Valvular heart disease
Drug induced valvular heart disease (DIVHD)

Author: R. Amita, M.D. (see Authors page)

Revised: 19 March 2018, last major update December 2014

Copyright: (c) 2014-2018, PathologyOutlines.com, Inc.

PubMed Search: Drug induced valvular heart disease [title]

Cite this page: Amita, R. Drug induced valvular heart disease (DIVHD). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/heartDIVHD.html. Accessed April 22nd, 2018.
Definition / general
  • Drug induced valvular heart disease (DIVHD) was first described in the 1960s (Heart 2013;99:7), often due to fenfluramine (Wikipedia: Fenfluramine [Accessed 2 March 2018]), phentermine (Wikipedia: Phentermine [Accessed 2 March 2018]) and benfluorex (Wikipedia: Benfluorex [Accessed 2 March 2018])
  • DIHVD is defined echocardiographically as abnormal thickening of valve leaflets or cusps, resulting in a restrictive motion in the absence of carcinoid syndrome, left ventricular remodelling (due to ischemic valve involvement), rheumatic heart disease, Libman-Sacks endocarditis and congenital abnormalities
  • Sites
    • Most frequently affects the aortic and the mitral valves
    • The serotonin 2B (5-HT2B) receptor is the culprit receptor
    • Stimulation of this receptor leads to the upregulation of target genes involved in the proliferation and stimulation of valvular interstitial cells through different intracellular pathways
    • These involve G protein mediated activation of protein kinase C, Src protein and extracellular regulated kinases 1 and 2 (ERK 1/2)
    • Transforming growth factor b (TGF-b) receptor activation is also involved in this process
    • Although both fenfluramine and phentermine lack 5-HT2B agonistic properties, norfenfluramine, the primary metabolite of fenfluramine and a metabolite of benfluorex, is a potent 5-HT2B agonist
    • 5-HT2B agonist effect is also found for pergolide, cabergoline, MDMA, ergotamine and methylergonovine, a metabolite of methysergide
    • The net valvulopathic effect is dependent on the 5-HT2B activity of the parent drug, and on the pharmacodynamic effects of their metabolites (Heart 2013;99:7)
    Diagrams / tables

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    5HT signaling pathways

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    Heart chambers, valves, and valvular histology

    • Ergot alkaloids (such as methysergide and ergotamine)
    • Ergot derived dopaminergic agonists (such as pergolide and cabergoline)
    • Drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and benfluorex)
    • Drugs for Parkinson disease, hyperprolactinemia
    • 3,4 methylendioxymetamphetamine (MDMA, 'Ecstasy'), guanfacine, oxymetazoline, quinidine, xylometazoline and fenoldapam
    • Echocardiography, with high spatial and temporal resolution, is the standard approach used in the diagnosis of DIVHD
    Radiology description
    • Echo:
      • In mitral disease, both the leaflets and the subvalvular apparatus may be affected
      • The leaflets are thickened, show reduced mobility and are more retracted towards the apex during systole (leaflet tenting) resulting in valve regurgitation
      • An affected aortic valve is characterised by systolic doming of the thickened leaflets with reduced mobility and incomplete diastolic coaptation which causes regurgitation
    • Score 1 to 4: from very likely to unlikely
      1. Proven restrictive valvular heard disease (confirmed with histopathology and / or regression after interruption of ergot treatment)
      2. Important restrictive valve disease (regurgitation > 2/4) or restrictive tricuspid disease, even with regurgitation less than 2/4
      3. Mild to moderate (regurgitation < 2/4) restrictive valve disease
      4. No restrictive valve dysfunction
    Prognostic factors
    • Older age
    • Higher diastolic blood pressure
    • Drug dosage
    • Duration
    • Severity of valvular abnormalities
    Case reports
    Gross description
    • In mitral and tricuspid valve disease, a prominent subvalvular disease with thickening and shortening of the chordae tendinae and leaflet tethering with malcoaptation contributes to the regurgitation
    • For the aortic valve, cusp thickening with doming and regurgitation is typically present without aortic root dilatation
    • Macroscopically, the valves and tendinous chords are both thickened and shortened and may have a shiny white appearance
    • Thickening of the valvular surface and subvalvular apparatus occurs by formation of fibromyxoid plaques
    • Calcification is not usually part of this process
    Microscopic (histologic) images

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    Mitral valve leaflets, Movat pentachrome stain

    Differential diagnosis
    • Other causes of restrictive valve motion need to be ruled out when diagnosing DIVHD:
      • Left ventricle remodelling (i.e. ischemic MR)
      • Rheumatic VHD: absence of commissural fusion and calcifications are helpful in differentiating when concomitant valve obstruction is absent
      • Carcinoid VHD
      • Libman-Sacks (antiphospholipid syndrome) endocarditis
      • Congenital abnormalities