This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levy, R. J. Search for Related Content PubMed PubMed Citation Articles by Levy, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Diseases Related Collections Valvular heart disease Receptor pharmacology Animal models of human disease

(Circulation. 2006;113:2-4.)
© 2006 American Heart Association, Inc.

Editorial

Serotonin Transporter Mechanisms and Cardiac Disease

Robert J. Levy, MD

From the Division of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, Pa.

Correspondence to Robert J. Levy, MD, Children’s Hospital of Philadelphia, Abramson Research Center, Suite 702, 3615 Civic Center Blvd, Philadelphia, PA 19104–4318. E-mail levyr{at}email.chop.edu

Key Words: Editorials • fibrosis • pathology • serotonin • valves

	Introduction

Top Introduction 5-HT Receptor and Transporter... 5-HT Processing, Cardiac... Clinical Implications References

 
Serotonin (5-HT)–related mechanisms have been explored extensively for pharmaceutical development, especially with regard to antidepressants and appetite suppressants. However, pharmacological agents acting through 5-HT-related pathways have been associated with a number of significant cardiovascular adverse effects, including pulmonary hypertension,^1,2 cardiac arrhythmias,² and cardiac valve abnormalities.^1–4 Evidence for a 5-HT valvulopathy has arisen from a variety of observations, including clinical,^3,4 animal model,⁵ and cell culture investigations.^6,7 Patients with carcinoid syndrome tumors,⁴ others treated with the diet drug combination fenfluramine-phentermine (Fen/Phen),³ and individuals treated with ergot derivatives⁸ have been observed to develop what is most likely a 5-HT valvulopathy with comparable heart valve pathology between these different clinical groupings. In patients with carcinoid syndrome tumors, high 5-HT levels were observed to be associated with fibrodysplasia affecting predominantly the right-side cardiac valves³; a comparable pattern of valve disease was observed in a number of reported patients treated with ergot derivatives.⁸ The reason for this right-side valvulopathy distribution (tricuspid and pulmonary valves) has been hypothetically attributed to pulmonary monoamine oxidase clearance of 5-HT, thereby resulting in left-side cardiac valves being exposed to relatively lower 5-HT levels^1,4 despite elevated systemic 5-HT. However, a recent animal study involving daily injection of 5-HT in rats demonstrated both elevated 5-HT levels and right- and left-side valve abnormalities.⁵

Article p 81

The Fen/Phen valvulopathy has been reported to affect both right- and left-side cardiac valves,³ and this was hypothesized to be due in part to pulmonary monoamine oxidase inhibition by Phen, resulting in increased 5-HT exposure for left-side cardiac valves.¹ However, the mechanisms responsible for the pathogenesis of the cardiac effects of 5-HT are likely linked to interactions involving both 5-HT receptors and the 5-HT transmembrane transporter (5-HTT). This issue of Circulation contains an important study⁹ of 5-HTT-knockout mice with cardiac valvulopathy and myocardial fibrosis that provides novel insights into 5-HT-related heart disease and the importance of 5-HTT in its pathogenesis.

	5-HT Receptor and Transporter Mechanisms

Top Introduction 5-HT Receptor and Transporter... 5-HT Processing, Cardiac... Clinical Implications References

 
5-HT signaling takes place via a plasma membrane receptor system that has at this time at least 15 cognate receptors divided into 7 families, and all but 1 of these are G-protein-coupled receptor superfamilies.² 5-HTT facilitates intracellular processing of 5-HT after receptor interactions.¹⁰ In nonneuronal tissues, 5-HT production is rate limited by tryptophan hydroxylase (Tph1).¹¹ Interestingly, Tph1-knockout mice demonstrate a dilated cardiomyopathy.¹¹ Although 5-HTT is present in embryonic myocardium and cardiac valves, it is not present in mature myocardium but persists in valvular cells.⁹

Because the Fen/Phen diet drug combination was demonstrated to be associated with a cardiac valvulopathy with valve cusp pathology comparable to the carcinoid valvulopathy, it is important to consider the potential contributions of each of these components (Fen/Phen) to the pathogenesis, especially in view of the potential role of 5-HTT in 5-HT valvulopathy.⁹ Fen is known to be both a 5-HT receptor agonist and a substrate for 5-HTT.¹⁰ However, Phen is a monoamine oxidase inhibitor and thus would be expected to delay the breakdown of 5-HT.^1,10 No patients treated with Phen alone have been observed to develop a cardiac valvulopathy¹⁰; however, both Fen/Phen and Fen-alone patients were reported to have developed valve disease.¹⁰ Furthermore, although it was hypothesized that Fen/Phen administration would result in elevation of 5-HT levels, this was never observed in Fen/Phen- or Fen-treated patients.¹⁰ In fact, Fen/Phen lowers 5-HT levels in human subjects.¹⁰ Thus, these prior results suggest that Fen, its metabolites, or 5-HT alone may have contributing mitogenic effects resulting in valvulopathy, and importantly, the processing of 5-HT or Fen via 5-HTT may play a major mechanistic role in 5-HT valvulopathy. Interference with 5-HT processing via knocking out 5-HTT⁹ resulted in valvulopathy in mice; thus, it is possible that because of an absence of transmembrane processing (via knocking out 5-HTT), there are increased and persistent 5-HT receptor interactions in the mice in these studies.⁹ This could result in the increased valvular mitogenic activity and extracellular matrix production noted in the 5-HTT-knockout mice.⁹

