Anthony H. Aletras

Retrospective Determination of the Area at Risk for Reperfused Acute Myocardial Infarction With T2-Weighted Cardiac Magnetic Resonance Imaging Histopathological and Displacement Encoding With Stimulated Echoes (DENSE) Functional Validations

Background— The aim of this study was to determine whether edema imaging by T2-weighted cardiac magnetic resonance (CMR) imaging could retrospectively delineate the area at risk in reperfused myocardial infarction. We hypothesized that the size of the area at risk during a transient occlusion would be similar to the T2-weighted hyperintense region observed 2 days later, that the T2-weighted hyperintense myocardium would show partial functional recovery after 2 months, and that the T2 abnormality would resolve over 2 months. Methods and Results— Seventeen dogs underwent a 90-minute coronary artery occlusion, followed by reperfusion. The area at risk, as measured with microspheres (9 animals), was comparable to the size of the hyperintense zone on T2-weighted images 2 days later (43.4±3.3% versus 43.0±3.4% of the left ventricle; P=NS), and the 2 measures correlated (R=0.84). The infarcted zone was significantly smaller (23.1±3.7; both P<0.001). To test whether the hyperintense myocardium would exhibit partial functional recovery over time, 8 animals were imaged on day 2 and 2 months later. Systolic strain was mapped with displacement encoding with stimulated echoes. Edema, as detected by a hyperintense zone on T2-weighted images, resolved, and regional radial systolic strain partially improved from 4.9±0.7 to 13.1±1.5 (P=0.001) over 2 months. Conclusions— These findings are consistent with the premise that the T2 abnormality depicts the area at risk, a zone of reversibly and irreversibly injured myocardium associated with reperfused subendocardial infarctions. The persistence of postischemic edema allows T2-weighted CMR to delineate the area at risk 2 days after reperfused myocardial infarction.

Phase-sensitive inversion recovery for detecting myocardial infarction using gadolinium-delayed hyperenhancement.

After administration of gadolinium, infarcted myocardium exhibits delayed hyperenhancement and can be imaged using an inversion recovery (IR) sequence. The performance of such a method when using magnitude‐reconstructed images is highly sensitive to the inversion recovery time (TI) selected. Using phase‐sensitive reconstruction, it is possible to use a nominal value of TI, eliminate several breath‐holds otherwise needed to find the precise null time for normal myocardium, and achieve a consistent contrast. Phase‐sensitive detection is used to remove the background phase while preserving the sign of the desired magnetization during IR. Experimental results are presented which demonstrate the benefits of both phase‐sensitive IR image reconstruction and surface coil intensity normalization for detecting myocardial infarction (MI). The phase‐sensitive reconstruction method reduces the variation in apparent infarct size that is observed in the magnitude images as TI is changed. Phase‐sensitive detection also has the advantage of decreasing the sensitivity to changes in tissue T1 with increasing delay from contrast agent injection. Magn Reson Med 47:372–383, 2002. Published 2002 Wiley‐Liss, Inc.

Detecting Acute Coronary Syndrome in the Emergency Department With Cardiac Magnetic Resonance Imaging

Background—Managing chest pain in the emergency department remains a challenge with current diagnostic strategies. We hypothesized that cardiac MRI could accurately identify patients with possible or probable acute coronary syndrome. Methods and Results—The diagnostic performance of MRI was evaluated in a prospective study of 161 consecutive patients. Enrollment required 30 minutes of chest pain compatible with myocardial ischemia but an ECG not diagnostic of acute myocardial infarction. MRI was performed at rest within 12 hours of presentation and included perfusion, left ventricular function, and gadolinium-enhanced myocardial infarction detection. MRI was interpreted qualitatively but also analyzed quantitatively. The sensitivity and specificity, respectively, for detecting acute coronary syndrome were 84% and 85% by MRI, 80% and 61% by an abnormal ECG, 16% and 95% for strict ECG criteria for ischemia (ST depression or T-wave inversion), 40% and 97% for peak troponin-I, and 48% and 85% for a TIMI risk score ≥3. The MRI was more sensitive than strict ECG criteria for ischemia (P <0.001), peak troponin-I (P <0.001), and the TIMI risk score (P =0.004), and MRI was more specific than an abnormal ECG (P <0.001). Multivariate logistic regression analysis showed MRI was the strongest predictor of acute coronary syndrome and added diagnostic value over clinical parameters (P <0.001). Conclusions—Resting cardiac MRI exhibited diagnostic operating characteristics suitable for triage of patients with chest pain in the emergency department. Performed urgently to evaluate chest pain, MRI accurately detected a high fraction of patients with acute coronary syndrome, including patients with enzyme-negative unstable angina.

