Jonathan P. Christiansen

Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi

Schumann PA, Christiansen JP, Quigley R, et al. Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol 2002;37:587–593. Rationale and Objectives.New targeted microbubbles directed to the GPIIb IIIa receptor have been developed. The objective was to determine whether targeting microbubbles to clots would enhance ultrasound imaging. Systematic studies were designed to determine whether in vitro methodology is an acceptable predictor of in vivo efficacy. Materials and Methods.Bioconjugate ligands were inserted into lipid-coated membranes of perfluorocarbon gas microbubbles and binding studies performed on activated platelets immobilized on cell culture plates. Targeted microbubble binding to clots in a flow through chamber was also assessed. Finally, microbubble binding studies on arteriolar and venular clots in a mouse cremasteric muscle model were conducted. Results.Binding studies on platelet-immobilized plates demonstrated an affinity for targeted microbubbles versus untargeted microbubbles. Semiquantitative light obscuration techniques helped to measure extent of targeted microbubble binding. Targeted microbubbles similarly bound to platelet clots in the flow model. Finally, studies in the mouse model confirmed binding of targeted microbubbles in both venules and arterioles. Conclusion.The use of receptor selective targeted microbubbles improved binding to vascular thrombi in both in vitro and in vivo settings.

Aortic Regurgitation Quantification Using Cardiovascular Magnetic Resonance Association With Clinical Outcome

Background— Current indications for surgery in patients with significant aortic regurgitation (AR) focus on symptoms and left ventricular dilation/dysfunction. However, prognosis is already reduced by this stage, and earlier identification of patients for surgery could be beneficial. Quantifying the regurgitation may help, but there are limited data on its link with outcome. Cardiovascular magnetic resonance (CMR) can accurately quantify AR, and we examined whether this was associated with the future need for surgery. Methods and Results— One hundred thirteen patients with echocardiographic moderate or severe AR were monitored for up to 9 years (mean 2.6±2.1 years) following a CMR scan, and the progression to symptoms or other indications for surgery was monitored. AR quantification identified outcome with high accuracy: 85% of the 39 subjects with regurgitant fraction >33% progressed to surgery (mostly within 3 years) in comparison with 8% of 74 subjects with regurgitant fraction ⩽33% (P<0.0001); the area under the curve on receiver operating characteristic analysis was 0.93 (P<0.0001). This ability remained strong on time-dependent Kaplan–Meier survival curves. CMR-derived left ventricular end-diastolic volume >246 mL had good, although lower, discriminatory ability (area under the curve 0.88), but the combination of this measure with regurgitant fraction provided the best discriminatory power. Conclusions— High degrees of CMR-quantified AR were associated with the development of symptoms or other indications for surgery. Quantifying AR showed slightly better discriminatory ability than “gold standard” CMR ventricular volume assessment. This could provide a new paradigm for the timing of surgical intervention but requires confirmation in a clinical trial.

Myocardial Scar Detected by Contrast-Enhanced Cardiac Magnetic Resonance Imaging is Associated with Ventricular Tachycardia in Hypertrophic Cardiomyopathy Patients

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is associated with myocardial scarring and ventricular tachycardia (VT). Contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) can quantify myocardial scar, and scar imaging has been documented in patients with HCM. We investigated the assessment of myocardial scar in HCM patients using CE-CMR, and its correlation with proven VT. METHODS Twenty-five patients (mean age 54 +/- 8) with HCM who underwent CE-CMR were identified, and clinical data obtained from chart review. Parameters of LV function were calculated from cine imaging, and myocardial scar was assessed using delayed enhancement imaging following gadolinium administration. RESULTS Myocardial scar was detected in 16 (64%) patients with a mean mass 9 +/- 15 g. Scar was patchy, mid-myocardial and located in the basal anteroseptum, and RV insertion sites. Scar was seen in septal, apical and concentric variants of HCM. Scar mass correlated with both LV Mass (r2 = 0.74) and maximal LV wall thickness (r2 = 0.42). VT occurred in 32% of patients, and was associated with both increased scar mass and wall thickness compared to non-VT patients (21 +/- 22 g vs. 4 +/- 6 g, and 2.4 +/- 0.5 cm vs. 1.8 +/- 0.5 cm, p < 0.05). LV size and function were similar in patients with and without VT. A scar mass of >7 g predicted the presence of VT with a sensitivity of 75% and specificity 82%. CONCLUSIONS Myocardial scar imaged by CE-CMR is common in patients with HCM, and is predictive of VT. Scar is seen in all HCM variants, and is associated with maximal wall thickness. There may be a role for CE-CMR in improved risk stratification for individual patients with HCM.

Contrast-enhanced cardiac magnetic resonance in a patient with familial isolated ventricular non-compaction.

