canary in the coal mine: is erectile dysfunction an early ... in the coal mine: is erectile...
TRANSCRIPT
Canary in the Coal Mine:
Is Erectile Dysfunction an Early
Indicator of Coronary Artery Disease?
Steve Kopecky MD FACC FAHA FACP
Professor of Medicine
Division of Cardiovascular Diseases
Mayo Clinic
Aug 1, 2015
Disclosure: Conflict of Interest Stephen L Kopecky
Research Grants
Regeneron/Sanofi-Research Grant
Amgen – Research Grant
Consultant
•Applied Clinical Intelligence: DSMB Chair
•Prime Therapeutics – Formulary Committee
•Merck- Atherosclerosis Advisory Board
Board of Directors
Mayo Clinic Support Services, Texas
American Society for Preventive Cardiology,
Immed Past President
American Society for Men‟s Health
• What is the pathophysiologic relationship ?
• What are the risk factors for both ?
• What is the temporal relationship ?
• What are the treatments for both ?
Erectile Dysfunction (ED) and
Coronary Artery Disease (CAD)
Endogenous Testosterone in the Norfolk Study:
Lower Levels Correlate w Increased Total and CV Mort
Khaw, Kay-Tee et al. Circ 2007, 116: 2694-2701
Cum
ula
tive
Surv
ival Total Survival CV Survival
Testosterone
Quartile
Testosterone
Quartile
Highest Highest
Lowest Lowest
Low Testosterone levels correlate w/ CV Mortality
Relationship of Coronary Calcium with ED
Chiurlia, E at al. 2005. JACC. 46: 1503-1506
ED No ED
Coronary Calcium Score Increases with ED
ED in Diabetics with Silent CAD : Lower Survival
Gazzaruso, C. et al., 2008. JACC. 51, 2040-44
Surv
ival R
ate
No ED
ED
Diabetics w/ ED have a lower survival
Prevalence and severity of ED in CHD risk cohort
Ponholzer et al Eur Urology Vol 48, Issue 3 2005 512 - 518
Obesity in men at reproductive age
Oligospermia in men
Sermondade et al Human Reprod Update 2013
With obesity, Aromatase increase leads to
decrease in testosterone levels
Dong, Jia-Yi, et al. 2011, JACC, 58: 1378-86
0.3 0.7 1 1.4 3
ED and Risk of Cardiovascular Diseases
CI confidence interval; RR relative risk.
Presence of ED Increases Risk of CV Diseases
Studies controlled for conventional CV risk factors,
including age, BMI, BP, DM, cholesterol, and smoking
Dong, Jia-Yi, et al. 2011, JACC, 58: 1378-86
ED and Risk of CHD, Stroke, and All-Cause Mortality
CHD
Stroke
All-Cause
Mortality
0.3 0.7 1 1.4 3
Increase independent of conventional CV risk factors
The Relationship between ED and
CVD in Various Multivariate Models
Age-adjusted 1.42 1.05–1.90 0.02
Model HR* 95% CI p Value†
*Hazard ratio (HR) compared with men with no ED.
†Wald chi-square test.
‡The multivariate model includes BMI and Framingham risk score variables :age, TC, HDL, smoking, and HTN
In 40-70 YO men followed for 12 years,
ED predicts development of CVD, independent of
age, traditional risk factors, and FRS
Multivariate-adjusted‡ 1.41 1.05–1.90 0.02
Adjusted for age and
Framingham risk score 1.40 1.04–1.88 0.03
Araujo et al JACC 2010;55:350–6
©2012 MFMER | slide-14
1. How do you rate your confidence
that you could get and keep an
erection?
Very Low
Low
Moderate
High
Very high
2. When you had erections with
sexual stimulation, how often were
your erections hard enough for
penetration?
Almost never or
never
A few times
(much less than
half the time)
Sometimes
(about half the
time)
Most times
(much more
than half the
time)
Almost
always or
always
3. During sexual intercourse, how
often were you able to maintain your
erection after you had penetrated
your partner?
Almost never or
never
A few times
(much less than
half the time)
Sometimes
(about half the
time)
Most times
(much more
than half the
time)
Almost
always or
always
4. During sexual intercourse, how
difficult was it to maintain your
erection to completion of
intercourse?
