Cardiac fibrosis

Cardiac fibrosis

Cardiac fibrosis refers to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts.

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 (Matoki-- a green banana) containing excess amounts of serotonin.

Connection with direct serotinergic agonist drugs

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 5HT2B 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tended to cause increased risk of heart valve damage and subsequent heart failure, which eventually led to them being withdrawn from the market.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 bound to 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 [ Accessed Nov. 25, 2007 ] .

Antiparkinsonian drugs which cross-react with serotonin 2B receptors

Certain anti-parkisonian drugs, although targeted at dopaminergic receptors, cross-react with serotoninergic 5-HT2B 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. [cite journal | url = | year = 2004 | month = August | title = Cardiac valvulopathy with pergolide | author = ADRAC | journal = Aust Adv Drug React Bull | volume = 23 | issue = 4 [ Free full text] from the Australian Therapeutic Goods Administration] In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.cite web | url = | title = MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents | publisher = U.S. Food and Drug Administration | date = March 29, 2007 | accessdate = 2007-03-30] [ [ Log In Problems ] ]

Among similar antiparkinsonian drugs, cabergoline but not lisuride exhibit this same type of serotonin receptor binding. [ Jähnichen S, Horowski R, Pertz H. PDFlink| [ "Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT2B Receptors".] |515 KiB Presentation. Retrieved on 2007-03-30.] In January, 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage. [cite journal |author=Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E |title=Dopamine agonists and the risk of cardiac-valve regurgitation |journal=N Engl J Med |volume=356 |issue=1 |pages=29–38 |year=2007 |pmid=17202453 |doi=10.1056/NEJMoa062222]

Other serotonergic pharmacologics in question

The SSRI antidepressants do not raise blood serotonin levels, and thus are not thought to present the same risk as drugs which do raise serotonin levels, or which are direct serotonin mimics. The amino acid L-tryptophan also raises brain but not blood serotonin, and so is not thought to present a risk of serotonin 2B receptor effects.

However, the tryptophan derivative 5-HTP (5-hydroxytryptophan), used in the treatment of depression, does raise blood serotonin levels and the urinary serotonin metabolite 5-HIAA. 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.


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