Gerald Wisenberg

The Use of 18F-FDG PET in the Diagnosis of Cardiac Sarcoidosis: A Systematic Review and Metaanalysis Including the Ontario Experience

Cardiac sarcoidosis is a potentially fatal complication of sarcoidosis. The 1993 guidelines of the Ministry of Health, Labour, and Welfare (MHLW) of Japan have been used as the diagnostic gold standard and for comparison with imaging modalities. 18F-FDG PET is not currently included in the guidelines. However, studies have shown promising data using 18F-FDG PET. We conducted a systematic review of studies that evaluated the accuracy of 18F-FDG PET for the diagnosis of cardiac sarcoidosis compared with MHLW guidelines. Data from a prospective Ontario provincial registry are also reported and included in the metaanalysis. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies that satisfied predetermined criteria. Quality evaluation using the Quality Assessment for Diagnostic Accuracy Studies was performed by 2 independent masked observers. Data were extracted and analyzed to measure study-specific and pooled accuracy for 18F-FDG PET compared with the MHLW as the reference. Results: A total of 519 titles was identified; 7 studies, including the Ontario registry, were selected for inclusion. Metaanalysis of these 7 studies was conducted, with a total of 164 patients, most of whom had been diagnosed with systemic sarcoidosis. The prevalence of cardiac sarcoidosis was 50% in the whole population. Pooled estimates for 18F-FDG PET yielded 89% sensitivity (95% confidence interval [CI], 79%–96%), 78% specificity (95% CI, 68%–86%), a 4.1 positive likelihood ratio (95% CI, 1.7–10), and a 0.19 negative likelihood ratio (95% CI, 0.1–0.4). The overall diagnostic odds ratio was 25.6 (95% CI, 7.3–89.5), and the area under the summary receiver operator characteristic curve was 93% ± 3.5. The Ontario study yielded sensitivity and specificity of 79% and 70%, respectively. Conclusion: The high diagnostic accuracy determined for 18F-FDG PET in this metaanalysis suggests potential value for diagnosis of cardiac sarcoidosis compared with the MHLW guidelines. These results may affect patient care by providing supportive evidence for more effective use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis. Large-scale multicenter studies are required to further evaluate this role.

Prediction of Arrhythmic Events in Ischemic and Dilated Cardiomyopathy Patients Referred for Implantable Cardiac Defibrillator Evaluation of Multiple Scar Quantification Measures for Late Gadolinium Enhancement Magnetic Resonance Imaging

Background— Scar signal quantification using late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) identifies patients at higher risk of future events, both in ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (DCM). However, the ability of scar signal burden to predict events in such patient groups at the time of referral for implantable cardioverter-defibrillator (ICD) has not been well explored. This study evaluates the predictive use of multiple scar quantification measures in ICM and DCM patients being referred for ICD. Methods and Results— One hundred twenty-four consecutive patients referred for ICD therapy (59 with ICM and 65 with DCM) underwent a standardized LGE-CMR protocol with blinded, multithreshold scar signal quantification and, for those with ICM, peri-infarct signal quantification. Patients were followed prospectively for the primary combined outcome of appropriate ICD therapy, survived cardiac arrest, or sudden cardiac death. At a mean follow-up of 632 ± 262 days, 18 patients (15%) had suffered the primary outcome. Total scar was significantly higher among those suffering a primary outcome, a relationship maintained within each cardiomyopathy cohort (P<0.01 for all comparisons). Total scar was the strongest independent predictor of the primary outcome and demonstrated a negative predictive value of 86%. In the ICM subcohort, peri-infarct signal showed only a nonsignificant trend toward elevation among those having a primary end point. Conclusions— Myocardial scar quantification by LGE-CMR predicts arrhythmic events in patients being evaluated for ICD eligibility irrespective of cardiomyopathy etiology.

In vivo quantitation of regional myocardial blood flow by positron-emission computed tomography.

The potential of positron-emission computed tomography (PCT) for external quantitation of myocardial indicator concentrations and regonal myocardial blood flow (RMBF) and the effect of left ventricular wall thickness on tracer concentration recovery by PCT was examined in seven open-chest dogs. RMBF was determined by the arterial reference technique in vivo and in vitro. Together with gamma-emitting Ce-141 microspheres, positron-emitting Ga-68-labeled microspheres were injected into the left atrium and their myocardial concentrations determined in vivo from gated and ungated cross-sectional PCT images. It is concluded that (1) myocardial indicator tissue concentrations, and thus, RMBF, can be accurately measured by PCT provided corrections are made for the effect of wall thickness on count recovery; (2) these corrections can be made using in vivo echocardiography; and (3) gated PCT imaging can be used to evaluate regional myocardial systolic wall thickening as an index of regional function and combined with measurements of RMBF or regional metabolism. The results represent a framework for the noninvasive measurement of RMBF and metabolism by PCT in the experimental animal and in man.