Extremely
difficult
Very difficult Difficult Slightly difficult Not difficult
5. When you attempted sexual
intercourse, how often was it
satisfactory for you?
Almost never or
never
A few times
(much less than
half the time)
Sometimes
(about half the
time)
Most times
(much more
than half the
time)
Almost
always or
always
TOTAL SCORE _______________
International Index of Erectile Function Questionnaire
Over the past 6 months :
1-7 Severe ED; 8-11 Mod ED; 12-16 Mi-Mod ED; 17-21 Mild ED; 22-25 No ED
Points 1 2 3 4 5
Severity of ED and Likelihood of CVD/Mortality
Banks, E. et al. PLOS Medicine, 1/2013.
More severe the ED, the greater the risk of CV Morbidity/Mortality
What is the temporal relationship between ED and
Acute Coronary Syndromes ?
1 Montorsi et al. Erectile dysfunction prevalence, time of onset and
association with risk factors in 300 consecutive patients with acute chest pain and
angiographically documented coronary artery disease. Eur Urol. 2003;44:360-364.
• 2/3 of patients with 1st onset of acute chest pain had ED 39 months prior 1
ED is an early warning sign of CAD 2
2 Meldrum et al. The link between erectile and cardiovascular health: The
canary in the coal mine. Am J Cardiol. 2011;108:599-606.
300 consecutive male patients with acute chest pain :
Asked them about ED and when it occurred
Incidence of CAD with respect to age
and erectile dysfunction (ED) status.
Mayo Clin Proc. 2009;84(2):108-113
1.3 2.5
5.2
48
Relative Risk
ED No ED
ED is a greater
CV risk factor at
younger age
Benefits of Nitric Oxide
• Inhibits platelet aggregation
• Inhibits leucocyte and platelet adhesion
• Relaxes vascular muscle tone
• Inhibits vascular smooth muscle proliferation
• Opposes vascular oxidative stress/inflammation
Critical signaling molecule with central role :
Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of
vascular diseases. Arch Pharm Res. 2009;32:1103-1108.
NO : Essential for erections Reduced in ED
Brachial Artery Flow Mediated Dilatation in Patients with Erectile Dysfunction
Kaiser, DR et al. JACC. 2004:34: 179-184
No ED
ED
CAD Risk Factors and Endothelial Dysfunction:
Oxidative Stress as a Common Mechanism
LDL
cholesterol
Diabetes Hypertension Cigarette
smoking
Homocysteine
Estrogen
withdrawal
O2-, H2O2
Endothelial dysfunction
Endothelial Cell
Vasoconstriction VSMC growth
Thrombosis Lipid
accumulation
Leukocyte
adhesion
Endothelial
apoptosis
Inflammation and
increased
angiotensin II
Sedentary High
Saturated Fat
“Free Radicals”
Effects of Testosterone Therapy on CV Events
Haddad, RM et al. Mayo Clinic Proc. 2007, 82: 29-39
A signal appeared that there may be increased CV Events
occurring in men placed on
Testosterone Replacement Therapy (TRT)
Testosterone Therapy and CV Events
Xu, Lin et al. BMOC Medicine, 2013, 11:108
OR 1.54
With more studies , the Odds Ratio was 1.54 ( 95% CI 1.09-2.18)
for increased CV Events on TRT
• Primary efficacy outcome :
Change in maximal muscle
strength in a leg-press exercise
• Secondary efficacy outcome :
Change in chest-press strength, 50-m
walking speed, stair-climbing speed and
power, and a lift-and lower test
Testosterone in Older Men with Mobility
Limitations (TOM Trial)
Basaria, S. et al. NEJM 7.2010
Testosterone in Older Men with Mobility Limitations
(TOM Trial) : CV Events Increased
Basaria, S. et al. NEJM 7.2010
Adverse Effects of Testosterone Therapy (TOM Trial)
Basaria, S. et al. NEJM 7.2010
In the TOM Trial, there was an increase for CV Events
in men placed on TRT
Possible explanations to TOM Trial Findings
• Doses : starting doses higher than recommended
• Endocrine Society recommends a lower goal
• May have been inadvertent over supplementation with
study drug.
