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David R. Meldrum, MD Clinical Professor UCLA and UCSD

David R. Meldrum, MD Clinical Professor UCLA and UCSD. The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Meldrum DR, et al. Amer J Cardiol 2011;108:599-606. ED is strongly linked to C-V disease.

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David R. Meldrum, MD Clinical Professor UCLA and UCSD

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  1. David R. Meldrum, MD Clinical Professor UCLA and UCSD The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Meldrum DR, et al. Amer J Cardiol 2011;108:599-606

  2. ED is strongly linked to C-V disease • Men with ED develop coronary artery calcification at a younger age than controls, and have a reduced response to nitroglycerine (penile angina)1 • A very strong correlation was found between penile systolic velocity and ischemic heart disease2 1. Chiurlia E, et al: J Amer Coll Cardiol 2005;46:1502-6 2. Shamloul R, et al: Int J Impot Res 2004;16:235-7

  3. ED is strongly linked to C-V disease • There is a strong correlation of ED and the metabolic syndrome1 • ED is correlated with a reduced HDL/cholesterol ratio2 • Coronary risk factors predict later development of ED3 1. Kupalian V, et al: J Urol 2006;176:222-6 2. Eaton CB, et al: Int J Impot Res 2007;19:218-25 3. Fung MM, et al: J Am Coll Cardiol 2004;14:1405-11

  4. ED is strongly linked to C-V disease • 67% of men with angiographically proven coronary artery disease had experienced symptoms of ED an average of 39 months earlier1 • “…a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proven otherwise.”2 1. Montorsi F, et al: EurUrol 2003;44:360-4 2. Jackson G: The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006;3:28-36

  5. Nitric Oxide and Flow Mediated Dilation * P < 0.001 * ED NO ED Chiurlia E, et al. J Am Coll Cardiol 2005;46:1503-1506

  6. Nitric oxide (NO) and erectile function • NO is the principle factor that mediates the effect of sexual arousal in causing engorgement of penile tissue and erection. • Nerve stimulation of human corpus cavernosum tissue indicated that NO was responsible for relaxation of the penile vasculature • NO caused smooth muscle relaxation through stimulation of cyclic GMP • A PDE-5 inhibitor enhanced the response Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ: New Engl J Med 1992;326:90-4

  7. Louis J. Ignarro, PhD, 1998 Nobel Laureate

  8. The penis is “just” a collection of specialized blood vessels within a tough fibrous sheath Relaxation of the penile artery through nNOS causes filling of the sinusoids of the corpora cavernosa NO also relaxes the smooth muscle surrounding the sinusoids (eNOS) Sufficient distention against the fibrous sheath then closes off the penile veins, maintaining the erection

  9. erection penile arteries NO constrict relax anxiety, stress sexual stimuli Physiology of Erectile Function* *www.Erectile-Function.com Cyclic GMP Break-down by PDE5 inhibit Viagra-like drugs

  10. Nitric oxide (NO) and erectile function • Nitric oxide synthase exists as a neuronal enzyme (nNOS), where it functions as a neurotransmitter • It also exists as an endothelial enzyme, eNOS, where it acts as an autocrine factor, for example by reducing senescence of the endothelium, and as a paracrine factor, diffusing into surrounding tissue preventing atherosclerosis, inhibiting platelet adhesion, and inhibiting vascular tone and proliferation of vascular smooth muscle

  11. Viagra-like drugs can inadvertently cover up more serious vascular disease • Inhibitors of PDE5 afford primarily symptomatic treatment by increasing cyclic-GMP, while not fully correcting the underlying problem of deficient nitric oxide (NO) production by unhealthy blood vessels (recent studies have established some beneficial vascular effects) • NO both stimulates cyclic-GMP and also reduces/prevents atherosclerosis and intra-arterial clotting, and reduces vascular tone and smooth muscle proliferation in artery/arteriolar walls

