Katherine C. Wu

Prognostic Significance of Microvascular Obstruction by Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction

BACKGROUND The extent of microvascular obstruction during acute coronary occlusion may determine the eventual magnitude of myocardial damage and thus, patient prognosis after infarction. By contrast-enhanced MRI, regions of profound microvascular obstruction at the infarct core are hypoenhanced and correspond to greater myocardial damage acutely. We investigated whether profound microvascular obstruction after infarction predicts 2-year cardiovascular morbidity and mortality. METHODS AND RESULTS Forty-four patients underwent MRI 10 +/- 6 days after infarction. Microvascular obstruction was defined as hypoenhancement seen 1 to 2 minutes after contrast injection. Infarct size was assessed as percent left ventricular mass hyperenhanced 5 to 10 minutes after contrast. Patients were followed clinically for 16 +/- 5 months. Seventeen patients returned 6 months after infarction for repeat MRI. Patients with microvascular obstruction (n = 11) had more cardiovascular events than those without (45% versus 9%; P=.016). In fact, microvascular status predicted occurrence of cardiovascular complications (chi2 = 6.46, P<.01). The risk of adverse events increased with infarct extent (30%, 43%, and 71% for small [n = 10], midsized [n = 14], and large [n = 14] infarcts, P<.05). Even after infarct size was controlled for, the presence of microvascular obstruction remained a prognostic marker of postinfarction complications (chi2 = 5.17, P<.05). Among those returning for follow-up imaging, the presence of microvascular obstruction was associated with fibrous scar formation (chi2 = 10.0, P<.01) and left ventricular remodeling (P<.05). CONCLUSIONS After infarction, MRI-determined microvascular obstruction predicts more frequent cardiovascular complications. In addition, infarct size determined by MRI also relates directly to long-term prognosis in patients with acute myocardial infarction. Moreover, microvascular status remains a strong prognostic marker even after control for infarct size.

Infarct Tissue Heterogeneity by Magnetic Resonance Imaging Identifies Enhanced Cardiac Arrhythmia Susceptibility in Patients With Left Ventricular Dysfunction

Background— The extent of the peri-infarct zone by magnetic resonance imaging (MRI) has been related to all-cause mortality in patients with coronary artery disease. This relationship may result from arrhythmogenesis in the infarct border. However, the relationship between tissue heterogeneity in the infarct periphery and arrhythmic substrate has not been investigated. In the present study, we quantify myocardial infarct heterogeneity by contrast-enhanced MRI and relate it to an electrophysiological marker of arrhythmic substrate in patients with left ventricular (LV) systolic dysfunction undergoing prophylactic implantable cardioverter defibrillator placement. Methods and Results— Before implantable cardioverter defibrillator implantation for primary prevention of sudden cardiac death, 47 patients underwent cine and contrast-enhanced MRI to measure LV function, volumes, mass, and infarct size. A method for quantifying the heterogeneous infarct periphery and the denser infarct core is described. MRI indices were related to inducibility of sustained monomorphic ventricular tachycardia during electrophysiological or device testing. For the noninducible versus inducible patients, LV ejection fraction (30±10% versus 29±7%, P=0.79), LV end-diastolic volume (220±70 versus 228±57 mL, P=0.68), and infarct size by standard contrast-enhanced MRI definitions (P=NS) were similar. Quantification of tissue heterogeneity at the infarct periphery was strongly associated with inducibility for monomorphic ventricular tachycardia (noninducible versus inducible: 13±9 versus 19±8 g, P=0.015) and was the single significant factor in a stepwise logistic regression. Conclusions— Tissue heterogeneity is present and quantifiable within human infarcts. More extensive tissue heterogeneity correlates with increased ventricular irritability by programmed electrical stimulation. These findings support the hypothesis that anatomic tissue heterogeneity increases susceptibility to ventricular arrhythmias in patients with prior myocardial infarction and LV dysfunction.

Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance Heralds an Adverse Prognosis in Nonischemic Cardiomyopathy

OBJECTIVES We examined whether the presence and extent of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) predict adverse outcomes in nonischemic cardiomyopathy (NICM) patients. BACKGROUND Morbidity and mortality is high in NICM patients. However, the clinical course of an individual patient is unpredictable and current risk stratification approaches are limited. Cardiovascular magnetic resonance detects myocardial fibrosis, which appears as LGE after contrast administration and may convey prognostic importance. METHODS In a prospective cohort study, 65 NICM patients with left ventricular (LV) ejection fraction < or =35% underwent CMR before placement of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death. The CMR images were analyzed for the presence and extent of LGE and for LV function, volumes, and mass. Patients were followed for an index composite end point of 3 cardiac events: hospitalization for heart failure, appropriate ICD firing, and cardiac death. RESULTS A total of 42% (n = 27) of patients had CMR LGE, averaging 10 +/- 13% of LV mass. During a 17-month median follow-up, 44% (n = 12) of patients with LGE had an index composite outcome event versus only 8% (n = 3) of those without LGE (p < 0.001 for Kaplan-Meier survival curves). After adjustment for LV volume index and functional class, patients with LGE had an 8-fold higher risk of experiencing the primary outcome (hazard ratio 8.2, 95% confidence interval 2.2 to 30.9; p = 0.002). CONCLUSIONS A CMR LGE in NICM patients strongly predicts adverse cardiac outcomes. The CMR LGE may represent the end-organ consequences of sustained adrenergic activation and adverse LV remodeling, and its identification may significantly improve risk stratification strategies in this high risk population. (Imaging Techniques for Identifying Factors of Sudden Cardiac Death Risk; NCT00181233).

Accuracy of Contrast-Enhanced Magnetic Resonance Imaging in Predicting Improvement of Regional Myocardial Function in Patients After Acute Myocardial Infarction

Background—Contrast-enhanced (CE) MRI demonstrates a pattern of hypoenhancement early after contrast injection in acute myocardial infarction (MI) and a pattern of hyperenhancement late after contrast injection. Because the significance of these CE patterns for myocardial viability remains debated, we evaluated their diagnostic accuracy to quantitatively predict late functional improvement of regional contractility. Methods and Results—Twenty patients underwent CE and tagged MRI at 4 days and again at 7 months after acute MI. Resting circumferential shortening strain (Ecc) was analyzed in 24 segments per patient, and its improvement was correlated with the presence or absence of the CE patterns. Immediately after MI, 389 segments were considered dysfunctional because of having less than mean±2 SD Ecc of the remote region (−18±4%). At follow-up, significant improvement of Ecc occurred in 170 dysfunctional segments with normal CE (from −4±7% to −12±7%, P <0.001) but not in 60 segments with early hypoenhancement (from −2±6% to −6±9% Ecc, P =NS). In 240 dysfunctional segments with delayed hyperenhancement, the improvement of Ecc (from −2±6% to −5±8%, P <0.001) decreased with increasing transmural extent of hyperenhancement. Receiver operating characteristic analysis demonstrated that absence of delayed hyperenhancement, compared with absence of early hypoenhancement, had better sensitivity (82% versus 19%, respectively;P <0.001) and accuracy (74% versus 49%, respectively;P <0.001) in predicting recovery of Ecc to any given level. Conclusions—Compared with lack of early hypoenhancement, lack of delayed hyperenhancement has better diagnostic accuracy in predicting functional improvement in dysfunctional segments. The early hypoenhanced regions, which represent only the fraction of infarcted tissue with concomitant microvascular obstruction, greatly underestimate the amount of irreversibly injured myocardium present after acute MI.

