Madeline Murguia Rice

A Sensitive Cardiac Troponin T Assay in Stable Coronary Artery Disease

BACKGROUND In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown. METHODS We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years. RESULTS With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 microg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 microg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P=0.11). CONCLUSIONS After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.

Prognostic Significance of the Centers for Disease Control/American Heart Association High-Sensitivity C-Reactive Protein Cut Points for Cardiovascular and Other Outcomes in Patients With Stable Coronary Artery Disease

Background— Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored. Methods and Results— We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even >1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81; P=0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02; P=0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted P<0.001 for trend) and new diabetes (adjusted P<0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes. Conclusions— In stable coronary artery disease, an elevated hs-CRP level, even >1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition.

Renal Function and Effectiveness of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients With Chronic Stable Coronary Disease in the Prevention of Events with ACE inhibition (PEACE) Trial

Background— Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post–myocardial infarction setting, angiotensin-converting enzyme (ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function. Methods and Results— We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial (PEACE). Patients (n=8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6±19.4, and 1355 (16.3%) patients had reduced renal function (eGFR <60 mg · mL−1 · 1.73 m−2). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P=0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR, 0.73; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94; 95% CI, 0.78 to 1.13). Conclusions— Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.

Prognostic Utility of Lipoprotein-Associated Phospholipase A2 for Cardiovascular Outcomes in Patients With Stable Coronary Artery Disease

Objective—To determine the prognostic utility of lipoprotein-associated phospholipase A2 (Lp-PLA2) for specific adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD), independent of traditional risk factors and high-sensitivity C-reactive protein (hs-CRP). Methods and Results—We measured Lp-PLA2 in 3766 patients with stable CAD from the PEACE trial. Patients were followed for a median of 4.8 years for adverse cardiovascular events including death, myocardial infarction (MI), coronary revascularization, hospitalization for unstable angina (UA), and stroke. Multivariable Cox regression was used to adjust for traditional cardiovascular risk factors and to conduct multimarker analyses that included hs-CRP. After adjustment for baseline characteristics, patients in higher quartiles of Lp-PLA2 remained at significantly greater risk for the composite of cardiovascular death, MI, coronary revascularization, UA, or stroke (P<0.001 for trend, adj HR 1.41, 95% CI 1.17 to 1.70, for patients in 4th versus 1st quartile). The association was consistent regardless of a patients sex, cholesterol levels, or use of lipid-lowering therapy. When analyzed together, both hs-CRP and Lp-PLA2 were highly significant predictors of acute coronary syndromes (cardiovascular death, MI, or UA) (P for trend <0.001 for hs-CRP and 0.005 for Lp-PLA2), whereas only Lp-PLA2 was a significant predictor of coronary revascularization (P=0.01 for trend). Conclusions—In stable CAD, an elevated level of Lp-PLA2 was a significant predictor of nonfatal adverse cardiovascular outcomes independent of traditional clinical risk factors and hs-CRP. Further investigation will be needed to establish whether therapies that lower Lp-PLA2 reduce cardiovascular risk.

The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies.

AbstractThe juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, “shawl-sign” rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and “mechanic’s hands,” and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes.

Long-Term Trandolapril Treatment Is Associated With Reduced Aortic Stiffness The Prevention of Events With Angiotensin-Converting Enzyme Inhibition Hemodynamic Substudy

The Prevention of Events with Angiotensin Converting Enzyme inhibition (PEACE) trial evaluated angiotensin-converting enzyme inhibition with trandolapril versus placebo added to conventional therapy in patients with stable coronary disease and preserved left ventricular function. The PEACE hemodynamic substudy evaluated effects of trandolapril on pulsatile hemodynamics. Hemodynamic studies were performed in 300 participants from 5 PEACE centers a median of 52 months (range, 25 to 80 months) after random assignment to trandolapril at a target dose of 4 mg per day or placebo. Central pulsatile hemodynamics and carotid–femoral pulse wave velocity were assessed by using echocardiography, tonometry of the carotid and femoral arteries, and body surface transit distances. Patients randomly assigned to trandolapril tended to be older (mean±SD: 64.2±7.9 versus 62.9±7.7 years; P=0.14), with a higher body mass index (28.5±4.0 versus 27.8±3.9 kg/m2; P=0.09) and lower ejection fraction (57.1±8.1% versus 58.7±8.4%; P<0.01). At the time of the hemodynamic substudy, the trandolapril group had lower mean arterial pressure (93.1±10.2 versus 96.3±11.3 mm Hg; P<0.01) and lower carotid-femoral pulse wave velocity (geometric mean [95% CI]: 10.4 m/s [10.0 to 10.9 m/s] versus 11.2 m/s [10.7 to 11.8 m/s]; P=0.02). The difference in carotid–femoral pulse wave velocity persisted (P<0.01) in an analysis that adjusted for baseline characteristics and follow-up mean pressure. In contrast, there was no difference in aortic compliance, characteristic impedance, augmentation index, or total arterial compliance. Angiotensin-converting enzyme inhibition with trandolapril produced a modest reduction in carotid–femoral pulse wave velocity, a measure of aortic wall stiffness, beyond what would be expected from blood pressure lowering or differences in baseline characteristics alone.

