Cardiovascular Biomarkers of Obesity and Overlap With Cardiometabolic Dysfunction.

Background Obesity may be associated with a range of cardiometabolic manifestations. We hypothesized that proteomic profiling may provide insights into the biological pathways that contribute to various obesity-associated cardiometabolic traits. We sought to identify proteomic signatures of obesity and examine overlap with related cardiometabolic traits, including abdominal adiposity, insulin resistance, and adipose depots. Methods and Results We measured 71 circulating cardiovascular disease protein biomarkers in 6981 participants (54% women; mean age, 49 years). We examined the associations of obesity, computed tomography measures of adiposity, cardiometabolic traits, and incident metabolic syndrome with biomarkers using multivariable regression models. Of the 71 biomarkers examined, 45 were significantly associated with obesity, of which 32 were positively associated and 13 were negatively associated with obesity (false discovery rate q<0.05 for all). There was significant overlap of biomarker profiles of obesity and cardiometabolic traits, but 23 biomarkers, including melanoma cell adhesion molecule (MCAM), growth differentiation factor-15 (GDF15), and lipoprotein(a) (LPA) were unique to metabolic traits only. Using hierarchical clustering, we found that the protein biomarkers clustered along 3 main trait axes: adipose, metabolic, and lipid traits. In longitudinal analyses, 6 biomarkers were significantly associated with incident metabolic syndrome: apolipoprotein B (apoB), insulin-like growth factor-binding protein 2 (IGFBP2), plasma kallikrein (KLKB1), complement C2 (C2), fibrinogen (FBN), and N-terminal pro-B-type natriuretic peptide (NT-proBNP); false discovery rate q<0.05 for all. Conclusions We found that the proteomic architecture of obesity overlaps considerably with associated cardiometabolic traits, implying shared pathways. Despite overlap, hierarchical clustering of proteomic profiles identified 3 distinct clusters of cardiometabolic traits: adipose, metabolic, and lipid. Further exploration of these novel protein targets and associated pathways may provide insight into the mechanisms responsible for the progression from obesity to cardiometabolic disease.

Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

BACKGROUND: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial. METHODS: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model. RESULTS: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy. CONCLUSIONS: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed. CLINICAL TRIALS REGISTRATION: NCT0234429.

European Society of Cardiology-Recommended Coronary Artery Disease Consortium Pretest Probability Scores More Accurately Predict Obstructive Coronary Disease and Cardiovascular Events Than the Diamond and Forrester Score: The Partners Registry.

BACKGROUND: The most appropriate score for evaluating the pretest probability of obstructive coronary artery disease (CAD) is unknown. We sought to compare the Diamond-Forrester (DF) score with the 2 CAD consortium scores recently recommended by the European Society of Cardiology. METHODS: We included 2274 consecutive patients (age, 56±13 years; 57% male) without prior CAD referred for coronary computed tomographic angiography. Computed tomographic angiography findings were used to determine the presence or absence of obstructive CAD (≥50% stenosis). We compared the DF score with the 2 CAD consortium scores with respect to their ability to predict obstructive CAD and the potential implications of these scores on the downstream use of testing for CAD, as recommended by current guidelines. RESULTS: The DF score did not satisfactorily fit the data and resulted in a significant overestimation of the prevalence of obstructive CAD (P<0.001); the CAD consortium basic score had no significant lack of fitness; and the CAD consortium clinical provided adequate goodness of fit (P=0.39). The DF score had a lower discrimination for obstructive CAD, with an area under the receiver-operating characteristics curve of 0.713 versus 0.752 and 0.791 for the CAD consortium models (P<0.001 for both). Consequently, the use of the DF score was associated with fewer individuals being categorized as requiring no additional testing (8.3%) compared with the CAD consortium models (24.6% and 30.0%; P<0.001). The proportion of individuals with a high pretest probability was 18% with the DF and only 1.1% with the CAD consortium scores (P<0.001) CONCLUSIONS: Among contemporary patients referred for noninvasive testing, the DF risk score overestimates the risk of obstructive CAD. On the other hand, the CAD consortium scores offered improved goodness of fit and discrimination; thus, their use could decrease the need for noninvasive or invasive testing while increasing the yield of such tests.

