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Preventing and Reversing Heart Disease Part Three by Jeffrey Dach MD

Posted Dec 31 2010 8:03am

Coronary angiogram cardiac cath cardiology LAD left anterior descendingPreventing and Reversing Heart Disease, Part Three

by Jeffrey Dach MD

A Man with Progressive Coronary Artery Disease Unresponsive to Statins

62 year old Jim came to see me after his third cardiac stent in 10 years.  About a year ago, Jim noticed a "tight feeling" in his chest radiating to his throat, was rushed to the ER, and doctors found he was having a heart attack. A coronary angiogram showed extensive coronary artery disease with irregular plaque formation virtually everywhere in his arteries.  For the past 10 years, Jim had been under the care of top cardiologists who prescribed a statin cholesterol drug, and Jim's cholesterol was kept below 140 all this time.  Jim's heart disease progressed relentlessly in spite of the low total cholesterol numbers clearly showing another causative agent is at work.  When heart disease progresses in spite of an extremely low total cholesterol, this suggests a different causative agent is at work.
 
Doctors advise Jim to Stop Testosterone

Jim had been taking testosterone topical gel for the past 5 years, and recently stopped it because of advice from his cardiologist who pointed a finger and said, "You should stop the testosterone. The testosterone is bad for your heart and probably caused your heart attack".  Jim came to see me for a second opinion.

Our Approach

I must preface these remarks with our approach to prevention and reversal of heart disease which is outlined in  Part One   and  Part Two   of this series.  We credit and rely heavily on the  " Track Your Plaque Program " by William Davis MD. 

Bioidentical Hormones For Prevention and Reversal of Heart Disease

In this article we will revisit the role of the testosterone and estradiol in prevention and reversal of heart disease, looking at the latest research.  Firstly, let's examine the hypothesis peoposed by Jim's doctor that Testosterone is somehow "bad" for men with heart disease.

Low Testosterone is Predictive for Increased Mortality from Heart Disease

If Jim's Doctor's advice was right, one would expect that men with high testosterone should have more heart disease, and men with low testosterone should have less heart disease.  This is exactly opposite of four major studies that show men with low testosterone have increased all-cause mortality and increased heart disease mortality(1-4)

Testosterone Levels in Men With Heart Disease

A recent study by  Malkin  looked at Testosterone levels in men with known underlying heart disease.  He showed that low Testosterone is common in men with underlying heart disease, and this is associated with almost double the mortality rate. ( 5 )  Again these findings suggest that higher Testosterone is protective and prevents progression of heart disease.  The assumption that Testosterone is somehow deleterious to the heart has been shown false.(6-9).

Above image: Cross section of arteries (left to right) showing development of fatty streak which enlarges into the atherosclerotic plaque.

Animal Studies on Mechanism of Protection

A number of elegant animal studies have been done to elucidate the mechanism by which Testosterone is protective of heart disease.  A 1999 study by Alexandersen in rabbits showed that testosterone reduced aortic atheroscleosis.  Castrated rabbits had low testosterone levels and significant increase of 100% in aortic atherosclerosis suggesting that testosterone has a strong preventive effect on male atherosclerosis. In the groups receiving testosterone or DHEA they found marked inhibition of atherosclerosis compared with placebo. The mechanism was not clearly defined.  They speculated on a non-lipid mediated mechanism, possibly related to aromatase conversion of testosterone to estrogen. ( 10 )

In an elegant 2001 study published in PNAS, Nathan et al used a mouse model of accelerated atherosclerosis to show that Testosterone inhibits atherosclerosis by conversion to estradiol by the aromatase enzyme.  Similar protection from atherosclerosis was obtained by administering estradiol.  In addition, blocking conversion of testosterone to estradiol with the aromatase inhibitor, anastrazole, eliminated the protective effect and these animals showed pregressive atherosclerosis.( 11 )  

Dr Nathan suggested that "testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall". This information suggests that men with heart disease should NOT take arimidex (anastrazole) along with their testosterone replacement therapy.

These findings were confirmed  by  Nettleship   in a 2007 study published in Circulation using the Tfm Mouse .  This is a mouse geneticlly altered to have a defective androgen receptor.  In these mice,  Testosterone cannot work through its normal genomic pathway, since there is no receptor.  In spite of the lack of androgen receptor, Nettleship found that testosterone replacement in these mice attenuated atherosclerotic changes (fatty streak formation), suggesting the protective effect of testosterone was independent of the testosterone receptor.  The authors concluded that the protective benefits of testosterone were through aromatase conversion to estradiol, and then via the estrogen receptor pathways.( 12

Dr Nettleship's findings were confirmed by  Bourghardt   in a Nov 2010 study published in Endocrinology which using "ARKO" mice, genetically modified to "knock out" the Androgen Receptor, as well modified to be Apo-E deficient (to accelerate atherosclerosis).  The authors showed that Testosterone therapy admistered to the ARKO mice inhibited atherosclerosis.  However inhibition of atherosclerosis was more profound in the wild type mice that still had intact androgen receptors.  The authors concluded the mechanism of protection of testosterone was due to both mechanisms, though the Androgen Receptor as well as through aromatase conversion to estradiol.( 13 )

Conclusion: These animal studies suggest that testosterone's cardio-protective benefits are due (at least in part) to conversion to estrogen, and that estrogen is the cardioprotective agent.  Both estrogen and testosterone are bioidentical hromones.

