Dose Dependency and Reversibility of Serotonin-Induced Valvular Heart Disease in Rats

Abstract

Serotonergic drugs may lead to valvular heart disease in humans and more recently also in rats. Although clinical data suggest that dose dependency and reversibility after drug cessation might occur, proof of this is lacking. For that purpose, a total of 106 rats were prospectively enrolled: 22 control animals and 7 groups of 12 rats that received daily subcutaneous serotonin injections (5, 10, 20, 30, 40, 50 and 60 mg/kg respectively) for 12 weeks. At 12 weeks, half of the animals of each group were killed for histological analysis, whereas the remaining rats were further followed (without serotonin injections) for an additional 8 weeks. After 12 weeks of serotonin treatment, aortic and mitral regurgitation (AR, MR) were more frequently observed in the high dose groups (>30 mg/kg) compared to controls. Moreover, aortic and mitral valves were also thicker in the high dose groups compared to controls. After 8 weeks free of serotonin injections, AR and MR were no longer significantly higher than controls. Moreover, aortic and mitral valve thickness had normalized, returning to control levels. In conclusion, this study provides evidence for a dose-dependent valvular toxicity of serotonergic drugs, which appears to be reversible after drug withdrawal.

Signaling pathways in mitral valve degeneration

“…18 Morphologically and functionally similar valvulopathy occurs in rats undergoing long-term serotonin injections. 36,37 Several drugs, including fenfluramine (with or without phenteramine) and ergot-derived drugs such as pergolide, are implicated in valvular heart disease, with the mitral valve being most commonly affected. 38e41 Evidence now strongly implicates specific activation of the serotonin 2B receptor (5HT 2B R) as the unifying mechanism for serotoninergic valvulopathy.…”

Integrated Backscatter for the In Vivo Quantification of Supraphysiological Vitamin D3-Induced Cardiovascular Calcifications in Rats

“…As previously reported [13], fractional area change (FAC) was calculated by using the LV cross-sectional area at end diastole (LVAd) and at end systole (LVAs), with the fol- For quantification of cardiovascular calcifications, we characterized the tissue by analyzing the IB of tissue Doppler ultrasound reflectivity [14,15]. IB values were calculated automatically from the average power of the ultrasound backscattered signal [4].…”

Case Report: Reversible cabergoline-associated cardiac valvulopathy post drug discontinuation

“…Although there are reports of reversibility of valvulopathy with other DAs 19 , this is the first case of reversal of valvular abnormalities after stopping cabergoline treatment in a patient with a prolactin-secreting adenoma. It is unclear if the risk of cardiac valvulopathy is associated with a high cumulative dose 19 or is gender related 20 .…”

“…In a rodent model, 12 weeks of serotonin injections induced both aortic and mitral regurgitation. Eight weeks after cessation of serotonin injections, the prevalence of valvulopathy was no longer higher than control and valvular thickness returned to baseline 19 . In 50 patients previously given fenfluramine or dexfenfluramine, valvular regurgitation in 17 of the 38 (45%) patients with mitral regurgitation and 19 of the 43 (44%) patients with aortic regurgitation improved after stopping the drug 12 .…”

“…It is unclear if the risk of cardiac valvulopathy is associated with a high cumulative dose 19 or is gender related 20 . However, this case highlights the potential reversibility of mild valvulopathy associated with cabergoline therapy if treatment is discontinued prior to the onset of severe structural abnormalities.…”