*Important* Heart disease kills more women than all types of cancer combined!
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 not satisfactorily manageable with even combinations of multiple existing drugs and medical options. Medical science can and must aspire to quantum leaps of understanding that will bring solutions and new paths for progress.
Immediate Dimera goals are focused on a novel medicine option that specifically responds to the major need for treatment of angina pectoris as the most common symptom of coronary artery disease in women. Thus unmet need was demonstrated by the unexpected negative (increased cardiovascular risks) outcome of the Women's Health Initiative (WHI) of the National Institutes of Health (NIH) (Rossouw 2007). The estrogen plus progestin part of WHI, with over 16,600 women studied for >5 years, is the largest randomized clinical women's health hormonal treatment study to date. Another massive multi-year clinical trial, the Women's International Study of long Duration Oestrogen after Menopause (WISDOM), was a randomized controlled trial in the United Kingdom, which was consistent with 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 followup 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).
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 followup to date), begun years after (average age 63) 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.
A 2003 US survey conducted by the American Heart Association reported that although about half of the women knew that heart disease is the leading cause of death in women, yet only 13% identified heart disease as their greatest individual life-limiting health risk. If these women did not choose heart disease, then what did they say was the greatest risk? Consistently, survey data suggest that on a day-to-day basis, women still worry more about getting breast cancer than heart disease-even though heart disease kills six times as many women every year as breast cancer. Why should there be this disconnect?
Notably, breast cancer affects body image, sexuality, and self-esteem in obvious ways that a diagnosis of heart disease does not. Also, heart disease increases with age (for a large fraction, a woman's first heart attack may occur at or after age 70), so the threat may not seem all that obvious to younger women. Even though most 50-year-old women know women their age who've had breast cancer, few know those who've had heart disease. Younger women with heart disease tend to survive 1st heart attacks less than men, and not to be observed being treated for many months by their friends, as is typical for breast cancer. In addition, many women report that their physicians are reluctant to talk to them about coronary risk and sometimes, don't even recognize typical women's symptoms, mistaking them instead for signs of panic disorder, stress, and even hypochondria.
Please notice carefully the most prevalent heart attack symptoms experienced by women but less commonly by men, with the % of the 1270 US women reporting each symptom preceding and during a heart attack shown in the parentheses (these data are summarized from McSweeney et al, Am J. Crit Care 19:63-73, 2010).
Preceding a heart attack, 95% of the women reported one or more of these symptoms
- Unusual fatigue (73%)
- Sleep disturbances (50%)
- Shortness of breath (45%)
- Anxiety (43%)
- Frequent Indigestion (39%)
- Chest pain or discomfort (38%)
- Heart rate abnormally high (27%)
- Arms weak and heavy (25%)
During a heart attack, 1267 out of 1270 (98%) reported one or more of these symptoms
- Shortness of breath (63%)
- Chest pain or discomfort (58%)
- Weakness (55%)
- Unusual fatigue (48%)
- Dizziness (44%)
- Cold sweats (40%)
- Nausea (36%)
- Arms weak and heavy (35%)
Life-time risk of death from is still nearly 50% for both women and men--without question the leading cause of death.
Here are some facts provided by the American Heart Association that must cause serious concern.
[Cardiovascular Disease (CVD) (ICD/10 codes I00-I99, Q20-Q28) (ICD/9 codes 390-459, 745-747)]
• One-third of all US female adults has some form of cardiovascular disease.
• For 20 years, CVD mortality in United States females exceeded that in males. [Females represented 52% of deaths from CVD in 2008.]
• Since 2003, all United States cardiovascular diseases combined claimed the lives of nearly 2 times as many women as all forms of cancer combined.
• In 2003, cardiovascular disease was the first listed diagnosis of 3,196,000 women discharged (including both alive and dead) from short-stay hospitals.
• Stroke can happen during a woman’s reproductive years. It strikes more than 13,000 women under the age of 45 every year, sometimes in their 30s or even 20s. (That’s 11% more strokes than in men in the same age group.)
For more information and authoritative references, be sure to visit the Links webpage.
Therefore, new randomized controlled clinical trials with multi-year study durations are urgently needed to test low dose, transdermal P (as contrasted with MPA that is the synthetic progestin in Prempro as was used in WHI, WISDOM, and all of the other randomized controlled trials that critically included at least 3 years of followup analysis). These new randomized controlled trials must be begun at earlier ages, perhaps in peri-menopausal women, to avoid years of estrogen and progesterone deficits, which 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, most often discovered as coronary artery dysfunction (angina pectoris). Typically, instead of exercise-induced chest pain, angina in women is not related to exercise (and thus 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 feeling of suffocation and anxiety that understandably accompanies sensations of restricted or ineffective breathing will, in addition, minimize consequent feelings of fear and the lack of energy that characterize--and would otherwise inevitably lead to unhealthy progressive declines in physical activity--untreated heart disease.