Aurantio-obtusin ameliorates obesity by activating PPARα-dependent mitochondrial thermogenesis in brown adipose tissues.

Obesity contributes to the progression of various chronic diseases, and shortens life expectancy. With abundant mitochondria, brown adipose tissue (BAT) dissipates energy through heat to limit weight gain and metabolic dysfunction in obesity. Our previous studies have shown that aurantio-obtusin (AO), a bioactive ingredient in Chinese traditional medicine Cassiae semen significantly improves hepatic lipid metabolism in a steatotic mouse model. In the current study we investigated the effects of AO on lipid metabolism in the BAT of diet-induced obesity mice and in oleic acid and palmitic acid (OAPA)-stimulated primary mature BAT adipocytes. Obese mice were established by feeding a HFHS diet for 4 weeks, and then administered AO (10 mg/kg, i.g.) for another 4 weeks. We showed that AO administration significantly increased the weight of BAT and accelerated energy expenditure to protect the weight increase in the obese mice. Using RNA sequencing and molecular biology analysis we found that AO significantly enhanced mitochondrial metabolism and UCP1 expression by activating PPARα both in vivo and in vitro in the primary BAT adipocytes. Interestingly, AO administration did not improve metabolic dysfunction in the liver and white adipose tissue of obese mice after interscapular BAT excision. We demonstrated that low temperature, a trigger of BAT thermogenesis, was not a decisive factor for AO to stimulate the growth and activation of BATs. This study uncovers a regulatory network of AO in activating BAT-dependent lipid consumption and brings up a new avenue for the pharmaceutical intervention in obesity and related comorbidities.

Metabolic activity of the left and right atria are differentially altered in patients with atrial fibrillation and LV dysfunction.

BACKGROUND: Alterations in atrial metabolism may play a role in the perpetuation of atrial fibrillation (AF). This study sought to compare 18F-fluorodeoxyglucose (FDG) uptake on PET, in patients with LV dysfunction versus those without AF. METHODS: Seventy-two patients who underwent myocardial viability assessment were evaluated. AF patients (36) had persistent or permanent AF based on history and ECG. Patients without AF (36) were matched to AF patients based on sex, diabetes, age, and LVEF. Maximum and mean FDG Standard Uptake Values (SUV) in the left atrial (LA) wall and right atrial (RA) wall were measured. Tissue-to-blood ratios (TBR) were calculated as atrial wall to blood-pool activity. Atrial volumes were measured by echocardiography. RESULTS: Maximum and mean FDG SUV and TBRs were significantly increased in the RA (but not the LA) of patients with AF compared to those without (P < 0.01). When accounting for changes in atrial volume, the presence of AF remained a significant predictor of higher RAMAX, but not RAMEAN FDG uptake. CONCLUSION: In patients with LV dysfunction from ischemic cardiomyopathy, LA and RA glucose metabolism are differentially altered in those with persistent atrial fibrillation. Further investigations should elucidate the temporal relationship between AF and glucose metabolic changes, as a potential target for therapy.

Internal validation of myocardial flow reserve PET imaging using stress/rest myocardial activity ratios with Rb-82 and N-13-ammonia.

BACKGROUND: Myocardial flow reserve (MFR) measurement provides incremental diagnostic and prognostic information. The objective of the current study was to investigate the application of a simplified model for the estimation of MFR using only the stress/rest myocardial activity ratio (MAR) in patients undergoing rest-stress cardiac PET MPI. METHODS AND RESULTS: Rest and dipyridamole stress dynamic PET imaging was performed in consecutive patients using 82Rb or 13NH3 (n = 250 each). Reference standard MFR was quantified using a standard one-tissue compartment model. Stress/rest myocardial activity ratio (MAR) was calculated using the LV-mean activity from 2 to 6 minutes post-injection. Simplified estimates of MFR (MFREST) were then calculated using an inverse power function. For 13NH3, there was good correlation between MFR and MFREST values (R = 0.63), with similar results for 82Rb (R = 0.73). There was no bias in the MFREST values with either tracer. The overall diagnostic performance of MFREST for detection of MFR < 2 was good with ROC area under the curve (AUC) = 83.2 ± 1.2% for 13NH3 and AUC = 90.4 ± 0.7% for 82Rb. CONCLUSION: MFR was estimated with good accuracy using 82Rb and 13NH3 with a simplified method that relies only on stress/rest activity ratios. This novel approach does not require dynamic imaging or tracer kinetic modeling. It may be useful for routine quality assurance of PET MFR measurements, or in scanners where full dynamic imaging and tracer kinetic modeling is not feasible for technical or logistical reasons.

Reproducible Quantification of Regional Sympathetic Denervation with [11C]meta-Hydroxyephedrine PET Imaging.

BACKGROUND: Regional cardiac sympathetic denervation is predictive of sudden cardiac arrest in patients with ischemic cardiomyopathy. The reproducibility of denervation scores between automated software programs has not been evaluated. This study seeks to (1) compare the inter-rater reliability of regional denervation measurements using two analysis programs: FlowQuant® and Corridor4DM®; (2) evaluate test-retest repeatability of regional denervation scores. METHODS: N = 190 dynamic [11C]meta-hydroxyephedrine (HED) PET scans were reviewed from the PAREPET trial in ischemic cardiomyopathy patients with reduced left ventricular ejection fraction(LVEF ≤ 35%). N = 12 scans were excluded due to non-diagnostic quality. N = 178 scans were analyzed using FlowQuant and Corridor4DM software, each by two observers. Test-retest scans from N = 20 patients with stable heart failure were utilized for test-retest analysis. Denervation scores were defined as extent × severity of relative uptake defects in LV regions with < 75% of maximal uptake. Results were evaluated using intraclass correlation coefficient (ICC) and Bland-Altman coefficient of repeatability (RPC). RESULTS: Inter-observer, inter-software, and test-retest ICC values were excellent (ICC = 94% to 99%) and measurement variability was small (RPC < 11%). Mean differences between observers ranged .2% to 1.1% for Corridor4DM (P = .28), FlowQuant (P < .001), and between software programs (P < .001). Kaplan-Meier analysis demonstrated HED scores from both programs were predictive of SCA. CONCLUSION: Inter-rater reliability for both analysis programs was excellent and test-retest repeatability was consistent. The minimal difference in scores between FlowQuant and Corridor4DM supports their use in future trials.

Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET.

PURPOSE: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). METHODS: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). RESULTS: Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. CONCLUSIONS: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Saline-push improves rubidium-82 PET image quality.

INTRODUCTION: Rubidium-82 (82Rb) PET is used widely for myocardial perfusion imaging. The purpose of this study was to investigate if an additional saline-push following the 82Rb elution improves PET image quality. METHODS: 82Rb PET scans were acquired with and without 26 mL saline-push in six patients as part of a clinical quality improvement program. Dynamic images were analyzed to measure the total activity delivered to the superior vena cava (SVC) and retained in the left ventricle (LV) myocardium. Tracer uptake images were used to measure blood background coefficient-of-variation (COV), myocardium-to-blood signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) to assess image quality. RESULTS: Similar eluted activity was measured with/without the saline-push (830 vs 795 MBq; P = 0.24). The activity delivered to the heart and retained in the myocardium was consistently increased more than twofold (SVC: + 114% and LV: + 104%; P < 0.001) with the saline-push. Image quality was improved in all patients, with lower background noise (COV: - 19%), higher SNR (+ 24%) and CNR (+ 27%) (all P ≤ 0.01). CONCLUSIONS: The saline-push used to flush 82Rb activity out of the infuser tubing, patient injection and intravenous access lines consistently increased the activity delivered to the heart by twofold. This technique is recommended to maximize image quality with 82Rb PET.

