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Review
. 2009 May;8(3):317-29.
doi: 10.1517/14740330902931524.

Serotonergic drugs and valvular heart disease

Richard B Rothman  1 , Michael H Baumann
Affiliations
Review

Serotonergic drugs and valvular heart disease

Richard B Rothman et al. Expert Opin Drug Saf. 2009 May.

Abstract

Background: The serotonin (5-HT) releasers (+/-)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the '5-HT hypothesis') suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease.

Objective: Here, we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease.

Methods: Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations.

Conclusions: The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT(2B) receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT(2B) agonist activity.

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Figures

Figure 1
Figure 1
Dose-response effects of (+)-fenfluramine on extracellular levels of 5-HT, NE and DA in rat frontal cortex. Rats undergoing in vivo microdialysis sampling received i.v. injections of 1.0 and 3.0 mg/kg (+)-fenfluramine at time zero and 60 min, respectively. Dialysate samples were collected at 20 min intervals and immediately assayed for 5-HT, NE and DA. Data are peak effects measured 20 min after drug injection, expressed as mean ± SEM for N=6 rats. 5-HT levels are normalized to % of preinjection baseline. * = P<0.05 with respect to preinjection control. Figure modified from .
Figure 2
Figure 2
Dose-response effects of (+)-norfenfluramine on extracellular levels of 5-HT, NE and DA in rat frontal cortex. Rats undergoing in vivo microdialysis sampling received i.v. injections of 1.0 and 3.0 mg/kg (+)-norfenfluramine at time zero and 60 min. Dialysate samples were collected at 20 min intervals and immediately assayed for 5-HT, NE and DA. Data are peak effects measured 20 min after drug injection, expressed as mean ± SEM for N=6 rats. 5-HT levels are normalized to % of preinjection baseline. * = P<0.05 with respect to preinjection control. Figure modified from .
Figure 3
Figure 3
Effects of amphetamine analogs and fluoxetine on dialysate 5-HT levels measured in blood from conscious rats. Drug or saline vehicle was administered i.v. at time zero. Serial blood samples were withdrawn at 15 min intervals and dialyzed ex vivo. Dialysate samples were assayed for 5-HT. Data are peak effects measured in the first sample after drug injection, expressed as mean ± SEM for N=6 rats/group. 5-HT levels are normalized to % of preinjection baseline. * = P<0.05 compared to saline controls. Figure modified from .
Figure 4
Figure 4
Acute in vivo effects of (±)-fenfluramine on dialysate 5-HT levels measured in blood from conscious rats previously treated with chronic administration of (±)-fenfluramine (fen) or fluoxetine (fluox). For chronic treatments, drugs were dissolved in saline (fen) or 50% ethanol/saline (fluox), and administered s.c. via osmotic minipumps for 2 weeks. On day 14, fenfluramine was dissolved in saline and administered i.v. at 0 min. Serial blood samples were withdrawn at 15 min intervals and immediately dialyzed. Data are mean ± SEM for N=9 rats/group. For Baseline effects, 5-HT levels are normalized to % of vehicle control groups. For acute fenfluramine challenge effects, 5-HT data are peak effects measured 15 min postinjection expressed % of preinjection baseline. * = P<0.05 compared to saline-pretreated controls. Figure modified from .
Figure 5
Figure 5
Effects of chronic administration of (±)-fenfluramine (fen) and fluoxetine (fluox) on whole blood 5-HT levels measured 7 and 13 days after minipump implantation. Drugs were dissolved in saline (fen) or 50% ethanol/saline (fluox), and administered s.c. via osmotic minipumps for 2 weeks. Blood samples were withdrawn via indwelling jugular catheters and serum 5-HT was measured using double-antibody RIA methods. Data are mean ± SEM for N=9 rats/group expressed as % of vehicle control values. * = P<0.05 compared to saline or ethanol/saline controls at corresponding time points. Figure modified from .
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