Cardiac fibrosis

Cardiac fibrosis may refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts but more commonly refers to the proliferation of fibroblasts in the cardiac muscle. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.

Fibrocyte cells normally secrete collagen, and function to provide structural support for the heart. When over-activated this process causes thickening and fibrosis of the valve, with white tissue building up primarily on the tricuspid valve, but also occurring on the pulmonary valve. The thickening and loss of flexibility eventually may lead to valvular dysfunction and right-sided heart failure.

Connection with excess blood serotonin (5-HT)

Certain diseases such as gastrointestinal carcinoid tumors of the mid-gut, which sometimes release large amounts of 5-hydroxytryptamine, commonly known as 5-HT or serotonin into the blood, may produce a characteristic pattern of mostly right-sided cardiac fibrosis which can be identified at autopsy. This pathology has also been seen in certain West-African tribes who eat foods (Matoke —a green banana) containing excess amounts of serotonin.

Connection with direct serotonergic agonist drugs

Elevated prevalence of cardiac fibrosis and related valvopathies was found to be associated with use of a number of unrelated drugs following long-term statistical analysis once the drugs had been on the market for some time. The cause of this was unknown at the time, but eventually it was realised that all the implicated drugs acted as agonists at 5-HT_2B receptors in the heart in addition to their intended sites of action elsewhere in the body. The precise mechanisms involved remain elusive however, as while the cardiotoxicity shows some dose-response relationship, it does not always develop, and consistent daily use over an extended period tends to be most strongly predictive of development of valvopathy. The drugs most classically associated with the condition are weight loss drugs such as fenfluramine and chlorphentermine, and anti-parkinsonian drugs such as pergolide and cabergoline, which are prescribed to be taken several times a day, often for months or years at a time. Drugs which act as 5-HT_2B agonists but are used only intermittently are capable of producing the same kind of heart damage, but tend to be less likely to do so. Also while the heart valve changes can result in permanent damage and life-threatening heart problems if use of the causative drug is continued, longitudinal studies of former patients suggest that the damage will heal over time to some extent at least.

Diet and weight loss drugs which stimulate serotonin receptors

Some appetite suppressant drugs such as fenfluramine, chlorphentermine, and aminorex induce a similar pattern of cardiac fibrosis (and also pulmonary hypertension), apparently by over-stimulating 5HT_2B receptors on the cardiac fibroblast cells. These drugs consequently tended to cause increased risk of heart valve damage and subsequent heart failure, which eventually led to them being withdrawn from the market.

Anti-migraine drugs targeted at vasoconstrictive serotonin receptors, which also bind to 5-HT_2B receptors

Certain anti-migraine drugs which are targeted at serotonin receptors as vasoconstrictive agents, have long been known to be associated with pulmonary hypertension and Raynaud's phenomenon (both vasoconstrictive effects), as well as retroperitoneal fibrosis (a fibrotic cell/fibrocyte proliferation effect, thought to be similar to cardiac valve fibrosis). These include ergotamine and methysergide. Both drugs can also cause cardiac fibrosis.

Antiparkinsonian drugs which cross-react with 5-HT_2B receptors

Certain anti-parkisonian drugs, although targeted at dopaminergic receptors, cross-react with serotoninergic 5-HT_2B receptors as well, and have been reported to cause cardiac fibrosis.

An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis. In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.

Among similar antiparkinsonian drugs, cabergoline but not lisuride exhibit this same type of serotonin receptor binding, as while lisuride also binds to the 5-HT_2B receptor, it is an antagonist rather than an agonist. In January, 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage.

Recreational drugs which also act at 5-HT_2B receptors

Several serotonergic recreational drugs, including the empathogens MDA and MDMA ("Ecstasy"), and some hallucinogens such as DOI and bromo-dragonfly, have all been shown to act as 5-HT_2B agonists in vitro, but how significant this may be as a risk factor associated with their recreational use is unclear. The piperazine derivative mCPP (a major metabolite of Trazodone) is a 5-HT_2B agonist in animal models, but actually behaves as a 5-HT_2B antagonist in humans. One study of human users of "ecstasy" found that they did have heart valve changes suggestive of early cardiac fibrosis, which were not present in non-ecstasy using controls, suggesting that ecstasy use certainly has the potential to cause this kind of heart damage. On the other hand, there is no statistical evidence as yet to suggest significant increases in rates of cardiac valvopathies in current or former MDMA users, and it is most likely that as with other 5-HT_2B agonists, development of heart valve damage will be highly dependent on the frequency and duration of use and the total cumulative exposure over time, and only a small proportion of the heaviest users are likely to face a substantial risk of heart damage.

The chemist Alexander Shulgin first popularized MDMA and MDA, and he invented DOI and many other recreational drugs that are also 5HT-2B receptor agonists. In 2008 Shulgin underwent surgery to replace a defective aortic heart valve. It is unknown whether or not Shulgin's lifelong use of psychedelic drugs caused the failure of his heart valve.

Other serotonergic pharmacologics in question

The SSRI antidepressants raise blood serotonin levels, and thus may be capable of the same risks, though it is thought that the risk is substantially lower with such drugs. The amino acid L-tryptophan also raises blood serotonin, and may present the same risk as well; though, again, the risk is considered to be low.

However, the tryptophan derivative 5-HTP (5-hydroxytryptophan), used in the treatment of depression, raises blood serotonin level considerably. It has yet to be reported to be associated with valve disease or other fibrosis, but for the previous theoretical reasons, it has been suggested as a possible danger.

When 5-HTP is used in medicine, it is generally administered along with carbidopa, which prevents the peripheral decarboxylation of 5-HTP to serotonin and so ensures that only brain serotonin levels are increased without producing peripheral side effects, however 5-HTP is also sold without carbidopa as a dietary supplement, and may have increased risks when taken by itself without carbidopa.

Possible treatments

The most obvious treatment for cardiac valve fibrosis or fibrosis in other locations, consists of stopping the stimulatory drug or production of serotonin. Surgical tricuspid valve replacement for severe stenosis (blockage of blood flow) has been necessary in some patients.

A compound found in red wine, resveratrol has been found to slow the development of cardiac fibrosis. More sophisticated approaches of countering cardiac fibrosis like microRNA inhibition (miR-21, for example) are being tested in animal models.