Robert G. Weiss

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).

Magnetic Resonance Assessment of the Substrate for Inducible Ventricular Tachycardia in Nonischemic Cardiomyopathy

Background— Patients with left ventricular dysfunction have an elevated risk of sudden cardiac death. However, the substrate for ventricular arrhythmia in patients with nonischemic cardiomyopathy remains poorly understood. We hypothesized that the distribution of scar identified by MRI is predictive of inducible ventricular tachycardia. Methods and Results— Short-axis cine steady-state free-precession and postcontrast inversion-recovery gradient-echo MRI sequences were obtained before electrophysiological study in 26 patients with nonischemic cardiomyopathy. Left ventricular ejection fraction was measured from end-diastolic and end-systolic cine images. The transmural extent of scar as a percentage of wall thickness (percent scar transmurality) in each of 12 radial sectors per slice was calculated in all myocardial slices. The percentages of sectors with 1% to 25%, 26% to 50%, 51% to 75%, and 76% to 100% scar transmurality were determined for each patient. Predominance of scar distribution involving 26% to 75% of wall thickness was significantly predictive of inducible ventricular tachycardia and remained independently predictive in the multivariable model after adjustment for left ventricular ejection fraction (odds ratio, 9.125; P=0.020). Conclusions— MR assessment of scar distribution can identify the substrate for inducible ventricular tachycardia and may identify high-risk patients with nonischemic cardiomyopathy currently missed by ejection fraction criteria.

Clinical utility and safety of a protocol for noncardiac and cardiac magnetic resonance imaging of patients with permanent pacemakers and implantable-cardioverter defibrillators at 1.5 tesla.

Background— Magnetic resonance imaging (MRI) is an important diagnostic modality currently unavailable for millions of patients because of the presence of implantable cardiac devices. We sought to evaluate the diagnostic utility and safety of noncardiac and cardiac MRI at 1.5T using a protocol that incorporates device selection and programming and limits the estimated specific absorption rate of MRI sequences. Methods and Results— Patients with no imaging alternative and with devices shown to be MRI safe by in vitro phantom and in vivo animal testing were enrolled. Of 55 patients who underwent 68 MRI studies, 31 had a pacemaker, and 24 had an implantable defibrillator. Pacing mode was changed to “asynchronous” for pacemaker-dependent patients and to “demand” for others. Magnet response and tachyarrhythmia functions were disabled. Blood pressure, ECG, oximetry, and symptoms were monitored. Efforts were made to limit the system-estimated whole-body average specific absorption rate to 2.0 W/kg (successful in >99% of sequences) while maintaining the diagnostic capability of MRI. No episodes of inappropriate inhibition or activation of pacing were observed. There were no significant differences between baseline and immediate or long-term (median 99 days after MRI) sensing amplitudes, lead impedances, or pacing thresholds. Diagnostic questions were answered in 100% of nonthoracic and 93% of thoracic studies. Clinical findings included diagnosis of vascular abnormalities (9 patients), diagnosis or staging of malignancy (9 patients), and assessment of cardiac viability (13 patients). Conclusions— Given appropriate precautions, noncardiac and cardiac MRI can potentially be safely performed in patients with selected implantable pacemaker and defibrillator systems.

Regional Myocardial Metabolism of High-Energy Phosphates during Isometric Exercise in Patients with Coronary Artery Disease

BACKGROUND The maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. In animals, severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP. METHODS To determine whether ischemic metabolic changes are detectable in humans, we recorded spatially localized phosphorus-31 nuclear-magnetic-resonance (31P NMR) spectra from the anterior myocardium before, during, and after isometric hand-grip exercise. RESULTS The mean (+/- SD) ratio of phosphocreatine to ATP in the left ventricular wall when subjects were at rest was 1.72 +/- 0.15 in normal subjects (n = 11) and 1.59 +/- 0.31 in patients with nonischemic heart disease (n = 9), and the ratio did not change during hand-grip exercise in either group. However, in patients with coronary heart disease and ischemia due to severe stenosis (greater than or equal to 70 percent) of the left anterior descending or left main coronary arteries (n = 16), the ratio decreased from 1.45 +/- 0.31 at rest to 0.91 +/- 0.24 during exercise (P less than 0.001) and recovered to 1.27 +/- 0.38 two minutes after exercise. Only three patients with coronary heart disease had clinical symptoms of ischemia during exercise. Repeat exercise testing in five patients after revascularization yielded values of 1.60 +/- 0.20 at rest and 1.62 +/- 0.18 during exercise (P not significant), as compared with 1.51 +/- 0.19 at rest and 1.02 +/- 0.26 during exercise before revascularization (P less than 0.02). CONCLUSIONS The decrease in the ratio of phosphocreatine to ATP during hand-grip exercise in patients with myocardial ischemia reflects a transient imbalance between oxygen supply and demand in myocardium with compromised blood flow. Exercise testing with 31P NMR is a useful method of assessing the effect of ischemia on myocardial metabolism of high-energy phosphates and of monitoring the response to treatment.

Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy.

Myocardial high-energy phosphate metabolism in patients with dilated cardiomyopathy (DCM) of ischemic or idiopathic etiology was assessed at rest by one-dimensional phase-encoded 31P-nuclear magnetic resonance (NMR) spectroscopy studies performed in conjunction with 1H imaging in 20 patients with DCM and in 12 normal volunteers. The measured values of anterior myocardial phosphocreatine/beta-adenosine triphosphate (PCr/beta-ATP), corrected for partial saturation and contamination of the spectra by blood metabolites, averaged 1.80 +/- 0.06 (mean +/- SE) in normal volunteers and 1.46 +/- 0.07 in the patients overall, a highly significant (p less than 0.001) decrease. In patients with DCM accompanied by coronary artery disease (n = 9), the PCr/beta-ATP ratio averaged 1.53 +/- 0.07, while in those with DCM alone it was 1.41 +/- 0.12 (n = 11), a value that was not significantly different. There was no significant correlation (r = 0.34) between myocardial PCr/ATP ratio and left ventricular ejection fraction in patients. These studies demonstrate that myocardial PCr/ATP ratios are reduced at rest in human ischemic and idiopathic dilated cardiomyopathy.