• Small total number of events and small N in the trial
209 patients at onset, only 83 w/ 9 month F/U
• Trial was designed to get older men more active
physically and increase their muscle strength
Phillips, GB. Letter to the Editor NEJM 2010
Estrogen Therapy 1996: Lessons to be learned ?
Circulation. 1996; 94: 2982-2985 doi: 10.1161/01.CIR.94.11.2982
• 1996 : NHLBI – 82% of cardiologists, internists,
family doctors, and general practitioners
prescribe hormone replacement therapy (HRT).
• 66% prescribe it for coronary heart disease.
• Not a proven indication - should not be
accepted until unequivocal clinical trial data are
available.
• “The bandwagon appears to be picking up in
speed and volume. The putative benefits of
HRT are being trumpeted to postmenopausal
women, with only transient muting for reports of
possible adverse effects.”
MI Rates in men pre- and post-initial
Testosterone Rx Increase past age 65 Yrs
RR= rate ratios ;CI= 95% confidence intervals
Finkle et al. (2014). PLoS ONE 9(1): e85805. doi:10.1371/journal.pone.0085805
All Ages Age <65 Years Age >65
Patients (n) 55,593 48,539 7,054
Pre-prescription
Rate per 1,000 PY
(95%CI) 3.48 3.22 5.27
(3.02, 4.01) (2.75, 3.77) (3.81, 7.27)
Post-prescription
Rate per 1,000 PY
(95%CI) 4.75 3.76 11.52
(3.72, 6.05) (2.81, 5.04) (7.43, 17.86)
Rate Ratio (post/pre)
(95%CI) 1.36 1.17 2.19
(1.03, 1.81) (0.84, 1.63) (1.27, 3.77)
Study name Difference in means and 95% CI Difference Lower Upper Relative in
means limit limit weight
Esposito et al, 2004 3.00 1.09 4.91 29.79
Esposito et al, 2006 3.40 1.23 5.57 24.38
Wing et al 0.90 -0.93 2.73 31.70 Lamina et al 2.79 -0.23 5.81 14.12
2.40 1.19 3.61
-4.00 -2.00 0.00 2.00 4.00
Meta Analysis : Randomized Trials
Favors control Favors intervention
I-squared=22%
Does Heart Healthy Lifestyle
Improve Erectile Dysfunction ?
Gupta, Kopecky, Nehra Archives IM 2011
ED Improves < 24 months after lifestyle change
ED precedes CAD Sx by ~3 years
How much can
BMI reduction/increase in physical activity
improve erectile dysfunction ?
•IIEF-5 score ≥ 22 = achievement of normal sexual function
•Diabetic men > 60 years of age have less reversible ED.
•Life style interventions 1-3 :
Reduce odds of ED (odds ratio 0.48; 95% CI 0.26 -.89)
Improves IIEF-5 score by 2.7
Lowers dose needed of PDE-5 inhibitors
1. Esposito K, Ciotola M, Giugliano F, et al. Mediterranean diet improves erectile function in subjects with the metabolic
syndrome. International Journal of Impotence Research. Jul-Aug 2006;18(4):405-410.
2. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized
controlled trial. JAMA. Jun 23 2004;291(24):2978-2984.
3. Wing RR, Rosen RC, Fava JL, et al. Effects of weight loss intervention on erectile function in older men with type 2 diabetes in
the Look AHEAD trial. Journal of Sexual Medicine. Jan 2010;7(1 Pt 1):156-165.
IIEF=International Index of Erectile Function Questionnaire
Erectile Dysfunction
Worsens1 Improves1
Diabetes Improved FBS
Metabolic Syndrome Physical Activity
Hypertension Weight Loss
Hyperlipidemia Stop Smoking
1 Giugliano et al. Determinants of erectile dysfunction in type 2 diabetes. Int J Impot Res. 2010;22:204-209
2 Fogari et al. Sexual activity in hypertensive men treated with valsartan or carvedilol Am J Hypertens. 2001;14:27-31
3 Baumhakel DO-IT Investigators. Effect of Irbesartan on erectile function in patients with hypertension and metabolic
syndrome. Int J Impot Res. 2008;20:493-500.