	5-HT Processing, Cardiac Valvulopathy, and Cardiomyopathy

Top Introduction 5-HT Receptor and Transporter... 5-HT Processing, Cardiac... Clinical Implications References

 
The 5-HT type 2B receptor (5-HT_2BR) has been demonstrated to be present in aortic valve tissue¹² and has been hypothesized to be the key target of the 5-HT agonists such as Fen and its analogues¹² that have been implicated in the anorexigen valvulopathy cases. However, other 5-HT receptor types have been demonstrated to be present in heart valve cells^7,9,13; thus, the impact of 5-HT on cardiac valve tissue may be both extensive and complex.

It is also of interest that 5-HT-mediated G-protein receptor signal transduction has been shown to result in upregulation of the cytokine TGFß1 in sheep heart valve interstitial cells in culture, followed by both increased production of collagen and glycosaminoglycans.^6,7 5-HTT-knockout mice demonstrated increased collagen accumulation in heart valve leaflets compared with controls,⁹ and human cardiac valve myofibroblasts demonstrated increased collagen production in response to 5-HT administration that was specifically inhibited by a 5-HT type IB/ID receptor inhibitor.⁹ However, 5-HTT-knockout mice also deficient in the 5-HT type IB receptor demonstrated no differences from the 5-HTT-knockout mice in terms of cardiac valve phenotype; both had equivalent valvulopathy, indicating that 5-HT type IB/ID receptor signaling is not critical in these mice.

Although valvular calcification typically has not been seen clinically with 5-HT valvulopathy,^3,4 chondroid metaplasia was present in a number of the cardiac valves from the 5-HTT-knockout mice.⁹ It is possible that the cardiac valve disease observed in these mice may be associated with cellular phenotype changes related to bonelike activity observed by others in pathology studies of human calcific valve disease.¹⁴ Other research has demonstrated that TGFß1-related mechanisms are strongly associated with calcific valve disease¹⁵; thus, TGFß1 mechanisms may be operative in 5-HTT-knockout mice via increased TGFß1 production resulting from sustained increased 5-HT receptor interactions⁶ because of 5-HTT deficiency.⁹

5-HT has been demonstrated in transgenic mouse studies to act on the myocardium via specific receptor pathways. 5-HT_2BR-knockout mice demonstrated diminished numbers of mitochondria and dilated cardiomyopathy.² In contrast, mice overexpressing 5-HT_2BR specifically in heart demonstrated mitochondrial proliferation and myocardial hypertrophy.² The observations of cardiac fibrosis in the 5-HTT-knockout mice⁹ are difficult to interpret in light of the 5-HT_2BR mouse studies.² The 5-HTT-knockout results⁹ may reflect myocardial fibrosis in the setting of heart failure associated with either cardiomyopathy, as a secondary result of significant cardiac valve dysfunction, or both.

	Clinical Implications

Top Introduction 5-HT Receptor and Transporter... 5-HT Processing, Cardiac... Clinical Implications References

 
The impact of 5-HT-related mechanisms on heart disease may be of concern at this time in light of the anorexigen-related clinical reports^1,3 and related experimental observations.^5–9 However, clinical studies since the initial Fen/Phen reports³ have not completely revealed the potential scope of 5-HT-related mechanisms on heart valve disease. A study of 292 patients receiving selective 5-HT-reuptake inhibitors (SSRIs) failed to show an association between use of these agents and cardiac valve abnormalities assessed with echocardiography.¹⁶ Furthermore, estimates of the incidence of valvulopathy in patients receiving Fen-Phen have varied widely, which most likely is due to the limitations of cardiac ultrasound evaluation of valvular function and study design issues.¹⁷ A meta-analysis of the published studies of patients treated with Fen/Phen estimated that 1 in 8 patients receiving these agents for >90 days had valvular disease.¹⁷ However, this investigation also acknowledged a number of limitations, including publication bias, that could have resulted in an overestimation of incidence.¹⁷

It is important to note that 5-HTT polymorphisms have been associated with variable pharmacological responsiveness to SSRIs in patients with psychiatric disorders,¹⁸ and 5-HTT polymorphisms have also been observed to be associated with the penetrance of clinical manifestation in a number of neurological diseases.¹⁹ The 5-HTT-knockout mouse results⁹ indicate that 5-HTT polymorphisms may be of potential interest for investigations of SSRIs and other agents that affect 5-HT metabolism with regard to susceptibility to 5-HT valvulopathy, myocardial disorders, and pulmonary hypertension. Furthermore, the unique responsiveness of heart valve interstitial cells to 5-HT and 5-HT agonists indicates that 5-HT receptor antagonists, agents targeting 5-HTT, and related specific inhibitors of G-protein signaling may merit investigation for treating selected types of heart valve disease.

