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-HT2B receptors in the heart in addition to their intended sites of action elsewhere in the body.[1][2] The precise mechanisms involved remain elusive however, as while the cardiotoxicity shows some dose-response relationship,[3] it does not always develop, and consistent daily use over an extended period tends to be most strongly predictive of development of valvopathy.[4][5][6] 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.[7][8]

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 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 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.[9]

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. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.[10] In March 2007, pergolide was withdrawn from the U.S. market due to serious valvular damage that was shown in two independent studies.[11] [12]

Among similar antiparkinsonian drugs, cabergoline but not lisuride exhibit this same type of serotonin receptor binding,[13] as while lisuride also binds to the 5-HT2B receptor, it is an antagonist rather than an agonist.[14] In January, 2007, cabergoline (Dostinex) was reported also to be associated with valvular proliferation heart damage.[15]

Recreational drugs which also act at 5-HT2B receptors

Several serotonergic recreational drugs, including the empathogens MDA and MDMA ("Ecstasy"),[16] and some hallucinogens such as DOI[17] and bromo-dragonfly,[18] 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.[19][20][21] 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,[22] 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.

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,[23][24] 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.[25][26][27] More sophisticated approaches of countering cardiac fibrosis like microRNA inhibition (miR-21, for example) are being tested in animal models.

