Journal: Circ Cardiovasc Imaging

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Abstract

Novel Imaging Approaches for Predicting Arrhythmic Risk.

Travin MI, Feng D, Taub CC
Determination of ventricular arrhythmic risk is crucial for guiding management of cardiac disease. Although for patients at increased risk an implantable cardioverter-defibrillator is recommended, it is widely acknowledged that current criteria for device use based predominantly on left ventricular ejection fraction are deficient. Genesis of ventricular arrhythmias involves a complex interaction of myocardial substrate abnormalities, precipitating triggers, and modulating factors. There are much data showing that by more directly assessing these factors, noninvasive imaging using echocardiography, radionuclide imaging, and cardiac magnetic resonance enhances arrhythmic risk stratification beyond ejection fraction and commonly used electrocardiographic and serum biomarkers. It is anticipated that further technological advancements studied in well-designed clinical trials will provide both more precise determination of risk and guide therapies to enhanced survival and patient well-being.

Circ Cardiovasc Imaging: 12 Nov 2015; 8
Travin MI, Feng D, Taub CC
Circ Cardiovasc Imaging: 12 Nov 2015; 8 | PMID: 26565012
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Evaluation of Known or Suspected Cardiac Sarcoidosis.

Blankstein R, Waller AH
Sarcoidosis is a multisystem disorder of unknown cause, and cardiac sarcoidosis affects at least 25% of patients and accounts for substantial mortality and morbidity from this disease. Cardiac sarcoidosis may present with heart failure, left ventricular systolic dysfunction, AV block, atrial or ventricular arrhythmias, and sudden cardiac death. Cardiac involvement can be challenging to detect and diagnose because of the focal nature of the disease, as well as the fact that clinical criteria have limited diagnostic accuracy. Nevertheless, the diagnosis of cardiac sarcoidosis can be enhanced by integrating both clinical and imaging findings. This article reviews the various roles that different imaging modalities provide in the evaluation and management of patients with known or suspected cardiac sarcoidosis.

Circ Cardiovasc Imaging: 29 Feb 2016; 9:e000867
Blankstein R, Waller AH
Circ Cardiovasc Imaging: 29 Feb 2016; 9:e000867 | PMID: 26926267
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Multimodality Cardiac Imaging for the Assessment of Left Atrial Function and the Association With Atrial Arrhythmias.

Olsen FJ, Bertelsen L, de Knegt MC, Christensen TE, ... Jensen JS, Biering-Sørensen T
Several cardiac imaging modalities are able to visualize the left atrium (LA) and, therefore, allow for quantification of both structural and functional properties of this cardiac chamber. In echocardiography, only the maximal LA volume is included in the assessment of diastolic function at the current moment. Numerous studies, however, have shown that functional measures may be superior to the maximal LA volume in several aspects and to possess clinical value even in the absence of structural abnormalities. Such functional measures could prove particularly useful in the setting of predicting atrial fibrillation, which will be a point of focus in this review. Pivotal cardiac magnetic resonance imaging studies have revealed high correlation between LA fibrosis and risk of atrial fibrillation recurrence after catheter ablation, and subsequent multimodality imaging studies have uncovered an inverse relationship between LA reservoir function and degree of LA fibrosis. This has sparked an increased interest into the application of advanced imaging modalities, including both speckle tracking echocardiography and tissue tracking by cardiac magnetic resonance imaging. Even though increasing evidence has supported the use of functional measures and proven its superiority to the maximal LA volume, they have still not been adopted in clinical guidelines. The reason for this discrepancy may rely on the fact that there is little to no agreement on how to technically perform deformation analysis of the LA. Such technical considerations, limitations, and alternate imaging prospects will be addressed in this review.

Circ Cardiovasc Imaging: 11 Oct 2016; 9
Olsen FJ, Bertelsen L, de Knegt MC, Christensen TE, ... Jensen JS, Biering-Sørensen T
Circ Cardiovasc Imaging: 11 Oct 2016; 9 | PMID: 27729358
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Non-invasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension.

Thibault HB, Kurtz B, Raher MJ, Shaik RS, ... Bloch KD, Scherrer-Crosbie M
Background: -Genetically-modified mice offer the unique opportunity to gain insights into the pathophysiology of pulmonary arterial hypertension (PAH). In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a non-invasive technique to assess RVSP in mice. Methods and results: -Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific over-expression of interleukin 6 (IL-6). Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetric at baseline to asymmetric at higher RVSPs. In wild-type and IL-6-over-expressing mice, the PAT correlated linearly with RVSP (r(2)=-0.67; p<0.0001), as did PAT/ET (r(2)=-0.76; p<0.0001). Sensitivity and specificity for detecting high RVSP (>32 mmHg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT <21 ms and PAT/ET <39%). Intra-observer and inter-observer variability of PAT and PAT/ET were less than 6%. Conclusions: -Right ventricular systolic pressure can be estimated non-invasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity, as well as to assess the effects of treatment on RVSP. This non-invasive technique may permit the characterization of the evolution of PAH in genetically-modified mice.

Circ Cardiovasc Imaging: 01 Jan 2010; epub ahead of print
Thibault HB, Kurtz B, Raher MJ, Shaik RS, ... Bloch KD, Scherrer-Crosbie M
Circ Cardiovasc Imaging: 01 Jan 2010; epub ahead of print | PMID: 20044514
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Abstract

Quantification of Diffuse Myocardial Fibrosis and its Association with Myocardial Dysfunction in Congenital Heart Disease.

Broberg CS, Chugh S, Conklin C, Sahn DJ, Jerosch-Herold M
Background: -The etiology of ventricular dysfunction in adult congenital heart disease (ACHD) is not well understood. Diffuse fibrosis is a likely common final pathway and is quantifiable using magnetic resonance imaging (MRI). Methods and results: -ACHD patients (N=50) were studied with cardiac MRI to quantify systemic ventricular volume and function, and diffuse fibrosis. The fibrosis index for a single mid-ventricular plane of the systemic ventricle was quantified by measuring T(1) values for blood pool and myocardium before and after administration of gadolinium (0.15 mmol/kg), then adjusted for hematocrit. Results were compared to healthy volunteers (normal controls, N=14) and patients with acquired heart failure (positive controls, N=4). Patients studied (age 37±12 years, 40% female) included 11 with a systemic right ventricle (RV), 17 with tetralogy of Fallot, 10 with cyanosis and 12 with other lesions. The fibrosis index was significantly elevated in ACHD patients compared to normal controls (31.9±4.9% vs. 24.8±2.0%, p=0.001). Values were highest in systemic RV patients (35.0±5.8%, p<0.001) and cyanotic patients (33.7±5.6%, p<0.001). The fibrosis index correlated with end-diastolic volume index (r=0.60, p<0.001) and ventricular ejection fraction (r=-0.53, p<0.001), but not with age, nor oxygen saturation in cyanotic patients. Late gadolinium enhancement did not account for the differences seen. Conclusions: -ACHD patients have evidence of diffuse, extracellular matrix remodeling, similar to patients with acquired heart failure. The fibrosis index may facilitate studies on the mechanisms and treatment of myocardial fibrosis and heart failure in these patients.

Circ Cardiovasc Imaging: 21 Sep 2010; epub ahead of print
Broberg CS, Chugh S, Conklin C, Sahn DJ, Jerosch-Herold M
Circ Cardiovasc Imaging: 21 Sep 2010; epub ahead of print | PMID: 20855860
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Abstract

Extent of Myocardium at Risk for Left Anterior Descending Artery, Right Coronary Artery, and Left Circumflex Artery Occlusion Depicted by Contrast-Enhanced Steady State Free Precession and T2-Weighted Short Tau Inversion Recovery Magnetic Resonance Imaging.

Nordlund D, Heiberg E, Carlsson M, Fründ ET, ... Engblom H, Arheden H
Contrast-enhanced steady state free precession (CE-SSFP) and T2-weighted short tau inversion recovery (T2-STIR) have been clinically validated to estimate myocardium at risk (MaR) by cardiovascular magnetic resonance while using myocardial perfusion single-photon emission computed tomography as reference standard. Myocardial perfusion single-photon emission computed tomography has been used to describe the coronary perfusion territories during myocardial ischemia. Compared with myocardial perfusion single-photon emission computed tomography, cardiovascular magnetic resonance offers superior image quality and practical advantages. Therefore, the aim was to describe the main coronary perfusion territories using CE-SSFP and T2-STIR cardiovascular magnetic resonance data in patients after acute ST-segment-elevation myocardial infarction.

Circ Cardiovasc Imaging: 13 Jul 2016; 9
Nordlund D, Heiberg E, Carlsson M, Fründ ET, ... Engblom H, Arheden H
Circ Cardiovasc Imaging: 13 Jul 2016; 9 | PMID: 27412659
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"Vascular Age" is Advanced in Children with Atherosclerosis Promoting Risk Factors.

Le J, Zhang D, Menees S, Chen J, Raghuveer G
Background: -Obesity and familial dyslipidemia in children are associated with accelerated atherosclerosis by pathological examination. We sought to determine if these children had increased carotid artery intima-media thickness (CIMT), a measure of subclinical atherosclerosis similar to 45 year-old adults. Adult CIMT percentile tables were used for comparison as there is limited normative CIMT data for children. Methods and results: -Seventy children, age 6-19 years, with obesity and atherosclerosis promoting risk factors such as dyslipidemia, hypertension, insulin resistance and tobacco smoke exposure; or with familial dyslipidemia, underwent carotid artery ultrasound. Advanced "vascular age" (VA) was defined as having maximum CIMT that was >/= 25(th) percentile for a race and sex matched 45 year-old. Mean age was 13.0+/-3.3 years. Forty (57%) of 70 children had body mass index (BMI) >/= 95(th) percentile for age and sex. Maximum CIMT for obese children was 0.53+/-0.05 mm; for familial dyslipidemic children 0.52+/-0.04 mm. Advanced VA was seen in 30 (75%) of obese children and 22 (73%) of familial dyslipidemic children. Thirty (75%) of obese children had > 3 mutable atherosclerosis-promoting risk factors; these children had a non significantly higher maximum CIMT compared to obese children with </= 3 risk factors (0.54+/-0.06 mm vs. 0.52+/-0.03 mm, p=0.07). Obese children with high fasting triglyceride levels were more likely to have an advanced VA. Conclusions: -VA is advanced and comparable in obese children with atherosclerosis promoting risk factors and in children with familial dyslipidemia. Advanced VA is prevalent in obese children with high fasting triglyceride levels.

Circ Cardiovasc Imaging: 18 Nov 2009; epub ahead of print
Le J, Zhang D, Menees S, Chen J, Raghuveer G
Circ Cardiovasc Imaging: 18 Nov 2009; epub ahead of print | PMID: 19920030
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Abstract

Diagnostic Value of Vena Contracta Area in the Quantification of Mitral Regurgitation Severity by Color Doppler 3D Echocardiography.

Zeng X, Levine RA, Hua L, Morris EL, ... Morgan NV, Hung J
Background: -Accurate quantification of mitral regurgitation (MR) is important for patient management and prognosis. Three-dimensional (3D) echocardiography allows for the direct measure of the regurgitant orifice area (ROA) by 3D guided planimetry of vena contracta area (VCA). We aimed to 1) establish 3D VCA ranges and cut-off values for MR grading, using the ASE recommended two dimensional (2D) integrative method as a reference; 2) Compare 2D and 3D methods of ROA to establish a common calibration for MR grading. Methods and results: -83 patients with at least mild MR underwent 2D and 3D echocardiography. Direct planimetry of VCA was performed by 3D echocardiography. 2D quantification of MR included 2D ROA by proximal isovelocity surface area (PISA) method, vena contracta width and ratio of jet area to left atrial area. There were significant differences in 3D VCA among patients with different MR grades. As assessed by receiver operating characteristic analysis, 3D VCA at a best cut-off value of 0.41cm(2) yielded 97% of sensitivity and 82% of specificity to differentiate moderate from severe MR. There was significant difference between 2D ROA and 3D VCA in patients with functional MR, resulting in an underestimation of ROA by 2D PISA method by 27% as compared with 3D VCA. Multivariable regression analysis showed functional MR as etiology was the only predictor of underestimation of ROA by 2D PISA method. Conclusions: -3D VCA provides a single, directly visualized and reliable measurement of ROA, which classifies MR severity comparable to current clinical practice using the ASE recommended 2D integrative method. 3D VCA method improves accuracy of MR grading compared with 2D PISA method by eliminating geometric and flow assumptions, allowing for uniform clinical grading cutoffs and ranges that apply regardless of etiology and orifice shape.

Circ Cardiovasc Imaging: 06 Jul 2011; epub ahead of print
Zeng X, Levine RA, Hua L, Morris EL, ... Morgan NV, Hung J
Circ Cardiovasc Imaging: 06 Jul 2011; epub ahead of print | PMID: 21730026
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Abstract

Cardiovascular Magnetic Resonance Myocardial Feature Tracking: Concepts and Clinical Applications.

Schuster A, Hor KN, Kowallick JT, Beerbaum P, Kutty S
Heart failure-induced cardiovascular morbidity and mortality constitute a major health problem worldwide and result from diverse pathogeneses, including coronary artery disease, nonischemic cardiomyopathies, and arrhythmias. Assessment of cardiovascular performance is important for early diagnosis and accurate management of patients at risk of heart failure. During the past decade, cardiovascular magnetic resonance myocardial feature tracking has emerged as a useful tool for the quantitative evaluation of cardiovascular function. The method allows quantification of biatrial and biventricular mechanics from measures of deformation: strain, torsion, and dyssynchrony. The purpose of this article is to review the basic principles, clinical applications, accuracy, and reproducibility of cardiovascular magnetic resonance myocardial feature tracking, highlighting the prognostic implications. It will also provide an outlook on how this field might evolve in the future.

Circ Cardiovasc Imaging: 23 Mar 2016; 9
Schuster A, Hor KN, Kowallick JT, Beerbaum P, Kutty S
Circ Cardiovasc Imaging: 23 Mar 2016; 9 | PMID: 27009468
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DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients with Coronary Artery Disease.

Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP
Background: -Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted post-prandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography (DSE) in patients with coronary artery disease (CAD) Methods and results: -Fourteen patients with CAD and preserved LV function awaiting revascularisation were studied. Following either a single dose of sitagliptin 100mg or placebo, 75g of glucose was given orally to promote GLP-1 secretion and DSE conducted with tissue Doppler imaging at rest, peak stress and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5 +/-; 10.7 vs 9.7 +/- 8.7 pg/ml; p = 0.003) and in recovery (12.4 +/- 5.5 vs 9.0 +/- 5.5 pg/ml; p = 0.01), and the LV response to stress was enhanced (ejection fraction 72.6 +/- 7.2 vs 63.9 +/- 7.9 %, p = 0.0001; mitral annular systolic velocity 12.54 +/- 3.18 vs 11.49 +/- 2.52 cm/s; p = 0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired non-apical segments assessed by peak systolic tissue Doppler (velocity 10.56 +/- 4.49 vs 9.81 +/- 4.26 cm/s, p = 0.002; strain -15.9 +/- 6.3 vs -14.6 +/- 6.6 %, p = 0.01 and strain rate -2.04 +/- 1.04 vs -1.75 +/- 0.98 s(-1), p = 0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments 9.77 +/- 4.18 vs 8.74 +/- 3.87, p = 0.007; velocity in non-ischemic segments 11.51 +/- 4.70 vs 11.14 +/- 4.38, p = 0.14). In recovery, sitagliptin attenuated the post ischemic stunning seen after the control study. Conclusions: -The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates post ischemic stunning in humans with coronary artery disease. Clinical Trial registration Information-URL: http://isrctn.org. Registration number: ISRCTN78649100.

Circ Cardiovasc Imaging: 15 Jan 2010; epub ahead of print
Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP
Circ Cardiovasc Imaging: 15 Jan 2010; epub ahead of print | PMID: 20075143
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Multimodality Imaging Strategies for the Assessment of Aortic Stenosis: Viewpoint of the Heart Valve Clinic International Database (HAVEC) Group.

Dulgheru R, Pibarot P, Sengupta PP, Piérard LA, ... Gillam L, Lancellotti P
Aortic stenosis is the most frequent valvular heart disease. In aortic stenosis, therapeutic decision essentially depends on symptomatic status, stenosis severity, and status of left ventricular systolic function. Surgical aortic valve replacement or transcatheter aortic valve implantation is the sole effective therapy in symptomatic patients with severe aortic stenosis, whereas the management of asymptomatic patients remains controversial and is mainly based on individual risk stratification. Imaging is fundamental for the initial diagnostic work-up, follow-up, and selection of the optimal timing and type of intervention. The present review provides specific recommendations for utilization of multimodality imaging to optimize risk stratification and therapeutic decision-making processes in aortic stenosis.

Circ Cardiovasc Imaging: 10 Feb 2016; 9:e004352
Dulgheru R, Pibarot P, Sengupta PP, Piérard LA, ... Gillam L, Lancellotti P
Circ Cardiovasc Imaging: 10 Feb 2016; 9:e004352 | PMID: 26863917
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Non-Invasive Assessment of Atherosclerotic Plaque Progression in ApoE-/- Mice Using Susceptibility Gradient Mapping.

Makowski MR, Varma G, Wiethoff A, Smith A, ... Schaeffter T, Botnar RM
Background: -Macrophages have been identified as a major contributor to plaque development and destabilization in atherosclerosis. The aim of this study was to non-invasively assess uptake of citrate coated very small iron oxide particles (VSOP) at different stages of plaque development in the brachiocephalic artery of apoE(-/-) mice. Susceptibility gradient mapping (SGM) was applied to generate positive contrast images and to quantify iron oxide uptake. Methods and results: -ApoE(-/-) mice were fed a high fat diet (HFD) for 4, 8 or 12 weeks. 300 μmol Fe/kg was injected 24 and 48 hours prior to final MR imaging. Increasing VSOP uptake was observed over the course of atherosclerotic plaque development. Simultaneous administration of pravastatin led to a significant decrease in VSOP uptake, assessed by mass spectroscopy and histology. SGM-MRI allowed the generation of positive contrast images and magnitudes (mT/m) of contrast enhancement in SG parameter maps significantly correlated with the absolute iron oxide content (R(2) = 0.70, P < 0.05) and the macrophage density (R(2) = 0.71, P < 0.05). Conclusions: -This study shows an increase in iron oxide uptake (measured by in vivo SGM-MRI, histology and mass spectroscopy) with the progression of plaque development in an apoE(-/-) mouse model of accelerated atherosclerosis. Positive contrast provided by SGM-MRI allowed for a clear visualization of intraplaque iron oxide depositions and magnitudes (mT/m) of contrast enhancement in SG parameter maps allowed for the quantification of intraplaque iron oxide particles.

Circ Cardiovasc Imaging: 22 Mar 2011; epub ahead of print
Makowski MR, Varma G, Wiethoff A, Smith A, ... Schaeffter T, Botnar RM
Circ Cardiovasc Imaging: 22 Mar 2011; epub ahead of print | PMID: 21422166
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Abstract

Dynamic Changes of Edema and Late Gadolinium Enhancement after Acute Myocardial Infarction and Their Relationship to Functional Recovery and Salvage Index.

Dall\'armellina E, Karia N, Lindsay AC, Karamitsos TD, ... Neubauer S, Choudhury RP
Background: -Changes in the myocardium in acute ischemia are dynamic and complex and the characteristics of myocardial tissue on cardiovascular magnetic resonance (CMR) in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute MI, relating these to global and segmental myocardial function at 6 months. Methods and results: -CMR scans were performed on 30 patients with ST elevation MI (STEMI) treated by primary PCI at each of 4 time points: 12-48 hours (24H); 5-7 days (1W); 14-17 days (2W); and 6 months (6M). All patients showed edema at 24H. The mean volume of edema (% LV) was 37 ± 16 at 24H and 39 ± 17 at 1W with a reduction to 24 ± 13 (P < 0.01) by 2W. Myocardial segments with edema also had increased signal on LGE at 24H (kappa = 0.77; P < 0.001). The volume of LGE decreased significantly between 24H and 6M (27 ± 15 % vs. 22 ± 12 %; P = 0.002). Of segments showing LGE at 24H, 50% showed resolution by six months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P < 0.0001). The area of LGE measured at 6M correlated more strongly with troponin at 48h (r = 0.9; P < 0.01) than LGE at 24H (r = 0.7). The difference in LGE between 24H and 6M had profound effects on the calculation of salvage index (26 ± 21 % at 24H vs. 42 ± 23 % at 6M; P = 0.02). Conclusions: -Myocardial edema is maximal and constant over the first week post MI, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium.

Circ Cardiovasc Imaging: 30 Mar 2011; epub ahead of print
Dall'armellina E, Karia N, Lindsay AC, Karamitsos TD, ... Neubauer S, Choudhury RP
Circ Cardiovasc Imaging: 30 Mar 2011; epub ahead of print | PMID: 21447711
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Abstract

Mechanisms of Acute Mitral Regurgitation in Patients with Tako-Tsubo Cardiomyopathy: An Echocardiographic Study.