Serial nuclear magnetic resonance imaging of acute myocardial infarction with and without reperfusion

To compare nuclear magnetic resonance (NMR) image-derived T1 and T2 changes during evolving infarction, 14 dogs were studied serially: (1) 1 to 2 hours after left anterior descending coronary occlusion, (2) 2 to 3 hours after coronary occlusion (n = 7) or in the first hour after reperfusion following 2 hours of occlusion (n = 7), and (3) 5 days and (4) 21 days after occlusion/reperfusion. In addition, the extent of T1 and T2 abnormalities was compared to the extent of infarction as determined histologically for each set of images. With sustained coronary occlusion, an increase versus control values (T1 = 351 +/- 11 msec; T2 = 41 +/- 2 msec) was observed in the second hour after occlusion (T1 = 448 +/- 51 msec; T2 = 51 +/- 8 msec), gradually reaching a maximum by day 5 (T1 = 490 +/- 64 msec; T2 = 63 +/- 9 msec). By 21 days, T1 had decreased to 427 +/- 43 msec and T2 to 55 +/- 11 msec. However, with myocardial reperfusion, an abrupt increase in both T1 and T2 occurred compared to prereperfusion values in the first hour after release of occlusion, from 445 +/- 32 msec to 555 +/- 65 msec and from 52 +/- 5 msec to 65 +/- 8 msec, respectively. Subsequently, T1 remained elevated whereas T2 normalized. Only on day 21 images was there a good correlation between the extent of T1 and T2 abnormalities and infarct size, in both nonreperfused (r = 0.87; p less than 0.05), and reperfused (r = 0.89; p less than 0.01) dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Early detection of canine myocardial infarction by magnetic resonance imaging in vivo.

This study was undertaken to assess the ability of proton magnetic resonance imaging (MRI) to detect myocardial ischemia shortly after coronary artery occlusion. Fifteen dogs were studied before and serially for up to 6 hr after anterior descending or circumflex coronary artery ligation in vivo by gated MRI with a 0.15 tesla resistive magnet (resonant frequency of hydrogen 6.25 MHz). Image acquisition was by single-spin echo, with echo times (TE) of 30 msec and TE 60 msec, and modified inversion recovery pulse sequences. Excellent anatomic definition was observed. By 4 hr after coronary artery occlusion the signal in the infarct zone increased to 36 +/- 20% greater than that in the adjacent normal myocardium for the TE 30 msec sequence (p less than .01) and to 116 +/- 100% for the TE 60 msec sequence (p less than .05). The most intense increase in signal was noted with the TE 60 msec pulse sequence and because normal myocardium is not well visualized by this technique, acutely ischemic myocardium was clearly delineated. Inversion recovery imaging did not show areas of ischemia. Changes seen on MR images correlated well with the location of ischemic changes noted on microscopic examination of the excised hearts. MRI thus provides a noninvasive means for detection of ischemia early in the course of myocardial infarction.

Serial imaging of canine myocardial infarction by in vivo nuclear magnetic resonance

Anterior infarction was produced in eight dogs to characterize serial changes in nuclear magnetic resonance signal intensity within the infarct zone. Magnetic resonance imaging was done on the day of infarction, on day 4, 5 or 6, on day 13 and day 20 using a 0.15 tesla (6.25 MHz) resistive imager. Electrocardiographically triggered spin echo (30, 45 and 60 ms echo times) and inversion recovery (400 to 500 ms inversion time) pulse sequences were employed to obtain single slice images. On day 20, the excised hearts were sectioned and examined to determine infarct location and extent. In the spin echo images, signal intensity within the ischemic zone was visibly increased in seven of the eight dogs on the day of infarction, and in all dogs by days 4 to 6. Signal intensity remained elevated in all but two dogs at day 20. With inversion recovery imaging, changes in the infarct zone were highly variable; both ill defined increases and decreases in signal intensity were noted. With a 30 ms echo time, signal intensity in the infarct zone was increased on average 29.8 +/- 24.1% above that in normal myocardium on the day of infarction. The relative signal intensity increased to 62.4 +/- 23.5% during the first 2 weeks after infarction (p less than 0.05), then decreased to 12.0 +/- 18.5% by day 20 (p less than 0.05). Similar changes were detected in the images using the 45 and 60 ms echo times. Nuclear magnetic resonance imaging therefore is able to detect regions of myocardial infarction and follow evolutionary changes in signal intensity within the infarct zone with healing.