Why Do Men Have More Heart Disease Than Women ?

Men and women are quite different when it comes to heart disease.  Men have more than twice the risk of dying from coronary disease than women. (14)  In women, coronary artery disease (CAD) develops on average 10 years later than in men.(15)  Could higher levels of estrogen (estradiol) in women explain the protection enjoyed by women? 

Dr Xing from the University of Alabama would say, yes of course.  In a  2009 article , Dr Xing   names a number of mechanisms by which estradiol protects both men and women from heart disease. He says, "estrogens have antiinflammatory and vasoprotective effects.  Natural endogenous estrogen 17β-estradiol (bioidentical) has been shown to cause rapid endothelium-independent dilation of coronary arteries of men and women, to augment endothelium-dependent relaxation of human coronary arteries, and improve endothelial function...Observational studies have shown substantial benefit (50% reduction in heart disease) of hormone therapy in women who choose to use menopausal hormones."( 15 )

Estrogen is Protective of Heart Disease

A 2010 study in European Heart by  Kitamura et al   compared males to female heart attack rates. They found 61% fewer heart attacks in women of reproductive age with high estrogen levels compared to males of the same age.  The authors conclude that estrogen confers cardioprotective benefits.(16)  A review of the Nurse Health Study published in the 2000 Annals  showed 40% reduction in heart disease in hormone replacement users and that "postmenopausal hormone use decreases risk for major coronary events." ( 17 ) (18) 

Coronary bypass surgeryComparing The Three Treatment Modalities for Heart Disease 

There are three mainstream treatment modalities for coronary artery disease. 

1) Surgery with coronary artery bypass.
2) Balloon angioplasty with stenting. 
3) Medical Therapy with drugs such as calcium channel blockers and beta blockers.

Which one of these treatment modalities confers the most benefit? The answer is none.  
Medical managmeent with drug treatments gave the same results as stenting in eleven randomized studies including 3,000 patients with stable coronary artery disease.  Treatment with  angioplasty and stenting showed the same mortality and heart attack rate as drug treatment (also known as medical management).  They both offer the same benefit.(19)(20) 

The  MASS II study   published in the 2007 Circulation showed medical managment with drugs to have similar outcome to stent or bypass. (21)    A troubling fact remains that after all these studies have been completed,  there is no conclusive evidence that intervention with CABG (coronary artery bypass graft) or coronary stent  is superior to medical therapy (drugs) for treating multivessel coronary artery disease with stable angina and preserved ventricular function.( 21 )  Sorano attempts to sort out the fine points of selecting between treatment modalities in her 2009 report . (22)

How Can Drugs Provide the Same Outcome as Surgery or Stenting?

The EPC.

Now we have an important question to ask.  How is it possible that the humble country doctor with a few drugs can provide similar outcomes when compared to the high and mighty cardiac surgeon and the interventional cardiologist?  How can drug treatment do as well or better than the cardiac stent or surgical bypass procedure?

I suggest the answer resides in the phenomenon known as "collateral vessel formation".  The heart has the ability to grow new blood vessels which provide blood flow around the blocked artery.  Medical treatment gives the heart time to grow new collateral vessels. The key to understanding this new vessel formation is the endothelial progenitor cell, also known as the EPC. The EPC is a special type of stem cell found in the bone marrow that circulates to injured myocardium where they promote local angiogenesis, making new blood vessels. (23)

Turning On The Endothelial Progenitor Cell - How to Do It?

A previous  article on telomeres and anti-aging  discussed the role of estrogen as an activator or telomerase which serves as an anti-aging therapy.  Recent research shows that estrogen  activates the telomeres on endothelial progenitor cells and improves the EPC functional capacity. (24)  Another study showed reduced numbers of EPC cells in the peripheral blood of men with low testosterone levels. (25)

Estradiol Enhances Recovery After Myocardial Infarction - Collateral Vessels

An elegant mouse study was published by Isakura in 2006 Circulation .  They used a mouse model in which myocardial infarction (heart atack) was induced by ligation of the left coronary artery.  The estradiol treated mice showed increased circulating EPC's and greater capillary density in the recovering myocardium.  This indicates enhanced recovery in the estradiol treated mice by regrowth of collateral vessels. (26)(27)(28)  A study from Bolego in Italy showed that the cardio protective benefits of estrogen could be duplicated with an estrogen receptor drug called PPT. They found that "myocardial ischemia-reperfusion injury was exacerbated by ovariectomy (which reduced estrogen levels).   This injury returned to baseline following treatment with estrogen-like drug PPT."  The protective effects were linked to increased levels of endothelial progenitor cells (EPCs).(29)

Conclusion

Recent research shows the cardioprotective benefits of the bioidentical hormones, testosterone and estrogen.  Testosterone benefits appear mediated through its conversion to estradiol via the aromatase enzyme.  Estradiol's benefits appear derived at least in part in the ability of estradiol to activate the Endothelial Progenitor Cells and invoke new collateral circulation in areas of injury.

