Female-specific pancreatic cancer survival from CT imaging of visceral fat implicates glutathione metabolism in solid tumors.

RATIONALE AND OBJECTIVES: To identify if body composition, assessed with preoperative CT-based visceral fat ratio quantification as well as tumor metabolic gene expression, predicts sex-dependent overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: This was a retrospective analysis of preoperative CT in 98 male and 107 female patients with PDAC. Relative visceral fat (rVFA; visceral fat normalized to total fat) was measured automatically using software and corrected manually. Median and optimized rVFA thresholds were determined according to published methods. Kaplan Meier and log-rank tests were used to estimate OS. Multivariate models were developed to identify interactions between sex, rVFA, and OS. Unsupervised gene expression analysis of PDAC tumors from The Cancer Genome Atlas (TCGA) was performed to identify metabolic pathways with similar survival patterns to rVFA. RESULTS: Optimized preoperative rVFA threshold of 38.9% predicted significantly different OS in females with a median OS of 15 months (above threshold) vs 24 months (below threshold; p = 0.004). No significant threshold was identified in males. This female-specific significance was independent of age, stage, and presence of chronic pancreatitis (p = 0.02). Tumor gene expression analysis identified female-specific stratification from a five-gene signature of glutathione S-transferases. This was observed for PDAC as well as clear cell renal carcinoma and glioblastoma. CONCLUSION: CT-based assessments of visceral fat can predict pancreatic cancer OS in females. Glutathione S-transferase expression in tumors predicts female-specific OS in a similar fashion.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. METHODS: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. RESULTS: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. CONCLUSIONS: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Risk of nonalcoholic fatty liver disease and associations with gastrointestinal cancers.

Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006-2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (<20%), intermediate (20%-49%), and high (≥50%). We also examined the associations by age of cancer diagnosis (earlier onset [<60] vs. ≥60). A total of 273 incident liver cancer and 4789 non-liver GI cancer cases were diagnosed. Compared with individuals at low risk for NAFLD, those at high risk had 2.41-fold risk of liver cancer (RR = 2.41, 95% CI: 1.73-3.35) and 23% increased risk of non-liver GI cancers (RR = 1.23, 95% CI: 1.14-1.32) (all ptrend < 0.001). Stronger associations were observed for men and individuals who were obese (all pinteraction < 0.05). NAFLD-associated elevated risk was stronger for earlier-onset cancers. For each 25% increase in NAFLD risk, the RRs for earlier-onset cancers were 1.32 (95% CI: 1.05-1.66) for esophageal cancer, 1.35 (95% CI: 1.06-1.72) for gastric cancer, 1.34 (95% CI: 1.09-1.65) for pancreatic cancer, and 1.10 (95% CI: 1.01-1.20) for colorectal cancer. Conclusion: NAFLD risk was associated with an increased risk of liver and most GI cancers, especially those of earlier onset.

Metabolic Biomarkers Assessed with PET/CT Predict Sex-Specific Longitudinal Outcomes in Patients with Diffuse Large B-Cell Lymphoma.

In many cancers, including lymphoma, males have higher incidence and mortality than females. Emerging evidence demonstrates that one mechanism underlying this phenomenon is sex differences in metabolism, both with respect to tumor nutrient consumption and systemic alterations in metabolism, i.e., obesity. We wanted to determine if visceral fat and tumor glucose uptake with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) could predict sex-dependent outcomes in patients with diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis of 160 patients (84 males; 76 females) with DLBCL who had imaging at initial staging and after completion of therapy. CT-based relative visceral fat area (rVFA), PET-based SUVmax normalized to lean body mass (SULmax), and end-of-treatment FDG-PET 5PS score were calculated. Increased rVFA at initial staging was an independent predictor of poor OS only in females. At the end of therapy, increase in visceral fat was a significant predictor of poor survival only in females. Combining the change in rVFA and 5PS scores identified a subgroup of females with visceral fat gain and high 5PS with exceptionally poor outcomes. These data suggest that visceral fat and tumor FDG uptake can predict outcomes in DLBCL patients in a sex-specific fashion.

Coronary circulatory function with increasing obesity: A complex U-turn.

AIMS: The aim of this investigation was to explore and characterize alterations in coronary circulatory function in function of increasing body weight with medically controlled cardiovascular risk factors and, thus, "metabolically" unhealthy obesity. MATERIALS AND METHODS: We prospectively enrolled 106 patients with suspected CAD but with normal stress-rest myocardial perfusion on 13 N-ammonia PET/CT and with medically controlled or no cardiovascular risk factors. 13 N-ammonia PET/CT concurrently determined myocardial blood flow (MBF) during pharmacologically induced hyperaemia and at rest. Based on body mass index (BMI), patients were grouped into normal weight (BMI: 20.0-24.9 kg/m2 , n = 22), overweight (BMI: 25.0-29.9 kg/m2 , n = 27), obese (BMI: 30.0-39.9 kg/m2 , n = 31), and morbidly obese (BMI ≥ 40kg/m2 , n = 26). RESULTS: Resting MBF was comparable among groups (1.09 ± 0.18 vs. 1.00 ± 0.15 vs. 0.96 ± 0.18 vs.. 1.06 ± 0.31 ml/g/min; p = .279 by ANOVA). Compared to normal weight individuals, the hyperaemic MBF progressively decreased in in overweight and obese groups, respectively (2.54 ± 0.48 vs. 2.02 ± 0.27 and 1.75 ± 0.39 ml/g/min; p < .0001), while it increased again in the group of morbidly obese individuals comparable to normal weight (2.44 ± 0.41 vs. 2.54 ± 0.48 ml/g/min, p = .192). The BMI of the study population correlated with the hyperaemic MBF in a quadratic or U-turn fashion (r = .34, SEE = 0.46; p ≤ .002). CONCLUSIONS: The U-turn of hyperaemic MBF from obesity to morbid obesity is likely to reflect contrasting effects of abdominal versus subcutaneous adipose tissue on coronary circulatory function indicative of two different disease entities, but needing further investigations.

Myocardial glucose and fatty acid metabolism is altered and associated with lower cardiac function in young adults with Barth syndrome.

BACKGROUND: Barth syndrome (BTHS) is a rare X-linked condition resulting in cardiomyopathy, however; the effects of BTHS on myocardial substrate metabolism and its relationships with cardiac high-energy phosphate metabolism and left ventricular (LV) function are unknown. We sought to characterize myocardial glucose, fatty acid (FA), and leucine metabolism in BTHS and unaffected controls and examine their relationships with cardiac high-energy phosphate metabolism and LV function. METHODS/RESULTS: Young adults with BTHS (n = 14) and unaffected controls (n = 11, Control, total n = 25) underwent bolus injections of 15O-water and 1-11C-glucose, palmitate, and leucine and concurrent positron emission tomography imaging. LV function and cardiac high-energy phosphate metabolism were examined via echocardiography and 31P magnetic resonance spectroscopy, respectively. Myocardial glucose extraction fraction (21 ± 14% vs 10 ± 8%, P = .03) and glucose utilization (828.0 ± 470.0 vs 393.2 ± 361.0 µmol·g-1·min-1, P = .02) were significantly higher in BTHS vs Control. Myocardial FA extraction fraction (31 ± 7% vs 41 ± 6%, P < .002) and uptake (0.25 ± 0.04 vs 0.29 ± 0.03 mL·g-1·min-1, P < .002) were significantly lower in BTHS vs Control. Altered myocardial metabolism was associated with lower cardiac function in BTHS. CONCLUSIONS: Myocardial substrate metabolism is altered and may contribute to LV dysfunction in BTHS. Clinical Trials #: NCT01625663.

Dietary Patterns, Ceramide Ratios, and Risk of All-Cause and Cause-Specific Mortality: The Framingham Offspring Study.

