The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Meldrum DR, et al....

The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Meldrum DR, et al. Amer J Cardiol 2011;108:599-606

David R. Meldrum, MDClinical ProfessorUCLA and UCSD

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)11

• A very strong correlation was found between penile systolic velocity and ischemic heart disease2

1. Chiurlia E, et al: J Amer Coll Cardiol 2005;46:1502-62. Shamloul R, et al: Int J Impot Res 2004;16:235-7

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;176:222-62. Eaton CB, et al: Int J Impot Res 2007;19:218-253. Fung MM, et al: J Am Coll Cardiol 2004;14:1405-11

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: Eur Urol 2003;44:360-42. Jackson G: The second Princeton consensus on sexual

dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006;3:28-36

* P < 0.001

ED NO ED

*

Nitric Oxide and Flow Mediated Dilation

Chiurlia E, et al. J Am Coll Cardiol 2005;46:1503-1506

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

Louis J. Ignarro, PhD, 1998 Nobel Laureate

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

penile arteries

anxiety, stress

constrict

sexual stimuli

relax

erection

NO

Physiology of Erectile Function* *www.Erectile-Function.com

Cyclic GMP

Break-down by PDE5

Viagra-like drugs

inhibit

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

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

L-arginine (and indirectly from L-citrulline)

NO

Antioxidants, folic acid, omega 3 fats, Ca, vit. C&E, exercise, and testosterone

promote

Cyclic GMP

promotes

Viagra-like drugs

inhibit

erection

inhibit

Break-down by PDE5

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

ED and exercise, alcohol

Sedentary or no alcohol

moderate active alcohol

Akkus E, et al: Eur Urol 2002;41:298-304Agostini CLM, et al: Int J Impot Res 2011;23:115-121

Cheng C, et al: Blood 2005;106:3691-8

Shear force induction of eNOS

no shear force shear force

NO and decreased fasting insulin concentration

Decrease in Fasting Insulin (uU/ml)

r2 = 0.68, p < 0.05

Roberts CK et al. Circulation 2002;106:2530-2

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

NI TRI C

OXID

E

FATTY ACIDS

SUGARS

alcohol?sm

oking

obesity

inactivity

www.Erectile-Function.com

ED and exercise, alcohol

Sedentary or no alcohol

moderate active alcohol

Akkus E, et al: Eur Urol 2002;41:298-304Cheng JYW, et al: Int J Impot Res 2007;19:343-352

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 Invest 2004; 27:665-669**Esposito K, et al: JAMA 2004; 291:2978-2984.

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

High Fat Load and Flow Mediated Dilation: Activity Level

active

inactive

Johnson BD, et al: Appl Physiol Nutr Metab 2011;36:368-375

Inflammatory and Adhesion Markers after a High Fat Meal

Nappo F, et al: J Am Coll Cardiol 2002; 39:1145-1150

baseline Vitamins C and E

diabeticcontrol

diabetic

control

Glucose load and inflammation: diabetics and controls

Esposito K, et al: Circulation 2002;106:2067-2072

baseline glutathione infusion

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

Calcium O

mega 3

fats

Anti-oxidants

F

olic

ac

id a

a Moens AL, et al: Am J Heart Circ Physiol 2008;49:H1971-8b van Mierlo LAJ, et al: J Hum Hypertens 2006;20:571-80c Okuda Y, et al: Biochem Biophys Res Commun 1997;232:487-91

bc

NO production by cultured human endothelial cells (nmol per mg protein)

0

10

20

30

40

50

60

70

0 3 10 30

control

EPA

*

*

Time after addition of EPA (minutes)

*

*P < 0.01

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

CalciumOmega 3

fats

Anti-oxidants

Fol

ic

acid

pomegranateblackberriesblueberriesstrawberrieschocolategreen teared wineFruits andvegetables*

* reference list under “resources” tab at www.erectile-function.com

0

500

1000

1500

2000

2500

0

500

1000

1500

2000

2500

ED Control

Red cell reduced glutathione (umol/L)

ED Control

*P < 0.001

*

Tagliabue M, et al: Int J Androl 2005;28:156-62

PON-1 and ED

Ciftci H, et al: Int J Impot Res 2007;19:517-520

*†

†

*

Vasodilatation due to cocoa(ml volume by PAT)

Baseline Day 5 90 minutes L-NAME

* P < 0.01

Fisher ND, et al: J Hypertens 2003;21:2281-6

Pycnogenol and ED

placebo

Stanislavov R,et al: J Sex Marital Ther 2003;29:207-13

80 mg 120 mg

% im

pro

vem

ent

of E

D

What about testosterone?