Articles with Related Content
Cardiac Bypass, Angioplasty and Stenting   

CAT Coronary Calcium Scoring, Reversing Heart Disease Part One

Reversing Heart Disease Part Two

Heart Disease, Ascorbate, Lysine and Linus Pauling   

Jeffrey Dach MD
7450 Griffin Road
Davie, Fl 33314
954-983-1443
http://www.jeffreydach.com  
http://www.drdach.com  
http://www.naturalmedicine101.com  
http://www.truemedmd.com   


Links and References

Low Testosterone Associated With Increased Mortality

1) http://www.ncbi.nlm.nih.gov/pubmed/15571546?dopt=Abstract
Shores MM, Moceri VM, Gruenewald DA, et al. Low testosterone is associated with decreased function and increased mortality risk: a preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc 2004;52:2077–81.

2) http://circ.ahajournals.org/cgi/content/full/116/23/2694
Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007;116:2694–

3) http://archinte.ama-assn.org/cgi/content/full/166/15/1660
Shores MM, Matsumoto AM, Sloan KL, et al. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;166:1660–5.

4) http://jcem.endojournals.org/cgi/content/full/93/1/68
Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68–75.

5) http://heart.bmj.com/content/96/22/1821.full
Heart 2010;96:1821-1825
Coronary artery disease, Low serum testosterone and increased mortality in men with coronary heart disease. Chris J Malkin1, Peter J Pugh1, Paul D Morris1, Sonia Asif1, T Hugh Jones2,3, Kevin S Channer

Conclusions In patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival.


6) http://www.sciencedaily.com/releases/2010/10/101019212921.htm
Low Testosterone Linked to Heightened Risk of Early Death
ScienceDaily (Oct. 21, 2010) — Low testosterone levels seem to be linked to a heightened risk of premature death from heart disease and all causes, suggests research published online in Heart.

7) http://www.medicinenet.com/script/main/art.asp?articlekey=121079
Low Testosterone Raises Heart Death Risk

8) http://mednewscenter.com/low-testosterone-associated-with-high-mortality-in-men-with-chd.htm
Low Testosterone Associated With High Mortality in Men With CHD
Oct.24, 2010 in Cardiology, Internal Medicine. Concerns Dismissed: Testosterone “Like Thyroid Hormone”. 

Channer also doesn’t understand what he sees as reticence from some quarters when testosterone as a potential therapy is discussed. “I’ve struggled to understand why endocrinologists don’t just accept that replacing testosterone is the same as replacing thyroid hormone, for example, what’s the matter with that?”

9) http://www.theheart.org/article/1139751.do
Low testosterone associated with high mortality in men with CHD
October 22, 2010 | Lisa Nainggolan

"This is the fourth epidemiologic study to have shown that low testosterone is a marker of early mortality," senior author Dr Kevin S Channer (Royal Hallamshire Hospital, Sheffield, UK) told heartwire. "But most crucially, it is the first in men with vascular disease; all of the other epidemiologic follow-up studies of testosterone have excluded this patient population."

Animal Studies Androgens Inhibit Atherosclerosis - Mechanism

10) http://circres.ahajournals.org/cgi/content/full/84/7/813
Alexandersen P, Haarbo J, Byrjalsen I, et al. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ Res 1999;84:813–19.

Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect.

(11) http://www.pnas.org/content/98/6/3589.full
PNAS March 13, 2001 vol. 98 no. 6 3589-3593
Testosterone inhibits early atherogenesis by conversion to estradiol: Critical role of aromatase. Lauren Nathan *, Weibin Shi † , ‡, Hillary Dinh §, Tapan K. Mukherjee §, Xuping Wang † , ‡, Aldons J. Lusis † , ‡, and Gautam Chaudhuri Los Angeles School of Medicine,

The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals.

Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels.

Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription–PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.

(12) http://circ.ahajournals.org/cgi/content/full/116/21/2427
Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Nettleship JE, Jones TH, Channer KS, et al.
Circulation 2007;116:2427–34.

Conclusion— Physiological testosterone replacement inhibited fatty streak formation in the Tfm mouse, an effect that was independent of the androgen receptor. The observed increase in HDLC is consistent with conversion to 17β-estradiol.

In summary, this study has demonstrated a beneficial action of testosterone on fatty streak formation. We have demonstrated that physiological concentrations of testosterone inhibit aortic fatty streak formation in cholesterol-fed mice, an action that is independent of the classic AR and mediated in part by conversion to 17β-estradiol. In addition, physiological testosterone treatment increased HDLC, an effect consistent with conversion to 17β-estradiol and subsequent activation of genomic, ER-dependent pathways. These data suggest that physiological testosterone replacement therapy may protect against atherogenesis and potentially confer cardiovascular benefits to men with hypotestosteronemia.

13) http://www.ncbi.nlm.nih.gov/pubmed/20861231?dopt=Abstract
Endocrinology. 2010 Nov;151(11):5428-37. Epub 2010 Sep 22.

Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Bourghardt J, Wilhelmson AS, Alexanderson C, De Gendt K, Verhoeven G, Krettek A, Ohlsson C, Tivesten A.  Gothenburg, Sweden.

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone.

We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root,

ARKO mice showed increased atherosclerotic lesion area (+80%, P < 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P < 0.001) and ARKO mice (by 24%, P < 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P < 0.05).

In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P < 0.05), whereas there was no significant effect in ARKO mice (P = 0.20).

In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

Why Are Women Protected? Women Have Less Heart Disease Than Men

14) http://atvb.ahajournals.org/cgi/content/full/29/3/277
Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:277.) Cardiovascular Disease in Women by Nigel Mackman; Susan Smyth

Younger women (20 to 39 years) tend to be protected from coronary heart disease, heart failure, stroke, and hypertension (Figure), yet CVD is more prevalent in older women relative to age-matched men (greater than 80 years). These differences appear to be attributable, in part, to the influence of sex hormones on the vasculature, platelets, and the expression of coagulation proteins.

In the last article, Xing and colleagues address "Estrogen and Mechanisms of Vascular Protection." The greater age of women at the time of presentation of atherosclerotic coronary disease has been attributed to beneficial effects of estrogen.

Estrogen Protects Women From Heart Disease

15) http://atvb.ahajournals.org/cgi/content/full/29/3/289
Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:289.)
Estrogen and Mechanisms of Vascular Protection
Dongqi Xing; Susan Nozell; Yiu-Fai Chen; Fadi Hage; Suzanne Oparil

Cardiovascular disease is the leading cause of death among women in the United States, and coronary heart disease (CHD) develops in women on average 10 years later than in men. This lag has been attributed, at least in part, to the protective effects of female sex hormones, particularly estrogens (defined as naturally occurring activators of estrogen receptors) before menopause.1–3

Mechanistic studies carried out in in vitro preparations and in laboratory animals have shown that both natural and synthetic estrogens have antiinflammatory and vasoprotective effects.4–18 Further, the natural endogenous estrogen 17β-estradiol has been shown to cause rapid endothelium-independent dilation of coronary arteries of men and women, to augment endothelium-dependent relaxation of human coronary arteries ex vivo, and to improve endothelial function as assessed by the brachial artery flow-mediated dilation response in postmenopausal women.

Observational studies have shown substantial benefit (50% reduction in CHD) of hormone therapy in women who choose to use menopausal hormones (and usually begin taking them in the perimenopausal or early postmenopausal period).

Fewer Out-Of-Hospital Heart Attacks in Young females with higher estrogen levels

(16) http://eurheartj.oxfordjournals.org/content/31/11/1365.abstract
Eur Heart J (2010) 31 (11): 1365-1372.

Reduction in incidence and fatality of out-of-hospital cardiac arrest in females of the reproductive age. Tetsuhisa Kitamura1, Taku Iwami1,*, Graham Nichol2, Tatsuya Nishiuchi3, Yasuyuki Hayashi4, Chika Nishiyama1, Tomohiko Sakai5, Kentaro Kajino6, Atsushi Hiraide7, Hisashi Ikeuchi8, Hiroshi Nonogi9, Takashi Kawamura1 and for the Utstein Osaka Project

Aims The aim of this study was to determine relative risk (RR) of incidence and fatality of out-of-hospital cardiac arrest (OHCA) by gender and oestrogen status.  Methods and results In a prospective, population-based observational study from 1998 through 2007, incidence and neurologically intact 1-month survival after OHCA were compared by gender after grouping: 0–12 years, 13–49 years, and ≥50 years according to menarche and menopause age. Among 26 940 cardiac arrests, there were 11 179 females and 15 701 males. Age-adjusted RR of females for OHCA incidence compared with males was
0.72 [95% confidence interval (CI), 0.58–0.91] in age 0–12 years,
0.39 (95% CI, 0.37–0.43) in age 13–49 years, and
0.54 (95% CI, 0.52–0.55) in age ≥50 years.

Females aged 13–49 years had a significantly higher good neurological outcome than males [adjusted odds ratio (OR), 2.00 (95% CI 1.21–3.32)]. This sex difference was larger than that in the other age groups [adjusted OR, 0.82 (95% CI, 0.06–12.02) in age 0–12 years and 1.23 (95% CI, 0.98–1.54) in age ≥50 years].

Conclusion: Reproductive females had a lower incidence and a better outcome of OHCA than females of other ages and males, which might be explained by cardioprotective effects of endogenous oestrogen on OHCA.

Post Menopausal Estrogen Use Decreases Heart Disease

(17) http://www.annals.org/content/133/12/933.long
http://www.ncbi.nlm.nih.gov/pubmed/11119394?dopt=Abstract
Ann Intern Med. 2000 Dec 19;133(12):933-41.  A Prospective, Observational Study of Postmenopausal Hormone Therapy and Primary Prevention of Cardiovascular Disease. Francine Grodstein, ScD; JoAnn E. Manson, MD; Graham A. Colditz, MD; Walter C. Willett, MD; Frank E. Speizer, MD; and Meir J. Stampfer, MD. Harvard Medical School Boston, Massachusetts.

