Challenges of cardiac inflammation imaging with F

Authors: Pradeep Bhambhvani

Publish Date: 2016/05/04

Volume: 24, Issue: 1, Pages: 100-102

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Abstract

Reliable hot spot inflammation imaging with fluorine18 fluorodeoxyglucose FDG positron emission tomography PET in suspected cardiac infection cardiac sarcoidosis or vulnerable coronary plaque is only possible when physiologic myocardial FDG uptake can be adequately suppressed The gamut of perfusionmetabolism patterns possible in cardiac sarcoidosis1 combined with the erratic and real possibility of inadequate suppression of normal myocardial FDG uptake is a sure recipe for head scratching and challenging image interpretation A number of preparation methods aimed at suppressing physiologic myocardial glucose utilization have been described without clear consensus on the optimal method In the present issue of the Journal of Nuclear Cardiology Osborne and colleagues doi 101007/s1235001605027 review various preparation protocols and success rates achieved in published studies for FDG cardiac PET and provide useful practical recommendationsA brief overview of cardiomyocyte metabolism is essential to appreciate the challenges and rationale of interventions The heart uses various substrates as energy sources including free fatty acids FFAs glucose and lactate In the fasting condition the normal myocardium utilizes FFAs as the major energy source 90 Other sources include glucose and lactate2 Postmeals or in the dysfunctional myocardium example ischemic heart disease myocardial metabolism shifts to glucose per the glucosefatty acid cycle23 Elevated blood insulin and glucose levels with decreased FFAs lead to a relative rise in myocardial glucose consumption In contrast during fasting there is an increase in FFAs with decrease in insulin and glucose levels shifting myocardial energy consumption away from glucose and toward FFAs Hence interventions that facilitate myocardial FFAs metabolism while at the same time suppress physiologic glucose metabolism are imperative for successful FDG PET cardiac inflammation imaging These include avoidance of strenuous exercise prior to imaging to prevent skeletal muscle glucose utilization highfat with low less than 5 g or no carbohydrate diet to increase blood FFAs and minimize glucose and insulin levels addition of a highfat drink to this diet prior to FDG injection to elevate blood FFAs fasting for 418 hours to decrease blood glucose and insulin levels and increase FFAs and certain pharmacologic maneuvers The latter include unfractionated heparin which induces lipolysis and up to fivefold increase in blood FFAs4 and calcium channel blockers which reduce myocardial FDG uptake5 Most studies combine two or more interventions with the goal of complete suppression of normal cardiac FDG uptakeTang and colleagues in a metaanalysis involving 16 studies and 559 patients evaluated for cardiac sarcoidosis examined various patient preparations that impact the diagnostic performance of FDG PET They conclude that duration of fasting and heparin administration significantly affected the diagnostic odds ratio P = 01 and 04 respectively whereas a high fat low cholesterol diet did not have a significant effect P = 176 Nonspecific findings that may indicate failed suppression and/or physiologic uptake and make image interpretation challenging included diffuse myocardial activity exceeding liver uptake or uptake in the lateral wall and/or ring shaped/circumferential basal uptake Nensa et al doi 101007/s12350016044317 or papillary muscle uptake89 Diffuse FDG uptake in the entire left ventricular wall without focal uptake generally does not indicate disease as cardiac sarcoidosis is histopathologically known to be localized and not diffuse10 Absence of contrast enhancement edema or wall motion abnormalities on cardiac MRI associated with these nonspecific FDG uptake patterns is useful in avoiding false positive interpretations Nensa et al doi 101007/s12350016044318Based on comprehensive literature review and their institutional experience Osborne and colleagues doi 101007/s1235001605027 recommend the use of at least two highfat and no carbohydrate HFNC meals for example at dinner the night before and breakfast on day of scan followed by a fast of at least four hours before FDG injection as the most effective preparation method for cardiac FDG PET inflammation imaging Another protocol involving unfractionated heparin administered 15 minutes before FDG injection and following at least one highfat and lowcarbohydrate HFLC meal example at dinner the night before scan and an overnight fast is equally effective but requires exposure to an intravenous medication with possible adverse effects They do not recommend the fasting only preparation method with exception for those who cannot eat or have dietary restrictions precluding the HFNC or HFLC diets and suggest fasting for at least 18 hours in such individuals Vigorous exercise should be avoided for 24 hours prior to minimize skeletal muscle uptake Furthermore the authors do not advocate the use of calcium channel blockers unrestricted diets and eating or drinking anything including highfat supplements within at least four hours of the test The authors believe adherence to the above recommendations should result in myocardial FDG suppression sufficient for diagnostic evaluation in greater than 80 of studiesFrom the 31 different dietary interventions with or without heparin/verapamil premedication reviewed by Osborne et al optimal suppression of myocardial FDG uptake was noted in 8793 of patients prepared with two HFNC meals and 4 hour fast18 leading them to recommend it as the most effective preparation method Strategies using intravenous heparin