Cardiac fibrosis commonly refers to the excess deposition of
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
in the cardiac muscle, but the term may also refer to an abnormal thickening of the
heart valves
A heart valve is a one-way valve that allows blood to flow in one direction through the chambers of the heart. Four valves are usually present in a mammalian heart and together they determine the pathway of blood flow through the heart. A heart v ...
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
The tricuspid valve, or right atrioventricular valve, is on the right dorsal side of the mammalian heart, at the superior portion of the right ventricle. The function of the valve is to allow blood to flow from the right atrium to the right ven ...
, but also occurring on the
pulmonary valve
The pulmonary valve (sometimes referred to as the pulmonic valve) is a valve of the heart that lies between the right ventricle and the pulmonary artery and has three cusps. It is one of the four valves of the heart and one of the two semilunar v ...
. The thickening and loss of flexibility eventually may lead to valvular dysfunction and right-sided
heart failure.
Types
Following are types of
myocardial
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
fibrosis:
* Interstitial fibrosis, which is unspecific, and has been described in congestive heart failure, hypertension, and normal aging.
* Subepicardial fibrosis, also unspecific, and is associated with non-infarction diagnoses such as myocarditis and non-ischemic cardiomyopathy.
* Replacement fibrosis, which indicates an older infarction.
File:Histopathology of interstitial fibrosis in dilated cardiomyopathy.jpg, Micrograph
A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken on a m ...
of healthy myocardium versus interstitial fibrosis in dilated cardiomyopathy. Alcian blue stain. The fibrosis is either evenly distributed between myocytes or follows anatomic structures such as blood vessels.
File:Histopathology of interstitial fibrosis of chronic ischemic heart disease.jpg, Interstitial fibrosis of chronic ischemic heart disease, H&E stain, with associated relatively well organized myocardial bundles
File:Subepicardial fibrosis.jpg, Subepicardial fibrosis (epicardium at top).
File:Histopathology of dense fibrous scar replacing myocyte loss in myocardial infarction.jpg, Replacement fibrosis in myocardial infarction, typically being boundless, dense and not conforming to the other types.
Connection with excess blood serotonin (5-HT)
Certain diseases such as
neuroendocrine tumor of the small intestine (also known by the obsolete term
carcinoid
A carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) ...
), 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 with
echocardiography. Cardiac fibrosis is a significant source of morbidity and mortality in patients with functional neuroendocrine tumors. This pathology has also been seen in certain East-African tribes who eat foods (
Matoke
Matoke, locally also known as matooke, amatooke in Buganda (Central Uganda), ekitookye in southwestern Uganda, ekitooke in western Uganda, kamatore in Lugisu ( Eastern Uganda), ebitooke in northwestern Tanzania, igitoki in Rwanda, Burundi and b ...
—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
The dose–response relationship, or exposure–response relationship, describes the magnitude of the response of an organism, as a function of exposure (or doses) to a stimulus or stressor (usually a chemical) after a certain exposure tim ...
,
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
Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212102s003lb ...
and
chlorphentermine
Chlorphentermine (trade names Apsedon, Desopimon, Lucofen) is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the 4-chloro derivative of the better known appetite suppressant phentermine, which is still in ...
, and
antiparkinson drugs such as
pergolide
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...
and
cabergoline
Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.
Cabergoline is an e ...
, 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
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" ...
drugs such as fenfluramine (which in combination with
phentermine
Phentermine ( phenyl- tertiary-butyl amine), with several brand names including Ionamin and Sentis, is a medication used together with diet and exercise to treat obesity. It is taken by mouth for up to a few weeks at a time, after which the ben ...
was marketed as ''Pondimin'' and commonly referred to as fen-phen), chlorphentermine, and
aminorex
Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, mea ...
(along with its analogue
4-Methylaminorex
4-Methylaminorex (4-MAR, 4-MAX) is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a s ...
which has seen sporadic use as a recreational drug) induce a similar pattern of cardiac fibrosis (and
pulmonary hypertension), apparently by overstimulating 5HT
2B 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
Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.
Treatment of acute sy ...
which are targeted at serotonin receptors as vasoconstrictive agents, have long been known to be associated with
pulmonary hypertension and
Raynaud's phenomenon
Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...
(both vasoconstrictive effects), as well as
retroperitoneal fibrosis
Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It may present wi ...
(a fibrotic cell/fibrocyte proliferation effect, thought to be similar to cardiac valve fibrosis).
These drugs include
ergotamine
Ergotamine, sold under the brand names Cafergot (with caffeine) and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural sim ...
and
methysergide
Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the ma ...
and both drugs can also cause cardiac fibrosis.
Antiparkinson drugs
Certain
antiparkinson drugs, although targeted at
dopaminergic receptors, cross-react with serotoninergic 5-HT
2B receptors as well, and have been reported to cause cardiac fibrosis.
These drugs include pergolide and cabergoline.
Antihypertensive drugs
Guanfacine
Guanfacine, sold under the brand name Tenex among others, is an oral medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. Guanfacine is FDA-approved for monotherapy treatment of ADHD as well as being ...
may be a 5-HT
2B 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-HT
2B 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
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desire ...
("ecstasy"),
and some
hallucinogen
Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...
s 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
Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and difficulties with sleep. The medication is taken orally.
Common side-effects include dry mouth, f ...
) is a 5-HT
2B agonist in animal models, but actually behaves as a 5-HT
2B ''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-HT
2B 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
Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.
SSRIs increase the extracellul ...
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 (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.
Uses
5-HTP is sold over the coun ...
(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
Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–br ...
, 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.
In non-human great apes
Cardiac fibrosis is common in non-human great apes in human care. The term idiopathic myocardial fibrosis was coined to emphasize this disease is likely different from the above described forms of cardiac fibrosis in humans. The etiology is not known, though vitamin D deficiency is a potential suspected cause at least in chimpanzees.
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. In the case of a functional
neuroendocrine tumor,
somatostatin analogs such as
octreotide
Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...
are used to reduce the production of serotonin by tumor cells, which often highly express inhibitory somatostatin receptors.
Surgical tricuspid
valve replacement
Valve replacement surgery is the replacement of one or more of the heart valves with either an artificial heart valve or a bioprosthesis (homograft from human tissue or xenograft e.g. from pig). It is an alternative to valve repair.
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, sometimes combined with a pulmonary valve replacement, can be 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.
References
{{DEFAULTSORT:Cardiac Fibrosis
Gross pathology
Cardiomyopathy