Izumo M, Nalawadi S, Shiota M, Das J, ... Siegel RJ, Shiota T
Background: -Recent studies have suggested acute mitral regurgitation (MR) as a potentially serious complication of Tako-Tsubo cardiomyopathy (TTC); however, the mechanism of acute MR in TTC remains unclear. The aim of this study was to elucidate the mechanisms of acute MR in patients with TTC. Methods and results: -Echocardiography was used to assess the mitral valve and left ventricular outflow tract (LVOT) pressure gradient in 47 patients with TTC confirmed by coronary angiography and left ventriculography. Mitral valve assessment included coaptation distance, tenting area at mid systole in the long axis view, and systolic anterior motion of the mitral valve (SAM). Of the study patients, 12 patients (25.5%) had significant (moderate or severe) acute MR. We found lower ejection fraction (31.3±6.2 vs. 41.5±10.6%, p=0.001) and higher systolic pulmonary artery pressure (49.3±7.4 vs. 35.5±8.9mmHg, p<0.001) in patients with acute MR than in those without acute MR. Moreover, 6 of the 12 patients with acute MR had SAM with peak LVOT pressure gradient > 20mmHg (average peak LVOT pressure gradient of 81.3±35.8mmHg). The remaining 6 patients with acute MR revealed significantly greater mitral valve coaptation distance (10.9±1.6 vs. 7.8±1.4mm, p<0.001) and tenting area (2.1±0.4 vs. 0.95±0.25cm(2), p<0.001) than those without acute MR. A multivariate analysis revealed that SAM and tenting area were independent predictors of acute MR in TTC patients (all p<0.001). Conclusions: -SAM and tethering of the mitral valve are independent mechanisms with differing pathophysiology that can lead to acute MR in TTC patients.

Circ Cardiovasc Imaging: 18 Apr 2011; epub ahead of print
Izumo M, Nalawadi S, Shiota M, Das J, ... Siegel RJ, Shiota T
Circ Cardiovasc Imaging: 18 Apr 2011; epub ahead of print | PMID: 21498669
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Multimodality Imaging Reveals a Gradual Increase in Matrix Metalloproteinase Activity at Aneurysmal Lesions in Live Fibulin-4 Mice.

Kaijzel E, van Heijningen P, Wielopolski P, Vermeij M, ... Löwik C, Essers J
Background: -We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence (NIRF) probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm using our genetically modified Fibulin-4 mouse models for aneurysm formation. Mice homozygous for the Fibulin-4 reduced expression allele (Fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of Fibulin-4 in the heterozygous Fibulin-4(+/R) mice occasionally results in modest aneurysm formation. Methods and results: -Aorta transcriptome and protein expression analysis of Fibulin-4(+/R) and Fibulin-4(R/R) animals identified excessive TGFbeta signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether perturbed elastin lamellar structure arose from induction of TGFbeta regulated MMPs, we performed gelatin-zymography and used a protease-activatable NIRF probe to monitor and quantify MMP upregulation in animals using various in vivo optical imaging modules and co-registration of the fluorescence signal with CT images of the same animals. Gelatin-zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of Fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the NIRF probe and subsequent isosurface concentration mapping from reconstructed tomographic images from Fibulin-4(+/R) and Fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions. Conclusions: -We aimed to develop molecular imaging procedures for faster, earlier and easier recognition of aortic aneurysms. Here we show that in vivo co-registration of MMP activity by non-invasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed.

Circ Cardiovasc Imaging: 01 Jul 2010; epub ahead of print
Kaijzel E, van Heijningen P, Wielopolski P, Vermeij M, ... Löwik C, Essers J
Circ Cardiovasc Imaging: 01 Jul 2010; epub ahead of print | PMID: 20592247
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Non-Invasive Vascular Function Measurement in the Community: Cross-Sectional Relations and Comparison of Methods.

Schnabel RB, Schulz A, Wild PS, Sinning CR, ... Blankenberg S, Münzel TF
Background: -Several methods of non-invasive vascular function testing have been suggested for cardiovascular risk screening in the community. A direct comparison of the different methods and their relation to classical cardiovascular risk factors in a large cohort is missing. Methods and results: -In 5000 individuals (mean age, 55.5±10.9 years, age range 35-74 years; 49.2% women) of the community-based Gutenberg Heart Study we performed simultaneous measurement of flow-mediated dilation (FMD) and peripheral arterial volume pulse determined by infrared photo(reflection index)- and pneumatic plethysmography (PAT) and explored their associations. All function measures were recorded at baseline and after reactive hyperemia induced by 5 minute brachial artery occlusion. Correlations between different measures of vascular function were statistically significant but moderate. The strongest association for hyperemic response variables was observed for PAT ratio and FMD (Spearman correlation coefficient r=0.17, age and sex-adjusted partial correlation 0.068). Classical risk factors explained between 15.8% (baseline reflection index) and 58.4% (brachial artery diameter) of the baseline values, but only accounted for 3.2% (reflection index), 15.4% (FMD) and 13.9% (PAT ratio) of the variability of reflective hyperemic response. Regression models varied in their relations to classical risk factors for the individual vascular function measures. Consistently associated with different vascular function methods were age, sex, body-mass-index, and indicators of hypertension. Peripheral tonometry also showed a relation to fasting glucose concentrations. Conclusions: -Non-invasive measures of conduit artery and peripheral arterial function are modestly correlated, differ in their relation to classical cardiovascular risk factors and may thus reflect different pathologies.

Circ Cardiovasc Imaging: 09 May 2011; epub ahead of print
Schnabel RB, Schulz A, Wild PS, Sinning CR, ... Blankenberg S, Münzel TF
Circ Cardiovasc Imaging: 09 May 2011; epub ahead of print | PMID: 21551420
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Risk Stratification and Prognosis of Human Immunodeficiency Virus Infected Patients with Known or Suspected Coronary Artery Disease Referred for Stress Echocardiography.

Wever Pinzon O, Silva Enciso J, Romero J, Makani H, ... Bangalore S, Chaudhry FA
Background: -Patients with Human Immunodeficiency Virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV infected patients with known or suspected CAD. Methods and results: -We evaluated 311 patients (52 ± 9 years; 74% males, left ventricular ejection fraction (LVEF) 54 ± 12%) with history of HIV undergoing SE (56% dobutamine). LV wall motion was evaluated on a 16-segment model 5-point scale. An abnormal SE was defined by a fixed (infarction), biphasic or new (ischemia) wall motion abnormality on stress. Follow-up for cardiac death and myocardial infarction (MI) was obtained. Seventy-nine (26%) patients had an abnormal SE. After 2.9 ± 1.9 years, 17 confirmed MI and 14 cardiac deaths occurred. SE risk stratified patients into normal versus abnormal subgroups (event rate 0.6%/year vs. 11.8%/year; p <0.0001). Both abnormal SE (HR 28.2, 95% CI 6.2-128.0, p<0.0001) and the presence of any ischemia on SE (HR 3.4, 95% CI 1.3-8.6, p=0.009) were independent predictors of cardiac events. On a forward conditional Cox proportional hazards regression model, SE provided incremental prognostic value over clinical, stress electrocardiographic and resting echocardiographic variables (global Chi-square increased from 17.8 to 24.5 to 65 to 109, p<0.05 across all groups). Conclusions: -SE can effectively risk stratify and prognosticate patients with HIV. The presence of ischemia and scar during SE provides independent and incremental prognostic value over traditional variables. A normal SE response portends a benign prognosis even in this high-risk subset.

Circ Cardiovasc Imaging: 13 Jul 2011; epub ahead of print
Wever Pinzon O, Silva Enciso J, Romero J, Makani H, ... Bangalore S, Chaudhry FA
Circ Cardiovasc Imaging: 13 Jul 2011; epub ahead of print | PMID: 21750273
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Adult Height and Prevalence of Coronary Artery Calcium: The NHLBI Family Heart Study.

Miedema MD, Petrone AB, Arnett DK, Dodson JA, ... Gaziano JM, Djoussé L
-Adult height has been hypothesized to be inversely associated with coronary heart disease but studies have produced conflicting results. We sought to examine the relationship between adult height and the prevalence of coronary artery calcium (CAC), a direct measure of subclinical atherosclerosis and surrogate marker of CHD. Method and Results-We evaluated the relationship between adult height and CAC in 2,703 participants from the NHLBI Family Heart Study who underwent cardiac computed tomography. We used generalized estimating equations to calculate the prevalence odds ratios for the presence of CAC (CAC>0) across sex-specific quartiles of height. The mean age of the sample was 54.8 years and 60.2% were female. There was an inverse association between adult height and CAC. After adjusting for age, race, field center, waist circumference, smoking, alcohol, physical activity, systolic blood pressure, antihypertensive medications, diabetes, diabetic medications, LDL cholesterol, HDL cholesterol, lipid-lowering medications, and income, individuals in the tallest quartile had 30% lower odds of having prevalent CAC. The odds ratios (95% CI) for the presence of CAC across consecutive sex-specific quartiles of height were 1.0 (reference), 1.15 (0.86-1.53), 0.95(0.73-1.22), and 0.70 (0.53-0.93), p for trend <0.01. There was no evidence of effect modification for the relationship between adult height and CAC by age or socioeconomic status.

Circ Cardiovasc Imaging: 15 Dec 2013; epub ahead of print
Miedema MD, Petrone AB, Arnett DK, Dodson JA, ... Gaziano JM, Djoussé L
Circ Cardiovasc Imaging: 15 Dec 2013; epub ahead of print | PMID: 24336983
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Abstract

Micro-computed Tomography Provides High Accuracy Congenital Heart Disease Diagnosis in Neonatal and Fetal Mice.

Kim AJ, Francis R, Liu X, Devine WA, ... Tobita K, Lo CW
Background: -Mice are well suited for modeling human congenital heart defects (CHD), given their four-chamber cardiac anatomy. However, mice with CHD invariably die prenatally/neonatally, causing CHD phenotypes to be missed. Therefore, we investigated the efficacy of noninvasive micro-computed tomography (micro-CT) to screen for CHD in stillborn/fetal mice. These studies were carried out using chemically mutagenized mice expected to be enriched for birth defects including CHD. Methods and results: -Stillborn/fetal mice obtained from the breeding of N-ethyl-N-nitrosourea (ENU) mutagenized mice were formalin-fixed and stained with iodine, then micro-CT scanned. Those diagnosed with CHD and some CHD-negative pups were necropsied. A subset of these were further analyzed by histopathology to confirm the CHD/no-CHD diagnosis. Micro-CT scanning of 2105 fetal/newborn mice revealed an abundance of ventricular septal defects (VSD) (n=307). Overall, we observed an accuracy of 89.8% for VSD diagnosis. Outflow tract anomalies identified by micro-CT included double outlet right ventricle (n=36), transposition of the great arteries (n=14), and persistent truncus arteriosus (n=3). These were diagnosed with a 97.4% accuracy. Aortic arch anomalies also were readily detected with an overall 99.6% accuracy. This included right aortic arch (n=28) and coarctation/interrupted aortic arch (n=12). Also detected by micro-CT were atrioventricular septal defects (n=22), tricuspid hypoplasia/atresia (n=13), and coronary artery fistulas (n=16). They yielded accuracies of 98.9%, 100%, and 97.8% respectively. Conclusions: -Contrast enhanced micro-CT imaging in neonatal/fetal mice can reliably detect a wide spectrum of CHD. We conclude micro-CT imaging can be used for routine rapid assessments of structural heart defects in fetal/newborn mice.

Circ Cardiovasc Imaging: 12 Jun 2013; epub ahead of print
Kim AJ, Francis R, Liu X, Devine WA, ... Tobita K, Lo CW
Circ Cardiovasc Imaging: 12 Jun 2013; epub ahead of print | PMID: 23759365
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Abstract

Prognostic Significance of Cardiac Magnetic Resonance Imaging in Children with Pulmonary Hypertension.

Moledina S, Pandya B, Bartsota M, Mortensen KH, ... Schulze-Neick I, Muthurangu V
Background: -There are very few validated prognostic markers in pediatric pulmonary hypertension (PH). Cardiac magnetic resonance imaging (CMR) is a useful, non-invasive method for determining prognosis in adults. The present study is the first to assess its prognostic value in children. Methods and results: -A total of 100 children with PH (median: 10.4 years, range: 0.5-17.6 years) were evaluated (idiopathic n=60, repaired congenital heart disease n=22, miscellaneous n=18). In all patients, ventricular volumes and great vessel flow were measured. Volumetric data was obtained using retrospectively gated cine imaging (n=37) or real time imaging (n=63) depending on patient\'s ability to breath-hold. During a median follow-up of 1.9 years, 11 patients died and 3 received lung transplantation. Of the CMR parameters measured, right ventricular ejection fraction and left ventricular stroke volume index were most strongly predictive of survival on univariate analysis (2.6 and 2.5 fold increase in mortality for every standard deviation fall respectively, p<0.05). These results were reflected in good separation of tertile based Kaplan Meier survival curves for these variables. Conclusions: -CMR measures correlate with clinical status and prognosis in children with PH. CMR is feasible and may be useful in clinical decision making in pediatric PH.

Circ Cardiovasc Imaging: 09 Apr 2013; epub ahead of print
Moledina S, Pandya B, Bartsota M, Mortensen KH, ... Schulze-Neick I, Muthurangu V
Circ Cardiovasc Imaging: 09 Apr 2013; epub ahead of print | PMID: 23572488
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Abstract

Myocardial Uptake of 7\'-(Z)-[123I]Iodorotenone During Vasodilator Stress in Dogs with Critical Coronary Stenoses.

Broisat A, Ruiz M, Goodman NC, Hanrahan SM, ... Vanbrocklin HF, Glover DK
Background: -There is a well-recognized need for a new generation of SPECT perfusion tracers with improved myocardial extraction over a wide flow range. Radiotracers that target complex I of the mitochondrial electron transport chain have been proposed as a new class of myocardial perfusion imaging (MPI) agents. 7-(Z)-[(125)I]Iodorotenone ((125)I-ZIROT) has demonstrated superior myocardial extraction and retention characteristics in rats and in isolated perfused rabbit hearts. We sought to fully characterize the biodistribution and myocardial extraction versus flow relationship of (123)I-ZIROT in an intact, large animal model. Methods and results: -(123)I-ZIROT was administered during adenosine A(2A) agonist-induced hyperemia in 5 anesthetized dogs with critical left anterior descending (LAD) stenoses. When left circumflex (LCx) flow was maximal, (123)I-ZIROT and microspheres were co-injected and the dogs euthanized 5 min later. (123)I-ZIROT biodistribution was evaluated in 2 additional dogs by in vivo planar imaging. At the time of (123)I-ZIROT injection, transmural LAD flow was unchanged from baseline (0.90±0.22 vs 0.87±0.11 ml/min/g, respectively P=0.92), whereas LCx zone flow increased significantly (3.25±0.51 vs 1.00±0.17 ml/min/g, P<0.05). Myocardial (123)I-ZIROT extraction tracked regional myocardial flow better than either thallium-201 or (99m)Tc-sestamibi from previous studies using a similar model. Furthermore, the (123)I-ZIROT LAD/LCx activity ratios by ex vivo imaging or well counting (0.42±0.08 and 0.45±0.1 respectively) only slightly underestimated the LAD/LCx microsphere flow ratio (0.32±0.09). Conclusions: -The ability of (123)I-ZIROT to more linearly track blood flow over a wide range makes it a very promising new SPECT MPI agent with potential for improved CAD detection and better quantitative estimation of the severity of flow impairment.

Circ Cardiovasc Imaging: 15 Sep 2011; epub ahead of print
Broisat A, Ruiz M, Goodman NC, Hanrahan SM, ... Vanbrocklin HF, Glover DK
Circ Cardiovasc Imaging: 15 Sep 2011; epub ahead of print | PMID: 21917783
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Abstract

Feasibility of Contrast Enhanced and Non-Enhanced MRI for Intra- and Postprocedural Lesion Visualization in Interventional Electrophysiology: Animal Studies and Early Delineation of Isthmus Ablation Lesions in Patients with Typical Atrial Flutter.

Nordbeck P, Hiller KH, Fidler F, Warmuth M, ... Bauer WR, Ritter O
Background: -Imaging of myocardial ablation lesions during electrophysiology (EP) procedures would enable superior guidance of interventions and immediate identification of potential complications. The aim of this study was to establish clinically suitable MRI-based imaging techniques for intraprocedural lesion visualization in interventional EP. Methods and results: -Interventional EP was performed under MR guidance in an animal model, using a custom setup including MR-conditional catheters. Various pulse sequences were explored for intraprocedural lesion visualization after RF ablation. The developed visualization techniques were then used to investigate lesion formation in patients immediately after ablation of atrial flutter. The animal studies in 9 mini pigs showed that Gadolinium-DTPA-enhanced T1-weighted and non-enhanced T2-weighted pulse sequences are particularly suitable for lesion visualization immediately after RF ablation. MRI-derived lesion size correlated well with autopsy (R(2)=0.799/0.709 for contrast enhanced/non-enhanced imaging). Non-contrast agent-enhanced techniques were suitable for repetitive lesion visualization during EP interventions, thus allowing for intraprocedural monitoring of ablation success. The patient studies in 24 patients with typical atrial flutter several minutes to hours after cavo-tricuspid isthmus ablation confirmed the results from the animal experiments. Therapeutic lesions could be visualized in all patients using contrast enhanced and also non-enhanced MRI with high contrast-to-noise ratio (94.6±35.2/111.1±32.6 vs. 48.0±29.0/68.0±37.3 for ventricular/atrial lesions and contrast enhanced vs. non-enhanced imaging). Conclusions: -MRI allows for precise lesion visualization in EP interventions just minutes after RF ablation. Non-enhanced T2-weighted MRI is particularly feasible for intraprocedural delineation of lesion formation as lesions are detectable within minutes after RF delivery and imaging can be repeated during interventions.

Circ Cardiovasc Imaging: 18 Mar 2011; epub ahead of print
Nordbeck P, Hiller KH, Fidler F, Warmuth M, ... Bauer WR, Ritter O
Circ Cardiovasc Imaging: 18 Mar 2011; epub ahead of print | PMID: 21415125
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Abstract

Early Impairment of Transmural Principal Strains in the Left Ventricle Wall Following Short-Term, High Fat Feeding of Mice Predisposed to Cardiac Steatosis.

Hankiewicz JH, Banke NH, Farjah M, Lewandowski ED
Background: -Myocardial lipid accumulation precedes some cardiomyopathies, but little is known of concurrent effects on ventricular mechanics. We tested the hypothesis that intramyocardial lipid accumulation, during short term high fat diet (HFD), affects 2-D strains in the heart. We examined hearts of nontransgenic (NTG) mice and transgenic mice predisposed to elevated triacylglyceride (TAG) storage linked to low-level overexpression of PPARα. Methods and results: -Myocardial lipid and transmural, principal strains E1 and E2 were determined in vivo with (1)H MRS/MRI before and after 2 weeks of HFD in both PPARα and NTG littermate mice. Baseline lipid was elevated in PPARα over NTG. HFD increased mobile lipid by 174% in NTG (P<0.05) and 79% in PPARα (P<0.05). After HFD, lipid and TAG were higher in PPARα versus NTG, by 63% and 81%, respectively. However, TAG in PPARα after HFD was similar to TAG in PPARα on regular diet, suggesting that the MRS signal from lipid is not exclusive to TAG. Only at the highest lipid contents, achieved in PPARα, were strains affected. Endocardial strain was most compromised, with a negative correlation to lipid (P<0.05), Conclusions: -Short term high fat diet elevated myocardial lipid measures via MRS which became dissociated from TAG content in hearts predisposed to cardiac steatosis. The increased lipid was associated with concurrent, transmural reductions in E1 and E2 strains across the LV wall. Strains were attenuated at the highest levels of lipid accumulation suggesting a threshold response. Thus, 2-D strains are impaired early and without LV diastolic dysfunction due to cardiac steatosis.

Circ Cardiovasc Imaging: 14 Sep 2010; epub ahead of print
Hankiewicz JH, Banke NH, Farjah M, Lewandowski ED
Circ Cardiovasc Imaging: 14 Sep 2010; epub ahead of print | PMID: 20837747
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Abstract

Quantification of Ventricular Resynchronization Reserve by Radionuclide Phase Analysis in Heart Failure Patients: A Prospective Long-Term Study.

Dauphin R, Nonin E, Bontemps L, Vincent M, ... Itti R, Chevalier P
Background: -Phase analysis, developed to assess dyssynchrony from electrocardiography-gated radionuclide ventriculography, has shown promising results. We hypothesized that quantifying the cardiac resynchronization reserve, i.e. the extent of response to cardiac resynchronization therapy (CRT), by radionuclide imaging could potentially identify patients who are best suited for CRT. Methods and results: -Seventy-four patients aged 64.8 ± 10.1 were prospectively studied from July 2004 to July 2006, of whom 62.2% and 37.8% respectively were NYHA class 3 and 4. Mean QRS width was 173 ± 25 ms. ECG-gated radionuclide ventriculography to quantify inter- and intraventricular dyssynchrony was performed at baseline with and without CRT and at the 3-month follow-up visit. NT-pro-BNP levels were also determined at baseline and at 3 months. During a mean follow-up of 10.1 ± 7.6 months, there were 37 (50%) clinical events that defined the nonresponder group, including cardiac death or readmission for worsening heart failure. In multivariate Cox-Model analysis, higher NT-pro-BNP blood levels were associated with a significant increase in the risk for event (Hazard Ratio (HR)=1.085 for a 100 pg/1 increase in NT-pro-BNP; 95% confidence interval: 1.014-1.161). Each 10° elevation in intraventricular dyssynchrony was associated with a decrease in the risk of events (HR=0.456, 95% CI: 0.304-0.683). Receiver operating characteristic (ROC) curve analysis demonstrated that an interventricular dyssynchrony cut-off value of 25.5° for intraventricular synchrony yielded 91.4% sensitivity and 84.4% specificity for predicting a good response to CRT. Conclusions: -The quantification of interventricular dyssynchrony with radionuclide phase analysis suggests that early post-implantation interventricular dyssynchrony may provide identification of CRT responders.