Background: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard.

Objective: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Design: Prospective, observational cohort study.  Nurses' Health Study, with follow-up from 1976 to 1996. Patients: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified. Measurements: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. 

Results: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]).

Conclusions: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease.  

(18) http://www.ncbi.nlm.nih.gov/pubmed/20138672
Emerging role of estrogen in the control of cardiometabolic disease
Andrea Cignarella1Mario Kratz2 and Chiara Bolego1
Trends in Pharmacological Sciences Volume 31, Issue 4, April 2010, Pages 183-189

Menopause is associated with an increased risk of cardiovascular and metabolic disease that is partly independent of aging. This increased risk is largely due to postmenopausal estrogen loss. Estrogen improves insulin sensitivity and ß-cell function. This is consistent with the increased risk of diabetes after menopause and the finding that menopausal hormone therapy (MHT) lowers the incidence of diabetes. Experimental data suggest that estrogen has anti-atherosclerotic and pro-thrombotic properties.


Mainstream Treatment for Heart Disease

(19) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941787/
Vasc Health Risk Manag. 2010; 6: 749–774.
Recent advances in the management of chronic stable angina II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization
by Richard Kones. 

Although several small trials prior to 2004 did confirm that PCI improved chest pain frequency and short-term exercise tolerance in patients with chronic angina, they failed to show that PCI either improved survival or prevented subsequent MI. In addition, there was significant persistence of angina and only minor reduction in the number of anti-anginal medications after the procedure. A meta-analysis of 11 randomized studies involving 2,950 patients with stable CAD treated with PCI showed no improvement in mortality, MI, or need for further revascularization, compared with medical management.

(20) http://www.ncbi.nlm.nih.gov/pubmed/15927966
Circulation. 2005 Jun 7;111(22):2906-12. Percutaneous coronary intervention versus conservative therapy in nonacute coronary artery disease: a meta-analysis.
Katritsis DG, Ioannidis JP.  Athens, Greece.

BACKGROUND: Percutaneous coronary intervention (PCI) has been shown to improve symptoms compared with conservative medical treatment in patients with stable coronary artery disease (CAD); however, there is limited evidence on the effect of PCI on the risk of death, myocardial infarction, and subsequent revascularization. Therefore, we performed a meta-analysis of 11 randomized trials comparing PCI to conservative treatment in patients with stable CAD.

METHODS AND RESULTS: A total of 2950 patients were included in the meta-analysis (1476 received PCI, and 1474 received conservative treatment). There was no significant difference between the 2 treatment strategies with regard to mortality, cardiac death or myocardial infarction, nonfatal myocardial infarction, CABG, or PCI during follow-up. By random effects, the risk ratios (95% CIs) for the PCI versus conservative treatment arms were 0.94 (0.72 to 1.24), 1.17 (0.88 to 1.57), 1.28 (0.94 to 1.75), 1.03 (0.80 to 1.33), and 1.23 (0.80 to 1.90) for these 5 outcomes, respectively. A possible survival benefit was seen for PCI only in trials of patients who had a relatively recent myocardial infarction (risk ratio 0.40, 95% CI 0.17 to 0.95). Except for PCI during follow-up, there was no significant between-study heterogeneity for any outcome.

CONCLUSIONS: In patients with chronic stable CAD, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment.

(21) http://circ.ahajournals.org/cgi/content/full/115/9/1082
(Circulation. 2007;115:1082-1089.)
Heart Disease in Latin America. Five-Year Follow-Up of the Medicine, Angioplasty, or Surgery Study (MASS II) A Randomized Controlled Clinical Trial of 3 Therapeutic Strategies for Multivessel Coronary Artery Disease

Background— Despite routine use of coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI), no conclusive evidence exists that either modality is superior to medical therapy (MT) alone for treating multivessel coronary artery disease with stable angina and preserved ventricular function.

Methods and Results— The primary end points were total mortality, Q-wave myocardial infarction, or refractory angina requiring revascularization. The study comprised 611 patients randomly assigned to undergo CABG (n=203), PCI (n=205), or MT (n=203). At the 5-year follow-up, the primary end points occurred in 21.2% of patients who underwent CABG compared with 32.7% treated with PCI and 36% receiving MT alone (P=0.0026).

No statistical differences were observed in overall mortality among the 3 groups. In addition, 9.4% of MT and 11.2% of PCI patients underwent repeat revascularization procedures compared with 3.9% of CABG patients (P=0.021). Moreover, 15.3%, 11.2%, and 8.3% of patients experienced nonfatal myocardial infarction in the MT, PCI, and CABG groups, respectively (P<0.001). The pairwise treatment comparisons of the primary end points showed no difference between PCI and MT (relative risk, 0.93; 95% confidence interval, 0.67 to 1.30) and a significant protective effect of CABG compared with MT (relative risk, 0.53; 95% confidence interval, 0.36 to 0.77).