Isolated ventricular non-compaction (IVNC) is an idiopathic form of cardiomyopathy. Recent clinical reports have suggested that this form of cardiomyopathy is more frequently associated with complications of congestive heart failure, thromboembolism and malignant ventricular arrhythmias. Contrast enhanced cardiac magnetic resonance imaging with its excellent spatial resolution, its large field of view and its ability to demonstrate thrombus and myocardial scar is an excellent modality to non-invasively assess patients with this form of cardiomyopathy. This paper presents a case of familial isolated ventricular non-compaction. We describe the echocardiographic, X-ray angiographic and cardiac MRI findings. Cine imaging using a steady-state free precession sequence (BFFE) was performed in axial and short axis planes. Left ventricular (LV) mass was estimated both with and without the incorporation of trabeculations from a contiguous stack of short axis images. Trabecular mass was expressed as a percentage of total left ventricular mass. We compared trabecular mass: total LV mass in 10 patients with dilated cardiomyopathy. The mean percentage trabecular mass: LV mass in dilated cardiomyopathy was 11.3% (range 1.5%-19%), and this differed significantly from the trabecular mass of the noncompaction patient (two-tailed Mann-Whitney test, p = 0.028). Trabecular mass of greater than 20% of total myocardial mass may be a useful index to suggest the diagnosis of IVNC. Gadolinium was administered (0.1 mmol/kg). Qualitative analysis of first pass perfusion suggested reduced trabecular perfusion. Early imaging with an inversion recovery sequence and a fixed long inversion time did not demonstrate LV thrombus. Late imaging with the same sequence (TI = 280-300 msec) did not demonstrate myocardial fibrosis.

Molecular and Cellular Imaging with Targeted Contrast Ultrasound

Molecular imaging is an expanding field that involves the noninvasive detection of cellular and molecular mediators of disease using a range of imaging modalities. Molecular imaging using contrast-enhanced ultrasound relies on the detection of novel site-targeted ultrasound contrast agents. Gas-filled encapsulated microbubbles provide a sensitive and high-resolution ultrasound contrast agent, and site-targeted imaging is facilitated by the manipulation of the shell surface of these microbubbles. Nonmicrobubble agents such as immunoliposomes and small nanoemulsion agents have also been developed for targeting purposes. These contrast agents are retained within regions of a specific pathophysiological process, thereby allowing noninvasive phenotypic characterization of tissue. Since microbubbles are pure intravascular tracers, they provide an optimal agent to assess molecular processes occurring on the vascular endothelial surface. Accordingly, the pathologic states that have been targeted include inflammation, angiogenesis associated with ischemia and neoplasms, and thrombus formation. This review describes: 1) the potential clinical and research uses for targeted imaging; 2) strategies that have been employed for the creation of site-targeted ultrasound contrast agents; 3) the unique challenges for imaging targeted ultrasound contrast agents; and 4) initial results and experience in the imaging of molecular events in animal models of disease.

Determination of Clinical Outcome in Mitral Regurgitation With Cardiovascular Magnetic Resonance Quantification

Background— Surgery for severe mitral regurgitation is indicated if symptoms or left ventricular dilation or dysfunction occur. However, prognosis is already reduced by this stage, and earlier surgery on asymptomatic patients has been advocated if valve repair is likely, but identifying suitable patients for early surgery is difficult. Quantifying the regurgitation may help, but evidence for its link with outcome is limited. Cardiovascular magnetic resonance (CMR) can accurately quantify mitral regurgitation, and we examined whether this was associated with the future need for surgery. Methods and Results— One hundred nine asymptomatic patients with echocardiographic moderate or severe mitral regurgitation had baseline CMR scans and were followed up for up to 8 years (mean, 2.5±1.9 years). CMR quantification accurately identified patients who progressed to symptoms or other indications for surgery: 91% of subjects with regurgitant volume ⩽55 mL survived to 5 years without surgery compared with only 21% with regurgitant volume >55 mL (P<0.0001). A similar separation was observed for regurgitant fraction ⩽40% and >40%. CMR-derived end-diastolic volume index showed a weaker association with outcome (proportions surviving without surgery at 5 years, 90% for left ventricular end-diastolic volume index <100 mL/m2 versus 48% for ≥100 mL/m2) and added little to the discriminatory power of regurgitant fraction/volume alone. Conclusions— CMR quantification of mitral regurgitation was associated with the development of symptoms or other indications for surgery and showed better discriminatory ability than the reference-standard CMR-derived ventricular volumes. CMR may be able to identify appropriate patients for early surgery, with the potential to change clinical practice, although the clinical benefits of early surgery require confirmation in a clinical trial.

Effects of nitroglycerin on erythrocyte rheology and oxygen unloading: novel role of S-nitrosohemoglobin in relieving myocardial ischemia.

