Comparing Two Waist-to-Height Ratio Measurements with Cardiometabolic Risk Factors among Youth with Diabetes

Background: Waist circumference (WC) is commonly measured by either the World Health Organization (WHO) or National Health and Nutrition Examination Survey (NHANES) protocol. Objective: Compare the associations of WHO vs. NHANES WC-to-height ratio (WHtR) protocols with cardiometabolic risk factors (CMRFs) in a sample of youth with diabetes. Methods: For youth (10–19 years old with type 1 [N=3082] or type 2 [N=533] diabetes) in the SEARCH for Diabetes in Youth Study, measurements were obtained of WC (by two protocols), weight, height, fasting lipids (total cholesterol, triglycerides, HDL cholesterol, Non-HDL cholesterol) and blood pressures. Associations of CMRFs with WHO and NHANES WHtR were modeled stratified by body mass index (BMI) percentiles for age/sex: lower BMI (<85th BMI percentile; N=2071) vs. higher BMI (≥85th percentile; N=1594). Results: Among lower-BMI participants, both NHANES and WHO WHtR were associated (p<0.005) with all CMRFs except blood pressure. Among higher-BMI participants, both NHANES and WHO WHtR were associated (p<0.05) with all CMRFs. WHO WHtR was more strongly associated (p<0.05) than NHANES WHtR with triglycerides, non-HDL cholesterol, and systolic blood pressure in lower-BMI participants. Among high-BMI participants, WHO WHtR was more strongly associated (p<0.05) than NHANES WHtR with triglycerides and systolic blood pressure. Conclusion: Among youth with diabetes, WHtR calculated from either WC protocol captures cardiometabolic risk. The WHO WC protocol may be preferable to NHANES WC

Doxorubicin exposure causes subacute cardiac atrophy dependent upon the striated muscle-specific ubiquitin ligase Muscle Ring Finger-1

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines

2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American heart Association Task Force on Practice Guidelines

1.1. Organization of the Work Group: The Risk Assessment Work Group (Work Group) was composed of 11 members and 5 ex-officio members, including internists, cardiologists, endocrinologists, and experts in cardiovascular epidemiology, biostatistics, healthcare management and economics, and guideline development. 1.2. Document Review and Approval: A formal peer review process, which included 12 expert reviewers and representatives of federal agencies, was initially completed under the auspices of the NHLBI. This document was also reviewed by 3 expert reviewers nominated by the ACC and the AHA when the management of the guideline transitioned to the ACC/AHA. The ACC and AHA Reviewers’ RWI information is published in this document (Appendix 2). This document was approved for publication by the governing bodies of the ACC and AHA and endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, American Society for Preventive Cardiology, American Society of Hypertension, Association of Black Cardiologists, National Lipid Association, Preventive Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women With Heart Disease. 1.3. Charge to the Work Group: The Work Group was 1 of 3 work groups appointed by the NHLBI to develop its own recommendations and provide cross-cutting input to 3 Panels for updating guidelines on blood cholesterol, blood pressure (BP), and overweight/obesity. The Work Group was asked to examine the scientific evidence on risk assessment for initial ASCVD events and to develop an approach for quantitative risk assessment that could be used in practice and used or adapted by the risk factor panels (blood cholesterol, hypertension, and obesity) in their guidelines and algorithms. Specifically, the Work Group was charged with 2 tasks: 1) To develop or recommend an approach to quantitative risk assessment that could be used to guide care; and 2) To use systematic review methodology to pose and address a small number of questions judged to be critical to refining and adopting risk assessment in clinical practice

Inhibition of Nampt activates AMPK signaling

<p>(A) Prostate tumor cells were treated with vehicle, FK866 (10 nM or 100 nM), or FK866 (100 nM) plus NAD⁺, Na or NMN. After 48 hours, ATP levels were measured by luminescence and normalized to DNA content (*p<0.0001). (B) The levels of pACC and ACC were determined in cells treated with vehicle (0.1%), or FK866 (100 nM) in the absence or presence of NAD⁺ for 48 hours (100 µM). (C) PC-3 cells were treated with vehicle, FK866 (100 nM), Compound C (CC, 10 µM), or the combination of both (FK+CC) for 48 hours and pACC, ACC, pAMPK, and AMPK levels were determined by western blot. (D) PC-3 cells were treated with vehicle, FK866, Compound C, or the combination of both for 48 hours and fatty acid synthesis was measured (*p<0.0001, #p = 0.0007). Cell killing was also determined by trypan blue exclusion (*p<0.0001).</p

Nampt activity is required for fatty acid synthesis in cancer cells

<p>(A) PCa cells were treated with FK866 (100 nM) in the absence or presence of NAD⁺, NMN, or Na for 48 hours and fatty acid synthesis was determined by the incorporation of ¹⁴C-acetate into the lipid (*p<0.0001). Expression of ACC, AceCS1, FASN, and β-actin was determined by western blot. (B) Fatty acid synthesis was measured in Snb-19 glioblastoma cells, Src-transformed 3T3 fibroblasts, and MCF-7 breast cancer cells as in (A) (*p<0.0001). (C) PC-3 cells were transfected with scrambled or Nampt-targeting siRNA (100 nM) and fatty acid synthesis was assayed 5 days post-transfection (*p<0.0001). (D) PC-3 cells were treated as indicated and the fatty acid profile was determined by GC-MS.</p

Sirtuin activity is required for lipogenesis in prostate cancer cells

<p>(A) PCa cells were treated as indicated for 48 hours and global protein acetylation was measured by western blot. (B) PCa cells were treated with DMSO (0.1%) or Sirtinol (100 µM) for 48 hours and ¹⁴C-acetate and -choline incorporation into lipid were measured (*p<0.0001). (C) PC-3 cells were treated with scrambled, SIRT1, or SIRT3 targeting siRNA (100 nM each) and fatty acid synthesis was measured. The expression levels of SIRT1, SIRT3, and β-actin were determined by western blot. (D) PC-3 and LNCaP cells were transfected with scrambled (200 nM) or the combination of SIRT1.2 and SIRT3.2 targeting siRNA (100 nM each). The incorporation of ¹⁴C-acetate and -choline into lipid were determined 5 days after transfection (*p = 0.0002). The levels of SIRT1, SIRT3, and β-actin were determined by western blot.</p

Nampt activity is required for phosphatidylcholine (PC) synthesis in cancer cells

<p>(A) PCa cells were treated for 48 hours with vehicle, or FK866 (100 nM) in the absence or presence of NAD⁺ (100 µM) and lipid synthesis was assessed by ¹⁴C-choline incorporation (*p<0.0001). (B) PC-3 cells were transfected with scrambled or Nampt-targeting siRNA (100 nM) and lipid synthesis was assayed 5 days post-transfection (*p<0.0001). (C) PC-3 cells were treated as indicated and the PC profile was determined by mass spectrometry (*p<0.05).</p

Nampt inhibition does not affect the phosphatidylserine (PS), phosphatidylethanolamine (PE), or phosphatidylinositol (PI) lipid classes.

<p>(A–C) PC-3 cells were treated with vehicle, FK866 (100 nM) in the absence or presence of NMN (500 µM) for 48 hours and the PS, PE, and PI profiles were determined by mass spectrometry (*p<0.05).</p

Doxorubicin exposure causes subacute cardiac atrophy dependent upon the striated muscle-specific ubiquitin ligase Muscle Ring Finger-1

Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines