Michael T. Osborne

Diffusion of myelin water.

We studied compartmentally specific characteristics of water diffusion in excised frog sciatic nerve by combining T1 or T2 selective acquisitions with pulse‐gradient spin‐echo (PGSE) diffusion weighting, with the specific objective of characterizing myelin water diffusion. Combining a PGSE with a Carr‐Purcell‐Meiboom‐Gill (CPMG) acquisition provided apparent diffusion coefficients (ADCs) for each of the three T2 components found in nerve, including the short‐lived component believed to be derived from myelin water. Double‐inversion‐recovery (DIR) preparation provided an alternate means of discriminating myelin water, and in combination with PGSE provided somewhat different measures of ADC. The DIR measures yielded myelin water ADCs of 0.37 μm2/ms (parallel to nerve) and 0.13 μm2/ms (perpendicular to nerve). These ADC estimates were postulated to be more accurate than those based on T2 discrimination, although the difference between the two findings is not clear. Magn Reson Med, 2006.

Cardiac sarcoidosis—state of the art review

Sarcoidosis is a multi-system inflammatory disorder of unknown etiology resulting in formation of non-caseating granulomas. Cardiac involvement-which is associated with worse prognosis-has been detected in approximately 25% of individuals based on autopsy or cardiac imaging studies. Nevertheless, the diagnosis of cardiac sarcoidosis is challenging due to the low yield of endomyocardial biopsy, and the limited accuracy of various clinical criteria. Thus, no gold standard diagnostic criterion exists. This review will summarize the pathophysiology, diagnosis, and treatment of cardiac sarcoidosis with a focus on advanced cardiovascular imaging, We review the evidence to support a role for cardiac magnetic resonance (CMR) imaging in the initial evaluation of selected patients with suspected cardiac sarcoidosis, with cardiac positron emission tomography (PET) as an alternative or complementary initial diagnostic test in a subgroup of patients in whom CMR may be contra-indicated or when CMR is negative with continued clinical concern for myocardial inflammation. In addition to the diagnostic value of these tests, CMR and PET are also useful in identifying patients who have higher risk of adverse events such as ventricular tachycardia or death, in whom preventive therapies such as defibrillators should be more strongly considered. Although no randomized controlled trials for treatment of cardiac sarcoidosis exist, immunosuppressive therapy is often used. We review emerging evidence regarding the use of cardiac PET to identify and quantity the amount of myocardial inflammation as well as to guide the use of immunotherapy. Future studies are needed to determine the benefit of imaging guided therapies aimed at improving patient outcomes.

Isolated cardiac sarcoidosis: A focused review of an under-recognized entity

There is accumulating evidence for the existence of a phenotype of isolated cardiac sarcoidosis (ICS), or sarcoidosis that only involves the heart. In the absence of biopsy-confirmed cardiac sarcoidosis (CS), existing diagnostic criteria require the presence of extra-cardiac sarcoidosis as an inclusion criterion for the diagnosis of CS. Consequently, in the absence of a positive endomyocardial biopsy, ICS is not diagnosable by current guidelines. Therefore, there is uncertainty regarding the epidemiology, pathobiology, clinical characteristics, prognosis, and optimal treatment of ICS. This review will summarize the available data related to the prevalence and prognosis of ICS and will discuss challenges surrounding the diagnosis and management of this under-recognized entity.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease

Background: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. Methods: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g−1·min−1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. Results: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38–2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84–1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9–3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3–2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6–1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3–0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. Conclusions: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Cardiac macrophages promote diastolic dysfunction

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Use of multimodality imaging to diagnose cardiac sarcoidosis as well as identify recurrence following heart transplantation.