Antihypertensive meds : worsen/no impact
except short-acting ARB
(ie, losartan), which improve ED2,3
Endothelial Function after Weight Change Loss Gain
Romero-Corral, et al. JACC. 8/17/2010
% Reduction in FMD % Increase in Artery Diameter
Arterial dilation : Worsens after weight gain;
Improves after weight loss, even small amounts
BL Wt Gain Wt Loss <8 cm2 8-16 cm2 >16cm2
Visceral Fat Gain
Effect of High and Low-Fat
Meals on FMD in Normal
Subjects
Egg McMuffin, Sausage
McMuffin, 2 Hash Browns
% Change in FMD and
Inflammatory Parameters
after a High-Fat Meal
* P <0.05
Vogel RA et al, Am J Cardiol 1997;79:350 Van Oostrom A et al, Circulation 2002;106:II-563
TG FMD Leuko- IL8
cytes
ED and Daily Vigorous Exercise
• Men with CAD : doubled endothelium-dependent
vasodilation. 2
• Daily exercise : four-fold higher level of NO
production. 1
• Moderate Physical activity :decreased ED by two-
thirds and high physical activity by over 80%. 1
• Ten-fold decrease of erectile difficulties varying
from mild dysfunction to full ED 2
1 Meldrum et al. The link between erectile and cardiovascular health: The
canary in the coal mine. Am J Cardiol. 2011;108:599-606.
2 Hambrecht R, Adams V, Erbs S, et al. Regular physical activity improves endothelial
function in patients with coronary artery disease by increasing phosphorylation of endothelial
nitric oxide synthase. Circulation. 2003;107:3152–3158.
2. Agostini LCM, Netto JMB, Miranda MV, et al. Erectile dysfunction association with physical
activity level and physical fitness in men aged 40-75 years. Int J Impot Res. 2011;23:115-121.
Risk Score For Developing Disease in 20 Years
Factor •Age (<47=0, 47-53=3 >53=4) •Sex (F=0,M=1) •BMI (<30=0, 30=2) •Exercise (Active 2X/wk;
30 min each w/gasp=0, Inactive=1)
•Chol (250=0, >250=2) •BP (>140=0,On Rx or>140=2) •Smoking (Y=2, Ex=1, N=0) •Education (0-6 yrs=3, 7-9=2, 10=0)
1% 2%
4%
7%
16%
0
2
4
6
8
10
12
14
16
18
0 -
5
6 -
7
8 -
9
10
- 1
1
12
- 1
5
Kivipelto,M et al Risk score for the prediction of dementia risk in 20 years among middle aged people
Lancet Neurology 2006:5:9, 735-741
What does this predict?
Similar risk factor relationship for Dementia, Coronary
Disease, Erectile Dysfunction, Breast & GI cancers
Dementia!
1 ACC/AHA 2013 2 Euro Urology 2005;48:495 3 Ann Int Med 2002;136:575 4 Lancet Neurology 2006:5:735 5 NEJM 2013;368:728
Risk Formulas for Predicting MI/Stroke, ED, DM,
Dementia, & Lung Cancer : How Much Overlap ? Disease
Factor
MI/Stroke 1 ED2 DM3 Dementia4 Lung
Cancer5
Age X X X X
Gender X X X X
Ethnicity X X X
DM FH 1st Degree X
Total Chol or HDL X X X
Sys BP/HTN Rx X X X X
DM/FBS X X X
Tobacco X X X X
BMI X X X
Physical Activity X
Education X X
CAD/PAD X
H/O Pelvic Surgery X
COPD /Any Malig X/X
G
e
n
e
t
i
c
L
i
f
e
s
t
y
l
e
M=Hi Risk
„Classic‟
CAD Risk
Factors
1 ACC/AHA 2013 2 Euro Urology 2005;48:495 3 Ann Int Med 2002;136:575 4 Lancet Neurology 2006:5:735 5 NEJM 2013;368:728
Risk Formulas for Predicting MI/Stroke, ED, DM,
Dementia, & Lung Cancer: How Much Overlap ? Disease
Factor
MI/Stroke 1 ED2 DM3 Dementia4 Lung
Cancer5
Age X X X X
Gender X X X X
Ethnicity X X X
DM FH 1st Degree X
Total Chol or HDL X X X
Sys BP/HTN Rx X X X X
DM/FBS X X X
Tobacco X X X X
BMI X X X
Physical Activity X
Education X X
CAD/PAD X
H/O Pelvic Surgery X
COPD /Any Malig X/X
G
e
n
e
t
i
c
L
i
f
e
s
t
y
l
e
M=Hi Risk
„Classic‟
CAD Risk
Factors
Effects of Dark Chocolate vs. White Chocolate on FMD
Subjects
given
100 g/day
X 3 days
of
DC vs.
