Michael D. Elliott

Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study

BACKGROUND Myocardial infarcts are routinely detected by nuclear imaging techniques such as single photon emission computed tomography (SPECT) myocardial perfusion imaging. A newly developed technique for infarct detection based on contrast-enhanced cardiovascular magnetic resonance (CMR) has higher spatial resolution than SPECT. We postulated that this technique would detect infarcts missed by SPECT. METHODS We did contrast-enhanced CMR and SPECT examinations in 91 patients with suspected or known coronary artery disease. All CMR and SPECT images were scored, using a 14-segment model, for the presence, location, and spatial extent of infarction. To compare each imaging modality to a gold standard, we also acquired contrast-enhanced CMR and SPECT images in 12 dogs with, and three dogs without, myocardial infarction as defined by histochemical staining. FINDINGS In animals, contrast-enhanced CMR and SPECT detected all segments with nearly transmural infarction (>75% transmural extent of the left-ventricular wall). CMR also identified 100 of the 109 segments (92%) with subendocardial infarction (<50% transmural extent of the left-ventricular wall), whereas SPECT identified only 31 (28%). SPECT and CMR showed high specificity for the detection of infarction (97% and 98%, respectively). In patients, all segments with nearly transmural infarction, as defined by contrast-enhanced CMR, were detected by SPECT. However, of the 181 segments with subendocardial infarction, 85 (47%) were not detected by SPECT. On a per patient basis, six (13%) individuals with subendocardial infarcts visible by CMR had no evidence of infarction by SPECT. INTERPRETATION SPECT and CMR detect transmural myocardial infarcts at similar rates. However, CMR systematically detects subendocardial infarcts that are missed by SPECT.

Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy

OBJECTIVES We sought to ascertain whether myocardial scarring occurs in living unselected patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Myocardial scarring is known to occur in select HCM patients, who were highly symptomatic prior to death or who died suddenly. The majority of HCM patients, however, are minimally symptomatic and have not suffered sudden death. METHODS Cine and gadolinium-enhanced magnetic resonance imaging was performed in 21 HCM patients who were predominantly asymptomatic. Gadolinium hyperenhancement was assumed to represent myocardial scar, and the extent of scar was compared to left ventricular (LV) morphology and function. RESULTS Scarring was present in 17 patients (81%). Scarring occurred only in hypertrophied regions (> or =10 mm), was patchy with multiple foci, and predominantly involved the middle third of the ventricular wall. All 17 patients had scarring at the junction of the interventricular septum and the right ventricular (RV) free wall. On a regional basis, the extent of scarring correlated positively with wall thickness (r = 0.36, p < 0.0001), and inversely with wall thickening (r = -0.21, p < 0.0001). On a per patient basis, the extent of scarring (mean, 8 +/- 9% of LV mass) was minimally related to maximum wall thickness (r = 0.40, p = 0.07) and LV mass (r = 0.33, p = 0.15), and correlated inversely with ejection fraction (r = -0.46, p = 0.04). CONCLUSIONS Myocardial scarring is common in asymptomatic or mildly symptomatic HCM patients who have not suffered sudden death. When present, scarring occurs in hypertrophied regions, is consistently localized to the junctions of the septum and RV free wall, and correlates positively with regional hypertrophy and inversely with regional contraction.

Reproducibility of Chronic Infarct Size Measurement by Contrast-Enhanced Magnetic Resonance Imaging

Background—The reproducibility of contrast-enhanced MRI has not been established. We compared MRI reproducibility for infarct size determination with that of 99mTc-sestamibi (MIBI) single photon emission computed tomography (SPECT). Methods and Results—Patients with chronic myocardial infarction defined by enzymes (peak creatine kinase-MB 173±119 U/L) were scanned twice by MRI (MRI I and MRI II, n=20) and twice by SPECT (SPECT I and SPECT II, n=15) on the same day. The MRI contrast agent was injected during MRI I but not MRI II to test the effect of imaging time after contrast. Resting Tc-MIBI SPECT images were acquired and infarct size was determined with commercial software. Infarct size in patients scanned by MRI and SPECT was 14±6% of left ventricular mass (%LV) by MRI (range 4%LV to 27%LV) and 14±7%LV by SPECT (range 4%LV to 26%LV). MRI I and II scans were performed 10±2 and 27±3 minutes after contrast, respectively. For MRI, the difference in infarct size between scans I and II (bias) was −0.1%LV, and the coefficient of repeatability was ±2.4%LV. For SPECT, bias was −1.3%LV, and the coefficient of repeatability was ±4.0%LV. Within individual patients, no systematic differences in infarct size were detected when the 2 MRI scans were compared, the 2 SPECT scans were compared, or MRI was compared to SPECT. Conclusion—The size of healed infarcts measured by contrast-enhanced MRI does not change between 10 and 30 minutes after contrast. The clinical reproducibility of contrast-enhanced MRI for infarct size determination compares favorably with that of routine clinical SPECT.