  12. Antioxidants, folic acid, omega 3 fats, Ca, vit. C&E, exercise, and testosterone erection promotes promote L-arginine (and indirectly from L-citrulline) Cyclic GMP NO inhibit Break-down by PDE5 inhibit Viagra-like drugs Biochemistry of Erectile Function* Meldrum DR, et al. Amer J Cardiol 2011;108:599-606 exercise, insulin, omega 3 fatty acids, calcium, folic acid, anti-oxidants, vitamin C, vitamin E, testosterone, weight reduction, moderate alcohol, PDE-5 inhibitors smoking, excessive alcohol, physical inactivity, dietary fat and sugar, abdominal obesity, diabetes, hypertension, insulin resistance, decreased antioxidant defenses

  13. Akkus E, et al: Eur Urol 2002;41:298-304 Agostini CLM, et al: Int J Impot Res 2011;23:115-121 Sedentary or no alcohol moderate active alcohol

  14. Shear force induction of eNOS no shear force shear force Cheng C, et al: Blood 2005;106:3691-8

  15. NO and decreased fasting insulin concentration Roberts CK et al. Circulation 2002;106:2530-2 r2 = 0.68, p < 0.05 Increase in NOx (mmol/24hr) Decrease in Fasting Insulin (uU/ml)

  16. PON-1 and exercise, alcohol • Multiple regression analysis • Exercise significant at 0.033 (positive) • Alcohol significant at 0.003 (positive) • Smoking significant at < 0.001 (negative) Senti M, et al: Eur J Int Med2003;14:178-184

  17. R N T C FATTY ACIDS I I O XI obesity D E inactivity smoking alcohol? SUGARS www.Erectile-Function.com

  18. Akkus E, et al: Eur Urol 2002;41:298-304 Cheng JYW, et al: Int J Impot Res 2007;19:343-352 Sedentary or no alcohol moderate active alcohol

  19. Obesity, inflammation, and NO • Obesity is well known to increase resistance to insulin and circulating glucose • Obesity also increases TNF-alpha, IL-6, and CRP, and decreases endothelial NO production* • IL-6 and CRP decreased and endothelial NO production and the IIEF score increased with weight loss and increased activity, and the decreases of BMI and CRP and the increase of physical activity each correlated independently with improvement of the IIEF score** *Giugliano F, et al: J Endocrinol Invest2004; 27:665-669 **Esposito K, et al: JAMA 2004; 291:2978-2984.

  20. Pellufo G, et al: Am J Physiol Heart Circ Physiol 2009;96: H1781-92

  21. High Fat Load and Flow Mediated Dilation: Activity Level active inactive Johnson BD, et al: Appl Physiol Nutr Metab 2011;36:368-375

  22. Inflammatory and Adhesion Markers after a High Fat Meal diabetic control Vitamins C and E baseline Nappo F, et al: J Am Coll Cardiol 2002; 39:1145-1150

  23. Glucose load and inflammation: diabetics and controls diabetic control glutathione infusion baseline Esposito K, et al: Circulation 2002;106:2067-2072

  24. b c NITRIC OXIDE Calcium Omega 3 fats Folicacid L-Arginine a L-Citrulline Anti-oxidants a Moens AL, et al: Am J Heart Circ Physiol 2008;49:H1971-8 b van Mierlo LAJ, et al: J Hum Hypertens 2006;20:571-80 c Okuda Y, et al: Biochem Biophys Res Commun 1997;232:487-91

  25. NITRIC OXIDE Omega 3 fats Calcium pomegranate blackberries blueberries strawberries chocolate green tea red wine Fruits and vegetables * Folicacid L-Arginine L-Citrulline Anti-oxidants * reference list under “resources” tab at www.erectile-function.com

  26. Red cell reduced glutathione (umol/L) *P < 0.001 * ED Control Tagliabue M, et al: Int J Androl 2005;28:156-62

  27. PON-1 and ED Ciftci H, et al: Int J Impot Res 2007;19:517-520

  28. Vasodilatation due to cocoa(ml volume by PAT) † * P < 0.01 *† * Baseline Day 5 90 minutes L-NAME Fisher ND, et al: J Hypertens 2003;21:2281-6