Circ Cardiovasc Imaging: 17 Jan 2011; epub ahead of print
Dauphin R, Nonin E, Bontemps L, Vincent M, ... Itti R, Chevalier P
Circ Cardiovasc Imaging: 17 Jan 2011; epub ahead of print | PMID: 21239562
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Abstract

Influence of Pacing Site Characteristics on Response to Cardiac Resynchronization Therapy.

Wong JA, Yee R, Stirrat J, Scholl D, ... Drangova M, White JA
Background: -Transmural scar occupying left ventricular pacing regions has been associated with reduced response to cardiac resynchronization therapy (CRT). However, spatial influences of lead tip delivery relative to scar at both pacing sites remains poorly explored. This study evaluated scar distribution relative to left ventricular (LV) and right ventricular (RV) lead tip placement through co-registration of Late Gadolinium Enhancement (LGE) MRI and cardiac computed tomography (CT) findings. Influences on CRT response were assessed by serial echocardiography. Methods and results: -Sixty patients receiving CRT underwent pre-implant LGE-MRI, post-implant cardiac CT and serial echocardiography. Blinded segmental evaluations of mechanical delay, percent scar burden, and lead tip location were performed. Response to CRT was defined as a reduction in LVESV ≥15% at 6 months. The mean age and LVEF were 64±9 years and 25±7%, respectively. Mean scar volume was higher among CRT non-responders for both the LV [23±23 vs. 8±14% (p=0.01) and RV pacing regions [40±32 vs. 24±30% (p=0.04)]. Significant pacing region scar was identified in 13% of LV pacing regions and 37% of RV pacing regions. Absence of scar in both regions was associated with an 81% response rate, compared to 55%, 25% and 0%, respectively when the RV, LV or both pacing regions contained scar. LV pacing region dysynchrony was not predictive of response. Conclusions: -Myocardial scar occupying the LV pacing region is associated with non-response to CRT. Scar occupying the RV pacing region is encountered at higher frequency and appears to provide a more intermediate influence on CRT response.

Circ Cardiovasc Imaging: 06 Jun 2013; epub ahead of print
Wong JA, Yee R, Stirrat J, Scholl D, ... Drangova M, White JA
Circ Cardiovasc Imaging: 06 Jun 2013; epub ahead of print | PMID: 23741053
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Abstract

A Prospective Pilot Study to Evaluate the Relationship between Acute Change in LV Synchrony after Cardiac Resynchronization Therapy and Patient Outcome Using a Single-Injection Gated-SPECT Protocol.

Friehling M, Chen J, Saba S, Bazaz R, ... Follansbee W, Soman P
Background: -There are ongoing efforts to optimize patient selection criteria for cardiac resynchronization therapy (CRT). In this regard, the relationship between acute change in left ventricular synchrony (LV) after CRT and patient outcome remains undefined. Methods and results: -A novel protocol was designed to evaluate acute change in left LV synchrony after CRT using phase analysis of standard gated Single-Photon Emission Computed Tomography (SPECT) myocardial perfusion imaging with a single injection of radiotracer, and prospectively applied to 44 patients undergoing CRT. Immediately after CRT, 18 (41%), 11 (25%) and 15 (34%) patients had an improvement, no change or a worsening in LV synchrony. An algorithm incorporating the presence of baseline dyssynchrony, myocardial scar burden and lead concordance predicted acute improvement or no change in LV synchrony with 72% sensitivity, 93% specificity, 96% positive predictive value and 64% negative predictive value (NPV), and had 96% NPV for acute deterioration in synchrony. Over a follow up period of 9.6±6.8 months, patients who had an acute deterioration in synchrony after CRT had a higher composite event rate of death, heart failure hospitalizations, appropriate defibrillator discharges and CRT device deactivation for worsening heart failure symptoms, compared to patients who had an improvement or no change [Hazard ratio 4.6 (1.3-16.0), Log rank test p=0.003] Conclusions: -In this single center pilot study, phase analysis of gated SPECT was successfully used to predict acute change in LV synchrony and patient outcome after CRT.

Circ Cardiovasc Imaging: 20 Jul 2011; epub ahead of print
Friehling M, Chen J, Saba S, Bazaz R, ... Follansbee W, Soman P
Circ Cardiovasc Imaging: 20 Jul 2011; epub ahead of print | PMID: 21772007
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Abstract

Nanoparticle PET-CT Detects Rejection and Immunomodulation in Cardiac Allografts.

Ueno T, Dutta P, Keliher E, Leuschner F, ... Weissleder R, Nahrendorf M
Background: -Macrophages (MΦ) predominate among the inflammatory cells in rejecting allografts. These innate immune cells, in addition to allospecific T cells, can damage cardiomyocytes directly. Methods and results: -We explored if sensitive PET/CT imaging of MΦ-avid nanoparticles detects rejection of heart allografts in mice. In addition, we employed the imaging method to follow the immunomodulatory impact of angiotensin converting enzyme inhibititor therapy (ACEi) on myeloid cells in allografts. Dextran nanoparticles were derivatized with the PET isotope copper-64 and imaged seven days after transplantation. C57/BL6 recipients of BALB/c allografts displayed robust PET signal (standard uptake value allograft, 2.8±0.3; isograft control, 1.7±0.2; p<0.05). Autoradiography and scintillation counting confirmed the in vivo findings. We then imaged the effects of ACEi (5mg/kg Enalapril). ACEi significantly decreased nanoparticle signal (p<0.05). Histology and flow cytometry showed a reduced number of myeloid cells in the graft, blood and lymph nodes, as well as diminished antigen presentation (p<0.05 versus untreated allografts). ACEi also significantly prolonged allograft survival (12 versus 7 days, p<0.0001). Conclusions: -Nanoparticle MΦ PET-CT detects heart transplant rejection and predicts organ survival by reporting on myeloid cells.

Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print
Ueno T, Dutta P, Keliher E, Leuschner F, ... Weissleder R, Nahrendorf M
Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print | PMID: 23771986
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Abstract

X-ray Magnetic Resonance Fusion to Internal Markers and Utility in Congenital Heart Disease Catheterization.

Dori Y, Sarmiento M, Glatz AC, Gillespie MJ, ... Fogel MA, Rome JJ
Background: -X-ray magnetic resonance fusion (XMRF) allows for utilization of 3D data during cardiac catheterization. However, to date, technical requirements have limited the use of this modality in clinical practice. Here we report on a new internal marker XMRF method that we have developed and describe how we used XMRF during cardiac catheterization in congenital heart disease. Methods and results: -XMRF was performed in a phantom and in 23 patients presenting for cardiac catheterization who also needed cardiac MRI for clinical reasons. The registration process was performed in less than 5 minutes per patient with minimal radiation (0.004 - 0.024 mSv) and without contrast. Registration error was calculated in a phantom and in 8 patients using the maximum distance between angiographic and 3D model boundaries. In the phantom the measured error in the AP projection had a mean of 1.15 mm (standard deviation 0.73). The measured error in patients had a median of 2.15 mm (IQR 1.65 - 2.56 mm). Internal markers included bones, airway, image artifact, calcifications, and the heart and vessel borders. The MRI data was used for road mapping in 17/23 (74%) cases and camera angle selection in 11/23 (48%) cases. Conclusions: -Internal markers based registration can be performed quickly, with minimal radiation, without the need for contrast, and with clinically acceptable accuracy using commercially available software. We have also demonstrated several potential uses for XMRF in routine clinical practice. This modality has the potential to reduce radiation exposure and improve catheterization outcomes.

Circ Cardiovasc Imaging: 03 May 2011; epub ahead of print
Dori Y, Sarmiento M, Glatz AC, Gillespie MJ, ... Fogel MA, Rome JJ
Circ Cardiovasc Imaging: 03 May 2011; epub ahead of print | PMID: 21536785
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Abstract

Echocardiography can Identify Patients with Increased Pulmonary Vascular Resistance by Assessing Pressure Reflection in the Pulmonary Circulation.

Bech-Hanssen O, Lindgren F, Selimovic N, Rundqvist B
Background: -Pulmonary hypertension is a frequent finding in patients with cardio-pulmonary disorders. It is important to recognize pulmonary hypertension due to increased pulmonary vascular resistance (PVR), as this affects treatment and prognosis. Patients with increased PVR have increased pulmonary pressure reflection. We hypothesized that pressure reflection can be described using echocardiography and that variables related to pressure reflection can identify patients with increased PVR. Methods and results: -The study comprised 98 patients investigated within 24 hours of right heart catheterization and 20 control subjects. The pressure reflection variables were obtained using pulsed Doppler in the pulmonary artery and continuous Doppler of the tricuspid regurgitation. We selected three variables related to pressure reflection: the interval from valve opening to peak velocity in the pulmonary artery (AcT, ms), the interval between pulmonary artery peak velocity and peak tricuspid velocity (tPV-PP, ms) and the right ventricular pressure increase after peak velocity in the pulmonary artery (augmented pressure, AP, mmHg). The correlation between simultaneous catheter- and echocardiography-determined AP was strong (n=19, R=0.83). The AcT/tPV-PP/AP in patients with a PVR of > 3 WU (n=71) was (mean+/-SD) 77 +/- 16/119 +/- 36/22 +/- 12 and differed from patients with a PVR </= of 3 WU (n=27, p<0.0001) 111 +/- 32/39 +/- 54/3 +/- 4 and controls 153 +/- 32/-19 +/- 45/0 (p<0.0001). The AcT/tPV-PP/AP did not correlate with capillary wedge pressure (R 0.08-0.16). The areas under the receiver operator characteristic curve (95% CI) for AcT/tPV-PP/AP were 0.87 (0.82-0.95)/0.94 (0.89-0.99)/0.98 (0.95-1.0). Conclusions: -In this study, we describe a novel echocardiography method assessing pressure reflection in the pulmonary circulation. This method can be used to identify patients with pulmonary hypertension due to increased PVR.

Circ Cardiovasc Imaging: 07 May 2010; epub ahead of print
Bech-Hanssen O, Lindgren F, Selimovic N, Rundqvist B
Circ Cardiovasc Imaging: 07 May 2010; epub ahead of print | PMID: 20448141
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Abstract

Echocardiographic Features Defining Right Dominant Unbalanced Atrioventricular Septal Defect: A Multi-institutional Congenital Heart Surgeons\' Society Study.

Cohen MS, Jegatheeswaran A, Baffa JM, Gremmels DB, ... McCrindle BW, Mertens L
Background: -Definition and management of right dominant unbalanced atrioventricular septal defect (AVSD) remains challenging, since unbalance entails a spectrum of left heart hypoplasia. Previous work has highlighted atrioventricular valve (AVV) index as a reasonable defining echocardiographic measure. We sought to assess which additional echocardiographic features might provide further characterization. Methods and results: -From a multiinstitutional cohort of complete AVSD, 52 pre-operative echocardiograms of patients with presumed right dominant unbalanced AVSD (based on AVV index) and 60 randomly selected pre-operative echocardiograms from patients with presumed balanced AVSD were reviewed. Cluster analysis of echocardiographic variables was used to group patients with similar features. Discriminant function analysis was used to explore which variables differentiated these groups. Three groups were identified from the cluster analysis. Echocardiographic variables that differentiated these groups were right ventricle:left ventricle inflow angle (RV/LV inflow angle), LV width/LV length, left AVV color diameter at smallest inflow, left AVV color diameter at annulus, right AVV overriding left atrium, and LV width. Based on procedures and outcomes, one group likely represented balanced patients, while two groups with similar outcomes likely represented unbalanced patients. The dominant differentiating echocardiographic variable between the 3 cluster groups was the RV/LV inflow angle (partial R(2)=0.86), defined as the angle between the base of the RV and LV free wall, using the crest of the ventricular septum as apex of the angle. Conclusions: -The angle of RV/LV inflow and other surrogates of inflow may be important defining echocardiographic measures of right dominant unbalanced AVSD, although confirmation is needed.

Circ Cardiovasc Imaging: 19 Jun 2013; epub ahead of print
Cohen MS, Jegatheeswaran A, Baffa JM, Gremmels DB, ... McCrindle BW, Mertens L
Circ Cardiovasc Imaging: 19 Jun 2013; epub ahead of print | PMID: 23784944
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Abstract

Non-Culprit Coronary Plaque Characteristics of Chronic Kidney Disease.

Kato K, Yonetsu T, Jia H, Abtahian F, ... Yu B, Jang IK
Background: -Chronic kidney disease (CKD) promotes the development of atherosclerosis and increases the risk of cardiovascular disease. The aim of the present study was to compare the coronary plaque characteristics of patients with and without CKD using optical coherence tomography (OCT). Methods and results: -We identified 463 non-culprit plaques from 287 patients from the MGH OCT Registry. CKD was defined as estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m(2). 402 plaques (250 patients) were in the non-CKD group and 61 plaques (37 patients) were in the CKD group. Compared to non-CKD plaques, plaques with CKD had a larger lipid index (mean lipid arc × lipid length, 1248.4±782.8 mm° [non-CKD] vs. 1716.1±1116.2 mm° [CKD], p = 0.003). Fibrous cap thickness was not significantly different between the groups. Calcification (34.8% [non-CKD] vs. 50.8% [CKD], p = 0.041), cholesterol crystals (11.2% [non-CKD] vs. 23.0% [CKD], p = 0.048), and plaque disruption (5.5% [non-CKD] vs. 13.1% [CKD], p = 0.049) were more frequently observed in the CKD group. In the multivariate linear regression model, a lower eGFR, and diabetes mellitus (DM) were independent risk factors for a larger lipid index. Conclusions: -Compared to non-CKD patients, the patients with CKD had a larger lipid index with a higher prevalence of calcium, cholesterol crystals and plaque disruption. The multivariate linear regression model demonstrated that a lower eGFR was an independent risk factor for a larger lipid index. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538.

Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print
Kato K, Yonetsu T, Jia H, Abtahian F, ... Yu B, Jang IK
Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print | PMID: 23536265
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Abstract

Relationship between Regional Myocardial Oxygenation and Perfusion in Patients with Coronary Artery Disease: Insights from Cardiovascular Magnetic Resonance and Positron Emission Tomography.

Karamitsos TD, Leccisotti L, Arnold JR, Recio-Mayoral A, ... Neubauer S, Selvanayagam JB
Background: -It is recognized that the interplay between myocardial ischemia, perfusion, and oxygenation in the setting of coronary artery disease (CAD) is complex and that myocardial oxygenation and perfusion may become dissociated. Blood oxygen level-dependent (BOLD) cardiovascular magnetic resonance (CMR) has the potential to non-invasively measure myocardial oxygenation, while positron emission tomography (PET) with oxygen-15 labeled water is the gold standard technique for myocardial blood flow (MBF) quantification. Thus, we sought to apply BOLD CMR at 3 Tesla and oxygen-15 labeled water PET in CAD patients and normal volunteers to better understand the relationship between regional myocardial oxygenation and blood flow during vasodilator stress. Methods and results: -Twenty-two patients (age 62+/-8 yrs, 16 men) with CAD (at least 1 stenosis >/=50% on quantitative coronary angiography-QCA) and 10 normal volunteers (age 58+/-6 yrs, 6 men) underwent 3T BOLD CMR and PET. For BOLD CMR 4-6 mid-ventricular short-axis images were acquired at rest and during adenosine stress (140 mug/kg/min). Using PET with oxygen-15 labeled water, MBF was measured at baseline and during adenosine in the same slices. BOLD images were divided into 6 segments and mean signal intensities (SI) calculated. Taking >/=50% stenosis on QCA as the gold standard, cut-off values for stress MBF (< 2.45ml/min/g - AUC 0.83) and BOLD SI change (< 3.74% - AUC 0.78) were determined to define ischemic segments. BOLD CMR and PET agreed on the presence or absence of ischemia in 18 of the 22 patients (82%), and in all normals. On a per segment analysis, 40% of myocardial segments with stress MBF below the cut-off of 2.45ml/min/g did not show deoxygenation, whereas 88% of segments with normal perfusion also had normal oxygenation measurements. Conclusions: -Regional myocardial perfusion and oxygenation may be dissociated, indicating that in patients with CAD reduced perfusion does not always lead to deoxygenation.

Circ Cardiovasc Imaging: 18 Nov 2009; epub ahead of print
Karamitsos TD, Leccisotti L, Arnold JR, Recio-Mayoral A, ... Neubauer S, Selvanayagam JB
Circ Cardiovasc Imaging: 18 Nov 2009; epub ahead of print | PMID: 19920032
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Abstract

Percutaneous Mitral Valve Repair in the Initial EVEREST Cohort: Evidence of Reverse Left Ventricular Remodeling.

Foster E, Kwan D, Feldman T, Weissman N, ... Lim S, Glower D
Background: -Percutaneous repair of MR permits examination of the effect of MR reduction without surgery and cardiopulmonary bypass on left ventricular (LV) dimensions and function. The goal of this analysis was to determine the extent of reverse remodeling at 12 months following successful percutaneous reduction of mitral regurgitation (MR) with the MitraClip device. Methods and results: -Of 64 patients with 3 and 4+ MR who achieved acute procedural success after treatment with the MitraClip device, 49 patients had moderate or less MR at 12 month follow-up. Their baseline and 12 month echocardiograms were compared between the group with and without LV dysfunction. In patients with persistent MR reduction and pre-existing LV dysfunction, there was a reduction in LV wall stress, reduced LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and increase in LV ejection fraction (LVEF) in contrast to those with normal baseline LV function, who showed reduction in LVEDV, LV wall stress, no change in LVESV and a fall in LVEF. Conclusions: -Patients with pre-existing LV dysfunction demonstrate reverse remodeling and improved LVEF after percutaneous mitral valve repair. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00209339, NCT00209274.

Circ Cardiovasc Imaging: 30 Apr 2013; epub ahead of print
Foster E, Kwan D, Feldman T, Weissman N, ... Lim S, Glower D
Circ Cardiovasc Imaging: 30 Apr 2013; epub ahead of print | PMID: 23633132
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Abstract

Implications of Early Aortic Stiffening in Patients with Transposition of the Great Arteries after Arterial Switch Operation.

Voges I, Jerosch-Herold M, Hedderich J, Hart C, ... Kramer HH, Rickers C
Background: -The elastic function of the aorta in patients with transposition of the great arteries (TGA) after arterial switch operation (ASO) is suspected to be important for long-term prognosis. Methods and results: -Fifty-one patients and 34 controls were studied at 3.0 Tesla with magnetic resonance imaging. Forty-three patients (12.8±6.9 years) underwent one-stage ASO, 8 patients (23.8±6.9 years) had prior pulmonary artery banding (two-stage ASO). Aortic dimensions, distensibility, pulse wave velocity (PWV), aortic arch angle, left ventricular (LV) mass, LV systolic function and left atrial (LA) volumes, and LA passive emptying function (LAEF(Passive)) as marker of LV diastolic function were assessed. Compared to controls, patients had increased aortic root areas (602.6±240.5 vs. 356.8±113.4 mm(2)/m, p<0.01) and reduced distensibility of the thoracic aorta most pronounced at the aortic root (3.2±2.0 vs. 9.1±4.7 10(-3) mmHg(-1), p<0.01). Aortic distensibility correlated negatively with the aortic areas (p<0.01). PWV was higher in adults after ASO (5.0±1.0 vs. 3.8±1.3 m/s, p<0.01). In contrast to controls PWV and distensibility correlated with age in patients (p=0.04-<0.01). LV mass was higher in patients (p=0.02). LA volumes correlated negatively with aortic root and ascending aortic distensibility and positively with PWV (p<0.05). In patients LAEF(Passive) was lower (27.3±8.9 vs. 41.1±6.0, p<0.01) and correlated with aortic root distensibility (p=0.004). Conclusions: -Reduced aortic bioelasticity and aortic root dilatation are present in TGA patients post ASO and are likely to contribute to LV diastolic dysfunction. Impaired aortic bioelasticity was strongly associated with age suggesting the usefulness of follow-up studies for early onset of degenerative cardiovascular disease.

Circ Cardiovasc Imaging: 30 Jan 2013; epub ahead of print
Voges I, Jerosch-Herold M, Hedderich J, Hart C, ... Kramer HH, Rickers C
Circ Cardiovasc Imaging: 30 Jan 2013; epub ahead of print | PMID: 23363578
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Abstract

Radial Strain Delay Based on Segmental Timing and Strain Amplitude Predicts Left Ventricular Reverse Remodeling and Survival following Cardiac Resynchronization Therapy.

Kydd AC, Khan FZ, O\'Halloran D, Pugh PJ, Virdee MS, Dutka DP
Background: -Dyssynchrony assessment based on the timing of regional contraction is inherently independent of underlying myocardial contractility. We tested the hypothesis that patient selection for cardiac resynchronization therapy (CRT) would be enhanced using a parameter derived from the net radial strain delay for the 12 basal and mid left ventricular (LV) segments (RSD(c)), based not only on timing but also amplitude of segmental strain. Method and Results-Echocardiographic data was analysed in 240 patients with symptomatic heart failure undergoing CRT (NYHA class III/IV, QRS>120ms, ejection fraction 23±7%). RSD(c) was calculated as the sum of difference between peak radial strain and radial strain at aortic valve closure before CRT implantation. CRT response was defined as >15% reduction in LV end-systolic volume (LVESV) at 6 months. In a derivation group (n=102) RSD(c) was higher in responders compared to non-responders (74±39 vs. 29±15%, p<0.001), and related to the change in LVESV (r=-0.53, p<0.001). RSD(c) >40% predicted remodeling (sensitivity 87%, specificity 88%). In the validation group (n=108) RSD(c) similarly predicted response (sensitivity 89%, specificity 84%). Survival at long-term follow up was greater in patients with RSD(c) >40 (p<0.0001). Conclusions: -RSD(c), based on both the timing and amplitude of segmental strain, has a strong predictive value for CRT remodeling response and long-term survival.

