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RR&D Center of Excellence for the Medical Consequences of Spinal Cord Injury William A. Bauman, M.D. Director Ann M.

RR&D Center of Excellence for the Medical Consequences of Spinal Cord Injury William A. Bauman, M.D. Director Ann M. Spungen , Ed.D Co-Director January 21 , 2010 Rancho Los Amigo National Rehabilitation Hospital. Program Lines of Study. Endocrine Program William A. Bauman, MD

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RR&D Center of Excellence for the Medical Consequences of Spinal Cord Injury William A. Bauman, M.D. Director Ann M.

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  1. RR&D Center of Excellence for the Medical Consequences of Spinal Cord InjuryWilliam A. Bauman, M.D.Director Ann M. Spungen, Ed.DCo-Director January 21, 2010 Rancho Los Amigo National Rehabilitation Hospital

  2. Program Lines of Study • Endocrine Program • William A. Bauman, MD • Pulmonary Program • Gregory J. Schilero • Automomic Program • Jill M. Wecht, EdD • GastrointestinalProgram • Mark A. Korsten, MD • Molecular Program • Christopher P. Cardozo, MD

  3. Endocrine Program • Disuse Osteoporosis • Anabolic Hormones • Carbohydrate Metabolism • Lipid Metabolism Coronary Heart Disease

  4. Osteoporosis in SCI • SCI is a nonweight bearing condition. • Bone is lost rapidly with acute SCI. • goal is to preserve bone architecture & mass • Bone continues to be lost years after SCI • goal is to replace bone mass

  5. Endocrine Program • Disuse Osteoporosis • Pharmacological intervention: • Acute SCI: pamidronate & zoledronate • Chronic SCI: Hectoral(1-α-hydroxyvitamin D2) • Low amplitude, high frequency mechanical stimulation • Evaluation of DXA vs. other imaging modalities • Vitamin D replacement therapy

  6. CalciumMetabolism in Chronic SCI • Absolute vitamin D deficiency state: 32 of 100 (32%) in SCI 8 of 50 (16%) Cont In Persons with SCI: • Negative Correlation: PTH &25 (OH) vitamin D levels • Positive Correlation: PTH & 1,25 (OH)2 vitamin D levels Bauman et al. Metabolism. 44:1612-1616, 1995.

  7. Relationship between Serum PTH and Urinary NTx Levels Ledger et al., J ClinEndocrinolMetab 80:3304-3310, 1995.

  8. Vitamin D Replacement: 2000 IU per Day for 3 Months Bauman et al., Unpublished observation.

  9. Endocrine Program • Anabolic Hormones • Baclofen to increase IGF-1 • Anabolic steroid agents • Testosterone replacement therapy

  10. Testosterone Replacement Therapy (TRT) • Intervention: 12 months of TRT • Endpoints: • Body composition • Muscle strength • Resting energy expenditure • Glucose tolerance • Autonomic function • Psychological assessment

  11. Characteristics of Subjects for the Testosterone Replacement Study Control 9 37±9 174±4 83.2±6.0 27.4±2.2 11±9 2/6 7/2 Count Age (yrs) Height (cm) Weight (kg) BMI (kg/m2) Duration of Injury Para/Tetra Complete/Incomplete TRT 6 43±5 180±7 87.8±15.7 26.8±3.1 13±10 2/9 4/2

  12. Testosterone Replacement Therapy P<0.05 Design: TRT for 12 mo Washout for 6 mo 60 P<0.05 58 56 54 55.0 54.8 52 53.4 TOTAL BODY LTM (kg) 52.7 50 52.2 51.1 48 46 44 42 40 Baseline Testosterone Washout 1700 1600 1500 1400 REE (Kcal/d) 1300 1200 1100 1000 900 800 Bauman et al., Unpublished observation. P<0.05  122 Kcal/d 1,508 1,386 1,341 1,349 Testosterone TRT CONTROL Control Baseline Testosterone

  13. Endocrine Program • Carbohydrate Metabolism • IV GTT • Oral GTT • Relationship to: • - Soft tissue (total & regional) • - Activity (V02max)

  14. 95 85 AB slope (-0.175, P<0.0001) 75 65 TOTAL BODY % LEAN 55 SCI slope (-0.341, P<0.0001) 45 35 25 10 20 30 40 50 60 70 80 AGE (y) Total Body Percent Lean Tissue & Age: Able-Bodied vs. SCI Spungenet al., J ApplPhysiol. 95:2398-2407, 2003.