Is Immigrant Status Associated With Cervical Cancer Screening Among Women in Canada? Results From a Cross-Sectional Study.

OBJECTIVE: Cervical cancer accounts for the highest mortality rate from cancer in women worldwide. Despite widespread availability of cervical cancer screening programs in Canada, immigrant women are largely underscreened. The most recently published Canadian-wide study evaluated screening uptake from 2001 to 2002. The objectives included identifying the prevalence of underscreened women in Canada, determining the risk of underscreening for cervical cancer among immigrant women, and providing an update on Canadian screening practices. METHODS: This study included women aged 20 to 69 who completed the Canadian Community Health Survey 2012. The prevalence of underscreening among Canadian-born and immigrant women was estimated. A log-binomial model was fit to estimate the relative risk (RR) of underscreening for immigrant women while controlling for age, income level, visible minority status, smoking status, and access to a regular physician. A secondary analysis compared immigrants residing in Canada for greater or less than 10 years to Canadian-born women. RESULTS: Of the 17 854 women eligible for this study, 18.6% of Canadian-born women and 28.9% of immigrant women were underscreened (P < 0.05). Immigrant women were at significantly higher risk of being underscreened compared with Canadian-born women (RR 1.32; 95% CI 1.20-1.45). The relative risk did not change when stratifying by length of time since immigration (RRrecent immigrant 1.32; 95% CI 1.16-1.50; and RRlong-term immigrant 1.32; 95% CI 1.19-1.47). CONCLUSION: Immigrant status continues to be associated with a significantly higher risk of underscreening, irrespective of time in Canada. Social and educational programs targeted towards immigrants are needed to mitigate the disparity in cervical cancer screening.

Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using 11C-acetate PET.

BACKGROUND: Non-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of 11C-acetate positron emission tomography (PET) imaging of oxidative metabolism. METHODS AND RESULTS: Dynamic 11C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction. Two observers blinded to patients' clinical data used FlowQuant® to evaluate test-retest repeatability, as well as intra- and inter-observer reproducibility of 11C-acetate tracer uptake and clearance rates, for the measurement of myocardial oxygen consumption (MVO2), myocardial external efficiency (MEE), work metabolic index (WMI), and myocardial blood flow. Reproducibility and repeatability were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient-of-repeatability (CR). Test-retest correlations and repeatability were better for MEE and WMI compared to MVO2. All intra- and inter-observer correlations were excellent (ICC = 0.95-0.99) and the reproducibility values (CR = 3%-6%) were significantly lower than the test-retest repeatability values (22%-54%, P < 0.001). Repeatability was improved for all parameters using a newer PET-computed tomography (CT) scanner compared to older PET-only instrumentation. CONCLUSION: 11C-acetate PET measurements of WMI and MEE exhibited excellent test-retest repeatability and operator reproducibility. Newer PET-CT scanners may be preferred for longitudinal tracking of cardiac efficiency.

Resolution of Cardiac Infiltration Following Autologous Stem Cell Transplantation for AL Amyloidosis.

A 43-year-old man presented with severe heart failure secondary to high-risk light chain cardiac amyloidosis. He underwent chemotherapy and autologous stem cell transplantation with complete hematologic response. Serial cardiac magnetic resonance imaging post-transplant demonstrated gradual normalization of biventricular function and myocardial T1, a surrogate measure of disease burden.

Elevated Troponin T in Immune-Checkpoint Inhibitor Myositis: A Case of Mistaken Myocarditis.

A patient with metastatic renal cell carcinoma on axitinib and pembrolizumab had elevated high-sensitivity cardiac troponin T and normal high-sensitivity cardiac troponin I with unremarkable cardiac investigations. A noncardiac cause (myositis) was the likely cause for cardiac troponin T elevation. Cardiac troponin I may be a more appropriate marker to support a myocarditis diagnosis with concurrent myositis.