Circ Cardiovasc Imaging: 30 Jan 2013; epub ahead of print
Kydd AC, Khan FZ, O'Halloran D, Pugh PJ, Virdee MS, Dutka DP
Circ Cardiovasc Imaging: 30 Jan 2013; epub ahead of print | PMID: 23363579
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Abstract

Aortic Dilation in Bicuspid Aortic Valve Disease: Flow Pattern Is a Major Contributor and Differs with Valve Fusion Type.

Bissell MM, Hess AT, Biasiolli L, Glaze SJ, ... Neubauer S, Myerson SG
Background: -Ascending aortic dilation is important in bicuspid aortic valve disease (BAV), with increased risk of aortic dissection. We used cardiovascular magnetic resonance (CMR) to understand the pathophysiology better by examining the links between 3-dimensional flow abnormalities, aortic function and aortic dilation. Methods and results: -142 subjects underwent CMR (mean age 40 years; 95 with BAV, 47 healthy volunteers [HV]). BAV patients had predominantly abnormal right-handed helical flow in the ascending aorta, larger ascending aortas (18.3 ±3.3 vs. 15.2±2.2mm/m(2), p<0.001), and higher rotational (helical) flow (31.7±15.8 vs. 2.9 ±3.9mm(2)/s, p<0.001), systolic flow angle (23.1±12.5 vs. 7.0±4.6°, p<0.001) and systolic wall shear stress (WSS) (0.85±0.28 vs. 0.59±0.17N/m(2), p<0.001) compared to HV. BAV with right-handed flow and right-non coronary cusp fusion (n= 31) showed more severe flow abnormalities (rotational flow 38.5±16.5 vs. 27.8±12.4mm(2)/s, p<0.001; systolic flow angle 29.4±10.9 vs. 19.4 ±11.4°, p<0.001; in-plane WSS 0.64 ±0.23 vs. 0.47 ±0.22N/m(2), p<0.001) and larger aortas (19.5±3.4 vs. 17.5±3.1mm/m(2), p<0.05) than right-left cusp fusion (n=55). BAV patients with normal flow patterns had similar aortic dimensions and WSS to HV and younger BAV patients showed abnormal flow patterns but no aortic dilation, both further supporting the importance of flow pattern in the etiology of aortic dilation. Aortic function measures (distensibility, aortic strain and pulse wave velocity) were similar across all groups. Conclusions: -Flow abnormalities may be a major contributor to aortic dilation in BAV. Fusion type affects the severity of flow abnormalities, and may allow better risk prediction and selection of patients for earlier surgical intervention.

Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print
Bissell MM, Hess AT, Biasiolli L, Glaze SJ, ... Neubauer S, Myerson SG
Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print | PMID: 23771987
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Abstract

Validation of 3-Dimensional Echocardiographic Assessment of Left Ventricular Volumes, Mass, and Ejection Fraction in Neonates and Infants with Congenital Heart Disease: A Comparison Study with Cardiac Magnetic Resonance Imaging.

Friedberg MK, Su X, Tworetzky W, Soriano BD, Powell AJ, Marx GR
Background: -Quantitative assessment and validation of left ventricular (LV) volumes and mass in neonates and infants with complex congenital heart disease (CHD) is important for clinical management, but has not been undertaken. We compared 3-dimensional echocardiography (3-D echo) measurements of volumes, mass, and ejection fraction with those measured by cardiac magnetic resonance imaging (MRI) in young patients with CHD and small LVs either due to young age and/ or LV hypoplasia. Methods and results: -Thirty-five patients aged < 4 years (median 0.8 years) undergoing MRI were prospectively enrolled. 3-D echo was acquired immediately after MRI and volume, mass, and ejection fraction measurements, using summation of discs methodology, compared with MRI. 3-D echo end-diastolic volume (24.4 ± 15.7 vs 24.8 ± 46.4 ml, p=0.01; ICC 0.96), and end systolic volume (12.3 ± 8.6 vs 9.6 ± 6.8, p<0.001; ICC 0.90) correlated with MRI with small mean differences (-0.49 ml, p=0.6 and 2.7 ml, p=0.001 respectively). 3-D echo ejection fraction was smaller than MRI by 9.3% (p<0.001). 3-D echo LV mass measurements were comparable to MRI (17.3 ± 10.3 vs 17.6 ± 12 g, p< 0.77; ICC 0.93), with small mean difference (1.1 g, p=0.28). There was good intra and inter-observer reliability for all measurements. Conclusions: -In neonates and infants with CHD and small LVs (age appropriate or hypoplastic), matrix-array 3-D echo measurements of mass and volumes compare well with MRI, providing an important modality for ventricular size and performance analysis in these patients, particularly in those with left heart obstructive lesions.

Circ Cardiovasc Imaging: 21 Sep 2010; epub ahead of print
Friedberg MK, Su X, Tworetzky W, Soriano BD, Powell AJ, Marx GR
Circ Cardiovasc Imaging: 21 Sep 2010; epub ahead of print | PMID: 20855861
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Abstract

Fluorescence Tomography of Rapamycin-Induced Autophagy and Cardioprotection In Vivo.

Chen HH, Mekkaoui C, Cho H, Ngoy S, ... Josephson L, Sosnovik DE
Background: -Autophagy is a biological process during which cells digest organelles in their cytoplasm and recycle the constituents. The impact of autophagy in the heart, however, remains unclear in part due to the inability to noninvasively image this process in living animals. Methods and results: -Here, we report the use of fluorescence molecular tomography (FMT) and a cathepsin activatable fluorochrome to image autophagy in the heart in vivo following ischemia-reperfusion and rapamycin therapy. We show that cathepsin-B activity in the lysosome is upregulated by rapamycin and that this allows the expanded lysosomal compartment in autophagy to be imaged in vivo with FMT. We further demonstrate that the delivery of diagnostic nanoparticles to the lysosome by endocytosis is enhanced during autophagy. The upregulation of autophagy by rapamycin was associated with a 23% reduction (p<0.05) of apoptosis in the area-at-risk (AAR), and a 45% reduction in final infarct size (19.6 ± 5.6% of AAR with rapamycin versus 35.9 ± 9.1% of AAR without rapamycin, p<0.05). Conclusions: -The ability to perform noninvasive tomographic imaging of autophagy in the heart has the potential to provide valuable insights into the pathophysiology of autophagy, particularly its role in cardiomyocyte salvage. While additional data are needed, our study supports the investigation of rapamycin therapy in patients with acute coronary syndromes.

Circ Cardiovasc Imaging: 28 Mar 2013; epub ahead of print
Chen HH, Mekkaoui C, Cho H, Ngoy S, ... Josephson L, Sosnovik DE
Circ Cardiovasc Imaging: 28 Mar 2013; epub ahead of print | PMID: 23537953
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Abstract

Comprehensive Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular Volume.

Miller CA, Naish J, Bishop P, Coutts G, ... Parker GJ, Schmitt M
Background: -Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T1-mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV), however the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of; A, dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T1 values measured before and after gadolinium bolus; and B, isolated measurement of myocardial T1, used as an ECV surrogate. Methods and results: -Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction (CVF), obtained from each of 16-segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR prior to transplantation (median interval between CMR and transplantation 29 days). DynEq-CMR-derived ECV was calculated from T1 measurements made using a modified look locker inversion recovery sequence before and 10- and 15-minutes post-contrast. In addition, ECV was measured 2-20 minutes post-contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR-derived ECV and histological CVF (p<0.001; within-subject r=0.745, p<0.001; r(2)=0.555; between-subject r=0.945, p<0.01, r(2)=0.893; for ECV calculated using 15-minute post-contrast T1). Correlation was maintained throughout the entire heart. Isolated post-contrast T1 measurement showed significant within-subject correlation with histological CVF (r=-0.741, p<0.001; r(2)=0.550 for 15 minute post-contrast T1), but between-subject correlations were not significant. DynEq-CMR-derived ECV varied significantly according to contrast dose, myocardial region and gender. Conclusions: -DynEq-CMR-derived ECV shows a good correlation with histological CVF throughout the whole heart. Isolated post-contrast T1 measurement is insufficient for ECV assessment.

Circ Cardiovasc Imaging: 03 Apr 2013; epub ahead of print
Miller CA, Naish J, Bishop P, Coutts G, ... Parker GJ, Schmitt M
Circ Cardiovasc Imaging: 03 Apr 2013; epub ahead of print | PMID: 23553570
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Abstract

99mTc-Pyrophosphate Scintigraphy for Differentiating Light-Chain Cardiac Amyloidosis from the Transthyretin-related Familial and Senile Cardiac Amyloidoses.

Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS
Background: -Differentiating immunoglobulin light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of (99m)Tc-pyrophosphate scintigraphy ((99m)Tc-PYP) in AL vs. TTR-related cardiac amyloidoses. Methods and results: -45 subjects (12 AL, 16 ATTR wild-type, and 17 ATTR mutants) underwent (99m)Tc-PYP planar and single-photon positive emission computed tomography (SPECT) cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects\' cohort assignment. Cardiac retention was assessed with both a semi-quantitative visual score (range 0, no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest (ROI) over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio (H/CL). Subjects with ATTR cardiac amyloid had a significantly higher semi-quantitative cardiac visual score than the AL cohort (2.9±0.06 vs. 0.8±0.27, p<0.0001) as well as a higher quantitative score (1.80±0.04 vs.1.21±0.04, p<0.0001). Using a H/CL ratio ≥1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, p<0.0001 for identifying ATTR cardiac amyloidosis. Conclusions: -(99m)Tc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis which should be studied in a larger prospective manner.

Circ Cardiovasc Imaging: 11 Feb 2013; epub ahead of print
Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS
Circ Cardiovasc Imaging: 11 Feb 2013; epub ahead of print | PMID: 23400849
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Abstract

Quantitative Assessment of Mitral Regurgitation: Comparison Between Three-dimensional Transesophageal Echocardiography and Magnetic Resonance Imaging.

Shanks M, Siebelink HM, Delgado V, van de Veire NR, ... de Roos A, Bax JJ
Background: -Quantification of mitral regurgitation severity with 2-dimensional (2D) imaging techniques remains challenging. The present study compared the accuracy of 2D transesophageal echocardiography (TEE) and 3-dimensional (3D) TEE for quantification of mitral regurgitation, using magnetic resonance imaging (MRI) as reference method. Methods and results: -2D and 3D TEE and cardiac MRI were performed in 30 patients with mitral regurgitation. Mitral effective regurgitant orifice area (EROA) and regurgitant volume (Rvol) were estimated with 2D and 3D TEE. With 3D TEE, EROA was calculated using planimetry of the color Doppler flow from "en face" views and Rvol was derived by multiplying the EROA by the velocity time integral of the regurgitant jet. Finally, using MRI mitral Rvol was quantified by subtracting the aortic flow volume from left ventricular stroke volume. Compared to 3D TEE, 2D TEE underestimated the EROA by a mean of 0.13 cm(2). In addition, 2D TEE underestimated the Rvol by 21.6% when compared to 3D TEE and by 21.3% when compared to MRI. In contrast, 3D TEE underestimated the Rvol by only 1.2% when compared to MRI. Finally, one third of the patients in grade 1 and >/=50% of the patients in grade 2 and 3, as assessed with 2D TEE, would have been upgraded to a more severe grade based on the 3D TEE and MRI measurements. Conclusions: -Quantification of mitral EROA and Rvol with 3D TEE is feasible and accurate as compared to MRI and results in less underestimation of the Rvol as compared to 2D TEE.

Circ Cardiovasc Imaging: 02 Sep 2010; epub ahead of print
Shanks M, Siebelink HM, Delgado V, van de Veire NR, ... de Roos A, Bax JJ
Circ Cardiovasc Imaging: 02 Sep 2010; epub ahead of print | PMID: 20810848
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Abstract

Coronary Artery Dimensions in Febrile Children without Kawasaki Disease.

Muniz JC, Dummer K, Gauvreau K, Colan SD, Fulton DR, Newburger JW
Background: -Coronary artery (CA) dilatation on echocardiography is a criterion for treatment with intravenous immunoglobulin for incomplete Kawasaki disease (KD). However, CA dimensions for febrile children are unknown. We compared CA dimensions in children with febrile illnesses other than KD to those of normal afebrile children and to KD patients. Methods and results: -We performed echocardiograms in 43 patients who met the following inclusion criteria: (1) age 3 months to 18 years, (2) daily fever >38 °C for ≥96 hours, and (3) a diagnosis other than KD. These subjects had mean CA z-scores greater than normative values (LMCA=0.66±0.75, P<0.001; RCA=0.28±0.81, P=0.03; LAD=0.35±1.0, P=0.03). Maximum CA z-score (zMax) >2 was found in 2 subjects (osteomyelitis, Mycoplasma pneumonia). Among demographic and laboratory measures, only higher platelet count was associated with greater LAD z-scores (P=0.004) and zMax (P=0.03). Non-KD febrile subjects, compared to 144 KD patients, had smaller CA z-scores (P=0.04, P<0.001, and P<0.001 for LMCA, RCA, and LAD, respectively), and lower white blood cell count, erythrocyte sedimentation rate, and platelet count (all P<0.001). A zMax cut-off of 2.0 had specificity of 95% (95%CI: 84%,99%) and sensitivity of 32% (95%CI: 25%,41%) in distinguishing non-KD febrile from KD patients; for zMax = 2.5, specificity was 98 and sensitivity was 20%. Conclusions: -This pilot study found that mean CA dimensions in children with non-KD febrile illnesses are larger than those in normative afebrile subjects but smaller than dimensions in patients with KD. Future studies should augment the available data on CA dimensions in children with more severe febrile illnesses.

Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print
Muniz JC, Dummer K, Gauvreau K, Colan SD, Fulton DR, Newburger JW
Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print | PMID: 23357243
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Abstract

Interpretation of Left Ventricular Diastolic Dysfunction in Children with Cardiomyopathy by Echocardiography: Problems and Limitations.

Dragulescu A, Mertens L, Friedberg MK
Background: -Left ventricular diastolic dysfunction(DD) is a key determinant of outcomes in pediatric cardiomyopathy(CM), but remains very challenging to diagnose and classify. Adult paradigms and guidelines relating to DD are currently applied in children. However, it is unknown whether these are applicable to children with CM. We investigated the assessment of DD in children with CM using adult and pediatric echocardiographic criteria and tested whether recent adult guidelines are applicable to this population. Methods and results: -Three investigators independently classified diastolic function in 4 study groups: controls; dilated(DCM), hypertrophic(HCM) and restrictive(RCM) cardiomyopathy. Agreement between investigators, failure to classify DD and the reasons for diagnostic failure were determined. The usefulness of individual echo parameters to diagnose and classify DD was assessed. 175 children (0-18yrs) were studied. DD diagnostic criteria were discrepant in the majority of patients. Delayed relaxation was diagnosed in only 14% of HCM patients and never in DCM and RCM, with 50% of those patients having co-existing findings of elevated filling pressures. Many key parameters, such as mitral and pulmonary venous Doppler were not informative. Agreement between investigators for grading of diastolic dysfunction was poor (36% of CM patients). Conclusions: -Assessment of DD in childhood cardiomyopathy seems inadequate using current guidelines. The large range of normal pediatric reference values allows diagnosis of diastolic dysfunction in only a small proportion of patients. Key echo parameters to assess DF are not sufficiently discriminatory in this population and discrepancies between criteria within individuals prevent further classification and result in poor inter-observer agreement.

Circ Cardiovasc Imaging: 23 Jan 2013; epub ahead of print
Dragulescu A, Mertens L, Friedberg MK
Circ Cardiovasc Imaging: 23 Jan 2013; epub ahead of print | PMID: 23343514
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Abstract

Intramyocardial Bone Marrow-Derived Mononuclear Cell Injection for Chronic Myocardial Ischemia: the Effect on Diastolic Function.

van Ramshorst J, Antoni ML, Beeres SL, Roes SD, ... Atsma DE, Bax JJ
Background: -The present substudy of a recently published randomized trial aimed to investigate the effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia. Methods and results: -In a total of 50 patients, diastolic function was evaluated before and 3 months after bone marrow cell injection using standard echocardiography and strain analysis. In addition, magnetic resonance imaging-derived transmitral flow measurements were obtained in a subset of 36 patients. Left ventricular ejection fraction increased from 50±5% to 54±7% in the bone marrow cell group, which was a significant improvement as compared to the placebo group (52±5% vs. 51±7%, P=0.001). Filling pressure estimate E/E\' ratio improved from 14±5 at baseline to 12±4 at 3 months in the bone marrow cell group, whereas no improvement was observed in the placebo group (13±4 vs. 13±5). The improvement in E/E\' ratio was significantly larger in the bone marrow cell group (P=0.008). Furthermore, the E/A peak flow ratio as assessed by MRI showed a significant increase in the bone marrow cell group as compared to the placebo group (+0.16±0.25 vs. -0.04±0.21, P=0.01), which was mainly related to an increase in the early (E) peak flow rate in the bone marrow cell group (from 407±96 mL/sec to 468±110 mL/sec, P=0.009 as compared to placebo group). Conclusions: -The current study demonstrates that intramyocardial bone marrow cell injection is associated with a beneficial effect on myocardial relaxation and filling pressures in patients with chronic myocardial ischemia. Clinical trial registration-URL: http://www.trialregister.nl. Unique identifier: NTR400/ISRCTN58194927.

Circ Cardiovasc Imaging: 06 Jan 2011; epub ahead of print
van Ramshorst J, Antoni ML, Beeres SL, Roes SD, ... Atsma DE, Bax JJ
Circ Cardiovasc Imaging: 06 Jan 2011; epub ahead of print | PMID: 21209073
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Abstract

Chronic Manifestation of Post-Reperfusion Intramyocardial Hemorrhage as Regional Iron Deposition: A Cardiovascular MR Study with Ex-vivo Validation.

Kali A, Kumar A, Cokic I, Tang RL, ... Friedrich MG, Dharmakumar R
Background: -Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the make-up and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored. Methods and results: -Patients (n = 15; 3 women), recruited after successful PCI for first ST-elevation myocardial infarction, underwent Cardiovascular Magnetic Resonance (CMR) imaging on day 3 and month 6 post-PCI. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* CMR on day 3 (n = 11), showed persistent T2* losses co-localized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than non-hemorrhagic (Hemo-) and remote territories (p<0.001); however, T2* values of non-hemorrhagic (Hemo-) and remote territories were not different (p=0.51. Canines (n = 20), subjected to ischemia-reperfusion (I/R) injury (n = 14), underwent CMR on days 3 and 56 post I/R injury. Similarly, sham-operated animals (Shams; n = 3) were imaged using CMR at similar time points. Subsequently, hearts were explanted, imaged ex-vivo, and samples of Hemo+, Hemo-, remote and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared to the other (control) groups (p<0.001), and Perl\'s stain confirmed localized iron deposition. Mean [Fe] of Hemo+ was nearly an order of magnitude greater than the control groups (p<0.001), but no significant differences were observed among the control groups. A strong linear relationship was observed between log(T2*) and -log([Fe]) (R(2)=0.7; p<0.001). The monoclonal antibody Mac387 stains, along with Perl\'s stains, showed preferential localization of newly recruited macrophages at the site of chronic iron deposition. Conclusions: -Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in chronic phase of myocardial infarction.

Circ Cardiovasc Imaging: 12 Feb 2013; epub ahead of print
Kali A, Kumar A, Cokic I, Tang RL, ... Friedrich MG, Dharmakumar R
Circ Cardiovasc Imaging: 12 Feb 2013; epub ahead of print | PMID: 23403335
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Abstract

Prognostic Significance of Exercise Induced Right Ventricular Dysfunction in Asymptomatic Degenerative Mitral Regurgitation.

Kusunose K, Popovic ZB, Motoki H, Marwick TH
Background: -The role of exercise-induced pulmonary hypertension (exPHT) in decision-making regarding surgical timing for asymptomatic chronic mitral regurgitation (MR) is controversial. We reasoned that the exPHT response could not be interpreted without knowledge of right ventricular (RV) function. The aim of this study was to assess the role of RV measures at rest and during exercise as predictors of prognosis in asymptomatic MR. Methods and results: -Comprehensive resting and exercise echocardiography was performed in 196 consecutive patients (56±13y; 64% male) with isolated moderate to severe MR (effective regurgitant orifice area 38±18 mm(2)) and preserved left ventricular (LV) function in whom initial management was expectant. LV and RV longitudinal strain were analyzed at rest using velocity vector imaging. Tricuspid annular plane systolic excursion (TAPSE) and systolic pulmonary arterial pressure (SPAP) were measured at rest and during exercise. Valve surgery was performed in 88 patients (45%) over 27±15 months. After adjustment for age and gender in a Cox proportional-hazards model, exercise TAPSE (HR=0.26, p<0.001), was associated with valve surgery-free survival, independent of resting LV strain (HR=1.09, p=0.027), exercise SPAP (HR=1.03, p<0.001) and resting RV strain (HR=1.10, p=0.004). In sequential Cox models, a model based on clinical data and LV strain (chi-square, 15.9) was improved by RV strain and RV chamber size (chi-square, 28.8, p=0.003) and exercise SPAP (chi-square, 40.1, p=0.002) and further increased by exercise TAPSE (chi-square, 52.2, p=0.002). Conclusions: -Exercise-induced RV dysfunction provides important incremental prognostic value in the management of asymptomatic MR.

Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print
Kusunose K, Popovic ZB, Motoki H, Marwick TH
Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print | PMID: 23357242
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Abstract

Usefulness of Exercise Test and Myocardial Perfusion Gated SPECT to Improve the Prediction of Major Events.

Candell-Riera J, Ferreira-González I, Marsal JR, Aguadé-Bruix S, ... Castell-Conesa J, García-Dorado D
Background: -The incremental prognostic value of myocardial perfusion gated-SPECT (MPGS) over exercise test has not yet been properly evaluated. Methods and results: -5,672 consecutive patients with known or suspected coronary disease undergoing exercise MPGS between 1,997 and 2,007 were included. Three years predictive models for total death and death from cardiovascular causes or acute myocardial infarction (i.e. major cardiovascular events (MCE)) were built employing Cox-regression modelling including only the clinical information. Then the exercise and MPGS information were sequentially added. The added discriminative ability of exercise test information and MPGS was assessed by the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI). The increase in predictive ability of exercise information for death and MCE was high as assessed by NRI (0.199 and 0.263) and by IDI (0.042 and 0.021). The only variable of MPGS associated with total death was ejection fraction (HR 0.84; 95% CI 0.79-0.89; p<0.001). Global stress ischemic score emerged as an additional variable associated with MCE (HR 1.07; 95% CI 1.02-1.12; p=0.007). Adding MPGS information barely improved the prognostic value for total death (NRI 0.017; IDI 0.013), but it increased for MCE (NRI 0.122; IDI 0.033). Conclusions: -Adding MPGS information to exercise information does not improve prediction of total death, although it allows a more accurate prediction of MCE.

Circ Cardiovasc Imaging: 13 Jun 2013; epub ahead of print
Candell-Riera J, Ferreira-González I, Marsal JR, Aguadé-Bruix S, ... Castell-Conesa J, García-Dorado D
Circ Cardiovasc Imaging: 13 Jun 2013; epub ahead of print | PMID: 23766340
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Abstract

T1 Measurements Identify Extracellular Volume Expansion in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy.

Ho CY, Abbasi SA, Neilan TG, Shah RV, ... Jerosch-Herold M, Kwong RY
Background: -Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations appear to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance (CMR) with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Methods and results: -Sarcomere mutation carriers with LVH (G+/LVH+, n = 37) and without LVH (G+/LVH-, n = 29); HCM patients without mutations (sarcomere-negative HCM, n = 11); and healthy controls (n = 11) underwent contrast CMR, measuring T1 times pre- and post-gadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared to controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV= 0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively, P≤0.001 for all comparisons). ECV correlated with NT-proBNP levels (r = 0.58, P<0.001) and global E\' velocity (r = -0.48, P<0.001). Late gadolinium enhancement (LGE) was present in >60% of overt HCM patients but absent from G+/LVH- subjects. Both ECV and LGE were more extensive in sarcomeric HCM than sarcomere-negative HCM. Conclusions: -Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

Circ Cardiovasc Imaging: 02 Apr 2013; epub ahead of print
Ho CY, Abbasi SA, Neilan TG, Shah RV, ... Jerosch-Herold M, Kwong RY
Circ Cardiovasc Imaging: 02 Apr 2013; epub ahead of print | PMID: 23549607
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Abstract

Integration of Three-Dimensional Imaging Data in the Assessment of Aortic Stenosis: Impact on Classification of Disease Severity.

O\'Brien B, Schoenhagen P, Kapadia SR, Svensson LG, ... Tuzcu EM, Desai MY
Background: -In patients with aortic stenosis (AS), precise assessment of severity is critical for treatment decisions. Estimation of aortic valve area (AVA) with transthoracic echocardiographic (TTE)-continuity equation (CE) assumes a circular left ventricular outflow tract (LVOT). We evaluated incremental utility of 3-dimensional multidetector computed tomography (MDCT) over TTE assessment of AS severity. Methods and results: -We included 51 patients (age 81 ± 8 years, 61% men, mean gradient 42 ± 12 mm Hg) with calcific AS that underwent evaluation for treatment options. TTE parameters included systolic LVOT diameter (D), continuous and pulsed wave (CW and PW) velocity time integrals (VTI) through LVOT and mean transaortic gradient. MDCT parameters included systolic LVOT area, ratio of maximal to minimal LVOT diameter ("eccentricity index"), and aortic planimetry (AVA(p)). TTE-CE AVA [(D(2) x 0.786 x VTIpw)/ VTIcw] and dimensionless index (DI) [VTIpw/ VTIcw] were calculated. "Corrected" AVA was calculated by substituting MDCT LVOT area into CE. Majority (96 %) of patients had eccentric LVOT. LVOT area, measured on MDCT was higher than on TTE (3.84 cm(2) ± 0.8 vs. 3.03 cm(2) ± 0.5, p < 0.01). TTE-AVA was smaller than AVA(p) and corrected AVA (0.67 ± 0.1, 0.82 ± 0.3 cm(2) and 0.86 ± 0.3 cm(2), p < 0.01). Using TTE measurements alone, 73% patients had congruence for severe AS (DI ≤ 0.25 and CE AVA < 0.8 cm(2)), which increased to 92 % using "corrected" CE. Conclusions: -In patients with suspected severe AS, incorporation of MDCT-LVOT area into CE improves congruence for AS severity.

Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print
O'Brien B, Schoenhagen P, Kapadia SR, Svensson LG, ... Tuzcu EM, Desai MY
Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print | PMID: 21737600
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Abstract

Cardiac-Selective Expression of EcSOD After Systemic Injection of AAV9 Protects the Heart Against Post-MI LV Remodeling.

Konkalmatt PR, Beyers RJ, O\'Connor DM, Xu Y, Seaman ME, French BA
Background: -Cardiac magnetic resonance (CMR) imaging has not previously been used to document the attenuation of LV remodeling after systemic gene delivery. We hypothesized that targeted expression of extracellular superoxide dismutase (EcSOD) via the cardiac Troponin-T (cTnT) promoter would protect the mouse heart against both myocardial infarction (MI) and subsequent LV remodeling. Methods and results: -Using reporter genes, we first compared the specificity, time course, magnitude and distribution of gene expression from AAV1, 2, 6, 8 and 9 following intravenous injection. The cTnT promoter restricted gene expression largely to the heart for all AAV serotypes tested. AAV1, 6, 8 and 9 provided early-onset gene expression that approached steady-state levels within 2 weeks. Gene expression was highest with AAV9, which required only 3.15x10(11) viral genomes/mouse to achieve an 84% transduction rate. AAV9 mediated, cardiac-selective gene expression elevated EcSOD enzyme activity in heart by 5.6-fold (p=0.015), which helped protect the heart against both acute MI and subsequent LV remodeling. In acute MI, infarct size in EcSOD-treated mice was reduced by 40% compared to controls (p=0.035). In addition, we found that cardiac-selective expression of EcSOD increased myocardial capillary fractional area and decreased neutrophil infiltration after MI. In a separate study of LV remodeling after a 60min coronary occlusion, CMR imaging revealed that LV volumes at days 7 and 28-post MI were significantly lower in the EcSOD group compared to controls. Conclusions: -Cardiac-selective expression of EcSOD from the cTnT promoter following systemic administration of AAV9 provides significant protection against both acute MI and LV remodeling.

Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print
Konkalmatt PR, Beyers RJ, O'Connor DM, Xu Y, Seaman ME, French BA
Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print | PMID: 23536266
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Abstract

Bright Blood T2 Weighted MRI Has Higher Diagnostic Accuracy Than Dark Blood STIR MRI for Detection of Acute Myocardial Infarction and for Assessment of the Ischemic Area-at-Risk and Myocardial Salvage.

Payne AR, Casey M, McClure J, McGeoch R, ... Tzemos N, Berry C
Background: -T(2)-weighted magnetic resonance imaging reveals myocardial edema and enables estimation of the ischemic area-at-risk and myocardial salvage in patients with acute myocardial infarction (MI). We compared the diagnostic accuracy of a new bright blood T(2)-weighted with a standard black blood T(2)-weighted MRI in patients with acute MI. Methods and results: -A breath hold bright blood T(2)-weighted ACUT(2)E pulse sequence with normalisation for coil sensitivity and a breath hold T(2) dark blood short tau inversion recovery (STIR) sequence were used to depict the area-at-risk in 54 consecutive acute MI patients. Infarct size was measured on gadolinium late contrast enhancement images. Compared with dark blood T(2)-weighted MRI, consensus agreements between independent observers for identification of myocardial edema were higher with bright blood T(2)-weighted MRI when evaluated per patient (p<0.001) and per segment of left ventricle (p<0.001). Compared to bright blood T(2)-weighted MRI, dark blood T(2)-weighted MRI under-estimated the area-at-risk compared to infarct size (p<0.001). The 95% limits of agreement for inter-observer agreements for the ischemic area-at-risk and myocardial salvage were wider with dark blood T(2)-weighted MRI than with bright blood T(2)-weighted MRI. Bright blood enabled more accurate identification of the culprit coronary artery with correct identification in 94% of cases compared to 61% for dark blood (p<0.001). Conclusions: -Bright blood T(2)-weighted MRI has higher diagnostic accuracy than dark blood T(2)-weighted MRI. Additionally, dark blood T(2)-weighted MRI may underestimate area-at-risk and myocardial salvage.

Circ Cardiovasc Imaging: 23 Mar 2011; epub ahead of print
Payne AR, Casey M, McClure J, McGeoch R, ... Tzemos N, Berry C
Circ Cardiovasc Imaging: 23 Mar 2011; epub ahead of print | PMID: 21427362
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Abstract

The Incremental Prognostic Value of Cardiac CT in CAD using CONFIRM (COroNary computed tomography angiography evaluation For clinical outcomes: an InteRnational Multicenter registry).

Chow BJ, Small G, Yam Y, Chen L, ... Villines TC, Min JK
Background: -Large multicenter studies validating the prognostic value of CCTA and LVEF are lacking. We sought to confirm the independent and incremental prognostic value of coronary artery disease (CAD) severity measured using 64-slice cardiac computed tomographic angiography (CCTA) over left ventricular ejection fraction (LVEF) and clinical variables. Methods and results: -A large international multicenter registry (CONFIRM Registry) was queried and CCTA patients with LVEF data on CCTA were screened. Patients with a history of myocardial infarction, coronary revascularization or cardiac transplantation were excluded. The NCEP/ATP III risk was calculated for each patient and CCTA was evaluated for CAD severity (normal, non-obstructive, non high-risk or high-risk CAD) and LVEF<50%. Patients were followed for an endpoint of all-cause mortality. 27,125 patients underwent CCTA at 12 participating centres with a total of 14,064 patients meeting the analysis criteria. Follow-up was available for 13,966 (99.3%) patients (mean follow-up of 22.5[95%CI: 22.3,22.7]months). All-cause mortality (271 deaths) occurred in 0.65% of patients without coronary atherosclerosis, 1.99% of patients with non-obstructive CAD, 2.90% of patients with non-high risk CAD, and 4.95% for patients with high risk CAD. Multivariable analysis confirmed that LVEF<50% (Hazard Ratio (HR): 2.74(2.12-3.51)) and CAD severity (HR:1.58;CI:1.42-1.76) were predictors of all-cause mortality and CAD severity had incremental value over LVEF and clinical variables. Conclusions: -Our results demonstrate that CCTA measures of CAD severity and LVEF have independent prognostic value. Incorporation of CAD severity provides incremental value for predicting all-cause death over routine clinical predictors and LVEF in patients with suspected obstructive CAD.

Circ Cardiovasc Imaging: 06 Jul 2011; epub ahead of print
Chow BJ, Small G, Yam Y, Chen L, ... Villines TC, Min JK
Circ Cardiovasc Imaging: 06 Jul 2011; epub ahead of print | PMID: 21730027
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Abstract

Left Ventricular Wall Thickness and the Presence of Asymmetric Hypertrophy in Healthy Young Army Recruits: Data from the LARGE Heart Study.

Lee PT, Dweck MR, Prasher S, Shah AS, ... Montgomery HE, Payne JR
Background: - To use cardiovascular magnetic resonance to investigate left ventricular (LV) wall thickness and the presence of asymmetric hypertrophy in young army recruits before and after a period of intense exercise training. Methods and results: - Using cardiovascular magnetic resonance the left ventricular wall thickness was measured in all 17-segments and a normal range calculated for each. The prevalence of asymmetric wall thickening was assessed before and after training and defined by a ventricular wall thickness ≥13.0 mm that was >1.5-times the thickness of the opposing myocardial segment. Five-hundred-and-forty-one males (mean age 20 ± 2) were recruited, 309 underwent repeat scanning. Considerable variation in wall thickness was observed across the ventricle with progressive thickening on moving from the apex to base (p<0.001) and in the basal and mid-cavity septum compared to the lateral wall (11.0 ± 1.4 mm vs. 10.1 ± 1.3 mm; p<0.001). Twenty-three percent had a maximal wall thickness ≥13.0mm, whilst the prevalence of asymmetric wall thickening increased from 2.2% to 10% following the exercise-training program. In those who developed asymmetry the wall thickness to diastolic volume ration remained normal (0.09 ± 0.02 mm x m(2) x ml(-1)) indicative of a remodelling response to exercise. Conclusions: - In a cohort of healthy young Caucasian males we have demonstrated that wall thickness frequently measures ≥13.0 mm and that asymmetric wall thickening is common and can develop as part of the physiological response to exercise. A diagnosis of hypertrophic cardiomyopathy in young athletic males should therefore not be made purely on the basis of regional wall thickening.

Circ Cardiovasc Imaging: 10 Jan 2013; epub ahead of print
Lee PT, Dweck MR, Prasher S, Shah AS, ... Montgomery HE, Payne JR
Circ Cardiovasc Imaging: 10 Jan 2013; epub ahead of print | PMID: 23307776
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Abstract

Free-Breathing, Motion-Corrected Late Gadolinium Enhancement Is Robust and Extends Risk Stratification to Vulnerable Patients.

Piehler KM, Wong TC, Puntil KS, Zareba KM, ... Kellman P, Schelbert EB
Background: -Routine clinical use of novel free-breathing, motion-corrected, averaged late gadolinium enhancement (moco-LGE) cardiovascular magnetic resonance may have advantages over conventional breath held LGE (bh-LGE) especially in vulnerable patients. Methods and results: -In 390 consecutive patients, we collected bh-LGE and moco-LGE with identical image matrix parameters. In 41 patients, bh-LGE was abandoned due to image quality issues, including 10 with myocardial infarction (MI). When both were acquired, MI detection was similar (McNemar test, p=0.4) with high agreement (kappa statistic 0.95). With artifact-free bh-LGE images, pixelwise MI measures correlated highly (R(2)=0.96) without bias. Moco-LGE was faster, and image quality and diagnostic confidence were higher on blinded review (p<0.001 for all). Over a median of 1.2 years, 20 heart failure hospitalizations and 18 deaths occurred. For bh-LGE, but not moco-LGE, inferior image quality and bh-LGE non acquisition were linked to patient vulnerability confirmed by adverse outcomes (logrank p<0.001). Moco-LGE significantly stratified risk on the full cohort (logrank p<0.001), but bh-LGE did not (logrank p=0.056) since a significant number of vulnerable patients did not receive bh-LGE (due to arrhythmia or inability to breath hold). Conclusions: -MI detection and quantification are similar between moco-LGE and bh-LGE when bh-LGE can be acquired well, but bh-LGE quality deteriorates with patient vulnerability. Acquisition time, image quality, diagnostic confidence and the number of successfully scanned patients are superior with moco-LGE which extends LGE-based risk stratification to include patients with vulnerability confirmed by outcomes. Moco-LGE may be suitable for routine clinical use.

Circ Cardiovasc Imaging: 18 Apr 2013; epub ahead of print
Piehler KM, Wong TC, Puntil KS, Zareba KM, ... Kellman P, Schelbert EB
Circ Cardiovasc Imaging: 18 Apr 2013; epub ahead of print | PMID: 23599309
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Abstract

The Prognostic Value of Normal Stress Cardiac Magnetic Resonance in Patients with Known or Suspected Coronary Artery Disease: A Meta-analysis.

Gargiulo P, Dellegrottaglie S, Bruzzese D, Savarese G, ... Trimarco B, Perrone Filardi P
Background: -Ischemia detection with stress cardiac magnetic resonance (CMR) is typically based on induction of myocardial perfusion defect (PD) and/or of wall motion abnormality (WMA). Single-center studies have shown the high value of stress-CMR for risk stratification. Aim of this study was to define the prognostic value of stress CMR for prediction of adverse cardiac events in patients with known or suspected coronary artery disease (CAD). Methods and results: -Studies published between January 1985 and April 2012 were identified by database search. A study was included if used stress CMR to evaluate subjects with known or suspected CAD and provided primary data on clinical outcomes of non-fatal myocardial infarction (MI) or cardiac death with a follow-up time ≥ 3 months. Total of 14 studies were finally included, recruiting 12178 patients. The negative predictive value for non-fatal MI and cardiac death of normal CMR was 98.12% (97.26-98.83%, 95% confidence interval [CI]) over a weighted mean follow-up of 25.3 months, resulting in estimate event rate after negative test (ERNT) equal to 1.88% (1.17 to 2.74%, 95% CI). The corresponding annualized ERNT was 1.03%. Comparable negative predictive values for major coronary events were obtained in studies considering the absence of inducible PD compared with those evaluating the absence of inducible WMA (98.39% vs. 97.31% respectively; p=0.227 by meta-regression analysis). Conclusions: -Stress CMR has a high negative predictive value for adverse cardiac events and the absence of inducible PD or WMA show a similar ability to identify low-risk patients with known or suspected CAD.

Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print
Gargiulo P, Dellegrottaglie S, Bruzzese D, Savarese G, ... Trimarco B, Perrone Filardi P
Circ Cardiovasc Imaging: 16 Jun 2013; epub ahead of print | PMID: 23771988
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Abstract

Prognostic Value of Cardiac Time Intervals by Tissue Doppler Imaging M-Mode in Patients with Acute ST Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention.

Biering-Sørensen T, Mogelvang R, Søgaard P, Pedersen SH, ... Jørgensen PG, Jensen JS
Background: -Color Tissue Doppler Imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to estimate all cardiac time intervals from one cardiac cycle and thereby obtaining the Myocardial Performance Index (MPI). However, the prognostic value of the cardiac time intervals and the MPI assessed by color TDI M-mode through the mitral leaflet in patients with ST-segment Elevation Myocardial Infarction (STEMI) is unknown. Methods and results: -In total 391 patients were admitted with a STEMI, treated with primary Percutaneous Coronary Intervention (pPCI) and were examined by echocardiography median 2 days after the STEMI. Outcome was assessed according to death (n=33), hospitalization with heart failure (CHF, n=53) or new myocardial infarction (re-MI, n=25). Follow-up time was median 25 months. The population was stratified according to tertiles of the MPI. The risk of a re-MI, being admitted with CHF or death, increased with increasing tertile of MPI, being approximately three times as high for the third tertile compared to the first tertile (HR 2.8, 95% CI 1.7 to 4.7, p<0.001). MPI provided independent prognostic information in a multivariable Cox regression model adjusted for age, gender, previous MI, peak troponin, systolic and diastolic echocardiographic parameters, with a HR of 1.24 (p=0.005) for the combined endpoint per each 0.1 increase in MPI. Conclusions: -MPI assessed by TDI M-mode is a simple and reproducible measure, which provides independent prognostic information, regardless of rhythm, incremental to conventional and novel echocardiographic parameters of systolic and diastolic function in patients with STEMI treated with pPCI.

Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print
Biering-Sørensen T, Mogelvang R, Søgaard P, Pedersen SH, ... Jørgensen PG, Jensen JS
Circ Cardiovasc Imaging: 27 Mar 2013; epub ahead of print | PMID: 23536267
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Abstract

Clinical Value of Absolute Quantification of Myocardial Perfusion with 15O-water in Coronary Artery Disease.

Kajander SA, Joutsiniemi E, Saraste M, Pietilä M, ... Hartiala J, Knuuti J
Background: -The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multi-vessel disease and/or endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow, and compared that with relative uptake. Methods and results: -104 patients with moderate (30-70%) pre-test likelihood of CAD were imaged with PET during adenosine stress using (15)O-water and dynamic imaging. Absolute myocardial blood flow was calculated, from which both standard relative myocardial perfusion images and images that were scaled to known absolute scale were produced. The patients and the regions were then classified as normal or abnormal and compared against the reference, conventional angiography with fractional flow reserve. In patient-based analysis, the PPV, NPV and accuracy of quantitative blood flow in the detection of obstructive CAD were 86%, 97% and 92%. The corresponding values with relative analysis were 61%, 83% and 73%, respectively. In region-based analysis, the ROC curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and the PPV were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis. Conclusions: -The measurement of myocardial blood flow in absolute terms has significant impact on the interpretation of myocardial perfusion. As expected, multi-vessel disease is more accurately detected. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

Circ Cardiovasc Imaging: 19 Sep 2011; epub ahead of print
Kajander SA, Joutsiniemi E, Saraste M, Pietilä M, ... Hartiala J, Knuuti J
Circ Cardiovasc Imaging: 19 Sep 2011; epub ahead of print | PMID: 21926262
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Abstract

Native Myocardial T1 Mapping by Cardiovascular Magnetic Resonance Imaging in Subclinical Cardiomyopathy in Patients with Systemic Lupus Erythematosus.