Contrast-Enhanced Multidetector Computed Tomography Viability Imaging After Myocardial Infarction: Characterization of Myocyte Death, Microvascular Obstruction, and Chronic Scar

Background— The ability to distinguish dysfunctional but viable myocardium from nonviable tissue has important prognostic implications after myocardial infarction. The purpose of this study was to validate the accuracy of contrast-enhanced multidetector computed tomography (MDCT) for quantifying myocardial necrosis, microvascular obstruction, and chronic scar after occlusion/reperfusion myocardial infarction. Methods and Results— Ten dogs and 7 pigs underwent balloon occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion. Contrast-enhanced (Visipaque, 150 mL, 325 mg/mL) MDCT (0.5 mm × 32 slice) was performed before occlusion and 90 minutes (canine) or 8 weeks (porcine) after reperfusion. MDCT images were analyzed to define infarct size/extent and microvascular obstruction and compared with postmortem myocardial staining (triphenyltetrazolium chloride) and microsphere blood flow measurements. Acute and chronic infarcts by MDCT were characterized by hyperenhancement, whereas regions of microvascular obstruction were characterized by hypoenhancement. MDCT infarct volume compared well with triphenyltetrazolium chloride staining (acute infarcts 21.1±7.2% versus 20.4±7.4%, mean difference 0.7%; chronic infarcts 4.15±1.93% versus 4.92±2.06%, mean difference −0.76%) and accurately reflected morphology and the transmural extent of injury in all animals. Peak hyperenhancement of infarcted regions occurred ≈5 minutes after contrast injection. MDCT-derived regions of microvascular obstruction were also identified accurately in acute studies and correlated with reduced flow regions as measured by microsphere blood flow. Conclusions— The spatial extent of acute and healed myocardial infarction can be determined and quantified accurately with contrast-enhanced MDCT. This feature, combined with existing high-resolution MDCT coronary angiography, may have important implications for the comprehensive assessment of cardiovascular disease.

ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography

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Quantification and Time Course of Microvascular Obstruction by Contrast-Enhanced Echocardiography and Magnetic Resonance Imaging Following Acute Myocardial Infarction and Reperfusion

OBJECTIVES We aimed to validate contrast-enhanced echocardiography (CE) in the quantification of microvascular obstruction (MO) against magnetic resonance imaging (MRI) and the histopathologic standards of radioactive microspheres and thioflavin-S staining. We also determined the time course of MO at days 2 and 9 after infarction and reperfusion. BACKGROUND Postinfarction MO occurs because prolonged ischemia produces microvessel occlusion at the infarct core, preventing adequate reperfusion. Microvascular obstruction expands up to 48 h after reperfusion; the time course beyond 2 days is unknown. Though used to study MO, CE has not been compared with MRI and thioflavin-S, which yield precise visual maps of MO. METHODS Ten closed-chest dogs underwent 90-min coronary artery occlusion and reperfusion. Both CE and MRI were performed at 2 and 9 days after reperfusion. The MO regions by both methods were quantified as percent left ventricular (% LV) mass. Radioactive microspheres were injected for blood flow determination. Postmortem, the myocardium was stained with thioflavin-S and 2,3,5-triphenyltetrazolium chloride. RESULTS Expressed as % total LV, MO by MRI matched in size MO by microspheres using a flow threshold of <40% remote (4.96+/-3.52% vs. 5.32+/-3.98%, p=NS). For matched LV cross sections, MO by CE matched in size MO by microspheres using a flow threshold of <60% remote (13.27+/-4.31% vs. 13.5+/-4.94%, p=NS). Both noninvasive techniques correlated well with microspheres (MRI vs. CE, r=0.87 vs. 0.74; p=NS). Microvascular obstruction by CE corresponded spatially to MRI-hypoenhanced regions and thioflavin-negative regions. For matched LV slices at 9 days after reperfusion, MO measured 12.94+/-4.51% by CE, 7.11+/-3.68% by MRI and 9.18+/-4.32% by thioflavin-S. Compared to thioflavin-S, both noninvasive techniques correlated well (CE vs. MRI, r=0.79 vs. 0.91; p=NS). Microvascular obstruction size was unchanged at 2 and 9 days (CE: 13.23+/-4.11% vs. 12.69+/-4.97%; MRI: 5.53+/-4.94% vs. 4.68+/-3.44%; p=NS for both). CONCLUSIONS Both CE and MRI can quantify MO. Both correlate well with the histopathologic standards. While MRI can detect regions of MO with blood flow <40% of remote, the threshold for MO by CE is <60% remote. The extent of MO is unchanged at 2 and 9 days after reperfusion.

