk of death or MACE. Conclusions—The metabolic syndrome but not BMI predicts future cardiovascular risk in women. Although it remains prudent to recommend weight loss in overweight and obese women, control of all modifiable risk factors in both normal and overweight persons to prevent transition to the metabolic syndrome should be considered the ultimate goal.

Serum Amyloid A as a Predictor of Coronary Artery Disease and Cardiovascular Outcome in Women The National Heart, Lung, and Blood Institute–Sponsored Women’s Ischemia Syndrome Evaluation (WISE)

Background—Serum amyloid-&agr; (SAA) is a sensitive marker of an acute inflammatory state. Like high-sensitivity C-reactive protein (hs-CRP), SAA has been linked to atherosclerosis. However, prior studies have yielded inconsistent results, and the independent predictive value of SAA for coronary artery disease (CAD) severity and cardiovascular events remains unclear. Methods and Results—A total of 705 women referred for coronary angiography for suspected myocardial ischemia underwent plasma assays for SAA and hs-CRP, quantitative angiographic assessment, and follow-up evaluation. Cardiovascular events were death, myocardial infarction, congestive heart failure, stroke, and other vascular events. The women’s mean age was 58 years (range 21 to 86 years), and 18% were nonwhite. SAA and hs-CRP were associated with a broad range of CAD risk factors. After adjustment for these risk factors, SAA levels were independently but moderately associated with angiographic CAD (P =0.004 to 0.04) and highly predictive of 3-year cardiovascular events (P <0.0001). By comparison, hs-CRP was not associated with angiographic CAD (P =0.08 to 0.35) but, like SAA, was strongly and independently predictive of adverse cardiovascular outcome (P <0.0001). Conclusions—Our results show a strong independent relationship between SAA and future cardiovascular events, similar to that found for hs-CRP. Although SAA was independently but moderately associated with angiographic CAD, this association was not found for hs-CRP. These results are consistent with the hypothesis that systemic inflammation, manifested by high SAA or hs-CRP levels, may promote atherosclerotic plaque destabilization, in addition to exerting a possible direct effect on atherogenesis.

A comparison of bare-metal and drug-eluting stents for off-label indications.

BACKGROUND Recent reports suggest that off-label use of drug-eluting stents is associated with an increased incidence of adverse events. Whether the use of bare-metal stents would yield different results is unknown. METHODS We analyzed data from 6551 patients in the National Heart, Lung, and Blood Institute Dynamic Registry according to whether they were treated with drug-eluting stents or bare-metal stents and whether use was standard or off-label. Patients were followed for 1 year for the occurrence of cardiovascular events and death. Off-label use was defined as use in restenotic lesions, lesions in a bypass graft, left main coronary artery disease, or ostial, bifurcated, or totally occluded lesions, as well as use in patients with a reference-vessel diameter of less than 2.5 mm or greater than 3.75 mm or a lesion length of more than 30 mm. RESULTS Off-label use occurred in 54.7% of all patients with bare-metal stents and 48.7% of patients with drug-eluting stents. As compared with patients with bare-metal stents, patients with drug-eluting stents had a higher prevalence of diabetes, hypertension, renal disease, previous percutaneous coronary intervention and coronary-artery bypass grafting, and multivessel coronary artery disease. One year after intervention, however, there were no significant differences in the adjusted risk of death or myocardial infarction in patients with drug-eluting stents as compared with those with bare-metal stents, whereas the risk of repeat revascularization was significantly lower among patients with drug-eluting stents. CONCLUSIONS Among patients with off-label indications, the use of drug-eluting stents was not associated with an increased risk of death or myocardial infarction but was associated with a lower rate of repeat revascularization at 1 year, as compared with bare-metal stents. These findings support the use of drug-eluting stents for off-label indications.

Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women. A report from the Women's Ischemia Syndrome Evaluation

Background—The metabolic syndrome, which is characterized by a constellation of fasting hyperglycemia, hypertriglyceridemia, low HDL cholesterol, hypertension, and/or abdominal obesity, is a risk factor for the development of coronary artery disease (CAD) and cardiovascular events. The interrelationship between metabolic status and CAD on cardiovascular risk in women is not known. Methods and Results—We evaluated interrelationships between angiographic CAD, the metabolic syndrome, and incident cardiovascular events among 755 women from the Women’s Ischemia Syndrome Evaluation (WISE) study who were referred for coronary angiography to evaluate suspected myocardial ischemia; 25% of the cohort had the metabolic syndrome at study entry. Compared with women with normal metabolic status, women with the metabolic syndrome had a significantly lower 4-year survival rate (94.3% versus 97.8%, P =0.03) and event-free survival from major adverse cardiovascular events (death, nonfatal myocardial infarction, stroke, or congestive heart failure; 87.8% versus 93.5%, P =0.003). When the subjects were stratified by the presence or absence of angiographically significant CAD at study entry, in women with angiographically significant CAD, the metabolic syndrome resulted in significantly higher risk of cardiovascular events than in women with normal metabolic status (hazard ratio 4.93, 95% CI 1.02 to 23.76; P =0.05), whereas it did not result in increased 4-year cardiovascular risk in women without angiographically significant CAD (hazard ratio 1.41, 95% CI 0.32 to 6.32; P =0.65). Conclusions—These data suggest that in women with suspected myocardial ischemia, the metabolic syndrome modifies the cardiovascular risk associated with angiographic CAD. Specifically, the metabolic syndrome was found to be a predictor of 4-year cardiovascular risk only when associated with significant angiographic CAD.

Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease.

BACKGROUND Prior trials suggest it is safe to defer transfusion at hemoglobin levels above 7 to 8 g/dL in most patients. Patients with acute coronary syndrome may benefit from higher hemoglobin levels. METHODS We performed a pilot trial in 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization and a hemoglobin <10 g/dL. Patients in the liberal transfusion strategy received one or more units of blood to raise the hemoglobin level ≥10 g/dL. Patients in the restrictive transfusion strategy were permitted to receive blood for symptoms from anemia or for a hemoglobin <8 g/dL. The predefined primary outcome was the composite of death, myocardial infarction, or unscheduled revascularization 30 days post randomization. RESULTS Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The mean number of units transfused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary outcome occurred in 6 patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence interval of difference 0.7% to 29.3%; P = .054 and adjusted for age P = .076). Death at 30 days was less frequent in liberal group (n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; P = .032). CONCLUSIONS The liberal transfusion strategy was associated with a trend for fewer major cardiac events and deaths than a more restrictive strategy. These results support the feasibility of and the need for a definitive trial.

The Problem With Composite End Points in Cardiovascular Studies The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention

OBJECTIVES Our purpose was to evaluate the heterogeneity and validity of composite end points, major adverse cardiac events (MACE) in particular, in cardiology research. BACKGROUND The term MACE is a commonly used end point for cardiovascular research. By definition, MACE is a composite of clinical events and usually includes end points reflecting safety and effectiveness. There is no standard definition for MACE, as individual outcomes used to make this composite end point vary by study. This inconsistency calls into question whether use of MACE in cardiology research is of value. METHODS We conducted a 2-phase literature review on the use of MACE as a composite end point: 1) studies that have compared use of bare-metal versus drug-eluting stents; and 2) studies published in the Journal in calendar year 2006. We subsequently tested 3 different definitions of MACE during 1-year of follow-up among 6,922 patients in the DEScover registry who received at least 1 drug-eluting stent. RESULTS The review identified substantial heterogeneity in the study-specific individual outcomes used to define MACE. Markedly different results were observed for selected patient subsets of acute myocardial infarction (MI) (vs. no MI) and multilesion stenting (vs. single-lesion stenting) according to the various definitions of MACE. CONCLUSIONS Varying definitions of composite end points, such as MACE, can lead to substantially different results and conclusions. Therefore, the term MACE, in particular, should not be used, and when composite study end points are desired, researchers should focus separately on safety and effectiveness outcomes, and construct separate composite end points to match these different clinical goals.

