Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model

BACKGROUND: The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome. METHODS: Myocardial and skeletal muscle glucose uptake was assessed with 2-[(18)F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings. RESULTS: TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes. CONCLUSIONS: These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients

Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function.</p> <p>Methods</p> <p>Cardiac sympathetic nervous integrity was investigated <it>in vivo </it>via biodistribution of the positron emission tomography radiotracer and NE analogue [¹¹C]<it>meta-</it>hydroxyephedrine ([¹¹C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements.</p> <p>Results</p> <p>The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [¹¹C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle.</p> <p>Conclusions</p> <p>Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment.</p

The Current Role of Viability Imaging to Guide Revascularization and Therapy Decisions in Patients With Heart Failure and Reduced Left Ventricular Function

This review describes the current evidence and controversies for viability imaging to direct revascularization decisions and the impact on patient outcomes. Balancing procedural risks and possible benefit from revascularization is a key question in patients with heart failure of ischemic origin (IHF). Different stages of ischemia induce adaptive changes in myocardial metabolism and function. Viable but dysfunctional myocardium has the potential to recover after restoring blood flow. Modern imaging techniques demonstrate different aspects of viable myocardium; perfusion (single-photon emission computed tomography [SPECT], positron emission tomography [PET], cardiovascular magnetic resonance [CMR]), cell metabolism (PET), cell membrane integrity and mitochondrial function (201Tl and 99mTc-based SPECT), contractile reserve (stress echocardiography, CMR) and scar (CMR). Observational studies suggest that patients with IHF and significant viable myocardium may benefit from revascularization compared with medical treatment alone but that in patients without significant viability, revascularization appears to offer no survival benefit or could even worsen the outcome. This was not supported by 2 randomized trials (Surgical Treatment for Ischemic Heart Failure [STICH] and PET and Recovery Following Revascularization [PARR] -2) although post-hoc analyses suggest that benefit can be achieved if decisions had been strictly based on viability imaging recommendations. Based on current evidence, viability testing should not be the routine for all patients with IHF considered for revascularization but rather integrated with clinical data to guide decisions on revascularization of high-risk patients with comorbidities.Peer reviewe

Imaging atherosclerosis with hybrid [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: What Leonardo da Vinci could not see

Prodigious efforts and landmark discoveries have led toward significant advances in our understanding of atherosclerosis. Despite significant efforts, atherosclerosis continues globally to be a leading cause of mortality and reduced quality of life. With surges in the prevalence of obesity and diabetes, atherosclerosis is expected to have an even more pronounced impact upon the global burden of disease. It is imperative to develop strategies for the early detection of disease. Positron emission tomography (PET) imaging utilizing [18F]fluorodeoxyglucose (FDG) may provide a non-invasive means of characterizing inflammatory activity within atherosclerotic plaque, thus serving as a surrogate biomarker for detecting vulnerable plaque. The aim of this review is to explore the rationale for performing FDG imaging, provide an overview into the mechanism of action, and summarize findings from the early application of FDG PET imaging in the clinical setting to evaluate vascular disease. Alternative imaging biomarkers and approaches are briefly discussed. © 2012 The Author(s)

Prognostic Value of Stress Myocardial Perfusion Positron Emission Tomography: Results From A Multicenter Observational Registry

ObjectivesThe primary objective of this multicenter registry was to study the prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) and the improved classification of risk in a large cohort of patients with suspected or known coronary artery disease (CAD).BackgroundLimited prognostic data are available for MPI with PET.MethodsA total of 7,061 patients from 4 centers underwent a clinically indicated rest/stress rubidium-82 PET MPI, with a median follow-up of 2.2 years. The primary outcome of this study was cardiac death (n = 169), and the secondary outcome was all-cause death (n = 570). Net reclassification improvement (NRI) and integrated discrimination analyses were performed.ResultsRisk-adjusted hazard of cardiac death increased with each 10% myocardium abnormal with mildly, moderately, or severely abnormal stress PET (hazard ratio [HR]: 2.3 [95% CI: 1.4 to 3.8; p = 0.001], HR: 4.2 [95% CI: 2.3 to 7.5; p < 0.001], and HR: 4.9 [95% CI: 2.5 to 9.6; p < 0.0001], respectively [normal MPI: referent]). Addition of percent myocardium ischemic and percent myocardium scarred to clinical information (age, female sex, body mass index, history of hypertension, diabetes, dyslipidemia, smoking, angina, beta-blocker use, prior revascularization, and resting heart rate) improved the model performance (C-statistic 0.805 [95% CI: 0.772 to 0.838] to 0.839 [95% CI: 0.809 to 0.869]) and risk reclassification for cardiac death (NRI 0.116 [95% CI: 0.021 to 0.210]), with smaller improvements in risk assessment for all-cause death.ConclusionsIn patients with known or suspected CAD, the extent and severity of ischemia and scar on PET MPI provided powerful and incremental risk estimates of cardiac death and all-cause death compared with traditional coronary risk factors