  15. Cross-Sectional Study: Chronic SCI P<0.0001 40 35 30 * * 25 Control Total Body Percent Fat 20 15 SCI 10 5 0 < 40 y  40 y * P<0.05 for Control vs. SCI Spungenet al., J ApplPhysiol.95:2398-2407, 2003.

  16. Body Mass Index Criteria for Normal, Overweight and Obesity BMI (m/kg2) <18.5 18.5-24.9 25-29.9 >30 Underweight Normal Overweight Obese Expert Panel on the Identification , Evaluation and Treatment of Overweight and Obesity in Adults. NIH NHLBI. 1998

  17. The Relationship of Percent Fat With Body Mass Index 60 50 40 30 Total Body% Fat 20 SCI Control 10 0 10 15 20 25 30 35 40 45 Body Mass Index (kg/m2) Spungen et al., J ApplPhysiol 95:2398-2407, 2003.

  18. Ruderman NB, et al. The “metabolically-obese,” normal-weight individual. Am J ClinNutr 34:1617-1621, 1981 Premise: Persons with metabolic disorders (type 2 DM, HTN, hypertriglyceridemia) who are not obese by standard weight tables or other readily available criteria, but who respond favorably to caloric restriction. It is proposed that such individuals might be characterized by hyperinsulinism and an increase in fat cell size. Inactivity may be a contributing factor. As such, these individuals may benefit from exercise therapy.

  19. St-Onge MP, et al. Metabolic syndrome in normal-weight Americans: new definition of the metabolically obese, normal-weight individual. Diabetes Care. 27:2222-2228, 2004. Prevalence rates MONW syndrome were determined in 7,602 adult participants of the Third National Health & Nutrition Examination Survey. BMI21-22.923-24.9 Men 4.13 5.35 Women 4.34 7.77 Odds ratios (OR) compared with those with BMI=18.5-20.9

  20. Effects of Spinal Cord Injury on the Determinants of Insulin Resistance Muscle mass ↓ Fat mass ↑ Activity ↓

  21. Oral Glucose Tolerance by Neurological Deficit Complete Tetraplegia Complete Paraplegia 6 % 23% 27% 18 % 76% 50% NL IGT DM Incomplete Tetraplegia Incomplete Paraplegia 14 % 20% 17 % 56% 24% 69% Bauman et al., Spinal Cord. 37:765-771, 1999.

  22. Frequency of Impaired Glucose Tolerance and/or Diabetes Mellitus by Neurological Deficit Neurological Subgroup Complete Tetra Incomplete Tetra Complete Para Incomplete Para Percent 73* 44 24 31 *p<0.0001 Bauman et al., Spinal Cord.37:765-771, 1999.

  23. Frequency of Hyperinsulinemia Group Tetra Para Percent 53* 37 *P<0.05 Bauman et al., Spinal Cord. 37:765-771, 1999.

  24. 250 225 200 175 150 DM Serum Glucose (mg/dL) IGT 125 NGT 100 75 50 25 0 0 30 60 90 120 Serum Glucose Results from a 75 g OGTT in SCI Time (minutes) Bauman et al., Unpublished observation.

  25. 180 160 140 120 DM 100 Plasma Insulin (U/ml) IGT 80 NGT 60 40 20 0 0 30 60 90 120 Time (minutes) Plasma Insulin Results from a 75 g OGTT in SCI Bauman et al., Unpublished observation.

