Drug-induced valvular heart disease (DIVHD) are conditions involving changes in the morphology and functionality of valvular leaflets secondary to exposure to various types of medications. DIVHD is mainly diagnosed by echocardiographic changes in the population at risk and was first associated with ergot alkaloids in the mid-1960s after echocardiographic changes were found in patients using these types of medications. It has been well documented that these medications produce the proliferation of valvular interstitial cells and subsequent insufficiency of the heart valves by stimulating 5-HT2B receptors.
Several medications have been related to DIVHD. In 1967, anti-migraine drugs such as ergotamine and methysergide were associated with valvular insufficiency.
In 2002, pergolide and cabergoline, used for the treatment of Parkinson disease and hyperprolactinemia, were also related to valvular changes among their users.
Anorexigens such as fenfluramine, dexfenfluramine, and phentermine, developed to suppress appetite and achieve weight reduction in obese patients, were also linked with human valvulopathies in several studies.
MDMA (3,4-methylenedioxymethamphetamine, commonly known as ecstasy), a substance that acts as a serotonin-norepinephrine-dopamine releasing agent and mainly used as a recreational drug, was linked to valvular insufficiency in 2007. Development of valvulopathy was reported in eight (28%) people in the study who took MDMA, an average of 3.6 tablets of MDMA per week for 6 years compared to none in the control group. A correlation was observed between the dose of MDMA and severity of valvulopathy.
The prevalence of DIVHD varies considerably between studies for the same group of medications.
Anorexigen use has been suggested to be linked to different degrees of valvulopathy, with prevalence ranging from 6% to 30% in various studies. A study conducted with 233 anorexic users and their matched control subjects showed that 22.7% of the anorexic group had cardiac valve abnormalities versus 1.3% of the control group.
Patients taking pergolide and cabergoline have an increased risk of valvular regurgitation compared to users of other dopamine agonists. A study conducted in 2007 showed an increased risk of valvular regurgitation of up to 23.4% in patients using pergolide and up to 28.65% in patients using cabergoline compared to users of agonists such as pramipexole and ropinirole. In 2007, another study exposed an increased incidence of valvular regurgitation of 7.1 fold in the group using pergolide and 4.9 fold in the group using cabergoline when they were compared with a group of patients using other dopamine agonists as ropinirole, pramipexole, bromocriptine, and lisuride.
In 1967, Graham published a study with 36 patients treated with methysergide who developed mitral and/or aortic regurgitation with the use of this medication. Then, in 1974, ergotamine was also shown to be associated with left-sided valvular heart disease for the first time.
Droogmans et al. conducted a study where 29 subjects using or having used MDMA and 29 gender and age-matched controls were blindly evaluated with echocardiography. Eight subjects (28%) who took MDMA had significant valvular regurgitation on echocardiographic results.
Normal heart valves are formed by two main types of cells: valvular endothelial cells (VECs) mainly covering the valve surfaces and valvular interstitial cells (VICs) that are located deeper than the VECs. It has been demonstrated that VICs have serotonin receptors and tumor growth factor beta receptor (TGFBR) on their plasma membrane.
Anorexigens (fenfluramine, dexfenfluramine, and their active metabolite norfenfluramine), dopamine agonists (pergolide and cabergoline), MDMA, ergot alkaloids (ergotamine, methysergide, and its active metabolite methylergonovine) are partial to full agonists of 5-hydroxytryptamine 2B receptors (5-HT2BR).
Activation of 5-HT2BR has a different mechanism from which increases the activation of transcription factors in the nucleus of the VICs, therefore, producing proliferation, resulting in valvulopathy.
One of the mechanisms by which 5-HT2BR activation produce VICs proliferation is by dissociation of guanine nucleotide regulatory proteins (G-proteins). The release of G-proteins leads to the activation of phospholipase-c beta with a subsequent calcium mobilization and diacylglycerol (DAG) release. Increased release of DAG will activate protein kinase C, which can by itself increase nuclear transcription factors (i.e., produce proliferation) or activate nuclear transcription factors by triggering cytoplasmic extracellular-regulated kinases 1 and 2.
SRC (proto-oncogene c-Src) can also be phosphorylated by G- proteins, activating the nuclear transcription factor or TGFB-1. The activation of TGFB-1 subsequently produces a complex formed by SMAD2, SMAD 3 and SMAD4 (which are intracellular proteins). This complex will enter into the nucleus and upregulate transcription factors and then will produce the proliferation of VICs.
This mechanism is described to be very similar to the valvulopathies produced by carcinoid disease.
Microscopic examination of tissue affected by DIVHD typically a proliferation of myxoid matrix with an irregular disposition of the vascular, interstitial cells and myofibroblasts, creating encased leaflets and chordal structures without identifiable disruption of the valves.
Patients’ symptoms will depend on the grade of valvular regurgitation and can include dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, and others. On physical examination, patients may exhibit significant cardiac murmurs.
An echocardiogram is the best tool to screen for DIVHD. Most of the time, DIVHD is not associated with symptoms. The FDA criterion for significant drug-induced heart valve regurgitation is mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation.
Usually these findings are associated with restricted valve motion, affecting predominantly the posterior leaflet in mitral valve regurgitation; however, less frequently the condition can affect the anterior mitral leaflet as well. In aortic regurgitation, variable degrees of leaflet retraction has been described as being responsible for this valve insufficiency. Both valves are associated with mild to moderate valve thickening in the absence of calcification of marked commissural fusion. Tricuspid and pulmonary DIVHDs are less common, but echocardiographic changes are similar to those seen in the mitral and aortic valve. DIVHD has not been related to valvular stenosis.
The grade of regurgitation will determine treatment, but in general, most patients experience improvements in the grade of valve regurgitation by discontinuing the medication causing the condition. However, some patients require surgical valve replacement even after years of medication cessation.
In September 1997, both fenfluramine and dexfenfluramine were withdrawn from the United States (US) market.
Pergolide was withdrawn from the US market in August 2007 because of its association with increased risk for valvulopathy.
Although rarely used now because of their adverse effects, methysergide and ergotamine remain licensed for migraine prophylaxis.