Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.

Radiomics of Coronary Artery Calcium in the Framingham Heart Study.

PURPOSE: To extract radiomic features from coronary artery calcium (CAC) on CT images and to determine whether this approach could improve the ability to identify individuals at risk for a composite endpoint of clinical events. MATERIALS AND METHODS: Participants from the Offspring and Third Generation cohorts of the community-based Framingham Heart Study underwent noncontrast cardiac CT (2002-2005) and were followed for more than a median of 9.1 years for composite major events. A total of 624 participants with CAC Agatston score (AS) of greater than 0 and good or excellent CT image quality were included for manual CAC segmentation and extraction of a predefined set of radiomic features reflecting intensity, shape, and texture. In a discovery cohort (n = 318), machine learning was used to select the 20 most informative and nonredundant CAC radiomic features, classify features predicting events, and define a radiomic-based score (RS). Performance of the RS was tested independently for the prediction of events in a validation cohort (n = 306). RESULTS: The RS had a median value of 0.08 (interquartile range, 0.007-0.71) and a weak and modest correlation with Framingham risk score (FRS) (r = 0.2) and AS (r = 0.39), respectively. The continuous RS unadjusted, adjusted for age and sex, FRS, AS, and FRS plus AS were significantly associated with events (hazard ratio [HR] = 2.2, P < .001; HR = 1.8, P = .002; HR = 2.0, P < .001; HR = 1.7, P = .02; and HR = 1.8, P = .01, respectively). In participants with AS of less than 300, RS association with events remained significant when unadjusted and adjusted for age and sex, FRS, AS, and FRS plus AS (HR = 2.4, 2.8, 2.8, 2.3, and 2.6; P < .001, respectively). In the same subgroup of participants, adding the RS to AS resulted in a significant improvement in the discriminatory ability for events as compared with the AS (area under the receiver operating curve: 0.80 vs 0.68, respectively; P = .03). CONCLUSION: A radiomic-based score, including the complex properties of CAC, may constitute an imaging biomarker to be further developed to identify individuals at risk for major adverse cardiovascular events in a community-based cohort. Supplemental material is available for this article. © RSNA, 2020.

Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial.

BACKGROUND: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. CONCLUSIONS: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.

Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study.

OBJECTIVES: The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC). BACKGROUND: Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans. METHODS: We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses. RESULTS: In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men. CONCLUSIONS: In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.

Calcium intake is not associated with increased coronary artery calcification: the Framingham Study.

BACKGROUND: Adequate calcium intake is known to protect the skeleton. However, studies that have reported adverse effects of calcium supplementation on vascular events have raised widespread concern. OBJECTIVE: We assessed the association between calcium intake (from diet and supplements) and coronary artery calcification, which is a measure of atherosclerosis that predicts risk of ischemic heart disease independent of other risk factors. DESIGN: This was an observational, prospective cohort study. Participants included 690 women and 588 men in the Framingham Offspring Study (mean age: 60 y; range: 36-83 y) who attended clinic visits and completed food-frequency questionnaires in 1998-2001 and underwent computed tomography scans 4 y later in 2002-2005. RESULTS: The mean age-adjusted coronary artery-calcification Agatston score decreased with increasing total calcium intake, and the trend was not significant after adjustment for age, BMI, smoking, alcohol consumption, vitamin D-supplement use, energy intake, and, for women, menopause status and estrogen use. Multivariable-adjusted mean Agatston scores were 2.36, 2.52, 2.16, and 2.39 (P-trend = 0.74) with an increasing quartile of total calcium intake in women and 4.32, 4.39, 4.19, and 4.37 (P-trend = 0.94) in men, respectively. Results were similar for dietary calcium and calcium supplement use. CONCLUSIONS: Our study does not support the hypothesis that high calcium intake increases coronary artery calcification, which is an important measure of atherosclerosis burden. The evidence is not sufficient to modify current recommendations for calcium intake to protect skeletal health with respect to vascular calcification risk.

