Heart
Valvular heart disease
Drug induced valvular heart disease (DIVHD)


Topic Completed: 1 December 2014

Revised: 25 February 2019

Copyright: 2014-2019, PathologyOutlines.com, Inc.

PubMed Search: Drug induced valvular heart disease [title]
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Cite this page: Amita R Drug induced valvular heart disease (DIVHD). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/heartDIVHD.html. Accessed March 20th, 2019.
Definition / general
Sites
  • Most frequently affects the aortic and the mitral valves
Pathophysiology
  • 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

Etiology
  • 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
Diagnosis
  • 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
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