WC
Grassi, D et al. Hypertension. 9/2012; 60: 827-832
Chateauneuf du
Pape
Vascular Biology-Endothelium
Chateauneuf
du Pape
Bordeaux
Barolo
Mosel-Riesling
Ethanol
Phenylephrine
Vasoconstriction
L-NMMA Human
Coronaries
Wine
NO cGMP
Vasodilation
High phenolic substances
& Stem
AJP Oct 1998;44:H1186
L-NMMA=inhibitor
of NO synthase
Johansen, D. et al. BMJ 2006;332:519-522
Likelihood of beer and wine buyers buying items of food
Wine
Beer
Eggs
Chips
Ready Cooked
Cold Cuts
Pork
Butter
Sausage
Soft Drinks
Olives
Low Fat Cheese
Fruits
Vegetables
Oil
Low Fat Milk
Wine Beer
Effect of Mental Stress and Video Viewing on
Flow-Mediated Dilation (FMD)
FM
D
Ghiadoni L, et al. Circulation 2000;102:2473
Miller M, et al. J Am Coll Cardiol 2005;45:408A
Mental Stress
PREDIMED : Primary End Point (MI, stroke, or CV Mort)
PREDIMED Study NEJM Feb 27,2013
EVOO : Hazard ratio, 0.70 (95% CI, 0.53–0.91); P=0.009
Nuts : Hazard ratio, 0.70 (95% CI, 0.53–0.94); P=0.02
Years
All benefit due
to stroke reduction
Study stopped by
DSMB at 4.8 yrs
EVOO=Extra Virgin Olive Oil
Which Lifestyle Changes Reduce CV Events ?
No difference by Age, Sex,
Race, Education, Income.
Survey of 152,805 people w/Behavioral
Risk Factor Surveillance System
1 Reeves Arch Intern Med 2005;165:854-857
If you do all 4, CV Event Rate decreased by :
87 % ( Retrospective1)
2 King et al Am J Med 2007;120,7:598-603
ARIC – Prospective study of 15,792
middle age men and women
% of US Adults w/ lifestyle
40% in 4 years (prospective2)
Poor, intermediate, and ideal CV health :
AHA 2020 goals US adults
Circulation. 2014;129:e28-e292
Smoking BMI Activity Diet Chol BP FBS
Key Points : ED & CAD
• Similar Risk Factors and Physiology
• ED often occurs ~ 3 years before CAD Sx
“Teachable Moment”
• TRT may increase CV Events but data conflicting
• Low testosterone levels linked to increased CAD
• Lifestyle modification : improves CV Risk < 3 mo;
Improves ED in 2 years;
• Extensive Overlap between Risk Factors for CAD,
ED, Dementia, DM, & Cancer
• Nitric oxide and vasodilatation play a
key role in CAD and ED
©2012 MFMER | slide-55
Intercourse Frequency and CV Risk
• In multivariate models adjusted for age, covariates, ED, and the Framingham risk score, a low frequency of sexual activity (once a month or less vs >2 times weekly) was associated with increased risk of CVD (hazard ratio 1.45, 95% confidence interval 1.04 to 2.01).
Am J Cardiol 2010;105:192–197
Subjects Without ED Subjects With ED
(n 952) (n 213)
Age (years) 53.8+/-8 59.8+/- 8
• Feldman HA et al. Erectile dysfunction and
coronary risk factors : prospective results from
the Massachusetts male aging study. Prev Med.
2000;30(4):328–38