Puntmann VO, D\'Cruz D, Smith Z, Pastor A, ... Schaeffter T, Nagel E
Background: -Increased systemic inflammation has been linked to myocardial dysfunction and heart failure in patients with systemic lupus erythematosus (SLE). Accurate detection of early myocardial changes may be able to guide preventive intervention. We investigated whether multiparametric imaging by cardiovascular magnetic resonance (CMR) can detect differences between controls and asymptomatic SLE patients. Methods and results: -A total of 33 SLE predominantly female patients (mean age 40±9 years) underwent CMR for routine assessment of myocardial perfusion, function and late gadolinium enhancement (LGE). T1 mapping was performed in single short axis slice before and 15 minutes after gadolinium administration. Twenty-one subjects with a low pre-test probability and normal CMR acted as a control group. Both groups had similar LV volumes and mass and normal global systolic function. SLE patients had significantly reduced longitudinal strain (controls vs. SLE: %, -20±2 vs. -17±3 p<0.01) and showed intramyocardial and pericardial LGE. SLE patients had significantly increased native myocardial T1 (msec, 1056±27 vs. 1152±46, p<0.001) and extracellular volume fraction (%, 26±5 vs. 30±6; p=0.007), and reduced postcontrast myocardial T1 (msec, 454±53 vs. 411±62, p=0.01). T1-derived indices were associated with longitudinal strain (r=0.37-0.47), but not with the presence of LGE. Native myocardial T1 values showed the greatest concordance with the presence of clinical diagnosis of SLE. Conclusions: -In patients with SLE and free of cardiac symptoms there is evidence of subclinical perimyocardial impairment. We further demonstrate that T1 mapping may bear a potential to detect subclinical myocardial involvement in patients with SLE.

Circ Cardiovasc Imaging: 12 Feb 2013; epub ahead of print
Puntmann VO, D'Cruz D, Smith Z, Pastor A, ... Schaeffter T, Nagel E
Circ Cardiovasc Imaging: 12 Feb 2013; epub ahead of print | PMID: 23403334
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Abstract

Biventricular Mechanics in Constrictive Pericarditis Comparison with Restrictive Cardiomyopathy and Impact of Pericardiectomy.

Kusunose K, Dahiya A, Popovic Z, Motoki H, ... Flamm SD, Klein AL
Background: -The aim of our study was to compare myocardial mechanics of constrictive pericarditis (CP) with restrictive cardiomyopathy (RCM), or healthy controls; to assess the impact of pericardial thickening detected by cardiac magnetic resonance (CMR) on regional myocardial mechanics in CP; and to quantitate the effect of pericardiectomy on myocardial mechanics in CP. Methods and results: -Myocardial mechanics were evaluated by 2-dimensional speckle tracking in 52 consecutive patients with CP who underwent CMR examination prior to pericardiectomy, 35 patients with RCM, and 26 control subjects. CP patients had selectively depressed left ventricular (LV) anterolateral wall (LWS) and right ventricular free wall longitudinal systolic strain (RVFWS) but preserved LV septal wall systolic strain (SWS). In a comparison of RCM and normals, CP patients had significantly lower regional longitudinal systolic strain ratios (CP vs. RCM and normal; LVLWS/LVSWS: 0.8±0.2 vs.1.1±0.2 and 1.0±0.2; p<0.001, RVFWS/LVSWS: 0.8±0.4 vs. 1.4±0.5 and 1.2±0.2; p<0.001). LVLWS/SWS was more robust than the LV lateral wall to LV septal wall ratio of early diastolic velocities at the LV base (LE\'/SE\') in differentiating CP from RCM (AUC=0.91 vs. 0.76; p=0.011). There was a significant inverse correlation between pericardial thickness and respective ventricular strains (p=0.001). Pericardiectomy resulted in the improvement of the depressed LVLWSW/LVSWS (0.83±0.18 to 0.95±0.12; p<0.001). Conclusions: -Regional longitudinal systolic strain ratios are robust novel diagnostic tools for CP. Regional myocardial mechanics inversely correlates with adjacent pericardial segment thickness detected by CMR and pericardiectomy leads to systolic strain improvement which is more pronounced in RV and LV free walls.

Circ Cardiovasc Imaging: 26 Mar 2013; epub ahead of print
Kusunose K, Dahiya A, Popovic Z, Motoki H, ... Flamm SD, Klein AL
Circ Cardiovasc Imaging: 26 Mar 2013; epub ahead of print | PMID: 23532508
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Abstract

Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in Porcine Model of Post-Infarct Remodeling: Relationship to Myocardial Dysfunction.

Sahul ZH, Mukherjee R, Song J, McAteer J, ... Spinale FG, Sinusas AJ
Background: -Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction post MI remains undefined. Methods and results: -MI was surgically induced in pigs (n=23) and cine MR and dual isotope hybrid SPECT/CT imaging obtained using thallium-201 ((201)Tl) and a technetium-99m labeled MMP targeted tracer ((99m)Tc-RP805) at 1, 2 and 4 weeks post MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial (99m)Tc-RP805 retention. MMP activation as assessed by in vivo and ex vivo (99m)Tc-RP805 imaging/retention studies was increased nearly 5-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e(0.48x), p=0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional (99m)Tc-RP805 uptake and ex vivo MMP-2 activity. Conclusions: -A novel, multimodality non-invasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased (99m)Tc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of (201)Tl perfusion. (99m)Tc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.

Circ Cardiovasc Imaging: 20 Apr 2011; epub ahead of print
Sahul ZH, Mukherjee R, Song J, McAteer J, ... Spinale FG, Sinusas AJ
Circ Cardiovasc Imaging: 20 Apr 2011; epub ahead of print | PMID: 21505092
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Abstract

Yield and Diagnostic Value of Stress Myocardial Perfusion Imaging in Patients Without Known Coronary Artery Disease Presenting with Syncope.

Aljaroudi WA, Alraies MC, Wazni O, Cerqueira MD, Jaber WA
Background: -ACC/AHA Appropriate Use Criteria recommend performing stress MPI for intermediate to high-risk patients presenting with syncope, but not for low-risk patients. However, there are limited data to support these recommendations. We investigated the yield of stress MPI for the evaluation of syncope in patients at risk but without known CAD Methods and results: -From the Cleveland Clinic IRB approved MPI database, we identified consecutive patients without known CAD, who underwent stress MPI between 2006-2012 for diagnostic workup of syncope. Patients were stratified into low, intermediate and high risk using Framingham score. For patients with abnormal MPI, left heart angiograms (LHC) were reviewed if performed. There were 700 patients (mean age 62±15years, 55% female) who had undergone stress MPI for syncope; 659 (94%) with normal perfusion. Of the 41 patients with abnormal MPI, 18 had LHC (9 were false positive); there were 23 remaining patients with abnormal MPI (16 having moderate to severe PDS) but who did not have a LHC and could have undiagnosed significant CAD. The diagnostic yield of stress MPI was similarly low among all cardiovascular risk categories. Conclusions: -Stress MPI for evaluation of syncope in patients without known CAD has a low diagnostic yield among all risk categories, and as such, reaffirmation and revision of the appropriateness criteria should be considered.

Circ Cardiovasc Imaging: 17 Feb 2013; epub ahead of print
Aljaroudi WA, Alraies MC, Wazni O, Cerqueira MD, Jaber WA
Circ Cardiovasc Imaging: 17 Feb 2013; epub ahead of print | PMID: 23418293
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Abstract

Prevalence and Predictors of Ischemia and Outcomes in Outpatient Diabetic Patients Referred for SPECT Myocardial Perfusion Imaging.

Bourque JM, Patel CA, Ali MM, Perez M, Watson DD, Beller GA
Background: -The prevalence of ischemia and its prediction of events are unclear in outpatient diabetic patients in the modern era of intensive medical management. We sought to identify the prevalence of ischemia, subsequent cardiac events, and impact of gender, stress type, and symptom status on these findings in a cohort of outpatient, stable diabetic patients referred for SPECT myocardial perfusion imaging (MPI). Methods and results: -The study cohort included 575 consecutive diabetic outpatients who underwent quantitative, gated-SPECT MPI. Clinical information, stress MPI variables, and cardiac events were prospectively collected and analyzed. The study population was at intermediate risk of coronary artery disease (CAD) or had known CAD (40.3%); 29% were asymptomatic at the time of stress testing. Scintigraphic ischemia and significant (≥10%) left ventricular (LV) ischemia were present in 126 (21.9%) and 29 (5.0%), respectively, and <1% had early revascularization. The risk of ischemia was increased >2-fold by male gender (p<0.001) but was not impacted by pharmacologic stress (p=0.15) or presence of symptoms (p=0.89). Over median 4.4 years follow-up, the rate of cardiac death/nonfatal myocardial infarction (MI) was moderate at 2.6%/year (cardiac death 0.8%/year) in the total cohort but was 5.7%/year in those with ischemia (p<0.001). Pharmacologic stress predicted a higher cardiac event rate (p<0.001) but symptoms did not (p=0.55). Conclusions: -This stable outpatient diabetic SPECT referral cohort had low rates of significant ischemia and early revascularization; an initially-low initial cardiac event rate increased after 2 years. Independent predictors of cardiac death/nonfatal MI were known CAD, pharmacologic stress, and MPI ischemia. Nearly one-third of those with events had a normal MPI, indicating a need for improved risk stratification.

Circ Cardiovasc Imaging: 01 Apr 2013; epub ahead of print
Bourque JM, Patel CA, Ali MM, Perez M, Watson DD, Beller GA
Circ Cardiovasc Imaging: 01 Apr 2013; epub ahead of print | PMID: 23547172
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Abstract

The Identification and Assessment of Anderson Fabry Disease by Cardiovascular Magnetic Resonance Non-Contrast Myocardial T1 Mapping.

Sado DM, White SK, Piechnik SK, Banypersad SM, ... Elliott PM, Moon JC
Background: -Anderson Fabry disease (AFD) is a rare but under-diagnosed intracellular lipid disorder which can cause left ventricular hypertrophy (LVH). Lipid is known to shorten the MRI parameter T1. We hypothesised that non-contrast T1 mapping by cardiovascular magnetic resonance would provide a novel and useful measure in this disease with potential to detect early cardiac involvement and distinguish AFD LVH from other causes. Methods and results: -227 subjects were studied: AFD patients (n=44, 55% with LVH), healthy volunteers (n=67, 0% with LVH), hypertension (n=41, 24% with LVH), hypertrophic cardiomyopathy (n=34, 100% with LVH), severe aortic stenosis (n=21, 81% with LVH) and definite AL cardiac amyloidosis (n=20, 100% with LVH). T1 mapping was performed using the Sh-MOLLI sequence on a 1.5T magnet before gadolinium administration with primary results derived from the basal and mid septum. Compared to health volunteers, septal T1 was lower in AFD and higher in other diseases (AFD vs healthy volunteers vs other patients, 882±47ms, 968±32ms, 1018±74ms, P<0.0001). In patients with LVH (n=105), T1 discriminated completely between AFD and other diseases with no overlap. In AFD, T1 correlated inversely with wall thickness (R=-0.51, P=0.0004) and was abnormal in 40% of subjects who did not have LVH. Segmentally, AFD showed pseudo-normalisation or elevation of T1 in the LV infero-lateral wall, correlating with the presence or absence of late gadolinium enhancement (1001±82ms vs 891±38ms, P<0.0001) Conclusions: -Non-contrast T1 mapping shows potential as a unique and powerful measurement in the imaging assessment of left ventricular hypertrophy and Anderson Fabry disease.

Circ Cardiovasc Imaging: 07 Apr 2013; epub ahead of print
Sado DM, White SK, Piechnik SK, Banypersad SM, ... Elliott PM, Moon JC
Circ Cardiovasc Imaging: 07 Apr 2013; epub ahead of print | PMID: 23564562
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Abstract

The Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy.

Bravo PE, Zimmerman SL, Luo HC, Pozios I, ... Abraham MR, Abraham TP
Background: -Presence of delayed enhancement (DE) on magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). We investigated the relationship between DE on CMR, and myocardial ischemia in HCM. Methods and results: -HCM patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography (PET) to quantify myocardial blood flow (MBF) and coronary flow reserve (CFR). The summed difference score (SDS) for regional myocardial perfusion (rMP) was also assessed. Patients in the DE-group (n=35) had greater LV wall thickness (2.09 ± 0.44 vs. 1.78 ± 0.34 cm; P 0.03). Stress MBF (2.25 ± 0.46 vs. 1.78 ± 0.43 ml/min/g, P = 0.01), and CFR (2.78 ± 0.32 vs. 2.01 ± 0.52, P < 0.001) were significantly lower in DE-positive patients. SDS (7.3 ± 6.6 vs. 0.9 ± 1.4, P < 0.0001) was significantly higher in patients with DE. A CFR < 2.00 was seen in 18 patients (51%) with DE, but in none of the DE-negative patients (P <0.0001). CMR and PET showed visually concordant DE and rMP abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal rMP, and 3 DE-negative patients had (apical) rMP abnormalities. Conclusions: -We found a close relationship between DE by CMR and microvascular function in the majority of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in HCM patients.

Circ Cardiovasc Imaging: 17 Feb 2013; epub ahead of print
Bravo PE, Zimmerman SL, Luo HC, Pozios I, ... Abraham MR, Abraham TP
Circ Cardiovasc Imaging: 17 Feb 2013; epub ahead of print | PMID: 23418294
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Abstract

Reference Values and Distribution of Conventional Echocardiographic Doppler Measures and Longitudinal Tissue Doppler Velocities in a Population Free from Cardiovascular Disease.

Dalen H, Thorstensen A, Vatten LJ, Aase SA, Stoylen A
Background: -We aimed to study the distribution of conventional Doppler measurements, pulsed wave and color tissue Doppler (pwTDI and cTDI) derived velocities by age and sex in a healthy population. Methods and results: -Longitudinal tissue Doppler velocities were determined in 1266 healthy individuals from standard apical four and two chamber views. By the pwTDI method, mean (SD) systolic mitral annular velocities were 8.2 cm/s (1.3) in women and 8.6 cm/s (1.4) in men, and 6.6 cm/s (1.1) and 6.9 cm/s (1.3) using cTDI. Using pwTDI, diastolic early mitral annular velocities were 11.8 cm/s (3.2) in women and 10.8 cm/s (3.0) in men, with corresponding E/e\' ratios 6.7 (0.8) in women and 6.4 (0.8) in men. By pwTDI, tricuspid annular systolic and early diastolic mean (SD) velocities were 12.5 (1.9) and 13.3 (3.0) in women, and 12.8 (2.2) and 12.5 (3.3) in men. There was a significant decrease in left and right ventricular function with increasing age. Conclusions: -The longitudinal mitral and tricuspid annular velocities from this population study are widely applicable as reference values. Reference values for annular velocities should be specified by sex and age. The average of inferoseptal and anterolateral wall velocities may be the preferred index of LV performance.

Circ Cardiovasc Imaging: 28 Jun 2010; epub ahead of print
Dalen H, Thorstensen A, Vatten LJ, Aase SA, Stoylen A
Circ Cardiovasc Imaging: 28 Jun 2010; epub ahead of print | PMID: 20581050
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Abstract

Reduced Pressure-Volume Response to Exercise: A Marker of Subclinical Myocardial Disease in Type 2 Diabetes.

Jellis CL, Jenkins C, Leano R, Martin JH, Marwick TH
Background: -Limitations in the predictive value of negative exercise echocardiography (ExE) in type 2 diabetes (T2DM) has been linked to a reduced end-systolic pressure-volume response (ESPVR). We sought whether abnormal ESPVR reflected subclinical diabetic heart disease (DHD), to examine the association between the ESPVR and markers of myocardial dysfunction and to establish if the change (Delta) or peak systolic blood pressure/end-systolic left ventricular volume ratio (SP/ESV) is a better marker of contractile reserve in T2DM. Methods and results: -Resting and ExE was performed in 167 apparently healthy T2DM (97 men, 55+/-10 years) without ischemia, other cardiac disease or non-cardiac complications of diabetes. Standard echocardiographic and color tissue Doppler measures (early diastolic tissue velocity [Em], strain and strain rate) were acquired at baseline and peak stress in apical long-axis views. Calibrated integrated backscatter (cIB) was calculated from a resting parasternal long-axis view. DeltaSP/ESV was calculated as [(peak stress SP/ESV) - (rest SP/ESV)]. The 83 subjects who demonstrated a DeltaSP/ESV </=;12 mmHg/ml/m(2) after exercise were older and had lower peak heart-rate (HR), resting diastolic (Em) and stress systolic (Sm) tissue velocity, stress ejection fraction (EF) and exercise capacity than the remainder. There was no significant association between DeltaSP/ESV and metabolic derangement or echocardiographic measures of deformation or backscatter. Change in Sm and stress EF were independent correlates of DeltaSP/ESV. Conclusions: -DeltaSP/ESV ratio is associated with established features of subclinical DHD as well as determinants of contractile reserve (peak hemodynamic response and stress systolic function). Peak ESPVR is poorly associated with markers of myocardial dysfunction.

Circ Cardiovasc Imaging: 24 May 2010; epub ahead of print
Jellis CL, Jenkins C, Leano R, Martin JH, Marwick TH
Circ Cardiovasc Imaging: 24 May 2010; epub ahead of print | PMID: 20494941
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Abstract

Fasting-Induced Myocardial Lipid Accumulation in Long-Chain Acyl-CoA Dehydrogenase Knock-Out Mice Is Accompanied by Impaired Left Ventricular Function.

Bakermans AJ, Geraedts TR, van Weeghel M, Denis S, ... Houten SM, Prompers JJ
Background: -Lipotoxicity may be a key contributor to the pathogenesis of cardiac abnormalities in mitochondrial long-chain fatty acid β-oxidation (FAO) disorders. Few data are available on myocardial lipid levels and cardiac performance in FAO deficiencies. The purpose of this animal study is to assess fasting-induced changes in cardiac morphology, function, and triglyceride (TG) storage as a consequence of FAO deficiency in a non-invasive fashion. Methods and results: -MRI and proton magnetic resonance spectroscopy ((1)H-MRS) were applied in vivo in long-chain acyl-CoA dehydrogenase (LCAD) knock-out (KO) mice and wild type (WT) mice (n=8 per genotype). Fasting was used to increase the heart\'s dependency on FAO for maintenance of energy homeostasis. In vivo data were complemented with ex vivo measurements of myocardial lipids. Left ventricular (LV) mass was higher in LCAD KO mice compared to WT mice (P<0.05), indicating LV myocardial hypertrophy. Myocardial TG content was higher in LCAD KO mice at baseline (P<0.001) and further increased in fasted LCAD KO mice (P<0.05). Concomitantly, LV ejection fraction (P<0.01) and diastolic filling rate (P<0.01) decreased after fasting, whereas these functional parameters did not change in fasted WT mice. Myocardial ceramide content was higher in fasted LCAD KO mice compared to fasted WT mice (P<0.05). Conclusions: -Using a non-invasive approach, this study reveals accumulation of myocardial TG in LCAD KO mice. Toxicity of accumulating lipid metabolites such as ceramide may be responsible for the fasting-induced impairment of cardiac function observed in the LCAD KO mouse.

Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print
Bakermans AJ, Geraedts TR, van Weeghel M, Denis S, ... Houten SM, Prompers JJ
Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print | PMID: 21737602
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Abstract

Vascular Inflammation in Patients with Impaired Glucose Tolerance and Type 2 Diabetes: Analysis with 18F-Fluorodeoxyglucose Positron Emission Tomography.

Kim TN, Kim S, Yang SJ, Yoo HJ, ... Choi DS, Choi KM
Background: -Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic cardiovascular disease. Vascular inflammation is a key factor in both the pathogenesis and outcome of atherosclerosis. (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising tool for indentifying and quantifying vascular inflammation within atherosclerotic plaques. This study was designed to examine the vascular inflammation measured using FDG-PET in patients with impaired glucose tolerance (IGT) and T2DM, in comparison with age- and gender-matched control subjects with normal glucose tolerance (NGT). Methods and results: -We investigated vascular inflammation using FDG-PET in ninety age- and gender-matched subjects with different glucose tolerance (30 NGT subjects, 30 IGT subjects and 30 T2DM subjects). Vascular 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). Both mean and maximum TBR measurements were significantly different based on glucose tolerance, although the carotid intima-media thickness measurements were not significantly different. The maximum TBR values in patients with IGT and T2DM were significantly increased compared to the normal subjects. In addition, subjects with metabolic syndrome (MetS) had increased maximum TBR values compared to those without MetS. Age-, gender- and BMI-adjusted maximum TBR levels were positively correlated with triglyceride, HbA1c, insulin resistance, hsCRP and Framingham risk score, and were negatively correlated with HDL cholesterol and adiponectin levels. Conclusions: -The results of the present study suggest that IGT and T2DM are associated with vascular inflammation in carotid atherosclerosis detected by FDG-PET.

Circ Cardiovasc Imaging: 11 Jan 2010; epub ahead of print
Kim TN, Kim S, Yang SJ, Yoo HJ, ... Choi DS, Choi KM
Circ Cardiovasc Imaging: 11 Jan 2010; epub ahead of print | PMID: 20061516
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Abstract

An Echocardiographic Model Predicting Severity of Aortic Regurgitation in Congenital Heart Disease.