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.

a Akishita: Hypertens res 2007;30:1029-34, b Traish: J Androl

2009;30:10-22, c Stanworth: Clin Interv Aging 2008;3:25-44

Impact of L-Arginine and pycnogenol on ED and circulating T

placebo L-A/P placebo L-A/P

* **P < 0.001

Stanislavov R, et al: Int J Impot Res 2008;20:173-80

L-citrulline versus L-arginine

0

50

100

150

200

250

300

350

1.5 gm L-citrulline 3.2 gm L-arginine1.5 gm L-citrulline 3.2 gm L-arginine

Hecker M, et al: Proc Natl Acad Sci 1990;87:8612-16

Schwedhelm E, et al: Br J Clin Pharmacol;2008;65:51-9

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

1. Exercise increases NO by the shear forces of increased blood flow, increased insulin sensitivity, and increased PON-1

1.

Pelvic Floor Exercises

Dorey G, et al: BJU Int 2005;96:595-7

Pelvic Floor Exercises

Dorey G, et al: Br J Gen Pract 2004;54:2019-25

Pelvic Floor Exercises

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

2. Omega-3 fats increase NO. Eat fatty fish and take fish oil to provide 500 to 1,000 mg daily

2.

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

3. Folic acid is a co-factor in the synthesis of NO. Take 200 to 400 micrograms daily.

3.

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

4. Increase intake of natural antioxidants

4.

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

5 Cutting out all sweets, sugary drinks, fried foods, fatty beef, and full fat dairy would be an excellent plan.

5.

Effects of Cocoa and Sugar on Flow Mediated Dilation

Faridi Z, et al. Am J Clin Nutr 2008;88:58-63Meldrum DR, et al. Amer J Cardiol 2011;108:599-606

ESHRE meeting, Stockholm ASRM meeting, Denver

Snack food for meeting break

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

6. Increase calcium intake with supplements as necessary to provide 1,200 mg daily.

6.

STRESS

7. Decrease stress.

Ten steps to improved erectile and vascular health

www.Erectile-Function.com

8. Pay attention to your relationship with your partner.

Ten steps to improved erectile and vascular health

www.Erectile-Function.com

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

9. Consider a stronger antioxidant (pycnogenol, 50-120 mg per day) and L-citrulline, 2 gm daily

9.

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

calcium

Omega 3 fats

pycnogenol F

olic

ac

id

NI RT IC

O XID

E

low fatlow sugar

weight loss

www.Erectile-Function.com

Ten steps to improved erectile and vascular health

10. Weight loss improves insulin sensitivity. Work at moderate weight loss (20-30 lb /year)

10.

NO

promote

Cyclic GMP

promotes

Viagra-like drugs

inhibit

erection

Break-down by PDE5

inhibit

Biochemistry of Erectile Function* *www.Erectile-Function.com

caution!

Antioxidants, folic acid, omega 3 fats, Ca, vit. C&E, exercise, and testosterone

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

Tadalafil and Serum Oxidant Status

TAS TOS PON-1

Tadalafil

Baseline

% d

iffer

ence

from

bas

elin

e

Verit A, et al. Int J Impot Res 2010;22:115-9.

*

*P < 0.0001

Tadalafil and Flow Mediated Dilation

Rosano GMC et al. Eur Urol 2005;47:214022.

ED and Diabetes• ED is 3 times as common in diabetics and is

negatively correlated with better glycemic control and physical activity1. Therefore early aggressive treatment of diabetes, exercise, and antioxidant supplementation would be expected to particularly benefit these men.

