https://en.wikipedia.org/wiki/Cardiac_fibrosis
Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. 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.
Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. 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 East-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-HT2B 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 antiparkinson drugs such as pergolide and cabergoline, which are prescribed for chronic use.
The heart valve changes seen with moderate and intermittent use
can result in permanent damage and life-threatening heart problems if
use of the causative drug is increased or continued, however
longitudinal studies of former patients suggest that the damage will
heal over time to some extent at least.
Anorectics
Some appetite suppressant drugs such as fenfluramine (which in combination with phentermine was marketed as Pondimin and commonly referred to as fen-phen), chlorphentermine, and aminorex (along with its analogue 4-Methylaminorex which has seen sporadic use as a recreational drug) induce a similar pattern of cardiac fibrosis (and pulmonary hypertension), apparently by over-stimulating 5HT2B receptors on the cardiac fibroblast cells.
These drugs consequently tend to cause increased risk of heart
valve damage and subsequent heart failure, which eventually led to them
being withdrawn from the market.
Antimigraine drugs
Certain antimigraine 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 drugs include ergotamine and methysergide and both drugs can also cause cardiac fibrosis.
Antiparkinson drugs
Certain antiparkinson drugs, although targeted at dopaminergic receptors, cross-react with serotoninergic 5-HT2B receptors as well, and have been reported to cause cardiac fibrosis.
These drugs include pergolide and cabergoline.
Antihypertensive drugs
Guanfacine may be a 5-HT2B agonist, based on the results of theoretical modeling and high-throughput screening.
Pergolide
Pergolide
was an antiparkinson medications that 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.
Cabergoline
Like
pergolide, cabergoline has been linked to cardiac damage. Among similar
antiparkinsonian drugs, cabergoline exhibits the same type of serotonin
receptor binding as pergolide. Although lisuride, a related drug, also binds to the 5-HT2B receptor, it acts as an antagonist rather than as an agonist.
In January 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage.
Recreational drugs
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-HT2B 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-HT2B agonist in animal models, but actually behaves as a 5-HT2B antagonist in humans.
MDMA
One study of
human users of MDMA ("ecstasy") found that they did have heart valve
changes suggestive of early cardiac fibrosis, which were not present in
non-MDMA using controls, suggesting that MDMA use certainly has the potential to cause this kind of heart damage.
On the other hand, there is as yet no statistical evidence to
establish or negate significant increases in rates of cardiac
valvopathies in current or former MDMA users. Absent studies on point,
it may be speculated that as with other 5-HT2B agonists,
development of heart valve damage may be dependent on the frequency and
duration of use and the total cumulative exposure over time. If that is
the case, then the heaviest users are likely to face the greatest risk
of heart damage.
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.