Beroukhim RS, Graham D, Margossian R, Brown DW, Geva T, Colan SD
Background: -Multiple echocardiographic parameters have been identified to predict the severity of aortic regurgitation (AR) with variable reliability. This study was performed to identify which echocardiographic parameters best predict the severity of AR in a cohort of patients with congenital heart disease, using cardiovascular magnetic resonance imaging (CMR) quantification as a reference standard. Methods and results: -The study involved 2 phases. In phase 1, predictive models were developed based on multivariable analysis of various morphometric and Doppler variables obtained from 174 echocardiograms that best predicted the severity of AR as defined by paired CMR examinations. A nonlinear estimate of regurgitation fraction, using the variables parasternal vena contracta derived area/BSA and abdominal aorta Doppler retrograde velocity time integral/antegrade velocity time integral, was identified through multivariable analysis as the best predictive model for AR fraction. In phase 2, the predictive models were prospectively tested on 43 echocardiographic examinations for which a paired CMR was performed. The agreement between the observed and predicted AR fraction was assessed using Bland Altman analysis. For the 30 studies of the validation dataset that had adequate quality images of both parasternal vena contracta width and abdominal aorta flow profile, the predicted aortic regurgitation values had a mean bias +/- SD of 0.4% +/- 7.3% (p=0.80). Conclusions: -A model using two variables, parasternal vena contracta derived area/BSA, and abdominal aorta Doppler retrograde velocity time integral/antegrade velocity time integral, can predict AR severity patients with a wide variety of congenital heart disease.

Circ Cardiovasc Imaging: 28 Jun 2010; epub ahead of print
Beroukhim RS, Graham D, Margossian R, Brown DW, Geva T, Colan SD
Circ Cardiovasc Imaging: 28 Jun 2010; epub ahead of print | PMID: 20581048
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Abstract

Selective In-Vivo Visualization of Immune-cell Infiltration in a Mouse Model of Autoimmune Myocarditis by Fluorine-19 Cardiac Magnetic Resonance.

van Heeswijk RB, De Blois J, Kania G, Gonzales C, ... Eriksson U, Schwitter J
Background: -The goal of this study was to characterize the performance of (19)F cardiac magnetic resonance (CMR) for the specific detection of inflammatory cells in a mouse model of myocarditis. Intravenously administered perfluorocarbons (PFC) are taken up by infiltrating inflammatory cells and can be detected by fluorine-19 ((19)F) CMR. (19)F-labeled cells should therefore generate an exclusive signal at the inflamed regions within the myocardium. Methods and results: -Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice. Following intravenous injection of 2x200μl of a PFC on day 19 and 20 (n=9) after immunization, in vivo (19)F-CMR was performed at the peak of myocardial inflammation (day 21). In 5 additional animals, PFC combined with fluorescein isothiocyanate (FITC) was administered for post-mortem immunofluorescence and flow cytometry analyses. Control experiments were performed in 9 animals. In vivo (19)F-CMR detected myocardial inflammation in all EAM-positive animals. Its resolution was sufficient to identify even small inflammatory foci e.g. at the surface of the right ventricle. Post-mortem immunohistochemistry and flow cytometry confirmed the presence of PFC in macrophages, dendritic cells and granulocytes, but not in lymphocytes. The myocardial volume of elevated (19)F signal (r(s)=0.96, p<0.001), the (19)F SNR (r(s)=0.92, p<0.001) and the (19)F signal integral (r(s)=0.96, p<0.001) at day 21 correlated with the histological myocarditis severity score. Conclusions: -In-vivo (19)F-CMR was successfully used to specifically and robustly visualize the inflammation in EAM, and thus allowed for an unprecedented insight into the involvement of inflammatory cells in the disease process.

Circ Cardiovasc Imaging: 23 Jan 2013; epub ahead of print
van Heeswijk RB, De Blois J, Kania G, Gonzales C, ... Eriksson U, Schwitter J
Circ Cardiovasc Imaging: 23 Jan 2013; epub ahead of print | PMID: 23343515
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Abstract

Evaluation of the Left Atrial Appendage with Real-Time Three-Dimensional Transesophageal Echocardiography: Implications For Catheter-Based Left Atrial Appendage Closure.

Nucifora G, Faletra FF, Regoli F, Pasotti E, ... Moccetti T, Auricchio A
Background: -Precise knowledge of left atrial appendage (LAA) orifice size is crucial for correct sizing of LAA closure devices. Aim of the present study was to determine the performance of real-time three-dimensional transesophageal echocardiography (RT3DTEE) for LAA orifice size assessment, compared to two-dimensional transesophageal echocardiography (2DTEE), and to investigate the impact of atrial fibrillation (AF) on LAA orifice size. Methods and results: -137 patients (38 controls, 31 with paroxysmal AF, 38 with persistent AF and 30 with permanent AF) underwent 2DTEE and RT3DTEE. Both techniques were used to measure LAA orifice area. Clinically-indicated 64-slice computed tomography (CT) was used as reference technique in 46 patients. 2DTEE underestimated LAA orifice area, compared to RT3DTEE (1.99±0.94 cm(2) vs. 3.05±1.27 cm(2); p<0.001). RT3DTEE showed higher correlation with CT for the assessment of LAA orifice area, compared to 2DTEE (r=0.92, 95%CI 0.85-0.95, vs. r=0.72, 95%CI 0.54-0.83, respectively). At Bland-Altman analysis, RT3DTEE and 2DTEE underestimated LAA orifice area, compared to CT. However, RT3DTEE showed smaller bias (0.07 cm(2) vs. 0.72 cm(2)) and narrower limits of agreement (-0.71 to 0.85 cm(2) vs. -0.58 to 2.02 cm(2)) with CT, compared to 2DTEE. Among AF patients, a progressive increase in RT3DTEE-derived LAA orifice area was observed with increasing frequency of AF (p<0.001). At multivariate analysis, AF and left atrial volume index (p<0.001 for both) were independently associated with RT3DTEE-derived LAA orifice area. Conclusions: -RT3DTEE is more accurate than 2DTEE for the assessment of LAA orifice size. A progressive increase in LAA orifice area is observed with increasing frequency of AF.

Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print
Nucifora G, Faletra FF, Regoli F, Pasotti E, ... Moccetti T, Auricchio A
Circ Cardiovasc Imaging: 08 Jul 2011; epub ahead of print | PMID: 21737601
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Abstract

Echocardiographic Indices Do Not Reliably Track Changes in Left-Sided Filling Pressure in Healthy Subjects or Patients with Heart Failure with Preserved Ejection Fraction.

Bhella PS, Pacini EL, Prasad A, Hastings JL, ... Grayburn PA, Levine BD
Background: -In select patient populations, Doppler echocardiographic indices may be used to estimate left sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important as it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure. Methods and results: -Forty seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e\' & E/Vp) were measured at two baselines and during four preload altering maneuvers: lower body negative pressure (LBNP) -15 mmHg; LBNP -30 mmHg; rapid saline infusion of 10-15 ml/kg; and rapid saline infusion of 20-30 ml/kg. A random coefficient mixed model regression of PCWP vs. E/e\' and PCWP vs. E/Vp was performed for: 1) a composite of all data points; 2) a composite of all data points within each of the three groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mmHg. For E/e\', the composite random effects mixed model regression was PCWP = 0.58xE/e\'+7.02 (p<0.001) confirming the weak but significant relationship between these two variables. Individual subject linear regression slopes (range: -6.76 to 11.03) and r(2) (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP = 1.95xE/Vp +7.48 (p=0.005); once again, individual subject linear regression slopes (range: -16.42 to 25.39) and r(2) (range: 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. Conclusions: -Within individual subjects the non-invasive indices E/e\' and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF.

Circ Cardiovasc Imaging: 26 Jul 2011; epub ahead of print
Bhella PS, Pacini EL, Prasad A, Hastings JL, ... Grayburn PA, Levine BD
Circ Cardiovasc Imaging: 26 Jul 2011; epub ahead of print | PMID: 21788358
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Abstract

Iodinated Contrast Opacification Gradients in Normal Coronary Arteries Imaged with Prospectively ECG-Gated Single Heart Beat 320-Detector Row Computed Tomography.

Steigner ML, Mitsouras D, Whitmore AG, Otero HJ, ... Dicarli MF, Rybicki FJ
Background: -To define and evaluate coronary contrast opacification gradients using prospectively ECG-gated single heart beat 320-detector row coronary angiography (CTA). Methods and results: -Thirty-six patients with normal coronary arteries determined by 320 x 0.5 mm detector row coronary CTA were retrospectively evaluated with customized image post-processing software to measure Hounsfield Units (HU) at 1 mm intervals orthogonal to the artery center line. Linear regression determined correlation between mean HU and distance from the coronary ostium (regression slope defined as the distance gradient G(d)), lumen cross-sectional area (G(a)), and lumen short axis diameter (G(s)). For each gradient, differences between the three coronary arteries were analyzed with ANOVA. Linear regression determined correlations between measured gradients, heart rate, body-mass index (BMI), and cardiac phase. To determine feasibility in lesions, all three gradients were evaluated in 22 consecutive patients with left anterior descending artery lesions greater than or equal to 50% stenosis. For all 3 coronary arteries in all patients, the gradients G(a) and G(s) were significantly different from zero (p<0.0001), highly linear (Pearson r values 0.77-0.84), and had no significant difference between the LAD, LCx, and RCA (p>0.503). The distance gradient G(d) demonstrated nonlinearities in a small number of vessels and was significantly smaller in the RCA when compared to the left coronary system (p<0.001). Gradient variations between cardiac phases, heart rates, BMI, and readers were low. Gradients in patients with lesions were significantly different (p<0.021) than in patients considered normal by CTA. Conclusions: -Measurement of contrast opacification gradients from temporally uniform coronary CTA demonstrates feasibility and reproducibility in patients with normal coronary arteries. For all patients the gradients defined with respect to the coronary lumen cross-sectional area and short axis diameters are highly linear, not significantly influenced by the coronary artery (LAD vs LCx vs RCA), and have only small variation with respect to patient parameters. Preliminary evaluation of gradients across coronary artery lesions is promising but requires additional study.

Circ Cardiovasc Imaging: 01 Jan 2010; epub ahead of print
Steigner ML, Mitsouras D, Whitmore AG, Otero HJ, ... Dicarli MF, Rybicki FJ
Circ Cardiovasc Imaging: 01 Jan 2010; epub ahead of print | PMID: 20044512
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Abstract

In vivo assessment of myocardial glucose uptake by positron emission tomography in adults with the PRKAG2 cardiac syndrome.

Ha AC, Renaud JM, Dekemp RA, Thorn S, ... Beanlands RS, Gollob MH
Background: The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans. Methods and results: Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue (18)F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 mumol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 mumol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar. Conclusions: The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, (18)F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.

Circ Cardiovasc Imaging: 20 Nov 2009; 2:485-91
Ha AC, Renaud JM, Dekemp RA, Thorn S, ... Beanlands RS, Gollob MH
Circ Cardiovasc Imaging: 20 Nov 2009; 2:485-91 | PMID: 19920047
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Abstract

Quantification of Regional Myocardial Oxygenation by Magnetic Resonance Imaging: Validation with Positron Emission Tomography.

McCommis KS, Goldstein TA, Abendschein DR, Herrero P, ... Gropler RJ, Zheng J
Background: -A comprehensive evaluation of myocardial ischemia requires measures of both oxygen supply and demand. Positron-emission tomography (PET) is currently the gold standard for such evaluations, but its use is limited due to its ionizing radiation, limited availability, and high cost. A cardiac magnetic resonance imaging (MRI) method was developed for assessing myocardial oxygenation. The purpose of this study was to evaluate and validate this technique compared to PET during pharmacologic stress in a canine model of coronary artery stenosis. Methods and results: -Twenty-one beagles and small mongrel dogs without coronary stenosis (controls), or with moderate to severe acute coronary artery stenosis underwent MRI and PET imaging at rest and during dipyridamole vasodilation or dobutamine stress to induce a wide range of changes in cardiac perfusion and oxygenation. MRI first-pass perfusion imaging was performed to quantify myocardial blood flow (MBF) and volume (MBV). The MRI blood-oxygen-level-dependent (BOLD) technique was used to determine the myocardial oxygen extraction fraction (OEF) during pharmacologic hyperemia. Myocardial oxygen consumption (MVO2) was determined by Fick\'s law. In the same dogs, (15)O-water and (11)C-acetate were used to measure MBF and MVO(2), respectively by PET. Regional assessments were performed for both MR and PET. MRI data correlated nicely with PET values for MBF (R(2) = 0.79, P < 0.001), MVO(2) (R(2) = 0.74, P < 0.001), and OEF (R(2) = 0.66, P < 0.01). Conclusions: -Cardiac MRI methods may provide an alternative to radionuclide imaging in settings of myocardial ischemia. Our newly developed quantitative MRI oxygenation imaging technique may be a valuable non-invasive tool to directly evaluate myocardial energetics and efficiency.

Circ Cardiovasc Imaging: 25 Nov 2009; epub ahead of print
McCommis KS, Goldstein TA, Abendschein DR, Herrero P, ... Gropler RJ, Zheng J
Circ Cardiovasc Imaging: 25 Nov 2009; epub ahead of print | PMID: 19933371
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Abstract

Echocardiographic Assessment of Cardiac Valvular Regurgitation with Lorcaserin from Analysis of Three Phase 3 Clinical Trials.

Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM
Background: -Lorcaserin is a selective 5-HT2C agonist evaluated for weight management in clinical trials. Echocardiographic monitoring was conducted to test the hypothesis that selective 5-HT2C agonism would avoid valvular heart disease. Methods and results: -Echocardiographic and weight change data from 5,249 obese and overweight patients in three phase 3 trials were integrated. Treatment duration with 10 mg lorcaserin BID or placebo was 52 weeks. The proportions of patients who developed FDA-defined valvulopathy (≥mild aortic or ≥moderate mitral regurgitation), and changes in regurgitant grade at each heart valve were evaluated. Possible associations between weight or BMI change and valvulopathy were explored. New valvulopathy was present in 2.04% of placebo and 2.37% of lorcaserin recipients at 52 weeks (risk difference 0.33%; 95% CI: -0.46 - 1.13; risk ratio 1.16 [all patients with sufficient echocardiographic data, last observation carried forward imputation]) or 1.03 [patients who completed 52 weeks]. Changes in weight and body mass index (BMI) were negatively associated with week 52 presence of valvulopathy (p=0.02 and p=0.04, respectively); a 5% decrease in weight was associated with an odds ratio of 1.15 for FDA-defined valvulopathy. Most changes in regurgitation were ±1 grade in both treatment groups at all heart valves. Conclusions: -In 3 prospective placebo-controlled trials with integrated data for 5,249 patients, the rate of echocardiographic valvulopathy was similar with lorcaserin and placebo. Point estimates for risk ratios ranged from 1.03 - 1.16, and may be at least partially influenced by greater weight loss in the lorcaserin group than in the placebo group. Clinical trial registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00395135, NCT00603291, NCT00603902.

Circ Cardiovasc Imaging: 09 May 2013; epub ahead of print
Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM
Circ Cardiovasc Imaging: 09 May 2013; epub ahead of print | PMID: 23661689
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Abstract

Dual-Energy Computed Tomography Imaging of Atherosclerotic Plaques in a Mouse Model Using a Liposomal-Iodine Nanoparticle Contrast Agent.

Bhavane R, Badea C, Ghaghada KB, Clark D, ... Willerson JT, Annapragada A
Background: -The accumulation of macrophages in inflamed atherosclerotic plaques has been long recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography (CT) imaging of macrophage-rich atherosclerotic plaques in a mouse model. Methods and results: -Liposomal-iodine formulations varying in particle size and polyethylene glycol coating were fabricated, and shown to stably encapsulate the iodine compound. In vitro uptake studies using optical and CT imaging in the RAW264.7 macrophage cell line identified the formulation that promoted maximal uptake. Dual-energy CT imaging using this formulation in Apolipoprotein E deficient (ApoE(-/-)) mice (n=8) and control C57BL/6 mice (n=6) followed by spectral decomposition of the dual-energy images enabled imaging of the liposomes localized in the plaque. Imaging cytometry confirmed the presence of liposomes in the plaque and their co-localization with a small fraction (~2%) of the macrophages in the plaque. Conclusions: -The results demonstrate the feasibility of imaging macrophage-rich atherosclerotic plaques using a liposomal-iodine nanoparticle contrast agent and dual-energy CT.

Circ Cardiovasc Imaging: 24 Jan 2013; epub ahead of print
Bhavane R, Badea C, Ghaghada KB, Clark D, ... Willerson JT, Annapragada A
Circ Cardiovasc Imaging: 24 Jan 2013; epub ahead of print | PMID: 23349231
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Abstract

Two-Dimensional Strain for the Assessment of Left Ventricular Function in Low Flow - Low Gradient Aortic Stenosis, Relationship to Hemodynamics and Outcome: A Substudy of the Multicenter TOPAS Study.

Bartko PE, Heinze G, Graf S, Clavel MA, ... Pibarot P, Mundigler G
Background: -Decision-making in patients with low flow - low gradient aortic stenosis (LFAS) mainly depends on the actual stenosis severity and left ventricular function, which is of prognostic importance. We used two-dimensional strain parameters measured by speckle-tracking at rest and during dobutamine stress echocardiography to document the extent of myocardial impairment, its relationship with hemodynamic variables and its prognostic value. Methods and results: -In 47 patients with LFAS global peak systolic longitudinal strain (PLS) and strain rate (PLSR) were analyzed. PLS and PLSR at rest and at peak stress were -7.56±2.34% and -7.41±2.89 (p=n.s.), and -0.38±0.12s(-1) and -0.53±0.18s(-1) (p<0.001), respectively. PLS and PLSR inversely correlated with LV ejection fraction (LVEF) at rest (r(s)=-0.52 p<0.0001 and -0.38 p=0.008) and peak stress (r(s)=-0.39 p=0.007 and -0.45 p=0.002). The overall two-year survival rate was 60%. Univariate predictors of survival were peak stress LVEF (p=0.0026), peak stress PLS (p=0.0002), peak stress PLSR (p<0.0001) and N-terminal pro B-type natriuretic peptide (NT-proBNP) (p<0.0001). Three hierarchically nested multivariable Cox regression models were constructed: Model 1: The Society of Thoracic Surgeons score as an indicator of clinical risk (AUROC=0.59); Model 2: Model 1 plus NT-proBNP and peak stress LVEF (AUROC=0.83, incremental p-value<0.0001); Model 3: Model 2 plus peak stress PLSR (AUROC=0.89, incremental p-value=0.035). Conclusions: -In patients with LFAS two-dimensional strain parameters are strong predictors of outcome. Peak stress PLSR may add incremental prognostic value beyond what is obtained from NT-pro BNP and peak stress LVEF. A larger study is needed to confirm these findings.

Circ Cardiovasc Imaging: 30 Dec 2012; epub ahead of print
Bartko PE, Heinze G, Graf S, Clavel MA, ... Pibarot P, Mundigler G
Circ Cardiovasc Imaging: 30 Dec 2012; epub ahead of print | PMID: 23275349
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Abstract

Detection of Left Atrial Appendage Thrombus by Cardiac Computed Tomography in Patients With Atrial Fibrillation: A Meta-Analysis.

Romero J, Arman Husain S, Kelesidis I, Sanz J, Medina HM, Garcia MJ
Background: -Transesophageal echocardiogram (TEE) is considered the gold standard modality in detecting left atrial/left atrial appendage thrombi (LA/LAA). However, this is a semi-invasive procedure with rare but potential life-threatening complications. Cardiac computed tomography (CCT) has been proposed as an alternative method. The purpose of this meta-analysis was to evaluate the diagnostic accuracy of CCT assessing LA/LAA thrombi in comparison with TEE. Methods and results: -A systematic review of Medline, Cochrane, and Embase to look for clinical trials assessing detection of LA/LAA thrombi by CCT when compared with TEE in patients with a history of atrial fibrillation (AF) prior to electrical cardioversion (EC)/pulmonary vein isolation (PVI) or after cardioembolic cerebrovascular accident (CVA) was performed using standard approach and bivariate analysis. Nineteen studies with 2955 patients [male: 71%, mean age 61 ± 4 years] fulfilled the inclusion criteria. Most studies (85%, 16 studies) used 64-slide multidetector computed tomography and 15 studies (79%) were electrocardiographic-gated. The incidence of LA/LAA thrombi was 8.9% ± 7). The mean sensitivity and specificity were 96% and 92%, whereas the PPV and NPV were 41% and 99%, respectively. The diagnostic accuracy was 94%. In a sub-analysis of studies in which delayed imaging was performed the diagnostic accuracy significantly improved to a mean weighted sensitivity and specificity of 100% and 99%, whereas the PPV and NPV increased to 92% and 100%, respectively. The accuracy for this technique was 99%. Conclusions: -CCT, particularly when delayed imaging is performed, is a reliable alternative to TEE for the detection of LA/LAA thrombi/clot, avoiding the discomfort and risks associated with TEE.

Circ Cardiovasc Imaging: 13 Feb 2013; epub ahead of print
Romero J, Arman Husain S, Kelesidis I, Sanz J, Medina HM, Garcia MJ
Circ Cardiovasc Imaging: 13 Feb 2013; epub ahead of print | PMID: 23406625
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Abstract

Stress Hypoperfusion and Tissue Injury in Hypertrophic Cardiomyopathy: Spatial Characterization Using High-Resolution 3-Tesla Magnetic Resonance Imaging.