Sex differences in post-operative outcomes following non-cardiac surgery.

It is uncertain whether sex is an independent risk factor for poor outcomes after non-cardiac surgery. We examined sex differences in short- and long-term mortality and morbidity in patients undergoing non-cardiac surgery in Alberta, Canada. Using linked administrative databases, we identified patients undergoing one of 45 different non-cardiac surgeries who were hospitalized between 2008 and 2019. Adjusted odds ratios (95% CI) were reported for mortality at 30-days, 6-months, and 1-year stratified by sex. Secondary outcomes including all-cause hospitalization, hospitalization for heart failure (HF), hospitalization for acute coronary syndrome (ACS), hospitalization for infection, hospitalization for stroke, and hospitalization for bleeding were also analyzed. Multivariate logistic regression was adjusted for age, sex, surgery type, the components of the Charlson Comorbidity Index, and the Revised Cardiac Risk Index. We identified 552,224 unique patients who underwent non-cardiac surgery of which 304,408 (55.1%) were female. Male sex was a predictor of mortality at 30-days (aOR 1.25 (1.14, 1.38), p<0.0001), 6-months (aOR 1.26 (1.20, 1.33), p<0.0001), and 1-year (aOR 1.25 (1.20, 1.31), p<0.0001). Similarly, male sex was a predictor of hospital readmission at 30-days (1.12 (1.09, 1.14), p<0.0001), 6-months (aOR 1.11 (1.10, 1.13), p<0.0001), and 1-year (aOR 1.06 (1.04, 1.07), p<0.0001). When the results were stratified by age, the effect of male sex on clinical outcome diminished for age ≥ 65years compared to younger patients. In conclusion, male patients undergoing non-cardiac surgery have higher risks of all-cause mortality and readmission after adjustment for baseline risk factor differences, particularly in those under 65-years-old. The overall incidence of readmission for stroke, bleeding, HF and ACS after non-cardiac surgery was low. The impact of male sex on clinical outcomes decreases with increasing age, suggesting the importance of considering the effect of both sex and age on clinical outcomes after non-cardiac surgery.

Does cardiac imaging surveillance strategy influence outcomes in patients with early breast cancer?

Background: Many patients with breast cancer receive therapies with the potential to cause cardiotoxicity. Echocardiography and multiple-gated acquisition (MUGA) scans are the most used modalities to assess cardiac function during treatment in high-risk patients; however, the optimal imaging strategy and the impact on outcome are unknown. Methods: Consecutive patients with stage 0-3 breast cancer undergoing pre-treatment echocardiography or MUGA were identified from a tertiary care cancer center from 2010-2019. Demographics, medical history, imaging data and clinical events were collected from hospital charts and administrative databases. The primary outcome is a composite of all-cause death or heart failure event. Clinical and imaging predictors of outcome were evaluated on univariable and multivariable analyses. Results: 1028 patients underwent pre-treatment MUGA and 1032 underwent echocardiography. The groups were well matched for most clinical characteristics except patients undergoing MUGA were younger, had more stage 3 breast cancer and more HER2 over-expressing and triple negative cases. Routine follow-up cardiac imaging scan was obtained in 39.3% of patients with MUGA and 38.0% with echocardiography. During a median follow-up of 2448 (1489, 3160) days, there were 194 deaths, including 7 cardiovascular deaths, and 28 heart failure events with no difference in events between the MUGA and echocardiography groups. There were no imaging predictors of the primary composite outcome or cardiac events. Patients without follow-up imaging had similar adjusted risk for the composite outcome compared to those with imaging follow-up, hazard ratio 0.8 (95% confidence interval 0.5,1.3), p=0.457. Conclusion: The selection of pretreatment echocardiography or MUGA did not influence the risk of death or heart failure in patients with early breast cancer. Many patients did not have any follow-up cardiac imaging and did not suffer worse outcomes. Cardiovascular deaths and heart failure event rates were low and the value of long-term cardiac imaging surveillance should be further evaluated.