Moderate-to-vigorous physical activity with accelerometry is associated with visceral adipose tissue in adults.

BACKGROUND: We examined the relation between objectively measured physical activity with accelerometry and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based sample. METHODS AND RESULTS: We evaluated 1249 participants of the Framingham Third Generation and Omni II cohorts (mean age 51.7 years, 47% women) who underwent assessment of moderate-to-vigorous physical activity (MVPA) with accelerometry over 5 to 7 days, and multi-detector computed tomography for measurement of SAT and VAT volume; fat attenuation was estimated by SAT and VAT hounsfield units (HU). In women, higher levels of MVPA were associated with decreased SAT (P<0.0001) and VAT volume (P<0.0001). The average decrement in VAT per 30 minute/day increase in MVPA was -453 cm(3) (95% CI -574, -331). The association was attenuated but persisted upon adjustment for BMI (-122 cm(3), P=0.002). Higher levels of MVPA were associated with higher SAT HU (all P≤0.01), a marker of fat quality, even after adjustment for SAT volume. Similar findings were observed in men but the magnitude of the association was less. Sedentary time was not associated with SAT or VAT volume or quality in men or women. CONCLUSIONS: MVPA was associated with less VAT and SAT and better fat quality.

Comparison of dual-source 64-slice adenosine stress CT perfusion with stress-gated SPECT-MPI for evaluation of left ventricular function and volumes.

BACKGROUND: Evaluation of left ventricular (LV) volumes and ejection fraction (LVEF) represent important components of pharmacologic stress imaging with either myocardial CT perfusion (CTP) or gated single-photon emission CT (SPECT) myocardial perfusion imaging (SPECT-MPI). OBJECTIVES: We compared measurements of left ventricular function and volumes obtained with CTP and SPECT-MPI. METHODS: Forty-seven patients (mean age, 62 ± 11 years; male, n = 39) underwent stress CTP and SPECT-MPI. LVEF (in %), end-systolic volume (ESV; in mL), and end-diastolic volume (EDV; in mL) derived from stress CTP images were compared with SPECT-MPI. RESULTS: Stress CTP was in good agreement with SPECT-MPI for quantification of LVEF (r = 0.91), EDV (r = 0.75), and ESV (r = 0.83; all P < 0.001). The mean LVEF measured by stress CTP (66% ± 17%) was similar to SPECT-MPI (64% ± 15%). Similar values were also derived for mean EDV (123 ± 30 mL vs 120 ± 34 mL) and ESV (44 ± 28 mL vs 51 ± 34 mL) for CTP and SPECT-MPI, respectively. Good agreement was also shown between both techniques for the assessment of regional wall motion with identical wall motion scores in 95.3% of the segments (κ = 0.79). CONCLUSIONS: LVEF and LV volume parameters as determined by dual-source 64-slice adenosine stress CTP show a high correlation with values obtained with stress-gated SPECT-MPI.

ACR Appropriateness Criteria® chronic chest pain--high probability of coronary artery disease.

Imaging is valuable in determining the presence, extent, and severity of myocardial ischemia and the severity of obstructive coronary lesions in patients with chronic chest pain in the setting of high probability of coronary artery disease. Imaging is critical for defining patients best suited for medical therapy or intervention, and findings can be used to predict long-term prognosis and the likely benefit from various therapeutic options. Chest radiography, radionuclide single photon-emission CT, radionuclide ventriculography, and conventional coronary angiography are the imaging modalities historically used in evaluating suspected chronic myocardial ischemia. Stress echocardiography, PET, cardiac MRI, and multidetector cardiac CT have all been more recently shown to be valuable in the evaluation of ischemic heart disease. Other imaging techniques may be helpful in those patients who do not present with signs classic for angina pectoris or in those patients who do not respond as expected to standard management. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® on chest pain, suggestive of acute coronary syndrome.