	Acknowledgments

 
Support from the NHLBI (P50 74731) and the William J. Rashkind Endowment of the Children’s Hospital of Philadelphia is acknowledged. Thanks are due Jennifer LeBold, the Children’s Hospital of Philadelphia, for her assistance in preparing this manuscript.

Disclosures

None.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction 5-HT Receptor and Transporter... 5-HT Processing, Cardiac... Clinical Implications References

 

1. Fishman AP. Aminorex to Fen/Phen: an epidemic foretold. Circulation. 1999; 99: 156–161.[Free Full Text]
   
2. Nebigil CG, Maroteaux L. Functional consequence of serotonin/5-HT2B receptor signaling in heart: role of mitochondria in transition between hypertrophy and heart failure? Circulation. 2003; 108: 902–908.[Free Full Text]
   
3. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997; 337: 581–588.[Abstract/Free Full Text]
   
4. Moller JE, Connolly HM, Rubin J, Seward JB, Modesto K, Pellikka PA. Factors associated with progression of carcinoid heart disease. N Engl J Med. 2003; 348: 1005–1015.[Abstract/Free Full Text]
   
5. Gustafsson BI, Tommeras K, Nordrum I, Loennechen JP, Brunsvik A, Solligard E, Fossmark R, Bakke I, Syversen U, Waldum H. Long-term serotonin administration induces heart valve disease in rats. Circulation. 2005; 111: 1517–1522.[Abstract/Free Full Text]
   
6. Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, Levy RJ. Serotonin mechanisms in heart valve disease, I: serotonin-induced up-regulation of transforming growth factor-ß1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002; 161: 2111–2121.[Abstract/Free Full Text]
   
7. Xu J, Jian B, Chu R, Lu Z, Li Q, Dunlop J, Rosenzweig-Lipson S, McGonigle P, Levy RJ, Liang B. Serotonin mechanisms in heart valve disease, II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. Am J Pathol. 2002; 161: 2209–2218.[Abstract/Free Full Text]
   
8. Horvath J, Fross RD, Kleiner-Fisman G, Lerch R, Stalder H, Liaudat S, Raskoff WJ, Flachsbart KD, Rakowski H, Pache JC, Burkhard PR, Lang AE. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord. 2004; 19: 656–662.[CrossRef][Medline] [Order article via Infotrieve]
   
9. Mekontso-Dessap A, Brouri F, Pascal O, Lechat P, Hanoun N, Lanfumey L, Seif I, Benhaiem-Sigaux N, Kirsch M, Hamon M, Adnot S, Eddahibi S. Deficiency in the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006; 113: 81–89.[Abstract/Free Full Text]
   
10. Rothman RB, Baumann MH. Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther. 2002; 95: 73–88.[CrossRef][Medline] [Order article via Infotrieve]
    
11. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA, Bayard E, Hanoun N, Saurini F, Lechat P, Dandolo L, Hamon M, Mallet J, Vodjdani G. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci U S A. 2003; 100: 13525–13530.[Abstract/Free Full Text]
    
12. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000; 102: 2836–2841.[Abstract/Free Full Text]
    
13. Elangbam CS, Lightfoot RM, Yoon LW, Creech DR, Geske RS, Crumbley CW, Gates LD, Wall HG. 5-Hydroxytryptamine (5HT) receptors in the heart valves of cynomolgus monkeys and Sprague-Dawley rats. J Histochem Cytochem. 2005; 53: 671–677.[Abstract/Free Full Text]
    
14. Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001; 103: 1522–1528.[Abstract/Free Full Text]
    
15. Jian B, Narula N, Li QY, Mohler ER 3rd, Levy RJ. Progression of aortic valve stenosis: TGF-ß1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg. 2003; 75: 457–465;discussion 465–466.[Free Full Text]
    
16. Mast ST, Gersing KR, Anstrom KJ, Krishnan KR, Califf RM, Jollis JG. Association between selective serotonin-reuptake inhibitor therapy and heart valve regurgitation. Am J Cardiol. 2001; 87: 989–993, A4.[CrossRef][Medline] [Order article via Infotrieve]
    
17. Sachdev M, Miller WC, Ryan T, Jollis JG. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J. 2002; 144: 1065–1073.[CrossRef][Medline] [Order article via Infotrieve]
    
18. Serretti A, Benedetti F, Zanardi R, Smeraldi E. The influence of serotonin transporter promoter polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 1074–1084.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005; 77: 265–279.[CrossRef][Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				J. Xu, B. Yao, X. Fan, M. M. Langworthy, M.-Z. Zhang, and R. C. Harris Characterization of a putative intrarenal serotonergic system Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1468 - F1475. [Abstract] [Full Text] [PDF]

				S. Droogmans, P. R. Franken, C. Garbar, C. Weytjens, B. Cosyns, T. Lahoutte, V. Caveliers, M. Pipeleers-Marichal, A. Bossuyt, D. Schoors, et al. In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology Eur. Heart J., September 1, 2007; 28(17): 2156 - 2162. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levy, R. J. Search for Related Content PubMed PubMed Citation Articles by Levy, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Diseases Related Collections Valvular heart disease Receptor pharmacology Animal models of human disease