  26. Percent of Subjects by SCI Group and FPI Category 40 TETRA 35 PARA 30 25 Percent 20 15 10 5 0 0-5 5-9 10-14 15-19 20-100 FPI Category Bauman et al., Unpublished observation.

  27. Percent of Subjects by Group & 2-Hour Insulin Category After a 75 g OGTT Percent Two-Hr Insulin Category Bauman et al., Unpublished observation.

  28. Endocrine Program • Lipid Metabolism • Descriptive data • Relationship to body fat • Intervention with Niaspan

  29. Protective Effect of HDL Cholesterol • Reverse cholesterol transport • Anti-oxidant • Anti-inflammatory • Direct vascular • Anti-platelet • Anti-coagulant

  30. Relationships between Insulin Sensitivity with VO2 max & HDL Cholesterol Bauman et al., Metab. 43:749-756, 1994.

  31. HDL as a Risk Factor in Persons with SCI Decreased plasma HDL cholesterol Elevated Total Cholesterol : HDL ratio HDL cholesterol < 40 mg/dL: 63% HDL cholesterol < 35 mg/dL: 44% HDL cholesterol < 30 mg/dL: 19% 50 Morbidity risk ratio (age-adjusted) 2.0 45 Average Risk HDL Cholesterol (mg/dL) 40 1.0 35 0 20 40 60 80 HDL (mg/dl) 30 Tetra Complete Tetra Incomplete Para Complete Para Incomplete HDL-Cholesterol & CHD Risk (Men in Framingham, MA) Bauman et al., Spinal Cord, 1998 Bauman et al., Metabolism, 1994 Bauman et al., Spinal Cord, 1999 Bauman et al., Topics in Spinal Cord Injury Rehab, 2008

  32. HDL Cholesterol by Ethnicity Bauman et al., Arch Phys Med Rehabil. 79:176-180, 1998.

  33. Guidelines for Assessment of Risk for CHD National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment Of High Blood Cholesterol in Adults » 1988 Adult Treatment Panel (ATP) I » 1993 ATP II » 2001 ATP III 2004 Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Over the years, the “target values” for LDL cholesterol have become more conservative.

  34. Nash MS, et al. A guideline driven assessment of need for cardiovascular disease risk intervention in persons with chronic paraplegia. Arch Phys Med Rehabil. 88:751-757, 2007 Subjects: 41 subjects with paraplegia • ASIA A & B: T6 to L1 • Age: 34±11 years Main Outcome Measure: % of subjects qualifying for intervention • Based on ATP III guidelines

  35. Nash MS, et al. Arch Phys Med Rehabil. 88:751-757, 2007 Results: 63% of subjects qualified for intervention » 76% had HDL cholesterol <40 mg/dL » ~1/3 had hypertension » 34% had the metabolic syndrome Conclusion: A high percentage of young, healthy persons with SCI are at risk for CVD & qualify for lipid-lowering intervention. Nash et al.Arch Phys Med Rehabil. 88:751-757, 2007.

  36. Risk Assessment for Coronary Heart Disease in a Veteran Population with Spinal Cord Injury. Topics in Spinal Cord Injury Rehabilitation. 12:35-53, 2007. Purpose: » To determine the conventional risk factors for CHD & calculate risk for CHD to determine the target level for serum LDL cholesterol. Population: » 224 outpatients with SCI associated with the VA Medical Center, Bronx, NY Method: » Conventional risk factors for CHD were defined by the ATP III guidelines.

  37. Characteristics of the Study Group Bauman et al., Topics in Spinal Cord InjRehabil. 12:35-53, 2007.

  38. Major Risk Factors for CHD Tetra (n=103) Para (n=119) Table 2 Bauman et al. Topics in Spinal Cord InjRehabil. 12:35-53, 2007.

  39. Ten-Year Risk Assessment Table 3 Bauman et al. Topics in Spinal Cord InjRehabil. 12:35-53, 2007.

  40. Major Risk Factors for CHD • Cigarette Smoking • Hypertension (>140/90 mm Hg or on anti-hypertensive medications • Low HDL cholesterol (<40 mg/dL) • Family history of premature CHD (male first degree relative < 55 years; female first-degree relative < 65 years) • Age (men > 45 years; women > 55 years

  41. Serum HDL Cholesterol Levels in the ATP III Stratification of Risk for CHD HDL cholesterol has a dual function: • Counted as a Major Risk Factor that • serves to modify LDL goals (2) Used to estimate the 10-year risk for developing CHD (using the Framingham risk scoring system) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

  42. Nash MS, et al. Extended-Release Niacin for Treatment of Dylipidemia in Chronic Tetraplegia Subjects: 54 persons with chronic tetraplegia and low HDL cholestrol Results: ↑ HDL (24.5%) ↓ LDL ↓ TC ↓ TC:HDL ↓ LDL:HDL Conclusion: Extended-release niacin is safe, tolerated, and effective for most persons with chronic tetraplegia. Unpublished observation. Supported by NIDRR, Department of Education

  43. Emerging Risk Factors For Coronary Heart Disease ● High-sensitivity CRP ● Interleukin-6 ● Fibrinogen ● Tumor Necrosis Factor-α ● Increased concentration of small, dense LDL particles ● Lp(a) ● Homocysteine ● Apolipoprotein A1 and B ● Postprandial lipemia ● Vitamin D ● Visceral fat

  44. Lee MY, et al. C-reactive protein, metabolic syndrome, and insulin resistance in individuals with spinal cord injury. J Spinal Cord Injury. 28:20-25, 2004. C-reactive protein levels and IR C-reactive protein levels and Dyslipidemia

  45. Mortality Ratios for Plasma Homocysteine Levels for Men and Women with SCI Bauman et al. J Spinal Cord Med. 24:81-86, 2001.

  46. Orakzai SH, et al. Measurement of coronary artery calcification by electron beam computerized tomography in persons with chronic spinal cord injury: evidence for increased atherosclerotic burden. Spinal Cord. 2007 Subjects: »91 persons (76 men & 15 women) with chronic SCI matched 3:1 for age, gender, ethnicity & risk factors for CHD Results: » The mean calcium score of the SCI group was significantly greater than the control group (75±218 versus 28±104, P<0.001) » The prevalence of any CAC score was greater in the SCI population than the control population (51 versus 39%, P<0.05). Conclusions: » Patients with SCI have greater atherosclerotic burden than able-bodied controls. This finding is beyond that explained by the traditional risk factors for CHD.

  47. Questions to be Addressed ● Are persons with SCI at increased risk for CHD? Is there a study that has determined CHD in persons with SCI compared with matched, able-bodied controls? ● Are the guidelines for treatment decisions to reduce risk for CHD transferable from the able-bodied population to persons with SCI? Are there studies that have stratified persons with SCI for risk of CHD on evidenced-based guidelines? ● What factors best predict risk for CHD? These questions have not been answered.

  48. Pulmonary Program PI: Gregory J. SchileroMD • Study of the pathophysiology of spinal cord injury & the lung • Intervention(s) to increase expiratory muscle strength • Markers of lung inflammation • Inhibition of lung nitric oxide & effects on airway tone

  49. Fitted Values for FVC Percent Predicted by Vertebral Level for Complete Motor Lesions 120 Normal Range 100 99 97 100 96 94 93 91 89 88 86 83 81 79 76 80 73 70 67 64 Percent Predicted FVC 60 60 55 49 42 40 20 0 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 Lin & Spungenet al., Spinal Cord. 2001; 39:263-268.

  50. LUNG VOLUMES Normal Tetraplegia Restrictive Findings Slight  TLC  FVC   ERV RV - Correlates with level of injury FVC FRC

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