A middle-aged man presented with a ventricular fibrillation arrest and five months later developed complete heart block requiring placement of permanent pacemaker and defibrillator. Coronary angiography showed no evidence of coronary artery disease. MRI demonstrated inflammatory lesions within the liver and spleen and subsequent mediastinoscopy with lymph node biopsy was diagnostic for sarcoidosis. The patient developed worsening symptoms of heart failure and was subsequently referred for a cardiac PET study to evaluate for cardiac sarcoidosis. Rest perfusion images using rubidium-82 identified the presence of a regional perfusion defect along the basal and mid inferior wall (Figure 1), while the fluorodeoxyglucose (FDG) images (acquired after high fat and low carbohydrate diet to suppress FDG uptake by normal myocardium without heparin infusion) showed heterogeneous and patchy FDG uptake involving the entire myocardium, with notable focal areas of more intense FDG uptake corresponding to focal perfusion defects. Despite steroid therapy, the patient’s heart failure progressed and, ultimately, he underwent an orthotopic heart transplant approximately seven months later. Gross pathology of the explanted heart (Figure 2, gross) demonstrated moderate biventricular dilatation with multiple foci of dense fibrosis involving the myocardium of both ventricles and the interventricular septum. Microscopic evaluation revealed multiple non-necrotizing granulomata with mild chronic inflammation and associated serpiginous fibrosis (Figure 2, microscopy). The imaging and gross pathological findings were concordant in identifying the presence and the location of perfusion defects due to fibrosis, while microscopic evaluation demonstrated the presence of active inflammation. Four months after transplantation, the patient developed reactivation of his sarcoidosis within the native pericardium and required pericardiectomy due to constrictive physiology. Focal granulomatous infiltration of the pericardium was noted on pathology. Subsequently, his cardiac function remained stable for 3 years. During this interval, his immunosuppressive medications and steroids were adjusted in light of other medical problems, including opportunistic infections of his skin and extremities. During a surveillance PET scan performed three years post OHT, he was found to have a new medium-sized perfusion defect of moderate intensity throughout the inferolateral and anterolateral walls with associated increased FDG uptake that is indicative of perfusion metabolic mismatch (Figure 3, panels A and B), and is suggestive of possible recurrence of cardiac sarcoidosis. This finding also correlated with a cardiac MRI, which identified small amount of fibrosis along the inferolateral wall (Figure 3, panel C). A subsequent right and left heart catheterization showed no evidence of coronary disease. A biopsy done on the same day as his positive PET scan did not demonstrate any evidence of rejection, granulomatous disease, infection, or ischemic changes. This article illustrates the role of non-invasive imaging in the evaluation of patients with suspected cardiac sarcoidosis and provides a unique comparison between PET/CT findings and pathology. In this case, the PET/CT study was used to identify the presence of myocardial inflammation, and subsequently led to the diagnosis of cardiac sarcoidosis, which was confirmed with pathology. In addition to diagnosis of cardiac sarcoidosis, PET/CT can be used to identify extracardiac From the Department of Medicine, Non-Invasive Cardiovascular Imaging Program, Department of Medicine (Cardiovascular Division) and Department of Radiology, Cardiovascular Division, Department of Medicine, Department of Pathology, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Boston, MA. Reprint requests: Michael Osborne, MD, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115; mosborne@partners.org. J Nucl Cardiol 2013;20:310–2. 1071-3581/

Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy

34.00 Copyright 2013 American Society of Nuclear Cardiology. doi:10.1007/s12350-013-9677-3

Updates on Stress Imaging Testing and Myocardial Viability With Advanced Imaging Modalities

Aims Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P < 0.001), respectively. Conclusion Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events.

Coronary Microvascular Dysfunction Identifies Patients at High Risk of Adverse Events Across Cardiometabolic Diseases

Opinion statementNon-invasive stress testing plays a key role in diagnosis and risk stratification in patients with coronary artery disease. Technical advances in CT, MRI, and PET have lead to increased utility of these modalities in myocardial perfusion imaging. The aim of the review is to provide a succinct update on CT, PET, and MRI for myocardial stress perfusion imaging.

Amygdalar activity predicts future incident diabetes independently of adiposity

Patients with metabolic syndrome (MetS) and diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD) and heart failure [(1)][1]. Impaired coronary flow reserve (CFR), the ratio of stress to rest myocardial blood flow, is a marker of coronary microvascular dysfunction (CMD) in