Background— We hypothesized that nitroglycerin improves O2 delivery to ischemic tissue by altering erythrocyte rheology and O2 unloading through an increase in bioactive nitric oxide (NO) content. Methods and Results— Twelve dogs with resting flow-reducing single-vessel stenosis were studied at rest and during intracoronary infusion of nitroglycerin (0.3 to 0.6 &mgr;g · kg−1 · min−1). Half the dogs also had occlusion of the remote coronary artery to remove any collateral effects. Systemic and coronary hemodynamics, myocardial blood flow (MBF), whole blood viscosity (WB&eegr;), erythrocyte charge (EC) and mobility (EM), regional myocardial O2 delivery and consumption, and tissue O2 pressure (Po2) were measured. No changes in systemic hemodynamics were seen with nitroglycerin. Despite flow-limiting stenosis, MBF increased significantly in the central 25% of the ischemic bed, which was associated with an approximately 19% decrease in WB&eegr;. There was a good correlation (r=0.87) between the two. The decrease in WB&eegr; was associated with a decrease in EC and an increase in EM (r=0.83). The nitroglycerin-induced increase in tissue Po2 was disproportionate to the increase in MBF, indicating enhanced O2 unloading. Erythrocyte S-nitrosothiol content (reflecting mainly S-nitrosohemoglobin) was significantly higher for blood exposed in vitro to 0.1 &mgr;mol/L nitroglycerin or the NO donor SNAP, as compared with control (18.9±8.8 and 10.5±6.5 versus 2.6±0.5×10−5, P<0.05). Conclusions— The augmented MBF in the ischemic microcirculation during nitroglycerin administration occurs in tandem with increased erythrocyte S-nitrosothiol content, EM, and O2 unloading. These additional microvascular mechanisms may contribute to the powerful antiischemic effects of nitroglycerin, especially during low-flow states.

Assessment of valvular heart disease by cardiovascular magnetic resonance imaging: a review.

CMR is a comprehensive non-invasive tool capable of evaluating all aspects of valvular heart disease. It has advantages over echo including direct quantification of regurgitant lesions, highly accurate assessment of ventricular size and function, visualisation myocardial scar, and interrogation of extracardiac abnormalities. Although these gains can be realised with current scanning techniques, CMRs full potential has yet to be realised, and further studies of clinical outcomes are needed before CMR data can be integrated into the management algorithms for patients with significant valvular lesions.

Reliability of Echocardiographic Indices of Dyssynchrony

Background: Echocardiographic indices of dyssynchrony are increasingly used to select candidates for cardiac resynchronization therapy. For widespread screening of heart failure patients, such variables need to be comparable when evaluated by different operators using different equipment. Objective and Methods: To evaluate the reproducibility and obtainability of echocardiographic indices of mechanical dyssynchrony, we studied 40 subjects stratified according to QRS morphology and systolic function. Two echocardiograms were performed on each patient by different sonographers on different machines and each study was analyzed by two observers. Results: All blood‐pool and tissue Doppler indices of dyssynchrony were obtainable in over 97% of cases. Blood‐pool Doppler measures were the most reproducible indices of intraventricular dyssynchrony (aortic ejection delay) and interventricular dyssynchrony (aortopulmonary difference in ejection delay). For annular tissue Doppler delays, the time to peak velocity was consistently more reproducible than the time to velocity onset. Conclusion: Differences in the reliability of echocardiographic indices may affect their suitability as screening tests for dyssynchrony.

Characteristics and Prognostic Importance of Myocardial Fibrosis in Patients with Dilated Cardiomyopathy Assessed by Contrast-Enhanced Cardiac Magnetic Resonance Imaging

Introduction Dilated cardiomyopathy (DCM) is associated with significant morbidity and mortality. Contrast-enhanced cardiac MRI (CE-CMR) can detect potentially prognostic myocardial fibrosis in DCM. We investigated the role of CE-CMR in New Zealand patients with DCM, both Maori and non-Maori, including the characteristics and prognostic importance of fibrosis. Methods One hundred and three patients (mean age 58 ± 13, 78 male) referred for CMR assessment of DCM were followed for 660 ± 346 days. Major adverse cardiac events (MACE) were defined as death, infarction, ventricular arrhythmias or rehospitalisation. CE-CMR used cines for functional analysis, and delayed enhancement to assess fibrosis. Results Myocardial fibrosis was present in 30% of patients, the majority of which was mid-myocardial (63%). Volumetric parameters were similar in patients with or without fibrosis. At 2 years patients with fibrosis had an increased rate of MACE (HR = 0.77, 95% CI 0.3-2.0). Patients with full thickness or subendocardial fibrosis had the highest MACE, even in the absence of CAD). More Maori had fibrosis on CE-CMR (40% vs. 28% for non-Maori), and the majority (75%) was mid-myocardial. Maori and non-Maori had similar outcomes (25% vs. 24% with events during follow-up). Conclusions DCM patients frequently have myocardial fibrosis detected on CE-CMR, the majority of which is mid-myocardial. Fibrosis is associated with worse outcome in the medium term. The information obtained using CE-CMR in DCM may be of incremental clinical benefit.