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Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[[sup.11]C]rolipram provides a direct index of the CAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[[sup.11]C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[[sup.11]C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction. Key words: diet-induced thermogenesis, sympathetic nervous system, noradrenergic signaling, (R)-[[sup.11]C]rolipram, positron emission tomography, high-fat diet, obesity. Une modification de l'activite nerveuse sympathique a ete liee au developpement et au maintien de l'obesite, decoulant en partie d'une suralimentation. La fixation de l'inhibiteur selectif de la phosphodiesterase-4 (PDE4) emetteur de positons, (R)-[[sup.11]C]rolipram, fournit un indice direct de l'enzyme PDE4 hydrolysant l'AMPc. La presente etude examine les modifications progressives de la PDE4 dans un modele animal obese soumis a une diete hyperlipidique. On a injecte le (R)-[[sup.11]C]rolipram a des rats rendus obeses par la diete (OD) et a des rats resistants a la diete (RD), sacrifie les animaux apres 45 min, extrait les tissus et quantifie la radioactivite. On a determine la reactivite de la PDE4 a une stimulation aigue induite par la noradrenaline (NA), 3 h apres un pretraitement avec l'inhibiteur de recapture de NA, desipramine. On a observe une variance minimale dans les mesures de l'apport calorique, de gain corporel, de glucose a jeun, d'insuline et de depense energetique (calorimetrie indirecte). La retention basale de (R)-[[sup.11]C]rolipram a ete comparable chez les rats OD et RD apres 2 ou 8 semaines de diete. L'augmentation normale des taux de PDE4 en reponse a l'augmentation de NA par le pretraitement a la desipramine a ete supprimee dans les tissus riches en PDE4, dont le cerveau, le coeur et le muscle squelettique, des animaux OD apres 8 semaines de diete hyperlipidique. Les rats RD maigres ont maintenu une reactivite de la PDE4 indiquant une transduction de signal normale par la NA. Mots-cles : thermogenese induite par la diete, systeme nerveux sympathique, signalisation noradrenergique, (R)-[[sup.11]C]rolipram, tomographie d'emission de positons, diete hyperlipidique, obesite. [Traduit par la Redaction], Introduction Obesity confers elevated risk for several comorbidities, including type 2 diabetes mellitus, hypertension, and cardiovascular disease (Kannel et al. 1967; Poirier et al. 2006). The sympathetic nervous system (SNS) [...]

Objective: To examine the prevalence of frailty in surgical patients and determine whether age and sex modify the relationship between frailty and long-term mortality. Background: Frailty is a complex and prevalent clinical syndrome. The cardiac surgery literature consists mostly of small, single-center studies, and the epidemiology of frailty remains to be fully elucidated in a real-world surgical population. Methods: This retrospective cohort study included patients who underwent coronary artery bypass grafting, and/or aortic, mitral or tricuspid valve surgery in Ontario, Canada, between 2008 and 2016. The primary outcome was all-cause mortality. Survival probabilities were calculated using the Kaplan-Meier method, and the association of covariates with the hazard of death was assessed using multivariable Cox proportional hazard models. Frailty was assessed using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. Results: Of 72,824 patients, 11,685 (16%) were frail. At median 5 +/- 2 years of follow-up, 2921 (25.0%) frail patients and 8637 (14.1%) non-frail patients had died [adjusted hazard ratio 1.60; 95% confidence interval (CI), 1.53-1.68]. The adjusted hazard ratio was highest in patients who underwent isolated mitral (2.18; 95% CI, 1.71-2.77) and mitral + aortic valve surgery (1.85; 95% CI, 1.33-2.58) and lowest after coronary artery bypass grafting + mitral valve surgery (1.38; 95% CI, 1.11-1.70). Age, but not sex, modified the effect of frailty on mortality; such that the rate of death decreased linearly with increasing patient age. Conclusions: We observed a high prevalence of frailty in patients undergoing cardiac surgery, and a statistically significant association between frailty and long-term mortality after cardiac procedures. Importantly, the rate of death was inversely proportional to age, such that frailty had a stronger adverse impact on younger patients. Our findings highlight the need to incorporate frailty into the preoperative risk stratification and investigate strategies to support younger patients who are frail. [ABSTRACT FROM AUTHOR]

Background: In ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [11C]meta-hydroxyephedrine (HED) vs [13N]ammonia (NH3), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination. Methods: This is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH3 uptake, as well as HED distribution volume and NH3 myocardial blood flow by kinetic modeling. Results: During 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH3, especially in the lowest tertile of perfusion abnormality (P <.001). Parametric defects were larger than their respective tracer uptake defects (P <.001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67). Conclusion: Quantification of HED distribution volume and NH3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone. [ABSTRACT FROM AUTHOR]

Background: Myocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation. Methods and Result: Heart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes. Conclusion: Low-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT. [ABSTRACT FROM AUTHOR]