BACKGROUND: Prior evidence suggests that diet modifies the association of blood ceramides with the risk of incident cardiovascular disease (CVD). It remains unknown if diet quality modifies the association of very long-chain-to-long-chain ceramide ratios with mortality in the community. OBJECTIVES: Our objectives were to determine how healthy dietary patterns associate with blood ceramide concentrations and to examine if healthy dietary patterns modify associations of ceramide ratios (C22:0/C16:0 and C24:0/C16:0) with all-cause and cause-specific mortality. METHODS: We examined 2157 participants of the Framingham Offspring Study (mean age = 66 y, 55% women). Blood ceramides were quantified using a validated assay. We evaluated prospective associations of the Dietary Guidelines Adherence Index (DGAI) and Mediterranean-style Diet Score (MDS) with incidence of all-cause and cause-specific mortality using Cox proportional hazards models. Cross-sectional associations of the DGAI and MDS with ceramides were evaluated using multivariable linear regression models. RESULTS: The C22:0/C16:0 and C24:0/C16:0 ceramide ratios were inversely associated with all-cause, CVD, and cancer mortality; multivariable-adjusted HRs (95% CIs) were 0.73 (0.67, 0.80) and 0.70 (0.63, 0.77) for all-cause mortality, 0.74 (0.60, 0.90) and 0.69 (0.55, 0.86) for CVD mortality, and 0.75 (0.65, 0.87) and 0.75 (0.64, 0.88) for cancer mortality, respectively. Inverse associations of the C22:0/C16:0 and C24:0/C16:0 ceramide ratios with cancer mortality were attenuated among individuals with a higher diet quality (DGAI or MDS above the median, all P-interaction ≤0.1). The DGAI and MDS had distinct associations with ceramide ratios (DGAI: lower C22:0/C16:0 across quartiles; MDS: higher C24:0/C16:0 across quartiles; all P-trend ≤0.01). CONCLUSION: In our community-based sample, ceramide ratios (C22:0/C16:0 and C24:0/C16:0) were associated with a lower risk of all-cause and cause-specific mortality. Further, we observed that a higher overall diet quality attenuates the association between blood ceramide ratios and cancer mortality and that dietary patterns have distinct relations with ceramide ratios.

Cardiovascular Safety of Abaloparatide in Postmenopausal Women With Osteoporosis: Analysis From the ACTIVE Phase 3 Trial.

CONTEXT: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. OBJECTIVES: We assessed the cardiovascular safety profile of abaloparatide. DESIGN: Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. RESULTS: Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACE + HF was longer with abaloparatide (P = 0.02 vs placebo) and teriparatide (P = 0.04 vs placebo). CONCLUSIONS: Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.

Bariatric Surgery-Induced Cardiac and Lipidomic Changes in Obesity-Related Heart Failure with Preserved Ejection Fraction.

OBJECTIVE: To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF). METHODS: A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22). RESULTS: After surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo-derived e' increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate. CONCLUSIONS: Surgery-induced weight loss in women with HFpEF and obesity was associated with improved symptoms, reverse cardiac remodeling, and improved relaxation. Although weight loss was associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. The results of this study suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis.

Myocardial oxygen consumption change predicts left ventricular relaxation improvement in obese humans after weight loss.

Obesity adversely affects myocardial metabolism, efficiency, and diastolic function. Our objective was to determine whether weight loss can ameliorate obesity-related myocardial metabolism and efficiency derangements and that these improvements directly relate to improved diastolic function in humans. We studied 30 obese (BMI >30 kg/m2) subjects with positron emission tomography (PET) (myocardial metabolism, blood flow) and echocardiography (structure, function) before and after marked weight loss from gastric bypass surgery (N = 10) or moderate weight loss from diet (N = 20). Baseline BMI, insulin resistance, hemodynamics, left ventricular (LV) mass, systolic function, myocardial oxygen consumption (MVO2), and fatty acid (FA) metabolism were similar between the groups. MVO2/g decreased after diet-induced weight loss (P = 0.009). Total MVO2 decreased after dietary (P = 0.02) and surgical weight loss (P = 0.0006) and was related to decreased BMI (P = 0.006). Total myocardial FA utilization decreased (P = 0.03), and FA oxidation trended lower (P = 0.06) only after surgery. FA esterification and LV efficiency were unchanged. After surgical weight loss, LV mass decreased by 23% (Doppler-derived) E/E' by 33%, and relaxation increased (improved) by 28%. Improved LV relaxation related significantly to decreased BMI, insulin resistance, total MVO2, and LV mass but not FA utilization. Decreased total MVO(2) predicted LV relaxation improvement independent of BMI change (P = 0.02). Weight loss can ameliorate the obesity-related derangements in myocardial metabolism and LV structure and diastolic function. Decreased total MVO2 independently predicted improved LV relaxation, suggesting that myocardial oxygen metabolism may be mechanistically important in determining cardiac relaxation.

