Diffuse myocardial fibrosis associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients.

Background: Diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate). Objectives: To evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing. Methods: Among patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy. Results: After a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not. Conclusions: DMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation.

Commercial 4-dimensional echocardiography for murine heart volumetric evaluation after myocardial infarction.

BACKGROUND: Traditional preclinical echocardiography (ECHO) modalities, including 1-dimensional motion-mode (M-Mode) and 2-dimensional long axis (2D-US), rely on geometric and temporal assumptions about the heart for volumetric measurements. Surgical animal models, such as the mouse coronary artery ligation (CAL) model of myocardial infarction, result in morphologic changes that do not fit these geometric assumptions. New ECHO technology, including 4-dimensional ultrasound (4D-US), improves on these traditional models. This paper aims to compare commercially available 4D-US to M-mode and 2D-US in a mouse model of CAL. METHODS: 37 mice underwent CAL surgery, of which 32 survived to a 4 week post-operative time point. ECHO was completed at baseline, 1 week, and 4 weeks after CAL. M-mode, 2D-US, and 4D-US were taken at each time point and evaluated by two separate echocardiographers. At 4 weeks, a subset (n = 12) of mice underwent cardiac magnetic resonance (CMR) imaging to serve as a reference standard. End systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) were compared among imaging modalities. Hearts were also collected for histologic evaluation of scar size (n = 16) and compared to ECHO-derived wall motion severity index (WMSI) and global longitudinal strain as well as gadolinium-enhanced CMR to compare scar assessment modalities. RESULTS: 4D-US provides close agreement of ESV (Bias: -2.55%, LOA: - 61.55 to 66.66) and EF (US Bias: 11.23%, LOA - 43.10 to 102.8) 4 weeks after CAL when compared to CMR, outperforming 2D-US and M-mode estimations. 4D-US has lower inter-user variability as measured by intraclass correlation (ICC) in the evaluation of EDV (0.91) and ESV (0.93) when compared to other modalities. 4D-US also allows for rapid assessment of WMSI, which correlates strongly with infarct size by histology (r = 0.77). CONCLUSION: 4D-US outperforms M-Mode and 2D-US for volumetric analysis 4 weeks after CAL and has higher inter-user reliability. 4D-US allows for rapid calculation of WMSI, which correlates well with histologic scar size.

Coronary artery plaque volume and obesity in patients with diabetes: the factor-64 study.

PURPOSE: To determine the relationship between coronary plaque detected with coronary computed tomographic (CT) angiography and clinical parameters and cardiovascular risk factors in asymptomatic patients with diabetes. MATERIALS AND METHODS: All patients signed institutional review board-approved informed consent forms before enrollment. Two hundred twenty-four asymptomatic diabetic patients (121 men; mean patient age, 61.8 years; mean duration of diabetes, 10.4 years) underwent coronary CT angiography. Total coronary artery wall volume in all three vessels was measured by using semiautomated software. The coronary plaque volume index (PVI) was determined by dividing the wall volume by the coronary length. The relationship between the PVI and cardiovascular risk factors was determined with multivariable analysis. RESULTS: The mean PVI (±standard deviation) was 11.2 mm(2) ± 2.7. The mean coronary artery calcium (CAC) score (determined with the Agatston method) was 382; 67% of total plaque was noncalcified. The PVI was related to age (standardized ß = 0.32, P < .001), male sex (standardized ß = 0.36, P < .001), body mass index (BMI) (standardized ß = 0.26, P < .001), and duration of diabetes (standardized ß = 0.14, P = .03). A greater percentage of soft plaque was present in younger individuals with a shorter disease duration (P = .02). The soft plaque percentage was directly related to BMI (P = .002). Patients with discrepancies between CAC score and PVI rank quartiles had a higher percentage of soft and fibrous plaque (18.7% ± 3.3 vs 17.4% ± 3.5 [P = .008] and 52.2% ± 7.2 vs 47.2% ± 8.8 [P < .0001], respectively). CONCLUSION: In asymptomatic diabetic patients, BMI was the primary modifiable risk factor that was associated with total and soft coronary plaque as assessed with coronary CT angiography.

3.0-T whole-heart coronary magnetic resonance angiography: comparison of gadobenate dimeglumine and gadofosveset trisodium.

Gadolinium enhanced coronary magnetic resonance angiography (MRA) at 3 T appears to be superior to non-contrast methods. Gadofosveset is an intravascular contrast agent that may be well suited to this application. The purpose of this study was to perform an intra-individual comparison of gadofosveset and gadobenate for coronary MRA at 3 T. In this prospective randomized study, 22 study subjects [8 (36%) male; 27.9 ± 6 years; BMI = 22.8 ± 2 kg/m(2)] underwent two studies using a contrast-enhanced inversion recovery three-dimensional fast low angle shot MRA at 3 T. The order of contrast agent administration was varied randomly, separated by an average of 30 ± 5 days, using either gadobenate dimeglumine (Gd-BOPTA; Bracco, 0.1 mmol/Kg) or gadofosveset trisodium (MS-325; Lantheus Med, 0.03 mmol/Kg). Acquisition time, signal-to-noise ratio (SNR) of coronary vessels and contrast-to-noise ratio (CNR) were evaluated. Of 308 coronary arteries and veins segment analyzed, overall SNR of coronary arteries and veins segments were not different for the two contrast agents (132 ± 79 for gadofosveset vs. 135 ± 78 for gadobenate, p = 0.69). Coronary artery CNR was greater for gadofosveset in comparison to gadobenate (73.5 ± 46.9 vs. 59.3 ± 75.7 respectively, p = 0.03). Gadofosveset-enhanced MRA images displayed better image quality than gadobenate-enhanced MRA images (2.77 ± 0.61 for gadofosveset vs. 2.11 ± 0.51, p < .001). Inter- and intra-reader variability was excellent (ICC > 0.90) for both contrast agents. Gadofosveset trisodium appears to show slightly better performance for coronary MRA at 3 T compared to gadobenate.