Depression, the metabolic syndrome and cardiovascular risk.

Background: The relationship between depression and the metabolic syndrome is unclear, and whether metabolic syndrome explains the association between depression and cardiovascular disease (CVD) risk is unknown. Methods: We studied 652 women who received coronary angiography as part of the Womens Ischemia Syndrome Evaluation (WISE) study and completed the Beck Depression Inventory (BDI). Women who had both elevated depressive symptoms (BDI ≥10) and a previous diagnosis of depression were considered at highest risk, whereas those with one of the two conditions represented an intermediate group. The metabolic syndrome was defined according to the ATP-III criteria. The main outcome was incidence of adverse CVD events (hospitalizations for myocardial infarction, stroke, congestive heart failure, and CVD-related mortality) over a median follow-up of 5.9 years. Results: After adjusting for demographic factors, lifestyle and functional status, both depression categories were associated with about 60% increased odds for metabolic syndrome compared with no depression (p = .03). The number of metabolic syndrome risk factors increased gradually across the three depression categories (p = .003). During follow-up, 104 women (15.9%) experienced CVD events. In multivariable analysis, women with both elevated symptoms and a previous diagnosis of depression had 2.6 times higher risk of CVD. When metabolic syndrome was added to the model, the risk associated with depression only decreased by 7%, and both depression and metabolic syndrome remained significant predictors of CVD. Conclusions: In women with suspected coronary artery disease, the metabolic syndrome is independently associated with depression but explains only a small portion of the association between depression and incident CVD. BDI = Beck Depression Inventory; CAD = coronary artery disease; CVD = cardiovascular disease; DASI = Duke Activity Status Inventory; HDL = high-density lipoprotein; LDL = low-density lipoprotein; WISE = Womens Ischemia Syndrome Evaluation; NHLBI = National Heart, Lung, and Blood Institute.

The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE).

UNLABELLED High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women. METHODS We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Womens Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. RESULTS Mean age was 57 +/- 11 years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% CI 1.05-3.64, P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% CI 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but became nonsignificant when angiographic results were included. CONCLUSION Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events.

A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure

RATIONALE Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). OBJECTIVE To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. METHODS AND RESULTS We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control). CONCLUSIONS Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

Extracorporeal Membrane Oxygenation for Advanced Refractory Shock in Acute and Chronic Cardiomyopathy

BACKGROUND Extracorporeal membrane oxygenation (ECMO) has been used to obtain rapid resuscitation and stabilization in advanced refractory cardiogenic shock (CS), but clear strategies to optimize outcomes and minimize futile support have not been established. METHODS We retrospectively reviewed our experience with ECMO in patients with advanced refractory CS, after an acute myocardial infarct (AMI) compared with patients receiving ECMO after an acute decompensating chronic cardiomyopathy (CCM). RESULTS Between January 2003 and February 2009, 33 patients required ECMO support for advanced refractory CS secondary to AMI (AMI-CS) and 9 patients were supported by ECMO in the presence of an acutely decompensated CCM (CCM-CS). Survival at 30 days, 1 and 2 years for patients with AMI-CS, was 64%, 48%, and 48% compared with 56%, 11%, and 11% at the same time points for those with CCM-CS (p = 0.05). In the AMI-CS group, 14 of 33 (42%) patients were weaned directly from ECMO after revascularization; 15 of 33 (45%) patients were bridged to ventricular assist device (VAD) support and subsequently either underwent heart transplantation (n = 6), were successfully weaned from VAD (n = 2) or died while on VAD support (n = 7). In the CCM-CS group, 7 patients were bridged to VAD support (77%), with 1 patient surviving after VAD weaning. CONCLUSIONS Extracorporeal membrane oxygenation in advanced refractory AMI-CS is associated with acceptable outcomes in a well-selected population. The ECMO in patients with an acute decompensation of a chronic CM should be carefully considered, to avoid futile support.