Magnetic Resonance Imaging Overestimates Ferumoxide-Labeled Stem Cell Survival After Transplantation in the Heart

Background— Stem cell labeling with iron oxide (ferumoxide) particles allows labeled cells to be detected by magnetic resonance imaging (MRI) and is commonly used to track stem cell engraftment. However, the validity of MRI for distinguishing surviving ferumoxide-labeled cells from other sources of MRI signal, for example, macrophages containing ferumoxides released from nonsurviving cells, has not been thoroughly investigated. We sought to determine the relationship between the persistence of iron-dependent MRI signals and cell survival 3 weeks after injection of syngeneic or xenogeneic ferumoxides-labeled stem cells (cardiac-derived stem cells) in rats. Methods and Results— We studied nonimmunoprivileged human and rat cardiac-derived stem cells and human mesenchymal stem cells doubly labeled with ferumoxides and β-galactosidase and injected intramyocardially into immunocompetent Wistar-Kyoto rats. Animals were imaged at 2 days and 3 weeks after stem cell injection in a clinical 3-T MRI scanner. At 2 days, injection sites of xenogeneic and syngeneic cells (cardiac-derived stem cells and mesenchymal stem cells) were identified by MRI as large intramyocardial signal voids that persisted at 3 weeks (50% to 90% of initial signal). Histology (at 3 weeks) revealed the presence of iron-containing macrophages at the injection site, identified by CD68 staining, but very few or no β-galactosidase–positive stem cells in the animals transplanted with syngeneic or xenogeneic cells, respectively. Conclusions— The persistence of significant iron-dependent MRI signal derived from ferumoxide-containing macrophages despite few or no viable stem cells 3 weeks after transplantation indicates that MRI of ferumoxide-labeled cells does not reliably report long-term stem cell engraftment in the heart.

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.

Non-invasive magnetic-resonance detection of creatine depletion in non-viable infarcted myocardium

BACKGROUND Preserved energy metabolism is essential for myocardial viability and the creatine kinase reaction is central to energy production and reserve. Although the appearance of myocardial creatine kinase enzyme in the blood is widely used to diagnose cardiac necrosis, there are no non-invasive ways to measure local creatine concentrations in the healthy and diseased human heart. METHODS We measured total myocardial creatine by spatially-localised, water-suppressed hydrogen magnetic-resonance spectroscopy (1H-MRS) on a clinical (1.5 T) magnetic-resonance-imaging system in ten healthy volunteers (controls) and ten patients with a history of myocardial infarction. We validated this technique by comparison of 1H-MRS values of creatine with biopsy assays in an animal model of infarction. FINDINGS Total creatine was measured in the posterior and anterior left ventricle and septum, and was significantly lower in regions of infarction (10 [9] SD micromol/g wet weight) than in non-infarcted regions (26 [11] micromol/g, p=0.001) of myocardium in patients or in the myocardium of healthy controls (28 [6] micromol/g, p<0.0001). INTERPRETATION Spatially localised 1H-MRS can be used to measure total creatine non-invasively throughout the human heart. The detection of regional creatine depletion may provide a metabolic means to distinguish healthy from infarcted non-viable myocardium.

Altered Creatine Kinase Adenosine Triphosphate Kinetics in Failing Hypertrophied Human Myocardium

Background— The progression of pressure-overload left ventricular hypertrophy (LVH) to chronic heart failure (CHF) may involve a relative deficit in energy supply and/or delivery. Methods and Results— We measured myocardial creatine kinase (CK) metabolite concentrations and adenosine triphosphate (ATP) synthesis through CK, the primary energy reserve of the heart, to test the hypothesis that ATP flux through CK is impaired in patients with LVH and CHF. Myocardial ATP levels were normal, but creatine phosphate levels were 35% lower in LVH patients (n=10) than in normal subjects (n=14, P<0.006). Left ventricular mass and CK metabolite levels in LVH were not different from those in patients with LVH and heart failure (LVH+CHF, n=10); however, the myocardial CK pseudo first-order rate constant was normal in LVH (0.36±0.04 s−1 in LVH versus 0.32±0.06 s−1 in normal subjects) but halved in LVH+CHF (0.17±0.06 s−1, P<0.001). The net ATP flux through CK was significantly reduced by 30% in LVH (2.2±0.7 &mgr;mol · g−1 · s−1, P=0.011) and by a dramatic 65% in LVH+CHF (1.1±0.4 &mgr;mol · g−1 · s−1, P<0.001) compared with normal subjects (3.1±0.8 &mgr;mol · g−1 · s−1). Conclusions— These first observations in human LVH demonstrate that it is not the relative or absolute CK metabolite pool sizes but rather the kinetics of ATP turnover through CK that distinguish failing from nonfailing hypertrophic hearts. Moreover, the deficit in ATP kinetics is similar in systolic and nonsystolic heart failure and is not related to the severity of hypertrophy but to the presence of CHF. Because CK temporally buffers ATP, these observations support the hypothesis that a deficit in myofibrillar energy delivery contributes to CHF pathophysiology in human LVH.