• ED predicts coronary artery disease (CAD) events in diabetic men with no evidence of coronary artery disease, and major cardiac events in men with type 2 diabetes who have established, asymptomatic CAD2.

1. Giugliano F, et al. Int J Impot Res 2010;22:204-2102. Meldrum DR, et al. Amer J Cardiol, e-pub 29 May, 2011

ED and Hypertension• ED is two to three times more common in men with

hypertension without diabetes or other medical conditions, and the incidence of ED increases with the duration and severity of elevated blood pressure1.

• ED predicts a doubling of the risks of myocardial infarction and cardiac death in hypertensive men2.

• All of the measures we have discussed that increase vascular NO will aid in blood pressure control 3.

1. Doumas M, et al. J Androl 2006;27:469-77.2. Bohm M, et al. Circulation 2010;121:1439-46.3. Meldrum DR, et al. Amer J Cardiol, e-pub 29 May, 2011

A B

Losartan and Flow Mediated Dilation, Oxidative Stress

Flammer AJ, et al. J Hypertens 2007;25:785-91.

ED as a Critical Warning Sign• We have indicated that ED in men with diabetes or

hypertension is an important warning sign for myocardial infarction and death.

• ED can also be a very important danger sign in younger men with ED and no evidence of cardiac disease. When followed for 10 years, such men age 40-49 had a fifty-fold increase of CAD, including death, whereas the predictive value decreased with increasing age as expected (5.4-fold for ages 50 to 59 years, 2.2-fold for ages 60 to 69 years, and 1.3-fold for age 70 years and older.

Inman BA, et al. Mayo Clin Proc 2009;84:108-113

www.Erectile-Function.com

How the Penis Works

Erectile and Vascular benefits of Exercise

Excess Weight and Erectile Function

Stress and Erectile Function

For Sexual Partners

Other Health Benefits

Self Assessment

Supplements

Forum

www.Erectile-Function.com

102 Y/O

Sexual Dysfunction and Treatment of ED

• Female sexual satisfaction resulting from treatment of ED

• 38 women whose partners had ED had highly significant decreases of various indices of sexual satisfaction

• Treatment of ED increased arousal and lubrication (p = 0.001, p = 0.002), and orgasm and satisfaction (p < 0.001)

Cayan S et al: J Sex Marital Ther 2004;30:333-41

Why is the biochemistry of NO so complex?

All of the factors we have discussed today increased the likelihood that early man would be able to pass on his genes into the next generation

- a firm and fit body not only enabled procreation, but also helped him to escape predators and protect his pregnant mate and offspring

Why is the biochemistry of NO so complex?

The remaining factors all relate to forms of energy and the effects of ingesting energy

- folic acid, vitamins, and antioxidants from fruits and vegetables

- omega-3’s from seafood

- calcium from dairy

- and all of these and meat provide protein and therefore L-arginine, and carbohydrates that stimulate insulin

Why is the biochemistry of NO so complex?

Because of the complex biochemistry of NO production, no matter how varied early man’s diet was from time to time or in different locales, he would have had the reproductive firmness to be able to procreate. On the other hand, during times of energy deprivation, the ability to reproduce would have been delayed until conditions were more conducive to success in carrying on his genes.

Why is the biochemistry of NO so complex?

Because early man seldom survived much past early adulthood, NO certainly did not evolve to protect him from heart attacks and strokes. It is clear that the complexity and redundancy of the biochemistry of NO evolved to maximize or minimize reproduction according to prevailing conditions.

Why is the biochemistry of NO so complex?

Fortunately this same redundancy now allows men to take advantage of multiple ways of maintaining NO production during a life span that extends far beyond the reproductive years and in an increasingly health-hostile environment of inactivity and excessive availability of calorie dense foods stripped of their nutritional value and containing too much fat and sugar.

ED is a “Wedge Issue” that can be used to encourage better

lifestyle choices

The combined impact of the sedentary lifestyle, atrocious diet, and excess body weight of most Americans threatens to break the back of our health care system

We must “bend the curve” of our disease burden as our population ages if we are to be able to provide optimal therapies and apply new advances that become available