Systolic displacement of one or both mitral leaflets into the left atrium, arising from myxomatous remodeling of the leaflet extracellular matrix. It is common - 2.4% of an unselected community population - and in the great majority of those people it is benign, with trace or mild regurgitation and no excess of heart failure, stroke, or arrhythmia. It is also responsible for 7% of sudden cardiac deaths in adults under 40, and 13% of those in young women. Both statements are true, and reconciling them is what this entry is for. There are two distinct diseases inside one echocardiographic finding, and they injure the heart by different routes. The familiar route is haemodynamic: severe regurgitation volume-loads the left ventricle, and outcome tracks the regurgitant orifice area. The other route is mechanical and does not require significant regurgitation at all. Where the leaflet hinge is detached from the ventricular myocardium - mitral annular disjunction - the annulus curls in systole and the prolapsing leaflet drags on the inferobasal wall and papillary muscles. That repeated traction produces regional hypertrophy and fibrosis, and the fibrosis is the arrhythmic substrate. The valve kills through the myocardium, not through the regurgitation, and it does so in patients whose valve lesion would otherwise be called mild. The practical consequence is that the two diseases need different measurements. Grading regurgitation severity is the right question for one and the wrong question for the other.
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name: Mitral Valve Prolapse
creation_date: "2026-08-11T00:00:00Z"
category: Acquired
disease_term:
preferred_term: mitral valve prolapse
term:
id: MONDO:0004910
label: mitral valve prolapse
description: >
Systolic displacement of one or both mitral leaflets into the left atrium,
arising from myxomatous remodeling of the leaflet extracellular matrix. It is
common - 2.4% of an unselected community population - and in the great majority
of those people it is benign, with trace or mild regurgitation and no excess of
heart failure, stroke, or arrhythmia. It is also responsible for 7% of sudden
cardiac deaths in adults under 40, and 13% of those in young women.
Both statements are true, and reconciling them is what this entry is for. There
are two distinct diseases inside one echocardiographic finding, and they injure
the heart by different routes. The familiar route is haemodynamic: severe
regurgitation volume-loads the left ventricle, and outcome tracks the
regurgitant orifice area. The other route is mechanical and does not require
significant regurgitation at all. Where the leaflet hinge is detached from the
ventricular myocardium - mitral annular disjunction - the annulus curls in
systole and the prolapsing leaflet drags on the inferobasal wall and papillary
muscles. That repeated traction produces regional hypertrophy and fibrosis, and
the fibrosis is the arrhythmic substrate. The valve kills through the
myocardium, not through the regurgitation, and it does so in patients whose
valve lesion would otherwise be called mild.
The practical consequence is that the two diseases need different
measurements. Grading regurgitation severity is the right question for one and
the wrong question for the other.
synonyms:
- Barlow's syndrome
- floppy mitral valve
- myxomatous mitral valve disease
notes: >
Scope. This entry covers non-syndromic mitral valve prolapse (MONDO:0004910).
It is deliberately not merged with the numbered familial myxomatous forms
(MONDO:0011915 MMVP2, MONDO:0012569 MMVP3) or with prolapse occurring as a
feature of Marfan syndrome, Ehlers-Danlos syndrome, or other connective-tissue
disorders already curated in this knowledge base. FLNA and DCHS1 are curated
here because both were identified in isolated non-syndromic families, which is
precisely what makes them informative about the common disease.
Deliberate non-conformance to `cardiac_ion_channel_repolarization`. Arrhythmic
mitral valve prolapse superficially fits: ventricular arrhythmia, syncope,
sudden death in young people. But that module is explicitly scoped to
"inherited arrhythmia syndromes in structurally normal hearts", and the whole
point of the arrhythmic MVP literature is that these hearts are not
structurally normal - the substrate is regional myocardial fibrosis
demonstrable at histology and by late gadolinium enhancement. Declaring
conformance would assert a channelopathy mechanism the evidence contradicts.
`fibrotic_response` conformance is declared at the myocardial fibrosis node
only. The module's `Tissue Injury` trigger is instantiated here by repetitive
mechanical traction rather than by chemical or inflammatory injury, which is an
unusual but legitimate substitution; the ECM-deposition effector node is
conserved. It is not declared on the leaflet myxomatous remodeling node, which
is a developmental/degenerative matrix disorder rather than a reparative
fibrotic response - the leaflet accumulates proteoglycan and becomes more
compliant, the opposite of the stiff collagenous scar the module describes.