  29. Pycnogenol and ED Stanislavov R,et al: J Sex Marital Ther 2003;29:207-13 % improvement of ED placebo 120 mg 80 mg

  30. What about testosterone?

  31. Male hypogonadism and ED • Male hypogonadism has been correlated with decreased vascular NO production a and with the metabolic syndrome, and testosterone replacement not only improves ED b, but gathering evidence has shown that it also improves various components of the metabolic syndrome, including a reduction of central adiposity and decreased insulin resistance c. aAkishita: Hypertens res 2007;30:1029-34, b Traish: J Androl 2009;30:10-22, c Stanworth: Clin Interv Aging 2008;3:25-44

  32. Impact of L-Arginine and pycnogenol on ED and circulating T * * *P < 0.001 placebo L-A/P placebo L-A/P Stanislavov R, et al: Int J Impot Res 2008;20:173-80

  33. L-citrulline versus L-arginine Hecker M, et al: Proc Natl Acad Sci 1990;87:8612-16 Circulating levels of L-arginine AUC umol h l-1 1.5 gm L-citrulline 3.2 gm L-arginine Schwedhelm E, et al: Br J Clin Pharmacol;2008;65:51-9

  34. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E 1. L-Citrulline pycnogenol weight loss 1. Exercise increases NO by the shear forces of increased blood flow, increased insulin sensitivity, and increased PON-1 www.Erectile-Function.com

  35. Pelvic Floor Exercises Dorey G, et al: BJU Int 2005;96:595-7

  36. Pelvic Floor Exercises Dorey G, et al: Br J Gen Pract 2004;54:2019-25

  37. Pelvic Floor Exercises

  38. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE 2. Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E L-Citrulline pycnogenol weight loss 2. Omega-3 fats increase NO. Eat fatty fish and take fish oil to provide 500 to 1,000 mg daily www.Erectile-Function.com

  39. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid 3. L-Arginine D E L-Citrulline pycnogenol weight loss 3. Folic acid is a co-factor in the synthesis of NO. Take 200 to 400 micrograms daily. www.Erectile-Function.com

  40. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E 4. L-Citrulline pycnogenol weight loss 4. Increase intake of natural antioxidants www.Erectile-Function.com

  41. Ten steps to improved erectile and vascular health low fat 5. low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E L-Citrulline pycnogenol weight loss 5 Cutting out all sweets, sugary drinks, fried foods, fatty beef, and full fat dairy would be an excellent plan. www.Erectile-Function.com

  42. Effects of Cocoa and Sugar on Flow Mediated Dilation Faridi Z, et al. Am J Clin Nutr 2008;88:58-63 Meldrum DR, et al. Amer J Cardiol 2011;108:599-606

  43. Snack food for meeting break ESHRE meeting, Stockholm ASRM meeting, Denver

  44. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE 6. Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E L-Citrulline pycnogenol weight loss 6. Increase calcium intake with supplements as necessary to provide 1,200 mg daily. www.Erectile-Function.com

  45. Ten steps to improved erectile and vascular health STRESS 7. Decrease stress. www.Erectile-Function.com

  46. Ten steps to improved erectile and vascular health 8. Pay attention to your relationship with your partner. www.Erectile-Function.com

  47. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E 9. L-Citrulline pycnogenol weight loss 9. Consider a stronger antioxidant (pycnogenol, 50-120 mg per day) and L-citrulline, 2 gm daily www.Erectile-Function.com

  48. Ten steps to improved erectile and vascular health low fat low sugar NITRIC OXIDE Omega 3 fats R calcium I C N I T O XI Folicacid L-Arginine D E L-Citrulline pycnogenol weight loss 10. 10. Weight loss improves insulin sensitivity. Work at moderate weight loss (20-30 lb /year) www.Erectile-Function.com

  49. Biochemistry of Erectile Function* *www.Erectile-Function.com erection promote promotes Cyclic GMP NO inhibit Break-down by PDE5 inhibit Viagra-like drugs Antioxidants, folic acid, omega 3 fats, Ca, vit. C&E, exercise, and testosterone caution! L-arginine (and indirectly from L-citrulline) smoking, excessive alcohol, physical inactivity, dietary fat and sugar, abdominal obesity, diabetes, hypertension, insulin resistance, decreased antioxidant defenses

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