Canary in the Coal Mine

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

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Erectile Dysfunction (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

Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ: New Engl J Med 1992;326:90-4

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 where it inhibits platelet adhesion, prevents atherosclerosis, inhibits prolipheration of surrounding smooth muscle, and reduces vascular muscle tone.

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

www.Erectile-Function.com

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

penile arteries

anxiety, stress

constrict

sexual stimuli

relax

sinusoids fill

veins are compressederection lasts

erectionNO

NO = Nitric Oxide

NO

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

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

Break-down by PDE5

inhibit

Biochemistry of Erectile Function* Meldrum DR, et al. Amer J Cardiol, e-pub 29 May, 2011

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 sugar, abdominal obesity, diabetes, hypertension, insulin resistance, decreased antioxidant defenses

ED and exercise, alcohol

Sedentary or no alcohol

moderate active alcohol

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

NI TRI C

OXID

E

FATTY ACIDS

SUGARS

alcohol?sm

oking

obesity

inactivity


ED and exercise, alcohol

Sedentary or no alcohol

moderate active alcohol

L-Arginine

NITRIC

OXID

E

L-Citr

ulline

CalciumOmega 3

fats

Anti-oxidants

Fol

ic

acid 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 wine*

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

Red cell reduced glutathione (umol/L)

ED Control

*P < 0.001

*

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

*†

†

*

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

Low testosterone and ED

• Male hypogonadism has been correlated with ED and with the metabolic syndrome, and testosterone replacement not only improves ED, 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.

Stanworth RD, et al: Clin Interven 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


Ten steps to improved erectile and vascular health

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

1.

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



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



3. Folic acid in 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



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



5. Decrease intake of sugar and fat. Cutting out all sugary drinks and fried foods 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, e-pub 29 May, 2011

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



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

6.

STRESS

7. Decrease stress.



8. Pay attention to your relationship with your partner.



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



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



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 sugar, abdominal obesity, diabetes, hypertension, insulin resistance, decreased antioxidant defenses

Tadadafil 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.

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


How the Penis Works

Erectile Function and Exercise

Excess Weight and Erectile Function

Stress and E.F.

For Sexual Partners

Other Health Benefits

Self Assessment

Supplements

Forum


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

Meldrum DR, et al. Amer J Cardiol, e-pub 29 May, 2011

Health & Medicine

Canary in the Coal Mine