Conclusions— All 3 treatment regimens yielded comparable, relatively low rates of death. MT was associated with an incidence of long-term events and rate of additional revascularization similar to those for PCI. CABG was superior to MT in terms of the primary end points, reaching a significant 44% reduction in primary end points at the 5-year follow-up of patients with stable multivessel coronary artery disease.

The findings of MASS II strongly suggest that a routine strategy of PCI for patients with stable multivessel CAD is not superior to CABG surgery or MT and may be associated with lower rates of event-free survival, driven by the need for repeat revascularization. Most patients with mild to moderate angina can be safely managed medically, whereas PCI or CABG is appropriate if symptoms are not adequately controlled by medication or if other high-risk features are apparent. Therefore, clinicians should be restrained in their recommendations for both PCI and CABG, reserving the interventions for patients whose symptoms of angina are not well controlled on medical treatment.

It should be emphasized, however, that important developments in PCI have taken place since this trial was started. The use of glycoprotein IIb/IIIa antiplatelet agents, the long-term use of the oral antiplatelet agent clopidogrel, and the development and more widespread application of drug-eluting stents have significantly reduced restenosis and revascularization rates. In addition, surgery without cardiopulmonary bypass could have a significant effect on surgical results. Similarly, aggressive medical treatment and lifestyle prescriptions with comprehensive risk factor modification will also enhance the MT strategy.

In summary, the MASS II trial found no differences in cardiac-related death or overall mortality in patients treated with CABG, PCI, or MT during a 5-year follow-up. In our PCI group, incomplete revascularization might in all probability contribute to a significantly greater need for additional revascularization procedures in patients undergoing angioplasty. Our results also suggest that CABG surgery is an independent predictor of lower rates of event-free survival.

(22) http://www.cardiac-risk-assessment.com/cardiac-healthcare-providers/professional-papers/pci-a-cabg-outcome-analysis

Percutaneous coronary intervention versus coronary artery bypass surgery in multivessel disease: a current perspective. Ozlem Sorana, Aarush Manchandab and Stephan Schuelerc. From the Cardiovascular Institute, University of Pittsburgh Medical Center, Geisinger Medical Center, Freeman Hospital, Newcastle upon Tyne, UK. Presented at the 56th International Congress of the European Society for Cardiovascular Surgery, Venice, Italy, May 17–20, 2007.

EPC's Endothelial Progenitor Cells and Bioidentical Hormones

(23) http://www.ncbi.nlm.nih.gov/pubmed/17659378
Arch Immunol Ther Exp (Warsz). 2007 Jul-Aug;55(4):247-59. Epub 2007 Jul 23.
Miller-Kasprzak E, Jagodziński PP. Department of Biochemistry and Molecular Biology, University of Medical Sciences, Swiecickiego 6, 60-781, Poznań, Poland.

Abstract
A special type of stem cells, defined as endothelial progenitor cells (EPCs), has been found in the bone marrow and peripheral blood. These EPCs are incorporated into injured vessels and become mature endothelial cells during re-endothelialization and neovascularization processes. Though a complete phenotypic description of EPCs remains unclear, these cells express several surface markers, the most relevant including CD34 and CD133 antigens. Furthermore, EPCs derived from other sources could also give rise to mature endothelial cells, which makes this group of cells more diverse.

The recruitment of EPCs from the bone marrow to homing sites of vasculogenesis is subject to regulation by many factors, including chemokines and growth factors. The precise mechanism of EPC mobilization and differentiation is not entirely elucidated and is still under investigation. Recent studies have suggested that EPCs may promote local angiogenesis by secreting angiogenic growth factors in a paracrine manner. The number and function of EPCs can be affected during pathological conditions, including diabetes mellitus, cardiovascular risk factors for ischemic disease, and graft vasculopathy. Additionally, EPC number and migration capacity could be improved by such factors as drugs, physical exercise, and growth factors. Transplantation of EPCs into ischemic tissues may emerge as a promising approach in the therapy of diseases associated with blood vessel disorders.

Estrogen EPC's and Telomerase

(24)  http://www.ncbi.nlm.nih.gov/pubmed/16093915
J Hypertens. 2005 Sep;23(9):1699-706.
Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity. Imanishi T, Hano T, Nishio I.  Wakayama 641-8510, Japan.  CONCLUSION: The inhibition of EPC senescence by estrogen in vitro may improve the functional activity of EPCs in a way that is important for potential cell therapy.

(25) http://jcem.endojournals.org/cgi/content/abstract/91/11/4599
J Clin Endocrinol Metab. 2006 Nov;91(11):4599-602.
Reduced Number of Circulating Endothelial Progenitor Cells in Hypogonadal Men
C. Foresta, N. Caretta, A. Lana, L. De Toni, A. Biagioli, A. Ferlin and A. Garolla
Department of Histology, Microbiology, and Medical Biotechnologies, Centre for Male Gamete Cryopreservation, University of Padova, 35121 Padova, Italy

(26)
http://circ.ahajournals.org/cgi/content/abstract/113/12/1605
Circulation. 2006;113:1605-1614.
Estradiol Enhances Recovery After Myocardial Infarction by Augmenting Incorporation of Bone Marrow–Derived Endothelial Progenitor Cells Into Sites of Ischemia-Induced Neovascularization via Endothelial Nitric Oxide Synthase–Mediated Activation of Matrix Metalloproteinase-9 by  Atsushi Iwakura et al

Methods and Results— Myocardial infarction (MI) was induced by ligation of the left coronary artery in ovariectomized mice receiving either 17ß-estradiol or placebo. Estradiol induced significant increases in circulating EPCs 2 and 3 weeks after MI in estradiol-treated animals, and capillary density was significantly greater in estradiol-treated animals.