Optimally Repeatable Kinetic Model Variant for Myocardial Blood Flow Measurements with 82Rb PET

Purpose. Myocardial blood flow (MBF) quantification with R b 82 positron emission tomography (PET) is gaining clinical adoption, but improvements in precision are desired. This study aims to identify analysis variants producing the most repeatable MBF measures. Methods. 12 volunteers underwent same-day test-retest rest and dipyridamole stress imaging with dynamic R b 82 PET, from which MBF was quantified usin

A Clinical Tool to Identify Candidates for Stress-First Myocardial Perfusion Imaging

Objectives: This study sought to develop a clinical model that identifies a lower-risk population for coronary artery disease that could benefit from stress-first myocardial perfusion imaging (MPI) protocols and that can be used at point of care to risk stratify patients. Background: There is an increasing interest in stress-first and stress-only imaging to reduce patient radiation exposure and improve patient workflow and experience. Methods: A secondary analysis was conducted on a single-center cohort of patients undergoing single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. Normal MPI was defined by the absence of perfusion abnormalities and other ischemic markers and the presence of normal left ventricular wall motion and left ventricular ejection fraction. A model was derived using a cohort of 18,389 consecutive patients who underwent SPECT and was validated in a separate cohort of patients who underwent SPECT (n = 5,819), 1 internal cohort of patients who underwent PET (n=4,631), and 1 external PET cohort (n = 7,028). Results: Final models were made for men and women and consisted of 9 variables including age, smoking, hypertension, diabetes, dyslipidemia, typical angina, prior percutaneous coronary intervention, prior coronary artery bypass graft, and prior myocardial infarction. Patients with a score ≤1 were stratified as low risk. The model was robust with areas under the curve of 0.684 (95% confidence interval [CI]: 0.674 to 0.694) and 0.681 (95% CI: 0.666 to 0.696) in the derivation cohort, 0.745 (95% CI: 0.728 to 0.762) and 0.701 (95% CI: 0.673 to 0.728) in the SPECT validation cohort, 0.672 (95% CI: 0.649 to 0.696) and 0.686 (95% CI: 0.663 to 0.710) in the internal PET validation cohort, and 0.756 (95% CI: 0.740 to 0.772) and 0.737 (95% CI: 0.716 to 0.757) in the external PET validation cohort in men and women, respectively. Men and women who scored ≤1 had negative likelihood ratios of 0.48 and 0.52, respectively. Conclusions: A novel model, based on easily obtained clinical variables, is proposed to identify patients with low probability of having abnormal MPI results. This point-of-care tool may be used to identify a population that might qualify for stress-first MPI protocols

Radionuclide Imaging of Viable Myocardium: Is it Underutilized?

Coronary artery disease is the major cause of heart failure in North America. Viability assessment is important as it aims to identify patients who stand to benefit from coronary revascularization. Radionuclide modalities currently used in the assessment of viability include 201Tl SPECT, 99mTc-based SPECT imaging, and 18F-fluorodexoyglucose (18F-FDG)-PET imaging. Different advances have been made in the last year to improve the sensitivity and specificity of these modalities. In addition, the optimum amount of viable (yet dysfunctional) myocardium is important to identify in patients, as a risk–benefit ratio must be considered. Patients with predominantly viable/hibernating myocardium can benefit from revascularization from a mortality and morbidity standpoint. However, in patients with minimal viability (predominantly scarred myocardium), revascularization risk may certainly be too high to justify revascularization without expected benefit. Understanding different radionuclide modalities and new developments in the assessment of viability in ischemic heart failure patients is the focus of this discussion