The Overall Pattern of Cardiac Contraction Depends on a Spatial Gradient of Myosin Regulatory Light Chain Phosphorylation

Evolution of the human heart has incorporated a variety of successful strategies for motion used throughout the animal kingdom. One such strategy is to add the efficiency of torsion to compression so that blood is wrung, as well as pumped, out of the heart. Models of cardiac torsion have assumed uniform contractile properties of muscle fibers throughout the heart. Here, we show how a spatial gradient of myosin light chain phosphorylation across the heart facilitates torsion by inversely altering tension production and the stretch activation response. To demonstrate the importance of cardiac light chain phosphorylation, we cloned a myosin light chain kinase from a human heart and have identified a gain-in-function mutation in two individuals with cardiac hypertrophy.

T2-prepared SSFP improves diagnostic confidence in edema imaging in acute myocardial infarction compared to turbo spin echo.

T2‐weighted MRI of edema in acute myocardial infarction (MI) provides a means of differentiating acute and chronic MI, and assessing the area at risk of infarction. Conventional T2‐weighted imaging of edema uses a turbo spin‐echo (TSE) readout with dark‐blood preparation. Clinical applications of dark‐blood TSE methods can be limited by artifacts such as posterior wall signal loss due to through‐plane motion, and bright subendocardial artifacts due to stagnant blood. Single‐shot imaging with a T2‐prepared SSFP readout provides an alternative to dark‐blood TSE and may be conducted during free breathing. We hypothesized that T2‐prepared SSFP would be a more reliable method than dark‐blood TSE for imaging of edema in patients with MI. In patients with MI (22 acute and nine chronic MI cases), T2‐weighted imaging with both methods was performed prior to contrast administration and delayed‐enhancement imaging. The T2‐weighted images using TSE were nondiagnostic in three of 31 cases, while six additional cases rated as being of diagnostic quality yielded incorrect diagnoses. In all 31 cases the T2‐prepared SSFP images were rated as diagnostic quality, correctly differentiated acute or chronic MI, and correctly determined the coronary territory. Free‐breathing T2‐prepared SSFP provides T2‐weighted images of acute MI with fewer artifacts and better diagnostic accuracy than conventional dark‐blood TSE. Magn Reson Med 57:891–897, 2007. Published 2007 Wiley‐Liss, Inc.

Myocardial Edema as Detected by Pre-Contrast T1 and T2 CMR Delineates Area at Risk Associated With Acute Myocardial Infarction

OBJECTIVES The aim of this study was to determine whether cardiac magnetic resonance (CMR) in vivo T1 mapping can measure myocardial area at risk (AAR) compared with microspheres or T2 mapping CMR. BACKGROUND If T2-weighted CMR is abnormal in the AAR due to edema related to myocardial ischemia, then T1-weighted CMR should also be able to detect and accurately quantify AAR. METHODS Dogs (n = 9) underwent a 2-h coronary occlusion followed by 4 h of reperfusion. CMR of the left ventricle was performed for mapping of T1 and T2 prior to any contrast administration. AAR was defined as regions that had a T1 or T2 value (ms) >2 SD from remote myocardium, and regions with microsphere blood flow (ml/min/g) during occlusion <2 SD from remote myocardium. Infarct size was determined by triphenyltetrazolium chloride staining. RESULTS The relaxation parameters T1 and T2 were increased in the AAR compared with remote myocardium (mean ± SD: T1, 1,133 ± 55 ms vs. 915 ± 33 ms; T2, 71 ± 6 ms vs. 49 ± 3 ms). On a slice-by-slice basis (n = 78 slices), AAR by T1 and T2 mapping correlated (R(2) = 0.95, p < 0.001) with good agreement (mean ± 2 SD: 0.4 ± 16.6% of slice). On a whole-heart analysis, T1 measurements of left ventricular mass, AAR, and myocardial salvage correlated to microsphere measures (R(2) = 0.94) with good agreement (mean ± 2 SD: -1.4 ± 11.2 g of myocardium). Corresponding T2 measurements of left ventricular mass, AAR, and salvage correlated to microsphere analysis (R(2) = 0.96; mean ± 2 SD: agreement 1.6 ± 9.2 g of myocardium). This yielded a median infarct size of 30% of the AAR (range 12% to 52% of AAR). CONCLUSIONS For determining AAR after acute myocardial infarction, noncontrast T1 mapping and T2 mapping sequences yield similar quantitative results, and both agree well with microspheres. The relaxation properties T1 and T2 both change in a way that is consistent with the presence of myocardial edema following myocardial ischemia/reperfusion.