References

  1. ↑ Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G (January 2007). "Valvular heart disease and the use of dopamine agonists for Parkinson's disease". The New England Journal of Medicine 356 (1): 39–46. doi:10.1056/NEJMoa054830. PMID 17202454.
  2. ↑ Andersohn F, Garbe E (January 2009). "Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists". Movement Disorders : Official Journal of the Movement Disorder Society 24 (1): 129–33. doi:10.1002/mds.22385. PMID 19170199.
  3. ↑ Corvol JC, Anzouan-Kacou JB, Fauveau E, Bonnet AM, Lebrun-Vignes B, Girault C, Agid Y, Lechat P, Isnard R, Lacomblez L (December 2007). "Heart valve regurgitation, pergolide use, and parkinson disease: an observational study and meta-analysis". Archives of Neurology 64 (12): 1721–6. doi:10.1001/archneur.64.12.1721. PMID 18071034.
  4. ↑ Sachdev M, Miller WC, Ryan T, Jollis JG (December 2002). "Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies". American Heart Journal 144 (6): 1065–73. doi:10.1067/mhj.2002.126733. PMID 12486432.
  5. ↑ Hopkins PN, Polukoff GI (June 2003). "Risk of valvular heart disease associated with use of fenfluramine". BMC Cardiovascular Disorders 3: 5. doi:10.1186/1471-2261-3-5. PMC 194859. PMID 12801402.
  6. ↑ Antonini A, Poewe W (September 2007). "Fibrotic heart-valve reactions to dopamine-agonist treatment in Parkinson's disease". Lancet Neurology 6 (9): 826–9. doi:10.1016/S1474-4422(07)70218-1. PMID 17706566.
  7. ↑ Hensrud DD, Connolly HM, Grogan M, Miller FA, Bailey KR, Jensen MD (December 1999). "Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine". Mayo Clinic Proceedings. Mayo Clinic 74 (12): 1191–7. doi:10.4065/74.12.1191. PMID 10593346.
  8. ↑ Fleming RM, Boyd LB (2007). "The longitudinal effects of fenfluramine-phentermine use". Angiology 58 (3): 353–9. doi:10.1177/0003319707302496. PMID 17626991.
  9. ↑ Baskin, Steven I (1991-09-23). Principles of Cardiac Toxicology. ISBN 9780849388095.
  10. ↑ ADRAC (August 2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull 23 (4). Free full text from the Australian Therapeutic Goods Administration
  11. ↑ "MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S. Food and Drug Administration. March 29, 2007. Retrieved 2007-03-30.
  12. ↑ Log In Problems
  13. ↑ Jähnichen S, Horowski R, Pertz H. "Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT2B Receptors". PDF (515 KiB) Presentation. Retrieved on 2007-03-30.
  14. ↑ Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B (2006). "Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis". Clinical Neuropharmacology 29 (2): 80–6. doi:10.1097/00002826-200603000-00005. PMID 16614540.
  15. ↑ Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E (2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". N Engl J Med 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453.
  16. ↑ Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (June 2003). "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–9. doi:10.1124/mol.63.6.1223. PMID 12761331.
  17. ↑ Schuhmacher M (2007). "[Chiral arylmethoxytryptamines as 5-HT2B-receptor antagonists: synthesis, analysis and in-vitro pharmacology] (German)" (PDF). Ph.D. Dissertation. University of Regensburg: 6–17. Retrieved 2008-08-11.
  18. ↑ Parker MA, Marona-Lewicka D, Lucaites VL, Nelson DL, Nichols DE (December 1998). "A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor". Journal of Medicinal Chemistry 41 (26): 5148–9. doi:10.1021/jm9803525. PMID 9857084.
  19. ↑ Gatch MB (August 2003). "Discriminative stimulus effects of m-chlorophenylpiperazine as a model of the role of serotonin receptors in anxiety". Life Sciences 73 (11): 1347–67. doi:10.1016/S0024-3205(03)00422-3. PMID 12850497.
  20. ↑ Nunes-de-Souza V, Nunes-de-Souza RL, Rodgers RJ, Canto-de-Souza A (February 2008). "5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behaviour in mice". Behavioural Brain Research 187 (1): 72–9. doi:10.1016/j.bbr.2007.08.030. PMID 17935799.
  21. ↑ Thomas, DR; Gager, TL; Holland, V; Brown, AM; Wood, MD (1996). "M-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor". NeuroReport 7 (9): 1457–60. doi:10.1097/00001756-199606170-00002. PMID 8856697.
  22. ↑ Droogmans S, Cosyns B, D'haenen H, Creeten E, Weytjens C, Franken PR, Scott B, Schoors D, Kemdem A, Close L, Vandenbossche JL, Bechet S, Van Camp G (November 2007). "Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease". The American Journal of Cardiology 100 (9): 1442–5. doi:10.1016/j.amjcard.2007.06.045. PMID 17950805.
  23. ↑ Magnussen, I; Van Woert, MH (1982). "Human pharmacokinetics of long term 5-hydroxytryptophan combined with decarboxylase inhibitors". European journal of clinical pharmacology 23 (1): 81–6. doi:10.1007/BF01061381. PMID 6182005.
  24. ↑ Genazzani, AR; Sandrini, G; Facchinetti, F; Rizzo, V; Alfonsi, E; Sances, G; Calvani, M; Nappi, G (1986). "Effects of L-5HTP with and without carbidopa on plasma beta-endorphin and pain perception: Possible implications in migraine prophylaxis". Cephalalgia : an international journal of headache 6 (3): 175–9. doi:10.1046/j.1468-2982.1986.0603175.x. PMID 2945645.
  25. ↑ Olson, ER; Naugle, JE; Zhang, X; Bomser, JA; Meszaros, JG (2005). "Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol". American Journal of Physiology. Heart and Circulatory Physiology 288 (3): H1131–8. doi:10.1152/ajpheart.00763.2004. PMID 15498824.
  26. ↑ Aubin, MC; Lajoie, C; Clément, R; Gosselin, H; Calderone, A; Perrault, LP (2008). "Female rats fed a high-fat diet were associated with vascular dysfunction and cardiac fibrosis in the absence of overt obesity and hyperlipidemia: Therapeutic potential of resveratrol". The Journal of Pharmacology and Experimental Therapeutics 325 (3): 961–8. doi:10.1124/jpet.107.135061. PMID 18356487.
  27. ↑ Sutra, T; Oiry, C; Azay-Milhau, J; Youl, E; Magous, R; Teissèdre, PL; Cristol, JP; Cros, G (2008). "Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: Involvement of osteopontin and oxidative stress". Journal of Agricultural and Food Chemistry 56 (24): 11683–7. doi:10.1021/jf802357g. PMID 19049292.
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