Beyond Coronary Stenosis: Coronary Computed Tomographic Angiography for the Assessment of Atherosclerotic Plaque Burden.

Coronary computed tomographic angiography (CCTA) is emerging as a key non-invasive method for assessing cardiovascular risk by measurement of coronary stenosis and coronary artery calcium (CAC). New advancements in CCTA technology have led to the ability to directly identify and quantify the so-called "vulnerable" plaques that have features of positive remodeling and low density components. In addition, CCTA presents a new opportunity for noninvasive measurement of total coronary plaque burden that has not previously been available. The use of CCTA needs also to be balanced by its risks and, in particular, the associated radiation exposure. We review current uses of CCTA, CCTA's ability to measure plaque quantity and characteristics, and new developments in risk stratification and CCTA technology. CCTA represents a quickly developing field that will play a growing role in the non-invasive management of cardiovascular disease.

Downstream coronary effects of drug-eluting stents.

BACKGROUND: Antiproliferative agents used in drug-eluting stents (DES) attenuate atherosclerosis, yet DES implantation has been linked to endothelial dysfunction. The downstream effects of DES on new lesion formation have not been previously directly examined. We sought to compare the development of de novo stenoses and need for treatment in the downstream coronary vessel of patients treated with DES or a bare-metal stent. METHODS: Angiographic images and procedural information were prospectively collected on 463 adults who underwent implantation of a single stent in a proximal coronary artery, had an appropriate control vessel for comparison, and subsequently returned for intervention. Propensity matching identified 89 pairs of patients. End points were defined as angiographic identification of a de novo stenosis or need for secondary intervention in the downstream vessel within 12 months of initial intervention. RESULTS: In the overall (P < .01) and propensity-matched cohort (P = .01), there was reduced risk of new lesions downstream to DES. No difference was seen in respective control vessels (P = .14 and P = .99). A reduced need for downstream intervention with DES was seen in both the overall (P = .01) and propensity-matched cohorts (P = .04). No difference was seen in the control vessels (P = .98 and P = .36). Multivariate proportional hazards modeling of known atherosclerosis risk factors identified stent type as the sole predictor for downstream lesions (P < .01) and downstream events (P = .02). CONCLUSIONS: Patients receiving DES appear less likely to develop downstream stenoses and events compared with patients receiving bare-metal stents, suggesting beneficial downstream drug delivery.

The effect of gemfibrozil, niacin and cholestyramine combination therapy on metabolic syndrome in the Armed Forces Regression Study.

INTRODUCTION: Metabolic syndrome is a powerful predictor of cardiovascular events independent of overt diabetes. Dietary restriction and weight loss modify metabolic syndrome components. This study addresses whether combination pharmacologic therapy focused on dyslipidemia provides additional benefit. METHODS: This study examines the effect of 1 year of gemfibrozil, niacin and cholestyramine therapy on a baseline of aggressive dietary and lifestyle intervention in 143 clinically stable, nondiabetic patients with coronary disease, randomized into a double-blind, placebo-controlled trial. RESULTS: Cohort characteristics included age 63 ± 7 years, 92% men, 43% with previous myocardial infarction, systolic blood pressure 139 ± 17 mm Hg, triglycerides 168 ± 81 mg/dL and high-density lipoprotein cholesterol 34 ± 6 mg/dL. The mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.5 ± 1.1, P < 0.001, and metabolic syndrome prevalence decreased from 38% to 18% (P < 0.001) for the entire cohort. In the lifestyle intervention and placebo group, the mean number of metabolic syndrome components decreased from 2.2 ± 0.9 to 1.9 ± 1.1 (P = 0.01), and prevalence of metabolic syndrome decreased from 44% to 30% (P = 0.15). A far more marked change was observed with lifestyle intervention and pharmacologic therapy: abnormal metabolic components decreased from 2.2 ± 0.9 to 1.0 ± 1.0 (P < 0.001), and prevalence of metabolic syndrome decreased from 32% to 6% (P < 0.001). CONCLUSIONS: The combination of gemfibrozil, niacin and cholestyramine has profound, beneficial effects on the components of metabolic syndrome. These benefits are additive to those seen with aggressive diet and lifestyle modification.

Engineering liver tissue spheroids with inverted colloidal crystal scaffolds.

Multicellular spheroids provide a new three-dimensional (3D) level of control over morphology and function of ex vivo cultured tissues. They also represent a valuable experimental technique for drug discovery and cell biology. Nevertheless, the dependence of many cellular processes on the cluster diameter remains unclear. To provide a tool for the systematic evaluation of such dependences, we introduce here inverted colloidal crystal (ICC) scaffolds. Uniformly sized pores in ICC cell matrixes afford a high yield production of controlled size spheroids in standard 96 well-plates. Transparent hydrogel matrix and ship-in-bottle effect also allows for convenient monitoring of cell processes by traditional optical techniques. Different developmental stages of 46.5-151.6 microm spheroids from HepG2 hepatocytes with vivid morphological similarities to liver tissue (bile canaliculi) were observed. The liver-specific functions of HepG2 cells were systematically investigated and compared for spheroids of different diameters as well as 2D cultures. Clear trends of albumin production and CYP450 activity were observed; diffusion processes and effect of cellular aggregation on metabolic activity were identified to be the primary contributors to the size dependence of the liver functions in HepG2 spheroids in ICC scaffolds. Since the aggregation of cells into clusters is a universal biological process, these findings and scaffolds can be applied to many other relevant cell types.