Intramyocardial triglyceride quantification by magnetic resonance spectroscopy: In vivo and ex vivo correlation in human subjects.

Accumulation of triglycerides (TG) in heart tissue has been associated with changes in left ventricular function. Proton magnetic resonance spectroscopy is currently the only noninvasive in vivo method to measure myocardial triglycerides content. The primary aim of this study was to determine if these in vivo measurements are specific to myocardial triglycerides in human subjects. Thus, in vivo proton magnetic resonance spectroscopy measurements were conducted on orthotopic heart transplant patients (n = 8) immediately before they underwent routine biopsies and ex vivo measurements were made on the endomyocardial biopsy samples. The correlation coefficient between the two measurements was 0.97, with P < 0.005, demonstrating for the first time the specificity of the in vivo measurement in human heart. From accompanying reliability experiments, the standardized typical error for the in vivo proton magnetic resonance spectroscopy method was estimated to be 7.0%, with a 95% confidence interval from 5.5 to 9.4%. These results suggest that proton magnetic resonance spectroscopy provides a specific and reliable measurement of myocardial triglycerides content and is suitable for routine studies.

Impact of hormone replacement on myocardial fatty acid metabolism: potential role of estrogen.

BACKGROUND: Estrogen increases fatty acid utilization and oxidation and may decrease glucose use in human skeletal muscle, whereas these effects are attenuated by progesterone. Whether these ovarian hormones exhibit similar effects on myocardial metabolism is unknown. METHODS AND RESULTS: Myocardial blood flow and oxygen consumption, as well as glucose and fatty acid metabolism, were examined retrospectively by use of positron emission tomography in 24 postmenopausal women receiving estrogen (n = 7), estrogen plus progesterone (n = 8), or no hormone replacement (n = 9) and in 22 age-matched men. Myocardial blood flow was higher in women regardless of hormone replacement status. Myocardial oxygen consumption was higher in women taking estrogen only when compared with men (7.3 +/- 1.6 micromol.g(-1).min(-1) vs 4.6 +/- 1.2 micromol.g(-1).min(-1), P < .001). Glucose utilization was not affected by gender or hormone replacement. Whereas fatty acid levels and the degree of myocardial fatty acid uptake were not distinguished by gender or hormone use, myocardial fatty acid utilization was higher in women taking estrogen when compared with men (259 +/- 68 nmol.g(-1).min(-1) vs 176 +/- 50 nmol.g(-1).min(-1), P = .01) and trended higher when compared with women not receiving hormonal therapy (185 +/- 46 nmol.g(-1).min(-1), P = .07) but was not different from that of women taking estrogen plus progesterone (205 +/- 58 nmol.g(-1).min(-1), P = not significant). CONCLUSIONS: In postmenopausal women, estrogen use is associated with increased myocardial fatty acid utilization. Thus, when the cardiac effects of hormone replacement therapy are being assessed, alterations in myocardial substrate metabolism should be considered.

The safety of performing diagnostic cardiac catheterizations in a mobile catheterization laboratory at primary care hospitals.

The benefits of mobile cardiac catheterization laboratories include keeping patients closer to their families, communities, local hospitals, and primary care physicians while receiving services comparable to those available at tertiary centers. However, there are very few studies regarding the safety of performing cardiac catheterization in mobile laboratories at remote locations. Thus, the authors performed an observational study of 1,775 consecutive patients undergoing a diagnostic cardiac catheterization in a mobile catheterization laboratory at primary care hospitals served by the Appleton Heart Institute (AHI) from August 1, 1991, to December 31, 1998. Twenty-three percent (1,775/7,637) of all AHI diagnostic cases in this time period were performed in the mobile catheterization laboratory. Urgent transfer to the tertiary care facility via ambulance or helicopter was used for 2.3% of patients (n = 41). The overall complication rate was 1.2% (n = 21). Of the patients who underwent cardiac catheterization in the mobile laboratory, 32.6% (n = 579) were subsequently referred for interventional or surgical revascularization. There were no deaths. Cardiac catheterizations can be performed safely in a mobile laboratory at primary care hospitals, provided that immediate transfer is available for those in need of urgent intervention or revascularization and that unstable patients are not studied in the mobile laboratory.