Acute chest pain suggestive of acute coronary syndrome is a frequent complaint in the emergency department. Acute coronary syndromes include myocardial infarction and unstable angina. Being able to establish the diagnosis rapidly and accurately may be lifesaving. A cardiac workup is indicated in this subset of patients in the acute setting, even if there are no ischemic changes on electrocardiography. If the clinical examination and initial cardiac workup suggest that a patient is having myocardial ischemia, the patient will usually be urgently referred for invasive coronary angiography and revascularization. In stable patients without evidence of ST elevation and ongoing myocardial ischemia, an initially conservative approach is sometimes considered. Cardiac risk stratification of this subgroup of patients who are at low and intermediate risk for coronary artery disease is recommended before discharge, and imaging is necessary to exclude ischemia as an etiology. Noninvasive cardiac imaging modalities include chest radiography, single photon-emission CT myocardial perfusion imaging, echocardiography, multidetector CT, PET, and MRI. Noncardiac etiologies of chest pain include aortic dissection, aortic aneurysm, pulmonary embolism, pericardial disease, and lung parenchymal disease. Noninvasive cardiac imaging in patients who are at low and intermediate risk for coronary artery disease may improve confidence regarding the safety of discharge from the emergency department. In addition to risk stratification, noncoronary etiologies for chest pain can be established with imaging.

Diagnostic and prognostic value of absence of coronary artery calcification.

OBJECTIVES: In this study, we systematically assessed the diagnostic and prognostic value of absence of coronary artery calcification (CAC) in asymptomatic and symptomatic individuals. BACKGROUND: Presence of CAC is a well-established marker of coronary plaque burden and is associated with a higher risk of adverse cardiovascular outcomes. Absence of CAC has been suggested to be associated with a very low risk of significant coronary artery disease, as well as minimal risk of future events. METHODS: We searched online databases (e.g., PubMed and MEDLINE) for original research articles published in English between January 1990 and March 2008 examining the diagnostic and prognostic utility of CAC. RESULTS: A systematic review of published articles revealed 49 studies that fulfilled our criteria for inclusion. These included 13 studies assessing the relationship of CAC with adverse cardiovascular outcomes in 64,873 asymptomatic patients. In this cohort, 146 of 25,903 patients without CAC (0.56%) had a cardiovascular event during a mean follow-up period of 51 months. In the 7 studies assessing the prognostic value of CAC in a symptomatic population, 1.80% of patients without CAC had a cardiovascular event. Overall, 18 studies demonstrated that the presence of any CAC had a pooled sensitivity and negative predictive value of 98% and 93%, respectively, for detection of significant coronary artery disease on invasive coronary angiography. In 4,870 individuals undergoing myocardial perfusion and CAC testing, in the absence of CAC, only 6% demonstrated any sign of ischemia. Finally, 3 studies demonstrated that absence of CAC had a negative predictive value of 99% for ruling out acute coronary syndrome. CONCLUSIONS: On the basis of our review of more than 85,000 patients, we conclude that the absence of CAC is associated with a very low risk of future cardiovascular events, with modest incremental value of other diagnostic tests in this very low-risk group.

Utility of cardiovascular magnetic resonance to predict left ventricular recovery after primary percutaneous coronary intervention for patients presenting with acute ST-segment elevation myocardial infarction.

Cardiac magnetic resonance (CMR) has been shown to predict left ventricular (LV) recovery in patients after acute ST-segment elevation myocardial infarction. The purpose of this investigation was to determine the relative values of infarct transmurality and microvascular obstruction (MVO) using delayed enhancement CMR to predict LV recovery. We studied 17 patients (mean age 60 +/- 10 years, 14 men) presenting with first acute ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention who underwent CMR within 6 days after presentation and again at 6 months. In total 680 myocardial segments were evaluated, of which 267 (39%) demonstrated delayed hyperenhancement (DHE) and 116 (18%) demonstrated MVO. Unadjusted odds ratio (OR) for any improvement in regional LV function with increasing DHE category (<50%, 51% to 75%, >75% transmurality) was 0.20 (95% confidence interval [CI] 0.13 to 0.30, p <0.0001), whereas it was 0.40 (95% CO 0.28 to 0.55, p <0.0001) with increasing MVO category (0, <50th, >50th percentile). However, when coadjusted together, the relation remained robust with regard to degree of transmurality of DHE (OR 0.21, 95% CI 0.13 to 0.36, p <0.0001), but the relation was lost for MVO (OR 0.90, 95% CI 0.58 to 1.40, p = 0.64). In conclusion, when using the delayed enhancement technique for assessment of DHE and MVO, degree of infarct transmurality appears to be a more powerful predictor of LV recovery by CMR.