Mild gestational diabetes mellitus and long-term child health

OBJECTIVE To evaluate whether treatment of mild gestational diabetes mellitus (GDM) confers sustained offspring health benefits, including a lower frequency of obesity. RESEARCH DESIGN AND METHODS Follow-up study of children (ages 5–10) of women enrolled in a multicenter trial of treatment versus no treatment of mild GDM. Height, weight, blood pressure, waist circumference, fasting glucose, fasting insulin, triglycerides, and HDL cholesterol were measured. RESULTS Five hundred of 905 eligible offspring (55%) were enrolled. Maternal baseline characteristics were similar between the follow-up treated and untreated groups. The frequencies of BMI ≥95th (20.8% and 22.9%) and 85th (32.6% and 38.6%) percentiles were not significantly different in treated versus untreated offspring (P = 0.69 and P = 0.26). No associations were observed for BMI z score, log waist circumference, log triglycerides, HDL cholesterol, blood pressure, or log HOMA-estimated insulin resistance (HOMA-IR). The effect of treatment was different by sex for fasting glucose and log HOMA-IR (P for interaction = 0.002 and 0.02, respectively) but not by age-group (5–6 and 7–10 years) for any outcomes. Female offspring of treated women had significantly lower fasting glucose levels. CONCLUSIONS Although treatment for mild GDM has been associated with neonatal benefits, no reduction in childhood obesity or metabolic dysfunction in the offspring of treated women was found. However, only female offspring of women treated for mild GDM had lower fasting glucose.

The Clinical Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

AbstractThe juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. Although juvenile dermatomyositis (JDM), the most common form of JIIM, has been well studied, the other major clinical subgroups of JIIM, including juvenile polymyositis (JPM) and juvenile myositis overlapping with another autoimmune or connective tissue disease (JCTM), have not been well characterized, and their similarity to the adult clinical subgroups is unknown. We enrolled 436 patients with JIIM, including 354 classified as JDM, 33 as JPM, and 49 as JCTM, in a nationwide registry study. The aim of the study was to compare demographics; clinical features; laboratory measures, including myositis autoantibodies; and outcomes among these clinical subgroups, as well as with published data on adult patients with idiopathic inflammatory myopathies (IIM) enrolled in a separate natural history study.We used random forest classification and logistic regression modeling to compare clinical subgroups, following univariate analysis. JDM was characterized by typical rashes, including Gottron papules, heliotrope rash, malar rash, periungual capillary changes, and other photosensitive and vasculopathic skin rashes. JPM was characterized by more severe weakness, higher creatine kinase levels, falling episodes, and more frequent cardiac disease. JCTM had more frequent interstitial lung disease, Raynaud phenomenon, arthralgia, and malar rash. Differences in autoantibody frequency were also evident, with anti-p155/140, anti-MJ, and anti-Mi-2 seen more frequently in patients with JDM, anti-signal recognition particle and anti-Jo-1 in JPM, and anti-U1-RNP, PM-Scl, and other myositis-associated autoantibodies more commonly present in JCTM. Mortality was highest in patients with JCTM, whereas hospitalizations and wheelchair use were highest in JPM patients. Several demographic and clinical features were shared between juvenile and adult IIM subgroups. However, JDM and JPM patients had a lower frequency of interstitial lung disease, Raynaud phenomenon, “mechanic’s hands” and carpal tunnel syndrome, and lower mortality than their adult counterparts. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct clinical subgroups, defined by varying clinical and demographic characteristics, laboratory features, and outcomes.

Estrogen Replacement Therapy and Cognitive Function in Postmenopausal Women Without Dementia

The epidemiologic evidence for an association between estrogen and cognitive function among healthy postmenopausal women remains controversial. Equivocal findings may be explained, in part, by differences in the methodologic approaches of these studies. Overall, the evidence for a positive relationship comes primarily from randomized clinical trials. These trials suggest an acute effect on specific tests of recent verbal memory and tasks incorporating concept formation and reasoning. The potential long-term effects of estrogen in slowing or delaying the age-related decline in cognitive function require further study. More data are needed to determine the effects of estrogen replacement therapy on cognitive function, independent of changes in mood and depressive symptoms. In addition, evidence suggests that progesterone may mitigate the beneficial effects of estrogen on mood. Research should be undertaken to determine the interactive effects of estrogen and progesterone on cognitive function. Lastly, there should be continued investigation by both epidemiologic and basic neuroscientific studies to further elucidate the specific cognitive domains that may respond to estrogen.

Influence of Albuminuria on Cardiovascular Risk in Patients With Stable Coronary Artery Disease

Background— Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. Methods and Results— We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 μg/mg for men and <25 μg/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 μg/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). Conclusions— Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.