Microvascular Obstruction and Left Ventricular Remodeling Early After Acute Myocardial Infarction

BACKGROUND The presence of microvascular obstruction (MO) within infarcted regions may adversely influence left ventricular (LV) remodeling after acute myocardial infarction. This study examined whether the extent of MO directly alters the mechanical properties of the infarcted myocardium. METHODS AND RESULTS Seventeen dogs underwent 90 minutes of balloon occlusion of the left anterior descending coronary artery, followed by reperfusion. Gadolinium-enhanced perfusion MRI and 3D-tagging were performed 4 to 6 and 48 hours (8 animals) and 10 days (9 animals) after reperfusion. Early increase in LV end-diastolic volume (from 42+/-9 to 54+/-14 mL, P<0.05) between 4 to 6 and 48 hours after reperfusion was predicted by both extent of MO (r=0.89, P<0.01) and infarct size (r=0.83, P<0.01), defined as MRI hypoenhanced and hyperenhanced regions, respectively. Multivariate analysis demonstrated that extent of MO had better and independent value to predict LV volume than overall infarct size. A strong inverse relationship existed between magnitude of first principal strain (r=-0.80, P<0.001) and relative extent of MO within infarcted myocardium. Also, infarcted myocardium involved by extensive areas of MO demonstrated reductions of circumferential (r=-0.61, P<0.01) and longitudinal (r=-0.53, P<0. 05) stretching. Furthermore, significant reductions of radial thickening (9+/-6% versus 14+/-3%, P<0.01) occurred in noninfarcted regions adjacent to infarcts that had increased (>35%) amounts of MO. CONCLUSIONS In the early healing phase of acute myocardial infarction, the extent of MO in infarcted tissue relates to reduced local myocardial deformation and dysfunction of noninfarcted adjacent myocardium. Such strain alterations might explain the increased remodeling observed in patients with large regions of MO.

Cardiac Magnetic Resonance Assessment of Dyssynchrony and Myocardial Scar Predicts Function Class Improvement Following Cardiac Resynchronization Therapy

OBJECTIVES We tested a circumferential mechanical dyssynchrony index (circumferential uniformity ratio estimate [CURE]; 0 to 1, 1 = synchrony) derived from magnetic resonance-myocardial tagging (MR-MT) for predicting clinical function class improvement following cardiac resynchronization therapy (CRT). BACKGROUND There remains a significant nonresponse rate to CRT. MR-MT provides high quality mechanical activation data throughout the heart, and delayed enhancement cardiac magnetic resonance (DE-CMR) offers precise characterization of myocardial scar. METHODS MR-MT was performed in 2 cohorts of heart failure patients with: 1) a CRT heart failure cohort (n = 20; left ventricular ejection fraction of 0.23 +/- 0.057) to evaluate the role of MR-MT and DE-CMR prior to CRT; and 2) a multimodality cohort (n = 27; ejection fraction of 0.20 +/- 0.066) to compare MR-MT and tissue Doppler imaging septal-lateral delay for assessment of mechanical dyssynchrony. MR-MT was also performed in 9 healthy control subjects. RESULTS MR-MT showed that control subjects had highly synchronous contraction (CURE 0.96 +/- 0.01), but tissue Doppler imaging indicated dyssynchrony in 44%. Using a cutoff of <0.75 for CURE based on receiver-operator characteristic analysis (area under the curve: 0.889), 56% of patients tested positive for mechanical dyssynchrony, and the MR-MT CURE predicted improved function class with 90% accuracy (positive and predictive values: 87%, 100%); adding DE-CMR (% total scar <15%) data improved accuracy further to 95% (positive and negative predictive values: 93%, 100%). The correlation between CURE and QRS duration was modest in all cardiomyopathy subjects (r = 0.58, p < 0.001). The multimodality cohort showed a 30% discordance rate between CURE and tissue Doppler imaging septal-lateral delay. CONCLUSIONS The MR-MT assessment of circumferential mechanical dyssynchrony predicts improvement in function class after CRT. The addition of scar imaging by DE-CMR further improves this predictive value.

Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) Trial

Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and Results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (−47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (−0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical Trial Registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.