at a dose of 50 IU·kg−1 15 minutes prior to FDG injection in combination with either a lowcarbohydrate diet + 12 hour fast11 or 18hour fasting with lowcarbohydrate diet12 led to adequate suppression in 88100 of patients Other investigators have questioned the efficacy of heparin713 Coulden et al reported successful myocardial suppression in 92 out of 94 oncology patients 98 who were compliant with only an “Atkins style” lowcarbohydrate diet less than 3 g the day before examination followed by an overnight fast14 26 out of 120 22 patients were noncompliant with the “Atkins style” diet While the shorter duration of fasting 46 hours after the two HFNC meals as recommended by Osborne and colleagues should lead to improved compliance the preceding no or lowcarbohydrate diet could however result in carbohydrate indiscretions in the less motivated/informed patient Since their review Nensa et al doi 101007/s1235001604431 have shown homogeneous suppression of myocardial FDG uptake in 79/94 84 patients prepared with a ≥24hour highfat lowcarbohydrate proteinpermitted diet without fasting and intravenous injection of unfractionated heparin 50 IU·kg−1 15 minutes prior to FDG administration using cardiac PET/MRThe pharmacologic interventions merit further discussion In 1979 Asmal et al demonstrated the anticoagulant and lipolytic actions of incremental doses of heparin in five healthy volunteers4 They noted a significant anticoagulant effect measured by partial thromboplastin time after intravenous heparin administration at a dose of 15 U·kg−1 and no significant change in partial thromboplastin time over the control value 36 ± 2 seconds with lower doses ie 5 and 10 U·kg−1 respectively P  1 FFAs were significantly higher after the 5 and 10 U·kg−1 doses P  0025 with further increments after higher heparin doses Asmal et al clearly illustrate the significant lipolytic action without significant anticoagulant effects with both the 5 and 10  U·kg−1 heparin doses The published cardiac FDG PET studies with unfractionated heparin that were successful in suppressing myocardial FDG uptake have been done at higher anticoagulant doses ie 50 U·kg−1 intravenously71112 etc To overcome the potentially detrimental anticoagulant effect while maintaining desired lipolysis as observed by Asmal et al studies evaluating the effectiveness of myocardial FDG suppression with lower doses of unfractionated heparin for example 510 U·kg−1 in combination with dietary preparation are much needed In addition to bleeding another safety concern with heparin use is the uncommon but potentially life threatening risk of heparininduced thrombocytopenia HIT and thrombosis No dose of heparin is too low to cause HIT as even small doses used for intravenous catheter flushes have been associated with HIT1516 In a metaanalysis the absolute risk for HIT with low molecular weight heparin was 02 95 CI 0104 and with unfractionated heparin was 26 95 CI 153817 The lower risk of developing HIT with low molecular weight heparin is countered by its inferior lipolytic effects when compared to unfractionated heparin18 While Persson et al showed superior lipolysis with unfractionated heparin fivefold increase in FFAs they also noted a threefold rise in FFAs with low molecular weight heparin compared to control18 This observation along with a lower incidence of HIT presents a research opportunity into the lipolytic effects of low molecular weight heparin in combination with HFNC/HFLC diet prior to FDG cardiac PETIn a mouse model Gaeta and colleagues showed significant reduction in myocardial FDG uptake following single administration of verapamil injected 1 hour prior to FDG administration at doses of 1 and 20 mg·kg−15 Similar results have not been reproduced in humans Demeure and colleagues demonstrated similar success in suppressing myocardial FDG uptake 89 in 9 volunteers pretreated with oral Verapamil 120 mg 1 hour before FDG injection who also ate a highfat lowcarbohydrate meal followed by a 12h fasting period when compared to 9 other volunteers who only ate a highfat lowcarbohydrate meal followed by a 12hour fasting period without verapamil premedication19In conclusion since patient preparation has such an important role in the determining cardiac FDG PET image quality the dietary fasting and exercise recommendations should be specified in a detailed information sheet reviewed with the patient and/or caregiver and reinforced prior to scan date and confirmed for compliance on day of scan Any deviation from written patient instructions should result in study cancelation and rescheduling to avoid the possibility of inadequate suppression of normal cardiac FDG uptake Nonspecific incomplete suppression patterns including diffuse myocardial uptake or lateral wall or basal ring distribution activity or papillary muscle activity despite adequate preparation can hamper image analysis and may need further characterization with MRI to exclude false positive interpretation With obvious exceptions of claustrophobia incompatible devices contrast allergy and renal dysfunction the positive attributes of the two modalities dovetail nicely for hybrid cardiac PET/MR inflammation imaging Further investigation into the lipolytic efficacy of the potentially safer lower doses of unfractionated heparin 510 U·kg−1 and low molecular weight heparin is in order as well Osborne et al rightfully point to the possibility of incomplete suppression of physiologic myocardial glucose uptake in a small proportion of studies despite all interventions and call for a continuous review of image quality and protocol tweaking as needed with a goal of 80 adequacy as well as the development of alternate and more specific inflammation imaging radiotracers

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