Heart & vascular pathology
Valvular disease
Drug induced valvular heart disease
Author: R. Amita, M.D.
Last author update: 1 December 2014
Last staff update: 31 December 2020
Copyright: 2014-2024, PathologyOutlines.com, Inc.
PubMed Search: Drug induced valvular heart disease [title]
Table of Contents
Definition / general | Sites | Pathophysiology | Diagrams / tables | Etiology | Diagnosis | Radiology description | Prognostic factors | Case reports | Gross description | Microscopic (histologic) images | Differential diagnosis | Additional referencesCite this page: Amita R. Drug induced valvular heart disease. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/heartDIVHD.html. Accessed December 18th, 2024.
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
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
Images hosted on other servers:
5HT signaling pathways
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
- Proven restrictive valvular heard disease (confirmed with histopathology and / or regression after interruption of ergot treatment)
- Important restrictive valve disease (regurgitation > 2/4) or restrictive tricuspid disease, even with regurgitation less than 2/4
- Mild to moderate (regurgitation < 2/4) restrictive valve disease
- No restrictive valve dysfunction
Prognostic factors
- Older age
- Higher diastolic blood pressure
- Drug dosage
- Duration
- Severity of valvular abnormalities
Case reports
- 52 year old woman with methysergide induced heart disease (Circulation 1977;56:889)
- Serotonergic drugs and valvular heart disease (Expert Opin Drug Saf 2009;8:317)
- Benfluorex and drug induced valvular heart disease (Eur J Echocardiogr 2011;12:263)
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
Images hosted on other servers:
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
Additional references