Greater numbers of BM-derived EPCs were observed at ischemic sites in estradiol-treated animals than in placebo-treated animals 1 and 4 weeks after MI. In eNOS-null mice, the effect of estradiol on mobilization of EPCs was lost, as was the functional improvement in recovery from acute myocardial ischemia. A decrease was found in matrix metalloproteinase-9 (MMP-9) expression in eNOS-null mice under basal and estradiol-stimulated conditions after MI, the mobilization of EPCs by estradiol was lost in MMP-9–null mice, and the functional benefit conferred by estradiol treatment after MI in wild-type mice was significantly attenuated.

Conclusions— Estradiol preserves the integrity of ischemic tissue by augmenting the mobilization and incorporation of BM-derived EPCs into sites of neovascularization by eNOS-mediated augmentation of MMP-9 expression in the BM. Moreover, these data have broader implications with regard to our understanding of the role of EPCs in post-MI recovery and on the sex discrepancy in cardiac events.

Conclusions— Estradiol preserves the integrity of ischemic tissue by augmenting the mobilization and incorporation of BM-derived EPCs into sites of neovascularization by eNOS-mediated augmentation of MMP-9 expression in the BM. Moreover, these data have broader implications with regard to our understanding of the role of EPCs in post-MI recovery and on the sex discrepancy in cardiac events.

(27) http://circ.ahajournals.org/cgi/content/full/108/25/3115
(Circulation. 2003;108:3115-3121.)
Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury .  Atsushi Iwakura, MD; Corinne Luedemann, BS; Shubha Shastry, PhD; Allison Hanley, BA; Marianne Kearney, BS; Ryuichi Aikawa, MD; Jeffrey M. Isner, MD; Takayuki Asahara, MD; Douglas W. Losordo, MD

Conclusions— Estradiol accelerates reendothelialization and attenuates medial thickening after carotid injury in part by augmenting mobilization and proliferation of bone marrow–derived EPCs and their incorporation into the recovering endohelium at the site of injury.

(28) http://circres.ahajournals.org/cgi/content/full/101/6/598
(Circulation Research. 2007;101:598.)  Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis. Haruchika Masuda et al Kobe, Japan. These findings demonstrate that physiological postnatal vasculogenesis involves cyclic, E2-regulated bioactivity of BM-derived EPCs, predominantly through the ER.

(29) http://www.fasebj.org/content/24/7/2262.abstract  
July 2010 The FASEB Journal vol. 24 no. 7 2262-2272
Selective estrogen receptor-α agonist provides widespread heart and vascular protection with enhanced endothelial progenitor cell mobilization in the absence of uterotrophic action by Chiara Bolego et al Padua, Italy.

The beneficial effects of estrogens on the cardiovascular system are associated with adverse effects on reproductive tissues. On the basis of previous work indicating a major role for estrogen receptor (ER)-α in maintaining cardiovascular health, we evaluated the tissue selectivity of the ERα-selective agonist propyl pyrazole triol (PPT) compared with 17β-estradiol (E2) in vivo. Four weeks postovariectomy, equimolar doses of PPT and E2 were administered to rats in subcutaneous implants for 5 d.

Both treatments restored rapid vasorelaxation of aortic tissue to estrogenic agents and prevented coronary hyperresponsiveness to angiotensin II in isolated heart preparations. Accordingly, multiple endpoints of myocardial ischemia-reperfusion injury exacerbated by ovariectomy returned to baseline following treatment. These protective effects were linked to increased in vivo levels of endothelial progenitor cells (EPCs). Human EPC function was enhanced in vitro after PPT treatment.

Cafffeine Enhances Migration of EPCs

Integrative Physiology/Experimental Medicine
Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1967.

Caffeine Enhances Endothelial Repair by an AMPK-Dependent Mechanism
Ioakim Spyridopoulos; Stephan Fichtlscherer; Rüdiger Popp; Stefan W. Toennes; Beate Fisslthaler; Thomas Trepels; Alma Zernecke; Elisa A. Liehn; Christian Weber; Andreas M. Zeiher; Stefanie Dimmeler; Judith Haendeler .  University of Duesseldorf GmbH, Germany.

Objective— Migratory capacity of endothelial progenitor cells (EPCs) and mature endothelial cells (ECs) is a key prerequisite for endothelial repair after denuding injury or endothelial damage.

