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