Detection of Myocardial Damage in Patients With Sarcoidosis

Background— In patients with sarcoidosis, sudden death is a leading cause of mortality, which may represent unrecognized cardiac involvement. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can detect minute amounts of myocardial damage. We sought to compare DE-CMR with standard clinical evaluation for the identification of cardiac involvement. Methods and Results— Eighty-one consecutive patients with biopsy-proven extracardiac sarcoidosis were prospectively recruited for a parallel and masked comparison of cardiac involvement between (1) DE-CMR and (2) standard clinical evaluation with the use of consensus criteria (modified Japanese Ministry of Health [JMH] guidelines). Standard evaluation included 12-lead ECG and at least 1 dedicated non-CMR cardiac study (echocardiography, radionuclide scintigraphy, or cardiac catheterization). Patients were followed for 21±8 months for major adverse events (death, defibrillator shock, or pacemaker requirement). Patients were predominantly middle-aged (46±11 years), female (62%), and black (73%) and had chronic sarcoidosis (median, 7 years) and preserved left ventricular ejection fraction (median, 56%). DE-CMR identified cardiac involvement in 21 patients (26%) and JMH criteria in 10 (12%, 8 overlapping), a >2-fold higher rate for DE-CMR (P=0.005). All patients with myocardial damage on DE-CMR had coronary disease excluded by x-ray angiography. Pathology evaluation in 15 patients (19%) identified 4 with cardiac sarcoidosis; all 4 were positive by DE-CMR, whereas 2 were JMH positive. On follow-up, 8 had adverse events, including 5 cardiac deaths. Patients with myocardial damage on DE-CMR had a 9-fold higher rate of adverse events and an 11.5-fold higher rate of cardiac death than patients without damage. Conclusions— In patients with sarcoidosis, DE-CMR is more than twice as sensitive for cardiac involvement as current consensus criteria. Myocardial damage detected by DE-CMR appears to be associated with future adverse events including cardiac death, but events were few, and this needs confirmation in a larger cohort.

Performance of Delayed-Enhancement Magnetic Resonance Imaging With Gadoversetamide Contrast for the Detection and Assessment of Myocardial Infarction An International, Multicenter, Double-Blinded, Randomized Trial

Background— The identification and assessment of myocardial infarction (MI) are important for therapeutic and prognostic purposes, yet current recommended diagnostic strategies have significant limitations. We prospectively tested the performance of delayed-enhancement magnetic resonance imaging (MRI) with gadolinium-based contrast for the detection of MI in an international, multicenter trial. Methods and Results— Patients with their first MI were enrolled in an acute (≤16 days after MI; n=282) or chronic (17 days to 6 months; n=284) arm and then randomized to 1 of 4 doses of gadoversetamide: 0.05, 0.1, 0.2, or 0.3 mmol/kg. Standard delayed-enhancement MRI was performed before contrast (control) and 10 and 30 minutes after gadoversetamide. For blinded analysis, precontrast and postcontrast MRIs were randomized and then scored for enhanced regions by 3 independent readers not associated with the study. The infarct-related artery perfusion territory was scored from x-ray angiograms separately. In total, 566 scans were performed in 26 centers using commercially available scanners from all major US/European vendors. All scans were included in the analysis. The sensitivity of MRI for detecting MI increased with rising dose of gadoversetamide (P<0.0001), reaching 99% (acute) and 94% (chronic) after contrast compared with 11% before contrast. Likewise, the accuracy of MRI for identifying MI location (compared with infarct-related artery perfusion territory) increased with rising dose of gadoversetamide (P<0.0001), reaching 99% (acute) and 91% (chronic) after contrast compared with 9% before contrast. For gadoversetamide doses ≥0.2 mmol/kg, 10- and 30-minute images provided equal performance, and peak creatine kinase-MB levels correlated with MRI infarct size (P<0.0001). Conclusions— Gadoversetamide-enhanced MRI using doses of ≥0.2 mmol/kg is effective in the detection and assessment of both acute and chronic MI. This study represents the first multicenter trial designed to evaluate an imaging approach for detecting MI.

Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial

BACKGROUND Secretory phospholipase A(2) (sPLA(2)) enzymes, produced and secreted in human blood vessels and hepatocytes, contribute to the development of atherosclerosis through mechanisms that are both dependent and independent of lipoprotein. We examined the effects of an sPLA(2) inhibitor on enzyme concentration and on plasma lipoproteins and inflammatory biomarkers in patients with coronary heart disease. METHODS Patients aged 18 years and older with stable coronary heart disease from the USA and Ukraine were eligible for enrolment in this phase II, randomised, double-blind, placebo-controlled, parallel-arm, dose-response study. 393 patients were randomly assigned by computer-generated sequence to receive either placebo (n=79) or one of four doses of an sPLA(2) inhibitor, A-002 (1-H-indole-3-glyoxamide; 50 mg [n=79], 100 mg [n=80], 250 mg [n=78], or 500 mg [n=77] twice daily), for 8 weeks. The primary endpoint was the change in sPLA(2) group IIA (sPLA(2)-IIA) concentration or activity from baseline to week 8. Analysis was by modified intention to treat (ITT). The ITT population consisted of all patients who received one dose of study treatment; data for patients who dropped out before the end of the study were carried forward from last observation. This trial is registered with ClinicalTrials.gov, number NCT00455546. FINDINGS All randomised patients received at least one dose and were included in the ITT population. Data for 45 patients were carried forward from last observation (36 in the A-002 group and nine in the placebo group); the main reason for dropout before completion was because of adverse events. 348 patients reached the primary endpoint (A-002 n=278, placebo n=70). Mean sPLA(2)-IIA concentration fell by 86.7%, from 157 pmol/L to 21 [corrected] pmol/L, in the overall active treatment group, and by 4.8%, from 157 pmol/L to 143 [corrected] pmol/L, in the placebo group (p<0.0001 treatment vs placebo). The reductions in sPLA(2)-IIA concentration in the A-002 groups were dose dependent (ranging from 69.2% in the 50 mg group to 95.8% in the 500 mg group) and differed significantly from placebo (p<0.0001 for all doses). In the 500 mg A-002 treatment group, there was one serious adverse event (exacerbation of underlying chronic obstructive pulmonary disease), but the proportion of patients reporting treatment-emergent adverse events did not differ from placebo. The main side-effects of the drug included headache (n=20), nausea (n=17), and diarrhoea (n=12). INTERPRETATION The reductions in sPLA(2)-IIA concentration suggest that A-002 might be an effective anti-atherosclerotic agent.

Rapid Detection of Myocardial Infarction by Subsecond, Free-Breathing Delayed Contrast-Enhancement Cardiovascular Magnetic Resonance

Background— An ultrafast, delayed contrast-enhancement cardiovascular magnetic resonance technique that can acquire subsecond, “snapshot” images during free breathing (subsecond) is becoming widely available. This technique provides myocardial infarction (MI) imaging with complete left ventricular coverage in <30 seconds. However, the accuracy of this technique is unknown. Methods and Results— We prospectively compared subsecond imaging with routine breath-hold delayed contrast-enhancement cardiovascular magnetic resonance (standard) in consecutive patients. Two cohorts with unambiguous standards of truth were prespecified: (1) patients with documented prior MI (n=135) and (2) patients without MI and with low likelihood of coronary disease (lowest Framingham risk category; n=103). Scans were scored masked to identity and clinical information. Sensitivity, specificity, and accuracy of subsecond imaging for MI diagnosis were 87%, 96%, and 91%, respectively. Compared with the standard technique (98%, 100%, 99%), the subsecond technique had modestly reduced sensitivity (P=0.0001), but specificity was excellent. Missed infarcts were generally small or subendocardial (87%). Overall, regional transmural extent of infarction scores were highly concordant (2083/2294; 91%); however, 51 of 337 regions (15%) considered predominantly infarcted (>50% transmural extent of infarction) by the standard technique were considered viable (≤25% transmural extent of infarction) by the subsecond technique. Quantitative analysis demonstrated moderately reduced contrast-to-noise ratios for subsecond imaging between infarct and remote myocardium (12.0±7.2 versus 20.1±6.6; P<0.0001) and infarct and left ventricular cavity (−2.5±2.7 versus 3.6±3.7; P<0.0001). Conclusions— MI can be rapidly detected by subsecond delayed contrast-enhancement cardiovascular magnetic resonance during free breathing with high accuracy. This technique could be considered the preferred approach in patients who are more acutely ill or unable to hold their breath. However, compared with standard imaging, sensitivity is mildly reduced, and the transmural extent of infarction may be underestimated.