Methods and Results— We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 µmol/L) induces migration of human EPCs as well as mature ECs. In patients with coronary artery disease (CAD), caffeinated coffee increased caffeine serum concentration from 2 µmol/L to 23 µmol/L, coinciding with a significant increase in migratory activity of patient-derived EPCs. Decaffeinated coffee neither affected caffeine serum levels nor migratory capacity of EPCs. Treatment with caffeine for 7 to 10 days in a mouse-model improved endothelial repair after denudation of the carotid artery. The enhancement of reendothelialization by caffeine was significantly reduced in AMPK knockout mice compared to wild-type animals. Transplantation of wild-type and AMPK–/– bone marrow into wild-type mice revealed no difference in caffeine challenged reendothelialization. ECs which were depleted of mitochondrial DNA did not migrate when challenged with caffeine, suggesting a potential role for mitochondria in caffeine-dependent migration.

Conclusion— These results provide evidence that caffeine enhances endothelial cell migration and reendothelialization in part through an AMPK-dependent mechanism, suggesting a beneficial role for caffeine in endothelial repair.

We demonstrate that caffeine in physiologically relevant concentrations (50 to 100 µmol/L) induces migration of human endothelial progenitor cells as well as mature endothelial cells. The enhancement of reendothelialization by caffeine in a mouse-model after denudation of the carotid artery was significantly reduced in AMPK knockout mice compared to wild-type animals.

Estrogen Improves Recovery after MI- Which Estrogen Receptor ?

http://www.surgjournal.com/article/S0039-6060(09)00312-2/abstract
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774782/?tool=pubmed
Surgery. 2009 August; 146(2): 145–154.

Acute Post-Ischemic Treatment with Estrogen Receptor-α Agonist or Estrogen Receptor-β Agonist Improves Myocardial Recovery. Nicholas D. Vornehm, MS.,2* Meijing Wang, M.D.,2* Aaron Abarbanell, M.D.,2 Jeremy Herrmann, M.D.,2 Brent Weil, M.D.,2 Jiangjing Tan, M.D.,2 Yue Wang, Ph.D.,2 Megan Kelly, M.S.,2 and Daniel R. Meldrum, M.D.1,2,3

Female hearts following ischemia/reperfusion (I/R) injury demonstrate improved functional recovery compared to male, which suggests a protective role for estrogen. Acute post-ischemic treatment with 17-β-estradiol (E2) attenuates myocardial dysfunction.

However, it is unknown by which estrogen receptor (ER) E2 mediates this acute cardioprotection during I/R. Therefore, we hypothesize that post-ischemic infusion of the selective ER-α agonist (PPT) or the selective ER-β agonist (DPN) will improve myocardial function following I/R.Methods

Isolated, perfused hearts (Langendorff) from adult male rats were subjected to 25-minute ischemia followed by 40-minute reperfusion. Hearts (n=4–6/group) were randomly infused with either perfusate, PPT or DPN at 1 nM, 10 nM, or 100 nM throughout reperfusion. After I/R, heart tissue was analyzed for TNF-α, IL-1β, VEGF and LDH.Results

Post-ischemic treatment with 10 nM of PPT significantly improved myocardial function. Additionally, 10 or 100 nM of DPN significantly increased myocardial functional recovery following I/R, with maximum benefit at the 10 nM dose. A trend towards lower levels of LDH was noted in DPN and PPT treated groups following I/R. Neither PPT nor DPN affected myocardial production of TNF-α or IL-1β. However, higher levels of myocardial VEGF were noted in the PPT treated group compared to control.

Conclusions Both ER-α and ER-β are involved in mediating E2-induced rapid cardioprotection following I/R. Advancing our understanding of both ER subtypes may be useful for the development of novel strategies that may benefit both males and females in response to myocardial ischemia.

Stroke in mouse model

JPET March 2010 vol. 332 no. 3 1006-1012 .  Combination Therapy of 17β-Estradiol and Recombinant Tissue Plasminogen Activator for Experimental Ischemic Stroke. Ran Liu, Qing Liu, Shaoqing He, James W. Simpkins and Shao-Hua Yang, Fort Worth, Texas

Abstract
Thrombolysis with recombinant tissue plasminogen activator (rtPA) in ischemic stroke is limited by the increased risk of hemorrhage transformation due to blood-brain barrier breakdown. We determined the interaction of 17β-estradiol (E2) and rtPA on activation of plasminogen system and matrix metalloproteinases (MMPs) in a transient middle cerebral artery occlusion (MCAO) model. Ovariectomized female rats were subjected to 1-h transient focal cerebral ischemia using a suture MCAO model. Ischemic lesion volume was significantly reduced with acute treatment of E2 despite of exogenous administration of rtPA. The expression and activation of urokinase (uPA), MMP2, and MMP9 were significantly increased in ischemic hemisphere after transient cerebral ischemia. Exogenous rtPA administration further enhanced expression and activation of uPA, MMP2, and MMP9, which was blocked by E2 treatment. We further determined the effect of combination therapy of E2 and rtPA in an embolic MCAO model. Although no protection was indicated upon acute treatment of E2 alone, combination treatment of E2 and rtPA provided protective action at 3 h after embolism. Collectively, the present study suggests that estrogen could be a candidate for combination therapy with rtPA to attenuate its side effect and hence expand its short therapeutic window for treatment of ischemic stroke

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