Cardiac fibrosis
Encyclopedia
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.
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.
, 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tended to cause increased risk of heart valve damage and subsequent heart failure, which eventually led to them being withdrawn from the market.
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.
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 In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.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-HT2B 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.
and MDMA ("Ecstasy"), the piperazine derivative mCPP
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. 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-HT2B 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, but it is suspected as such.
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.
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.
Fibrocyte cells normally secrete collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, 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
Tricuspid valve
The tricuspid valve, or right atrioventricular valve, is on the right dorsal side of the mammalian heart, between the right atrium and the right ventricle. The normal tricuspid valve usually has three leaflets and three papillary muscles. They are connected to the papillary muscles by the chordae...
, but also occurring on the pulmonary valve
Pulmonary valve
The pulmonary valve is the semilunar valve of the heart that lies between the right ventricle and the pulmonary artery and has three cusps. Similar to the aortic valve, the pulmonary valve opens in ventricular systole, when the pressure in the right ventricle rises above the pressure in the...
. 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 carcinoidCarcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
tumors of the mid-gut, which sometimes release large amounts of 5-hydroxytryptamine, commonly known as 5-HT or serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
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 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 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-HT2B 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 fenfluramineFenfluramine
Fenfluramine is a drug that was part of the Fen-Phen anti-obesity medication . Fenfluramine was introduced on the U.S. market in 1973. It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine...
, chlorphentermine
Chlorphentermine
Chlorphentermine is an appetite suppressant of the phenethylamine class. Developed in 1962, it is the 4-chloro derivative of the better known appetite suppressant phentermine, which is still in current use.Chlorphentermine itself is a relatively weak stimulant with little abuse potential, but is...
, and aminorex
Aminorex
Aminorex is an anorectic stimulant drug of the 2-amino-5-aryl oxazoline class developed by a team at McNeil in 1962. It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine...
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 bind to 5-HT2B receptors
Certain anti-migraine drugs which are targeted at serotonin receptors as vasoconstrictive agents, have long been known to be associated with pulmonary hypertensionPulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
and Raynaud's phenomenon
Raynaud's phenomenon
In medicine, Raynaud's phenomenon is a vasospastic disorder causing discoloration of the fingers, toes, and occasionally other areas. This condition can also cause nails to become brittle with longitudinal ridges. Named for French physician Maurice Raynaud , the phenomenon is believed to be the...
(both vasoconstrictive effects), as well as retroperitoneal fibrosis
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 with lower back pain, renal failure, hypertension, deep...
(a fibrotic cell/fibrocyte proliferation effect, thought to be similar to cardiac valve fibrosis). These include ergotamine and methysergide
Methysergide
Methysergide is a prescription drug used for prophylaxis of migraine headaches and is sold under the brand names Sansert and Deseril in 2 mg dosages.-Pharmacology:Methysergide interacts with serotonin receptors...
. Both drugs can also cause cardiac fibrosis.
Antiparkinsonian drugs which cross-react with 5-HT2B 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
Pergolide
Pergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....
. 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
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...
but not lisuride
Lisuride
Lisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...
exhibit this same type of serotonin receptor binding, as while lisuride also binds to the 5-HT2B receptor, it is an antagonist rather than an agonist. In January, 2007, cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...
(Dostinex) was reported also to be associated with valvular proliferation heart damage.
Recreational drugs which also act at 5-HT2B receptors
Several serotonergic recreational drugs, including the empathogens MDA3,4-Methylenedioxyamphetamine
3,4-Methylenedioxyamphetamine , also known as tenamfetamine , is a psychedelic and entactogenic drug of the phenethylamine and amphetamine chemical classes...
and MDMA ("Ecstasy"), the piperazine derivative mCPP
1-(3-Chlorophenyl)piperazine
meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a designer drug in the mid-2000s...
and some hallucinogens such as DOI
2,5-Dimethoxy-4-iodoamphetamine
2,5-dimethoxy-4-iodoamphetamine is a psychedelic drug and a substituted amphetamine of the phenethylamine family. It is also a powerful anti-inflammatory that is effective at doses on the order of 100 micrograms in humans, far below its effective dose as a psychedelic. Despite being a substituted...
and bromo-dragonfly
Bromo-DragonFLY
Bromo-DragonFLY is a psychedelic hallucinogenic drug related to the phenethylamine family. Bromo-DragonFLY is considered an extremely potent hallucinogen, only slightly less potent than LSD with a normal dose in the region of 200 μg to 800 μg, and it has an extremely long duration of action up to...
, 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. 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-HT2B 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
Alexander Shulgin
Alexander "Sasha" Theodore Shulgin is an American pharmacologist, chemist, artist, and drug developer.Shulgin is credited with the popularization of MDMA, commonly known as ecstasy, in the late 1970s and early 1980s, especially for psychopharmaceutical use and the treatment of depression and...
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, but it is suspected as such.
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
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
, 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
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
has been found to slow the development of cardiac fibrosis. More sophisticated approaches of countering cardiac fibrosis like microRNA inhibition (miR-21
MIRN21
microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.MIRN21 was one of the first mammalian microRNAs identified. The mature miR-21 sequence is strongly conserved throughout evolution...
, for example) are being tested in animal models.