Vitamin K supplementation and progression of coronary artery calcium in older men and women.

BACKGROUND: Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE: The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN: CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS: In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS: Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.

Calcium concentration of individual coronary calcified plaques as measured by multidetector row computed tomography.

BACKGROUND: Characteristics of individual calcified plaques, especially calcium concentration (CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and evaluation of therapeutic intervention. In this study, therefore, we assessed the characteristics of individual calcified plaques and their relationship to other parameters derived from CT analysis of coronary calcium in a community-based cross-sectional cohort. METHODS AND RESULTS: Coronary artery calcium (CAC) was analyzed in 612 participants of the Framingham Heart Study (third-generation and offspring cohorts) using prospectively ECG-triggered multidetector CT. We determined the CC, Agatston score, calcified volume, and mineral mass of individual calcified plaques in each subject. Heterogeneity of CC was defined as the standard deviation of CC of all individual calcified plaques in a subject. CAC was detected in 274 of 605 subjects. After excluding 57 subjects (21%) because of motion artifacts, we identified a total of 956 calcified coronary plaques in 217 subjects (74 women, 143 men; mean age, 57.1+/-10.8 years) with detectable CAC and no image artifacts. CC of individual calcified plaques was independent of subject age (P=0.76) and sex (197.8+/-74.8 versus 183.6+/-52.8 mg/cm3 for men versus women; P=0.21). Among a subgroup of 125 subjects with multiple (> or =3) individual calcified plaques, CC was heterogeneous within individual subjects (mean SD of CC, 43.6+/-23.1 mg/cm3). The degree of heterogeneity of CC in these subjects was independent of age (P=0.60), sex (P=0.99), and number of plaques (P=0.06). CONCLUSIONS: The CC of individual calcified plaques is independent of age and sex but heterogeneous within a subject, which may reflect that the pathological process of calcified plaque formation and progression is the same in men and women regardless of age. CC may have incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and the evaluation of therapeutic intervention. Further studies are warranted to confirm that individual plaque analysis is preferable to global CAC scores to evaluate progression of atherosclerosis and to assess whether individual plaque analysis may be complementary to global CAC measures to assess coronary event risk.

MRA of the lower extremities in patients with pulmonary embolism using a blood pool contrast agent: initial experience.

PURPOSE: To evaluate the feasibility of blood pool contrast-enhanced magnetic resonance angiography (MRA) to visualize the arterial and venous vessel tree and to detect deep venous thrombosis (DVT) of the lower extremities. MATERIALS AND METHODS: Nine consecutive patients with pulmonary embolism (mean age = 46 +/- 9) were randomized to various doses of NC100150 (between 0.75 and 6 mg of Fe/kg of body weight). A T1-weighted (T1W) 3D gradient recalled echo (GRE) sequence (TE = 2.0 msec, TR = 5.0 msec) was used. Two observers blinded to the dose of contrast agent assessed image quality, contrast attenuation, and appearance of thrombi. RESULTS: Qualitative assessment of overall MRA image quality and semiquantitative vessel scoring revealed good to excellent delineation of venous and arterial vessel segments independent of the dose of NC100150. However, quantitative region of interest analysis revealed a significantly higher signal-to-noise ratio (SNR) in the high-dose group than in the mid- and low-dose groups of NC100150 (P < 0.01). Between dose groups, the SNR was independent of vessel type (artery or vein) and vessel segment localization (proximal or distal). All seven venous thrombi (mean length = 7.2 +/- 0.95 cm) were characterized by a very low signal intensity (SI), which was only 16.6 +/- 7% of the SI in adjacent venous segments (P < 0.0001). CONCLUSION: High-quality MR angiograms of the lower extremities can be obtained using low concentrations of NC100150 in combination with a strong T1W 3D GRE sequence. The obvious delineation of venous thrombi suggests that this technique may be potentially used as a noninvasive "one-stop shopping" tool in the evaluation of thromboembolic disease.