Active Cardiac Sarcoidosis First Clinical Experience of Simultaneous Positron Emission Tomography- Magnetic Resonance Imaging for the Diagnosis of Cardiac Disease

The hybridization of positron emission tomography (PET) and magnetic resonance imaging (MRI) within a single imaging bore is a major advance in noninvasive imaging. Intrinsic coregistration of metabolic/molecular probe imaging with morphological, functional, and tissue imaging presents new opportunities for disease characterization. Sarcoidosis is a multisystem inflammatory disease hallmarked by inflammation, noncaseating granuloma formation, and organ dysfunction. Cardiac involvement accounts for up to 25% of disease-related mortality and is conventionally diagnosed with the Japanese Ministry criteria.1 However, studies using cardiac PET and MRI suggest a robust capacity to identify cardiac involvement2,3—PET through identification of active inflammation and MRI through identification of mature fibrosis or scar. In this report, we describe the first clinical use of simultaneous PET-MRI to assist in the diagnosis of cardiac disease: active cardiac sarcoidosis. A 72-year-old woman was referred with a 12-month history of increasing shortness of breath and intermittent chest pain. A coronary angiogram and echocardiogram showed normal coronary arteries but an ejection fraction of 35%. Her history was significant for inflammatory polyarthritis, treated with etanercept and hydroxycholoquine, and biopsy of an enlarged scalene lymph node showing noncaseating granulomas. …

Comparison of Initial Cell Retention and Clearance Kinetics After Subendocardial or Subepicardial Injections of Endothelial Progenitor Cells in a Canine Myocardial Infarction Model

Neither intravenous nor intracoronary routes provide targeted stem cell delivery to recently infarcted myocardium in sufficient quantities. Direct routes appear preferable. However, most prior studies have used epicardial injections, which are not practical for routine clinical use. The objective of this study was to compare cell retention and clearance kinetics between a subepicardial and a subendocardial technique. Methods: We evaluated 7 dogs with each technique, using 111In-tropolone–labeled endothelial progenitor cells and serial SPECT/CT for 15 d after injection. Results: In vivo indium imaging demonstrated comparable degrees of retention: 57% ± 15% for the subepicardial injections and 54% ± 26% for the subendocardial injections. Clearance half-lives were also similar at 69 ± 26 and 60 ± 21 h, respectively. Conclusion: This study demonstrates that subendocardial injections, clinically more practical, show clearance kinetics comparable to those of subepicardial injections and will facilitate the ultimate clinical use of this treatment modality.

Contrast‐enhanced MRI for the assessment of myocardial viability after permanent coronary artery occlusion

Previous studies in a model of ischemia/reperfusion using a constant infusion of Gd‐DTPA have shown that distribution volume (λ) is increased in infarcted myocardial tissue. This study examined this technique in the setting of permanent coronary artery occlusion. Ten beagles underwent permanent occlusion of a coronary artery for 2 days (N = 3), 1 week (N = 4), or 3 weeks (N = 3). Imaging was performed at 2 days and, depending on the length of occlusion, 1 week, 2 weeks, and 3 weeks to follow changes in λ in vivo. At sacrifice, 201Tl was injected and the extent of the hyperenhanced region was compared to pathology. λ was increased in infarcted tissue by 2 days post occlusion and this increase persisted for 3 weeks. At sacrifice, λ correlated strongly with 201Tl uptake (r = −0.86 to −0.95, P < 0.05; i.e., λ increased in infarcted tissue) and the size of the hyperenhanced region was comparable to pathological infarct size (slope 1.006, r = 0.96, P < 0.0001). Thus, beyond 2 days after coronary occlusion, MRI, during a constant infusion of Gd‐DTPA, can assess myocardial viability regardless of the success of reperfusion. Magn Reson Med 44:309–316, 2000.

A literature review: the cardiovascular effects of exposure to extremely low frequency electromagnetic fields

The effects of exposure to extremely low frequency (ELF) electromagnetic fields (EMFs) on human cardiovascular parameters remain undetermined. Epidemiological studies have utilized dosimetry estimations of employee workplace exposure using altered heart rate variability (HRV) as predictive of certain cardiovascular pathologies. Laboratory studies have focused on macrocirculatory indicators including heart rate, HRV and blood pressure. Few studies have been conducted on the response of the microcirculatory system to EMF exposure. Attempts to replicate both epidemiological and laboratory studies have been mostly unsuccessful as study design, small sample populations and confounding variables have hampered progress to date. Identification of these problems, in the current context of international exposure guideline re-evaluation, is essential for future EMF studies. These studies should address the possible deleterious health effects of EMFs as well as the detection and characterization of subtle physiological changes they may induce. Recommendations for future work include investigating the macro- and microcirculatory relationship and the use of laboratory geomagnetic shielding.