Quantitative myocardial infarction on delayed enhancement MRI. Part I: Animal validation of an automated feature analysis and combined thresholding infarct sizing algorithm

To develop a computer algorithm to measure myocardial infarct size in gadolinium‐enhanced magnetic resonance (MR) imaging and to validate this method using a canine histopathological reference.

Prevalence and Prognosis of Unrecognized Myocardial Infarction Determined by Cardiac Magnetic Resonance in Older Adults

CONTEXT Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI). OBJECTIVE Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals. DESIGN, SETTING, AND PARTICIPANTS ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. MAIN OUTCOME MEASURES Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI). RESULTS Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001). CONCLUSIONS In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01322568.

Nitrite Anion Provides Potent Cytoprotective and Antiapoptotic Effects as Adjunctive Therapy to Reperfusion for Acute Myocardial Infarction

Background— Accumulating evidence suggests that the ubiquitous anion nitrite (NO2−) is a physiological signaling molecule, with roles in intravascular endocrine nitric oxide transport, hypoxic vasodilation, signaling, and cytoprotection. Thus, nitrite could enhance the efficacy of reperfusion therapy for acute myocardial infarction. The specific aims of this study were (1) to assess the efficacy of nitrite in reducing necrosis and apoptosis in canine myocardial infarction and (2) to determine the relative role of nitrite versus chemical intermediates, such as S-nitrosothiols. Methods and Results— We evaluated infarct size, microvascular perfusion, and left ventricular function by histopathology, microspheres, and magnetic resonance imaging in 27 canines subjected to 120 minutes of coronary artery occlusion. This was a blinded, prospective study comparing a saline control group (n=9) with intravenous nitrite during the last 60 minutes of ischemia (n=9) and during the last 5 minutes of ischemia (n=9). In saline-treated control animals, 70±10% of the area at risk was infarcted compared with 23±5% in animals treated with a 60-minute nitrite infusion. Remarkably, a nitrite infusion in the last 5 minutes of ischemia also limited the extent of infarction (36±8% of area at risk). Nitrite improved microvascular perfusion, reduced apoptosis, and improved contractile function. S-Nitrosothiol and iron-nitrosyl-protein adducts did not accumulate in the 5-minute nitrite infusion, suggesting that nitrite is the bioactive intravascular nitric oxide species accounting for cardioprotection. Conclusions— Nitrite has significant potential as adjunctive therapy to enhance the efficacy of reperfusion therapy for acute myocardial infarction.

ACUT2E TSE-SSFP: a hybrid method for T2-weighted imaging of edema in the heart.

ACUT2E TSE‐SSFP is a hybrid between steady state free precession (SSFP) and turbo spin echo (TSE) for bright‐blood T2‐weighted imaging with signal‐to‐noise ratio (SNR) and contrast‐to‐noise ratio (CNR) similar to dark‐blood TSE. TSE‐SSFP uses a segmented SSFP readout during diastole with 180° pulses following a 90° preparation. The 180° refocusing pulses make TSE‐SSFP similar to TSE but TSE‐SSFP uses gradient moment nulling, whereas TSE uses gradient crushing. TSE‐SSFP produced T2‐weighted images with minimal T1 weighting. TSE‐SSFP and TSE had similar SNR (155.9 ± 6.0 vs 160.9 ± 7.0; P = NS) for acute myocardial infarction (MI) and twice the SNR of T2‐prepared SSFP (73.1 ± 3.4, P < 0.001). TSE‐SSFP and TSE had approximately double the CNR of T2‐prepared SSFP for differentiating acute MI from normal myocardium. Imperfect blood suppression, present in all animals on some TSE images, was a problem eliminated by TSE‐SSFP and T2‐prepared SSFP. Magn Reson Med 59:229–235, 2008.