Vasospasm

[an example of heart pathophysiology]

The problem

This angiogram illustrates the occurrence of a vasospasm due to focal coronary hyperreactivity (shown in both the original angiogram and the artist's drawing by narrowings known as vasoconstriction) forming stereotypic hourglass patterns. Prolonged focal vasoconstriction occurs in some individuals, often independent of plaques or clots that are another important cause of heart attacks. This distinction is important because vasoconstriction of coronary arteries for shorter times in fact occurs normally, and serves the function of locally regulating blood flow. But it is the persistence of coronary (or other) artery vasoconstriction for more than 5 min that defines the abnormal function (i.e., this pathophysiology that we have termed "hyperreactivity").

In the example, the monkey heart showed 5 or more regions of prolonged (>5 minute duration) focal narrowing with downstream vasodilation, i.e., vasospasm. Dimera has found that such persistent focal constrictions to diameters between 15 and 33% of the control (unprovoked) diameter occur in response to a provocative constrictor stimulus in >90% of the surgically menopausal (ovariectomized) monkeys IF replacement ovarian steroids are not administered daily for at least 7 days previous to the provocative challenge. This new recognition of a functional component in coronary artery disease by Dimera was made possible through support provided by research grants from the National Institutes of Health (NIH).

New Insight

The conceptual advance is the discovery that low dose slow release progesterone, applied as vanishing cream, effectively normalized coronary function in these rigorously controlled experiments. The correlation of hormone levels and coronary responsiveness found in rhesus are hypothesized by Dimera to be predictive of those in people, with the promise of improving aspects of the human condition.

An important simplifying design factor that allowed the recognition of the major virtue of transdermal progesterone in these studies is that these rhesus monkeys, which were never fed atherogenic diets predictably and reliably did not develop coronary plaques or occlusions (which would almost always be present in people). Fiber-fed rhesus thus avoided an important confounding factor and allowed uncomplicated interpretation of the major benefits on reactivity to be discovered by Dimera scientists. Isolation and exploration of functional reactivity changes, had not previously been explored without complications of atherosclerotic plaques that present a major confounding complication when studied in people.

Later Dimera rhesus research with 19 months of high fat diet demonstrated that hyperreactivty is an independent underlying factor in blood vessel disease, as this functional condition significantly amplifies structural abnormalities of the type caused by atherosclerosis (Hermsmeyer 2004). Monkey coronary hyperreactivity, as revealed in the Dimera protocol by provocation with the simulated blood platelet release substances thromboxane A2 and serotonin, appears to be independently superimposed upon structural phenomena. Such dangerously persistent episodes of locally reduced blood flow (ischemia) are hypothesized by Dimera to aggravate and exacerbate the adversity due to plaques, clots, and other structural abnormalities.

A particular difficulty for heart disease research is that this functional abnormality is fleetingly transient, and therefore presents a major challenge for scientists and physicians to detect. Transience, intermittency, and the resulting unpredictability further frustrate detection and systematic analysis. Persistent abnormal vasoconstriction due to brief 15 to 30 second exposures to blood platelet release of serotonin and thromboxane A2 can, in fact, today only be detected in response to a provoking stimulus during continuous measures of coronary dynamics and blood flow, i.e., in the catheterization (cath) lab.

Traditional pathological plaque and clot histopathology approaches are not designed to recognize such functional causes of blood flow reduction, but rather to focus on and readily detect structural causes. What can be seen, photographed, and readily measured is of course most convincing. However, it is only with the above limited availability, advanced techniques that such functional phenomena can be detected to allow a firm diagnosis.

The angiogram above shows an example of long duration vasospasms. By definition, hyperreactivity (abnormally persistent severe vasoconstriction, with or without these stereotypic hourglass figures that are called vasospasm) would go unrecognized without angiography during the event. Further NIH supported studies are continuing at Dimera and in other laboratories to further analyze the role played by these previously unexplored hyperreactivity phenomena in coronary artery disease.

Treatment plan

Dimera has demonstrated the value preclinically of replacing the progesterone deficit with progesterone absorbed via the skin. The transdermal progesterone cream was developed by Dimera as a slow release formulation to provide a low dose that has the virtue of being practically free of side effects. Transdermal progesterone cream (in a base that is a vanishing cream) provides a new alternative therapy that contrasts in many important elements with widely used synthetic progestins (usually given as pills) that have been discovered to exhibit adverse effects on coronary arteries. The most popular progestin, MPA (medroxyprogesterone acetate), has unequivocally adverse actions on coronary arteries in monkeys--both females and males (Miyagawa 1997, Minshall 2001, Mishra 2005). Key studies contrasting genomic cardiovascular actions of progesterone versus MPA are provided in the References Cited list.

Ongoing clinical trials will test whether the predicted differences between progesterone and synthetic progestins, such as MPA, are also found in women. Coronary ischemia due to small vessel dysfunction, which is also called "microvascular angina," presents as chest pain with "normal" (non-obstructed) coronary arteries, and is much more frequent in women than in men. Even with angiography, the microvasculature causing the problem is too small to detect by X-ray angiography. Only with more powerful Magnetic Resonance (MR) or Positron Emission Tomography (PET) dynamic perfusion studies can such small arteries in the heart be detected.

Comparisons of low dose progesterone cream multi-week treatment during progesterone deficiency have revealed a clear benefit of replacing the deficit on coronary artery function. The new tests are important and surprisingly unique. There has never been any test of low dose transdermal progesterone to relieve heart disease. What the outcome of large randomized clinical trials--e.g, HERS (heart estrogen/progestin replacement study), WHI (the National Institutes of Health Women's Health Initiative), and WISDOM--might have been if there had been a low dose, transdermal progesterone treatment group (with or without estrogen) is unknown.

Failure of MPA treatment (which was effectively the only progestin used in both HERS and WHI studies) to show optimum cardiovascular benefits had been predicted by two 1997 publications by Dimera scientists in Nature Medicine and American Journal of Physiology (see References Cited) of adverse MPA actions on primate coronary arteries. The 2004 ATVB paper shows that the hyperreactivity mechanism appears independent of, and represents a dominant determinant of prolonged ischemia even in the face of atherosclerosis. The 2005 Mishra JCEM 2005 paper shows that genomically based hyperreactivity importantly impacts male as well as female monkeys. Coronary hyperreactivity as a consequence of declining progesterone levels (that occur with advancing age) can be predicted (unless the deficiencies are corrected).

Blood vessel abnormalities due to previously unrecognized progesterone deficits represent an abnormality that adversely affects coronary reactivity and may provide for major advances in reducing cardiovascular risk factors. In menopause, progesterone deficits occur in addition to estrogen imbalances. Estrogen can provide important benefits under the right conditions. The most effective scenario can logically be predicted to involve a physiological balance of steroid influences. Estrogen suppression of hyperreactivity is hypothesized in a recent scientific paper (Mishra 2006) to result from genomic estrogen actions through the recently discovered estrogen receptor beta (ERß).