Dimera goals are to develop new concepts leading to drugs and diagnostic insights to reduce the risk of heart disease and related maladies in women and their families. The Dimera mission is to identify the underlying causes and provide effective treatment for heart disease in women that is refractory to treatment, in other words, is not satisfactorily manageable, even with combinations of existing drugs and medical options. Medical science can--and must!--aspire to quantum leaps of understanding that will bring acceptable health to women with angina pectoris (chest symptoms of cardiac origin).
Immediate Dimera goals are focused on a novel medicine option that specifically responds to the major need for treatment of coronary artery disease in women, as demonstrated by the negative (increased cardiovascular risks) outcome of the Women's Health Initiative (WHI) of the NIH, the largest randomized clinical women's health study to date (Rossouw 2007). The massive multi-year Women's International Study of long Duration Oestrogen after Menopause (WISDOM), a randomized controlled trial in the United Kingdom, reported a similar outcome to the WHI outcome in showing that hormone replacement with Premarin (conjugated estrogen), with or without MPA (as Prempro), started an average of 12 years after menopause, increased--rather than decreased--cardiovascular and thromboembolic risk (Vickers 2007). Furthermore, for at least 3 years after discontinuing the Prempro (or Premphase) oral treatment studied in 15,730 women, increased risk of cancer (12% greater than in the placebo group) continued (Heiss 2008). Part of the problem is missing information about what accounts for heart disease in women. Heart problems can involve nonstructural causes, which in fact more commonly occur in women than men. Functional causes such as increased reactivity (exaggerated duration of coronary artery constriction) appear to occur significantly more prevalently in women than in men.
Coronary artery reactivity modulation is a rarely recognized, but important, function of steroid hormone actions on coronary, cerebral, renal, urogenital, and other important blood vessels. Coronary hyperreactivity that we hypothesize is due to falling levels of P has profound significance for aging, particularly as it affects postmenopausal women, but also as falling P affects men (in whom progesterone is also present and significant). Dimera has advanced the concept of coronary hyperreactivity as a significant element of heart disease, symptoms, and treatment to investigate elements of heart disease more frequently occurring in women.
The major increase in risk of heart disease in women after menopause is strongly correlated with falling levels of estrogens, but even more profoundly of progesterone, which occurs in the presence of continued adrenal testosterone and other androgenic steroids. This imbalance (of estrogens, progesterone, and androgens) is hypothesized by Dimera to lead to loss of a protected state of the heart that existed in the presence of the threshold progesterone concentration. Previously, we showed that return of subphysiological levels (less than half of that occurring naturally at peak serum concentrations during each menstrual cycle) of progesterone, administered steadily over about 8 hours via the transdermal (rather than oral) route, restore normal coronary reactivity in ovariectomized primates. Such low (less than normal pre-menopausal cycle) levels of progesterone (contrasted with all prescribed doses of synthetic progestins) are practically (or perhaps literally) without side-effects.
The failure to provide a net benefit and premature halt in July 2002 of the estrogen plus progestin arm of the first large, prospective study with multi-year treatment and follow up of women's coronary artery disease prevention (the NIH sponsored Women's Health Initiative, WHI) has called conventional medical treatment of postmenopausal women into question. Dimera publications had in fact predicted the adverse outcome of the Prempro arm of WHI based on the outcome of our basic science discoveries culminating in our 1997 primate coronary artery function breakthrough (Nature Medicine 3:324-327, American J Physiology 272:H2645-2654). [Also please see the References page.]
That prediction was made based on the fact that a major limitation of the WHI study was that only synthetic progestins (in fact, almost exclusively medroxyprogesterone acetate, also known as MPA, Provera, Depo Provera, Prempro, and Premphase) at very high (one-size-fits-all) doses were included. The evidence-based logical conclusions to be drawn from WHI are that conventional hormone treatment (with Prempro, the only drug containing a progestin that has been tested in a large prospective trial with follow up to date), begun years after rather than before menopause, failed to provide a net benefit, considering the increased risks encountered. Four definitive recent papers on the References page (Barrett-Connor, Hsai, Grodstein, Rossouw) have reached the same conclusion.
Therefore, new randomized controlled clinical trials with multi-year study durations are urgently needed to test low dose, transdermal P (as contrasted with MPA, the synthetic progestin in Prempro that was used nearly universally in WHI, WISDOM, and all of the other randomized controlled trials that included at least 3 years of follow up analysis). These new randomized controlled trials with P should target earlier ages, beginning before menopause, to avoid allowing years of progesterone deficits. Such a preventive approach is more likely to achieve improved quality-of-life goals--in addition to predictably and effectively relieving the different signs and symptoms with which women typically experience heart disease. Heart disease in women is most likely to be discovered as coronary artery dysfunction (angina pectoris) that may occur at rest, often appearing as heart related pain or malaise that severely disturbs sleep.
Typical angina as found in men is exercise-induced; however, angina in women is more often not related to exercise (and thus is called atypical angina). Relief in women of lack of energy, shortness of breath, referred arm, jaw, back, or neck pains, other exertional pains, and the sensation of impending suffocation (and anxiety) would importantly, and in addition, minimize the tendency toward fear and hopelessness. This understandable fear of decline and even collapse severely limits freedom of movement--and would otherwise inevitably lead to unhealthy progressive reduction of physical activity.
The heart disease symptoms prevalent in women are not presented in TV programs that portray only the male heart attack stereotype, causing women to ignore warning signals. The risk of untreated angina symptoms related to heart disease, and the consequently self-limited exercise, leads to further deterioration of heart function, in an endless accelerating cycle. Effective treatment of angina in women promises new hope and significantly improved quality of life that can break her out of the downward spiral and start the steps to improving her health.
What can each concerned person do about the present unacceptable state of affairs? First, publicize and support that for women as well as men, 50% of us can expect to die of cardiovascular causes. More research is needed to address unmet needs and accelerate the decline in deaths due to heart attacks, strokes, hypertension, and other underappreciated killers. Second, (assuming that you are already a non-smoker) understand that the strategy inherent in the 10,000 steps program (please see the Links page) and other calls to daily, consistent physical activity reduce your risk of cardiovascular disease, regardless of your body mass index, gender, or age. An energetic outlook with optimism goes a long way toward improved health. Third, read avidly about the underlying causes of heart disease and "atypical" presentations prevalent in women. Discussion of this topic may greatly enhance the needed transition from research and diagnostics that only considers the typical situation in men. The Red Dress campaign of the National Heart Lung and Blood Institute of the National Institutes of Health and the American Heart Association presented on the Links page is worthy of your interest and encouragement. Next February, plan a local Red Dress event for your group. The excellent progress in cancer research brought by superb popularization programs for understanding and conquering cancer should be noted and followed to create similar pervasive programs for all people to improve prevention and management of heart and blood vessel disease.
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