An Unusual Case of Obstructive Shock.

A 54-year-old man presented in profound obstructive shock. Investigations revealed a right atrial mass causing severe right ventricular inflow obstruction and compromised cardiac output. The patient was treated with emergency balloon catheter intervention to relieve the obstruction, with resulting hemodynamic stability. The pathology report later returned a positive result for diffuse large B-cell lymphoma. (Level of Difficulty: Intermediate.).

Differential association of diabetes mellitus and female sex with impaired myocardial flow reserve across the spectrum of epicardial coronary disease.

AIMS: Diabetes mellitus (DM) affects the macro- and microvasculature, leading to impairment in coronary vascular reactivity. Microvascular dysfunction is more prevalent in females compared to males, leading to increased cardiovascular risk in women. The purpose of this study was to quantify the association between diabetes and female sex on myocardial flow reserve (MFR) across the spectrum of epicardial coronary artery disease (CAD). METHODS AND RESULTS: In 222 patients with known or suspected CAD (63.7 ± 10.7 years, 66 females, 85 with diabetes) who had rubidium-82 positron emission tomography (PET) and invasive coronary angiography within 6 months, a multiple linear regression model was developed to predict MFR based on clinical risk factors and imaging results across a spectrum of regional epicardial disease. A significant interaction effect suggested that impairment of MFR is accelerated in diabetics with increasing severity of epicardial disease. Furthermore, female sex (-13%), decade of age (-6%), ischaemia on electrocardiogram (-10%), resting rate-pressure product (-3%), and rest end-diastolic volume (-0.2%) were associated with reductions in MFR independent of the combined extent and severity of epicardial disease. CONCLUSION: In the presence of significant obstructive epicardial disease, MFR decreases more rapidly in patients with DM compared to those without. Additional patient demographics and risk factors such as female sex and older age, and stress PET functional parameters should also be considered in the clinical interpretation of MFR. This has implications for the diagnosis and management of CAD patients with these and other risk factors for microvascular disease.

Reproducible quantification of cardiac sympathetic innervation using graphical modeling of carbon-11-meta-hydroxyephedrine kinetics with dynamic PET-CT imaging.

BACKGROUND: Graphical methods of radiotracer kinetic modeling in PET are ideal for parametric imaging and data quality assurance but can suffer from noise bias. This study compared the Logan and Multilinear Analysis-1 (MA1) graphical models to the standard one-tissue-compartment (1TC) model, including correction for partial-volume effects, in dynamic PET-CT studies of myocardial sympathetic innervation in the left ventricle (LV) using [11C]HED. METHODS: Test and retest [11C]HED PET imaging (47 ± 22 days apart) was performed in 18 subjects with heart failure symptoms. Myocardial tissue volume of distribution (VT) was estimated using Logan and MA1 graphical methods and compared to the 1TC standard model values using intraclass correlation (ICC) and Bland-Altman analysis of the non-parametric reproducibility coefficient (NPC). RESULTS: A modeling start-time of t* = 5 min gave the best fit for both Logan and MA1 (R2 = 0.95) methods. Logan slightly underestimated VT relative to 1TC (p = 0.002), whereas MA1 did not (p = 0.96). Both the MA1 and Logan models exhibited good-to-excellent agreement with the 1TC (MA1-1TC ICC = 0.96; Logan-1TC ICC = 0.93) with no significant differences in NPC between the two comparisons (p = 0.92). All methods exhibited good-to-excellent test-retest repeatability with no significant differences in NPC (p = 0.57). CONCLUSIONS: Logan and MA1 models exhibited similar agreement and variability compared to the 1TC for modeling of [11C]HED kinetics. Using t* = 5 min and partial-volume correction produced accurate estimates of VT as an index of myocardial sympathetic innervation.