Effects of Varespladib Methyl on Biomarkers and Major Cardiovascular Events in Acute Coronary Syndrome Patients

OBJECTIVES The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients. BACKGROUND Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients. METHODS This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months. RESULTS After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed. CONCLUSIONS Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).

Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease

AIMS To investigate the effects of secretory phospholipase A2 (sPLA(2)) inhibition on plasma lipoproteins. Secretory phospholipase A2 isoenzymes promote atherosclerosis by mechanisms that include lipoprotein modification, retention, and oxidation. METHODS AND RESULTS Phospholipase Levels And Serological Markers of Atherosclerosis II (PLASMA II) is a Phase II, randomized, double-blind, placebo-controlled parallel-arm study of two once-daily doses of the novel sPLA(2) inhibitor, 1-H-indole-3-glyoxamide or varespladib methyl (Anthera Pharmaceuticals, Hayward, CA, USA). One hundred and thirty-five stable coronary heart disease patients were treated with either varespladib methyl 250 mg once daily, varespladib methyl 500 mg once daily, or placebo for 8 weeks. Varespladib methyl treatment resulted in statistically significant dose-dependent reductions that were different from placebo in sPLA(2) concentration, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (HDL) cholesterol. When compared with placebo, varespladib methyl 500 mg once daily reduced LDL cholesterol by 15% (P < 0.001), non-HDL cholesterol by 15% (P < 0.001), total very LDL (VLDL) particle concentration by 14% (P = 0.022), and small VLDL particle concentration by 24% (P = 0.030). Relative to baseline, varespladib methyl 500 mg once daily reduced total LDL particle concentration (7%, P = 0.002) and small LDL particle concentration (11%, P = 0.014). CONCLUSION Reductions in atherogenic lipoproteins suggest that varespladib methyl 500 mg once daily may be an effective anti-atherosclerotic agent. Trial registered at ClinicalTrials.gov, identifier: NCT00525954.

Impact of limited treadmill exercise on adenosine Tc-99m sestamibi single-photon emission computed tomographic myocardial perfusion imaging in coronary artery disease

Limited exercise combined with dipyridamole increases myocardial perfusion defect severity compared with dipyridamole alone. The impact of limited exercise combined with adenosine on myocardial perfusion defect severity is unknown. This study compares myocardial perfusion defect severity with adenosine alone and adenosine combined with limited exercise. Thirty-two patients with coronary artery disease underwent on separate days and in randomized order technetium-99m sestamibi (25 to 30 mCi) single-photon emission computed tomographic imaging at rest, after adenosine (140 microg/kg/min x 6 minutes), and after adenosine (140 microg/kg/min x 4 minutes) during 6 minutes of modified Bruce treadmill exercise (adenosine-exercise). Radiopharmaceutical was injected at 3 and 5 minutes during adenosine and adenosine-exercise, respectively. Images were interpreted by a consensus agreement of 3 nuclear cardiologists without knowledge of patient identity, stress protocol, or clinical data using a 17-segment model and 5-point scoring system. A summed stress score (SSS), summed rest score (SRS), and summed difference (SSS-SRS) score (SDS) were calculated for each image. Peak stress heart rate and rate-pressure product were higher for adenosine-exercise than adenosine (102 +/- 19 vs 81 +/- 11 beats/min and 13,972 +/- 4,265 vs 10,623 +/- 2,131, respectively; both p <0.001). Sensitivity for detection of > or = 50% coronary stenosis was 75% and 72% for adenosine-exercise and adenosine, respectively (p = NS). There were no differences in SSS and SDS between adenosine-exercise and adenosine (8.2 +/- 5.9 vs 8.1 +/- 6.3 and 4.9 +/- 4.1 vs 5.2 +/- 4.6, respectively; both p = NS). Thus, in patients with coronary artery disease, limited treadmill exercise combined with adenosine does not increase myocardial perfusion defect severity compared with standard adenosine technetium-99m sestamibi single-photon emission computed tomographic myocardial perfusion imaging.