Tyan CC, Armstrong S, Scholl D, Stirrat J, ... Drangova M, White JA
Background: -Ischemia and tissue injury are common in patients with hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) imaging offers combined evaluations of each phenomenon at sufficiently high resolution to examine transmural spatial distribution. In this prospective cohort study we examine the spatial distribution of stress perfusion abnormalities and tissue injury in patients with HCM. Methods and results: -One hundred consecutive patients with HCM underwent CMR imaging. Cine, stress perfusion (SP), late gadolinium enhancement (LGE) and T2-weighted imaging techniques were employed. Each was spatially co-registered according to pre-defined segmental and sub-segmental models and blindly analyzed for abnormalities using validated techniques. Spatial associations between SP, LGE and T2 imaging were made at segmental and sub-segmental levels. Of the 100 patients studied the phenotype was septal in 86 and apical in 14. LGE imaging was abnormal in 79 (79%). Eighty-six patients met pre-specified safety criteria to undergo SP and ischemia was identified in 46 (57%). T2 imaging was available in 81 patients and was abnormal in 19 (29%). The dominant distribution of all 3 findings was to segments with hypertrophy. Sub-segmental analysis revealed geographic dominance of ischemia within the subendocardial zones. However, this zone was most commonly spared from LGE and T2 abnormalities, typically seen in mid-wall and sub-epicardial zones. Conclusions: -Inducible hypoperfusion is a common finding in HCM and is typically identified within segments exhibiting imaging markers of tissue injury. However, the respective transmural dominance of these phenomena appears distinct. Alternate factors contributing to a regional susceptibility to tissue injury are deserving of further study.

Circ Cardiovasc Imaging: 14 Feb 2013; epub ahead of print
Tyan CC, Armstrong S, Scholl D, Stirrat J, ... Drangova M, White JA
Circ Cardiovasc Imaging: 14 Feb 2013; epub ahead of print | PMID: 23413422
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Abstract

Regions of Low Endothelial Shear Stress Co-localize with Positive Vascular Remodeling and Atherosclerotic Plaque Disruption: An in vivo MRI Study.

Phinikaridou A, Hua N, Pham T, Hamilton JA
Background: -Local hemodynamic factors, particularly low endothelial shear stress (ESS), play a role in the focal formation of atherosclerosis. We employed in vivo magnetic resonance imaging (MRI) to investigate the role of the magnitude of ESS on vascular remodeling, plaque burden and disruption using a rabbit model of controlled atherothrombosis. Methods and results: -Atherosclerosis was induced in New Zealand White rabbits by cholesterol diet and endothelial denudation. MRI was performed before (pre-trigger) and after (post-trigger) inducing plaque disruption with Russell\'s-viper-venom and histamine. Of the 134 vascular segments studied, 28 contained thrombus (disrupted) and 106 did not (non-disrupted). Disrupted plaques were histologically characterized by a thin, inflamed fibrous cap, a dense lipid-core, and mural thrombus. Pre-triggered MRI revealed that disrupted plaques clustered at regions with low mean ESS (11.55±5.3 versus 20.9±9.74 dynes/cm(2), P<0.001) and low peak ESS (21.5±11.2 versus 49.2±21.5 dynes/cm(2), P<0.001) compared to non-disrupted plaques. The peak ESS negatively correlated with the plaque area (r=-0.56, P<0.001) and remodeling ratio (r=-0.4, P=0.008). There was also a negative correlation between the mean ESS and the remodeling ratio (r=-0.55, P<0.001). Both the peak ESS and the mean ESS did not correlate with the % stenosis; there was a weak but statistically significant correlation with the % cross-sectional narrowing (r=0.3, P=0.002 and r=0.2, P=0.04, respectively). ROC analysis showed that both mean (AUC=0.78, 95%CI=0.69-0.87) and peak ESS (AUC=0.85, 95% CI=0.78-0.93) identified disrupted plaques. Conclusions: -We demonstrated that low ESS is associated with plaque burden, positive vascular remodeling, and plaque disruption in a rabbit model. Assessment of ESS by non-invasive MRI might be useful for assessing atherosclerotic risk.

Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print
Phinikaridou A, Hua N, Pham T, Hamilton JA
Circ Cardiovasc Imaging: 28 Jan 2013; epub ahead of print | PMID: 23357244
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Abstract

Identification of Therapeutic Benefit from Revascularization in Patients with Left Ventricular Systolic Dysfunction: Inducible Ischemia versus Hibernating Myocardium.

Ling LF, Marwick TH, Flores DR, Jaber WA, ... Cerqueira MD, Hachamovitch R
Background: -Although the recent STICH substudy reported that revascularization of viable myocardium did not improve survival, these results were limited by the viability imaging technique used and the lack of inducible ischemia information. We examined the relative impact of stress-rest rubidium-82/ F-18 fluorodeoxyglucose positron emission tomography (PET) identified ischemia, scar, and hibernating myocardium on the survival benefit associated with revascularization in patients with systolic dysfunction. Methods and results: -The extent of perfusion defects and metabolism-perfusion mismatch was measured with an automated quantitative method in 648 consecutive patients (age 65±12 years, 23% female, mean LVEF 31±12%) undergoing PET. Follow-up time began at 92 days (to avoid waiting-time bias); deaths before 92 days were excluded from the analysis. Over a mean follow-up of 2.8±1.2 years, 165 (27.5%) deaths occurred. Cox proportional hazards modeling was used to adjust for potential confounders, including a propensity score to adjust for nonrandomized treatment allocation. Early revascularization was performed within 92 days of PET in 199 patients (33%). Hibernating myocardium, ischemic myocardium, and scarred myocardium were associated with all cause death (p=0.0015, 0.0038, and 0.0010, respectively). An interaction between treatment and hibernating myocardium was present such that early revascularization in the setting of significant hibernating myocardium was associated with improved survival compared to medical therapy, especially when the extent of viability exceeded 10% of the myocardium. Conclusions: -Among patients with ischemic cardiomyopathy, hibernating, but not ischemic, myocardium identifies which patients may accrue a survival benefit with revascularization versus medical therapy.

Circ Cardiovasc Imaging: 17 Apr 2013; epub ahead of print
Ling LF, Marwick TH, Flores DR, Jaber WA, ... Cerqueira MD, Hachamovitch R
Circ Cardiovasc Imaging: 17 Apr 2013; epub ahead of print | PMID: 23595888
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Abstract

In Vivo Magnetization Transfer and Diffusion Weighted MRI Detects Thrombus Composition in a Mouse Model of Deep Vein Thrombosis.

Phinikaridou A, Andia ME, Saha P, Modarai B, Smith A, Botnar RM
Background: -Deep vein thrombosis (DVT) remains a major health problem necessitating accurate diagnosis. Thrombolysis is associated with significant morbidity and is only effective for treatment of unorganized thrombus. We tested the feasibility of in vivo magnetization transfer (MT) and diffusion weighted (DW) magnetic resonance imaging (MRI) to detect thrombus organization in a murine model of DVT. Methods and results: -DVT was induced in the inferior vena cava of male BALB/C mice. MRI was performed at day 1, 7, 14, 21, and 28 after thrombus induction using MT, DW, inversion recovery, and T1 mapping protocols. Delayed-enhancement and T1 mapping were repeated 2hr post-injection of a fibrin contrast agent. Finally, excised thrombi were used for histology. We found that MT and DW imaging can detect histological changes associated with thrombus aging. Magnetization transfer rate (MTR) maps and %MTR allowed visualization and quantification of the thrombus protein content, respectively. The %MTR increased with thrombus organization and was significantly higher at day 14, 21, and 28 after thrombus induction [day 1, 7, 14, 21, 28: %MTR =2483±451, 2079±1210, 7029±2490, 10295±4356, 32994±25449, Panova<0.05]. There was a significant positive correlation between the %MTR and the histological protein content of the thrombus (r=0.70, P<0.05). The apparent diffusion coefficient (ADC) was lower in erythrocyte-rich and collagen-rich thrombus [0.72±0.10 and 0.69±0.05 (x10(-3)mm(2)/s)]. Thrombus at day 7 and 14 had the highest ADC values [0.95±0.09 and 1.10±0.18 (x10(-3)mm(2)/s)]. Conclusions: -Magnetization transfer and diffusion weighted MRI sequences are promising for the staging of thrombus composition and could be useful in guiding medical intervention.

Circ Cardiovasc Imaging: 07 Apr 2013; epub ahead of print
Phinikaridou A, Andia ME, Saha P, Modarai B, Smith A, Botnar RM
Circ Cardiovasc Imaging: 07 Apr 2013; epub ahead of print | PMID: 23564561
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Abstract

Pulmonary Vascular Resistance as Assessed by Bicycle Stress Echocardiography in Patients with ASD Type Secundum.

Van De Bruaene A, La Gerche A, Prior DL, Voigt JU, Delcroix M, Budts W
Background: -Volume overload of the pulmonary circulation in patients with atrial septal defect (ASD) type secundum causes pulmonary vascular disease over a long period of time. This study aimed at (1) evaluating pulmonary vascular resistance (PVR) and (2) investigating the relation between PVR and exercise capacity in patients with open and closed ASD. Methods and results: -Forty-six patients with ASD type secundum (18 open, 28 closed) and 20 age-matched controls were enrolled. All underwent standard and symptom-limited bicycle stress echocardiography and cardiopulmonary exercise testing. PVR was calculated as the slope of a pulmonary artery pressure (PAP)-flow plot or as the ratio of PAP to cardiac output (total PVR). The slope of PAP-flow was higher in patients with open (5.1±2.2 versus 3.0±0.8 mmHg/L/min; P=0.002) and closed ASD (4.0±1.7 versus 3.0±0.8 mmHg/L/min) when compared to controls. In patients with an open ASD, total PVR did not change from rest to peak exercise. In patients with a closed ASD and controls, total PVR decreased from rest to peak exercise. However, in patients with an ASD closed later in life (≥34 years, median age at repair), the slope of PAP-flow was higher (5.1±1.4 versus 3.0±0.8 mmHg/L/min; P<0.0001) but total PVR did not change from rest to peak exercise. Peak oxygen consumption correlated inversely with the slope of the PAP-flow plots in patients with open (P=0.013) and closed ASD (P=0.005). Conclusions: -In patients with an open ASD, the slope of PAP-flow was higher and total PVR did not change from rest to peak exercise. In patients with an ASD closed later in life, the slope of PAP-flow was higher and total PVR did not change from rest to peak exercise, indicating altered pulmonary hemodynamics in these patients.

Circ Cardiovasc Imaging: 01 Mar 2011; epub ahead of print
Van De Bruaene A, La Gerche A, Prior DL, Voigt JU, Delcroix M, Budts W
Circ Cardiovasc Imaging: 01 Mar 2011; epub ahead of print | PMID: 21357444
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Abstract

Relief of Mitral Leaflet Tethering Following Chronic Myocardial Infarction by Chordal Cutting Diminishes Left Ventricular Remodeling.

Messas E, Bel A, Szymanski C, Cohen I, ... Hagège AA, Levine RA
Background: -One of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling which exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing two second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. Methods and results: -A posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, sheep were randomized to sham surgery (control group, n=6) versus second-order chordal cutting (n=12, half with anterior leaflet and half with bileaflet chordal cutting, both of which are techniques in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-MI (sacrifice), we measured LV end-diastolic and end-systolic volume (EDV and ESV), ejection fraction (EF), wall motion score index (WMSi), and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echo. All measurements were comparable among groups at baseline and chronic MI. At sacrifice, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls, versus 30.5±6.1% with chordal cutting (p<0.01) (LVESV=82.5±2.6ml in controls vs. 60.6±5.1ml and 61.8±4.1ml). LVEDV increased by 63±2.0% in controls vs. 26±5.5% and 22±3.4% with chordal cutting (p<0.01). LVEF and WMSi were not significantly different at follow-up among chordal cutting and control groups. MR progressively increased to moderate in controls but decreased to trace-to-mild with AntL and BiL chordal cutting (MR vena contracta 5.9±1.1mm in controls, vs. 2.6±0.1mm vs 1.7±0.1mm vs, p<0.01). BiL chordal cutting provided greater PL mobility (decreased PL restriction angle to 54.2±5.0° versus 83±3.2° with AntL chordal cutting, p<0.01). Conclusions: -Reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes.

Circ Cardiovasc Imaging: 09 Sep 2010; epub ahead of print
Messas E, Bel A, Szymanski C, Cohen I, ... Hagège AA, Levine RA
Circ Cardiovasc Imaging: 09 Sep 2010; epub ahead of print | PMID: 20826595
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Abstract

Automated Quantitative 3-D Modeling of the Aortic Valve and Root By 3-D Transesophageal Echocardiography in Normals, Aortic Regurgitation and, Aortic Stenosis: Comparison to Computed Tomography in Normals and Clinical Implications.

Calleja A, Thavendiranathan P, Ionasec RI, Houle H, ... Ryan T, Vannan MA
Background: -We tested the ability of a novel automated 3-D algorithm to model and quantify the aortic root from 3-D TEE and CT data. Methods and results: -We compared the quantitative parameters obtained by automated modeling from 3-D TEE (n=20) and CT data (n=20) to those made by 2-D TEE and targeted 2-D from 3-D TEE and CT in patients without valve disease ("normals"). We also compared the automated 3-D TEE measurements in severe AS (n=14), dilated root without AR (n=15) and dilated root with AR (n=20). The automated 3-D TEE saggital annular diameter was significantly greater than the 2-D TEE measurements (p=0.004). This was the also true for the 3-D TEE and CT coronal annular diameters (p<0.01). The average 3-D TEE and CT annular diameter was greater than both their respective 2-D and 3-D sagittal diameters (p<0.001). There was no significant difference in 2-D and 3-D measurements of the sino-tubular junction and sinus of Valsalva diameters (p>0.05) in normals, but these were significantly different (p<0.05) in abnormals. The 3 automated inter-commissural distance and leaflet length and height did not show significant differences in the normals (p>0.05), but all three were significantly different compared to the abnormal group (p<0.05). The automated 3-D annulus-commissure-coronary ostia distances in normals showed significant difference between 3-D TEE and CT (p<0.05); also these parameters by automated 3-D TEE were significantly different in abnormal (p<0.05). Lastly, the automated 3-D measurements showed excellent reproducibility for all parameters. Conclusions: -Automated quantitative 3-D modeling of the aortic root from 3-D TEE or CT data is technically feasible and provides unique data which may aid surgical and trans-catheter interventions.

Circ Cardiovasc Imaging: 11 Dec 2012; epub ahead of print
Calleja A, Thavendiranathan P, Ionasec RI, Houle H, ... Ryan T, Vannan MA
Circ Cardiovasc Imaging: 11 Dec 2012; epub ahead of print | PMID: 23233743
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Abstract

Distribution and Categorization of Left Ventricular Measurements in the General Population: Results from the Population-Based Gutenberg-Heart Study.

Wild PS, Sinning CR, Roth A, Wilde S, ... Münzel TF, Blankenberg S
Background: -Echocardiography-the dominant imaging modality for quantification of left ventricular metric-has undergone a continuing development in the last decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale epidemiological study using state-of-the-art imaging technology and methods. Methods and results: -The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 Mid-Europeans from the Gutenberg-Heart-Study (GHS), Germany. The randomly selected noninstitutionalized sample provides data on apparently healthy individuals, as well as on those with prevalent disease. Standardized echocardiograms were recorded in a comprehensive data set at a single site with a centralized training and certification of sonographers. Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated and nomograms created using quantile regression. Detailed information is given on the association between left ventricular geometry and age. Conclusions: -The rapidly evolving echocardiographic technology with persistent improvements in image quality and the new measurement conventions require the evaluation of new reference limits for left ventricular metric. The present investigation formulates reference limits and nomograms using state-of-the-art technology and methods based on a large population-based data set. The distribution of echocardiographic measures of left ventricular geometry presents in part non-linear associations with age, which should be the subject of future investigations.

Circ Cardiovasc Imaging: 20 Jul 2010; epub ahead of print
Wild PS, Sinning CR, Roth A, Wilde S, ... Münzel TF, Blankenberg S
Circ Cardiovasc Imaging: 20 Jul 2010; epub ahead of print | PMID: 20643817
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Abstract

Infarct Size Determines Myocardial Uptake of CD34+ Cells in the Peri-Infarct Zone: Results from a Study of 99mTc-extamatazime-labeled Cells Visualization Integrated with Cardiac Magnetic Resonance Infarct Imaging.

Musialek P, Tekieli L, Kostkiewicz M, Miszalski-Jamka T, ... Podolec P, Wojakowski W
Background: -Effective progenitor cell recruitment to ischemic injury zone is a prerequisite for any potential therapeutic effect. Cell uptake determinants in humans with recent MI are not defined. We tested the hypothesis that myocardial uptake of autologous CD34(+) cells delivered intracoronary after recent MI is related to LVEF and infarct size (IS). Methods and results: -Thirty-one subjects (age 36-69 years, 28 men) with pPCI-treated anterior STEMI and significant myocardial injury (peak TnI 138 [58-356ng/dL]; median [limits]) and sustained LVEF depression at ≤45%) were recruited. On day 10 [7-12], 4.3x10(6) [0.7-9.9x10(6)] (99m)Tc-extametazime-labeled autologous bone-marrow CD34(+) cells (activity 77 [45.9-86.7]MBq) were administered transcoronary (LAD). (99m)Tc-MIBI-SPECT prior to cell delivery showed 7 [2-11] (of 17) segments with definitely-abnormal/absent perfusion. Gadolinium late-enhanced infarct core (LGE(CORE)) mass was 21.7 [4.4-45.9]g and infarct border-zone mass (LGE(IBZ)) was 29.8 [3.9-60.2]g (full-width-at-half-maximum, FWHM, signal intensity thresholding algorithm). One hour after administration, 5.2% [1.7-9.9%] of labeled cells activity localized in the myocardium (whole-body planar γ-scan). Image fusion of labeled cells SPECT with LV perfusion SPECT or with cMRI infarct imaging indicated cell uptake in the peri-infarct zone. Myocardial uptake of labeled cells activity correlated in particular with LGE(IBZ) (r=0.84, p<0.0001) and with peak TnI (r=0.76, p<0.001); it also correlated with severely-abnormal/absent perfusion segments number (r=0.45, p=0.008 and LGE(CORE) (r=0.58 and r=0.84, p<0.0001) but not with echo-LVEF (r=-0.07, p=0.68) or GSPECT-LVEF (r=-0.28, p=0.16). The correlation with cMRI-LVEF was weak (r=-0.38, p=0.04). Conclusions: -This largest human study with labeled bone marrow CD34(+) cells transcoronary transplantation after recent STEMI found that myocardial cell uptake is determined by infarct size rather than LVEF, and it occurs preferentially in the peri-infarct zone.

Circ Cardiovasc Imaging: 27 Dec 2012; epub ahead of print
Musialek P, Tekieli L, Kostkiewicz M, Miszalski-Jamka T, ... Podolec P, Wojakowski W
Circ Cardiovasc Imaging: 27 Dec 2012; epub ahead of print | PMID: 23271789
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Abstract

Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis: Effects of Antioxidant Therapy with NADPH Oxidase Inhibition.

Liu YN, Davidson BP, Yue Q, Belcik T, ... Kaufmann BA, Lindner JR
Background: -In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype. Methods and results: -Mice deficient for both the LDL receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg/day orally). In vivo molecular imaging of VCAM-1, P-selectin and platelet GPIbα in the thoracic aorta was performed with targeted contrast-enhanced ultrasound (CEU) molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultra-high frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in non-treated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 wks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group. Conclusions: -Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion; which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.

Circ Cardiovasc Imaging: 13 Dec 2012; epub ahead of print
Liu YN, Davidson BP, Yue Q, Belcik T, ... Kaufmann BA, Lindner JR
Circ Cardiovasc Imaging: 13 Dec 2012; epub ahead of print | PMID: 23239832
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Abstract

Validation and Prognosis of Coronary Artery Calcium Scoring inNon-Triggered Thoracic Computed Tomography: Systematic Review and Meta-Analysis.

Xie X, Zhao Y, de Bock GH, de Jong PA, ... Oudkerk M, Vliegenthart R
Background: -Coronary calcium score (CS), traditionally based on electrocardiography (ECG)-triggered computed tomography (CT), predicts cardiovascular risk. Nowadays, non-triggered thoracic CT is extensively utilized, such as in lung cancer screening. The study-purpose was to determine the correlation in CS between non-triggered and ECG-triggered CT, and to evaluate the prognostic performance of the CS derived from non-triggered CT. Methods and results: -PubMed, Embase and Web of Knowledge were searched until November, 2012. Two reviewers independently screened 2,120 records to identify studies reporting the CS in non-triggered CT, and extracted information. Study quality was evaluated by standardized assessment tools. Cohen\'s κ was extracted for agreement of CS categories between non-triggered and ECG-triggered CT (validation). Hazard ratio was extracted for prognostic performance. Five studies comprising 1,316 individuals were included regarding validation. Five studies comprising 34,028 cardiac asymptomatic individuals, mainly from lung cancer screening trials, were included regarding prognosis. All studies were of high quality. Meta-analysis could only be performed for validation studies, as studies on prognostic performance were highly heterogeneous. Pooled Cohen\'s κ for agreement between the two techniques was 0.89 (95%CI: 0.83 to 0.95) for increasing CS categories. Increasing CS categories were associated with increasing risk of cardiovascular death or events. Non-triggered CT yielded false-negative CS in 8.8% of individuals, and underestimated high CS in 19.1%. Conclusions: -Our analysis shows the prognostic value and potential role of non-triggered assessment of coronary calcium, but it does not suggest that ECG-triggered CT should be replaced by non-triggered exams.

Circ Cardiovasc Imaging: 11 Jun 2013; epub ahead of print
Xie X, Zhao Y, de Bock GH, de Jong PA, ... Oudkerk M, Vliegenthart R
Circ Cardiovasc Imaging: 11 Jun 2013; epub ahead of print | PMID: 23756678
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