The 2.4% Framingham prevalence and the 7%/13% sudden-death fractions are not
in tension once the denominators are read: the first is a prevalence in a
community population, the second a proportion of an autopsy series of sudden
deaths in the young. Neither licenses a statement about absolute arrhythmic
risk for an individual with prolapse, and none is made here.
pathophysiology:
- name: Myxomatous Leaflet Remodeling
biological_scale: TISSUE
role: trigger
description: >
The primary lesion. Mitral valve interstitial cells remodel the leaflet
extracellular matrix, producing thickened, redundant, abnormally compliant
leaflets - the myxomatous or "floppy" valve. Leaflet thickness of 5 mm or
more distinguishes classic from non-classic prolapse echocardiographically
and is not a cosmetic distinction: it marks the more substantially remodeled
valve. Myxomatous valve disease is among the commonest indications for
valvular surgery.
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
cell_types:
- preferred_term: mitral valve interstitial cell
term:
id: CL:4030032
label: valve interstitial cell
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: ABNORMAL
evidence:
- reference: PMID:17190868
reference_title: "Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Myxomatous dystrophy of the cardiac valves affects approximately 3% of the
population and remains one of the most common indications for valvular
surgery.
explanation: >-
Establishes myxomatous valve dystrophy as the underlying lesion and its
population and surgical burden.
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Classic mitral-valve prolapse was defined as superior displacement of the
mitral leaflets of more than 2 mm during systole and as a maximal leaflet
thickness of at least 5 mm during diastasis
explanation: >-
Supplies the leaflet-thickness criterion that operationalizes myxomatous
remodeling in the classic phenotype.
downstream:
- target: Systolic Leaflet Prolapse
causal_link_type: DIRECT
description: >-
Redundant, abnormally compliant leaflets billow into the left atrium under
systolic pressure.
- name: Valve Developmental and Cytoskeletal Gene Lesion
biological_scale: MOLECULAR
role: trigger
description: >
Non-syndromic prolapse has a clear heritable component, and two genes
identified in isolated families implicate different layers of valve biology.
FLNA, encoding the actin-crosslinking protein filamin A, causes X-linked
myxomatous valvular dystrophy with complete penetrance in men and incomplete
penetrance in women - a cytoskeletal, mechanotransductive lesion. DCHS1,
the human homologue of the Drosophila planar-cell-polarity gene dachsous,
causes autosomal prolapse through impaired valve interstitial cell migration
and patterning, and the mouse heterozygote traces adult prolapse back to
developmental errors in valve morphogenesis. Together they suggest the adult
valve lesion is in part a developmental one.
genes:
- preferred_term: FLNA
term:
id: hgnc:3754
label: FLNA
- preferred_term: DCHS1
term:
id: hgnc:13681
label: DCHS1
evidence:
- reference: PMID:17190868
reference_title: "Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our data demonstrate that FLNA is the first gene known to cause isolated
nonsyndromic MVD.
explanation: >-
Establishes FLNA as causal for isolated, non-syndromic myxomatous valve
disease - the point that makes it relevant to the common disease rather
than to a syndrome.
- reference: PMID:26258302
reference_title: "Mutations in DCHS1 cause mitral valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report a missense mutation in the DCHS1 gene, the human homologue of the
Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the
family.
explanation: >-
Establishes DCHS1 segregation with non-syndromic prolapse in a
multigenerational family.
- reference: PMID:26258302
reference_title: "Mutations in DCHS1 cause mitral valve prolapse."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be
traced back to developmental errors in valve morphogenesis.
explanation: >-
Supports a developmental origin for the adult leaflet lesion. Evidence
source is MODEL_ORGANISM because the tracing was done in mice.
downstream:
- target: Myxomatous Leaflet Remodeling
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Impaired interstitial cell patterning, migration, and mechanotransduction
yield an abnormally remodeled leaflet matrix.
- name: Systolic Leaflet Prolapse
biological_scale: TISSUE
description: >
Superior displacement of one or both leaflets more than 2 mm past the annular
plane during systole - the defining finding, and the audible midsystolic
click. In the community the prolapsing valve is usually competent or nearly
so: Framingham subjects with prolapse had more regurgitation than those
without, but on average only trace or mild. Bileaflet involvement is
disproportionately represented in the arrhythmic phenotype, being present in
70% of both sudden-death cases and living patients with complex ventricular
arrhythmia.
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The subjects with prolapse were leaner (P<0.001) and had a greater degree
of mitral regurgitation than those without prolapse, but on average the
regurgitation was classified as trace or mild.
explanation: >-
Establishes that prolapse in the community is usually associated with only
trivial regurgitation, which is what separates the anatomic finding from
the haemodynamic disease.
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A bileaflet involvement was found in 70%.
explanation: >-
Quantifies bileaflet involvement in sudden-death cases with prolapse as the
only identified cause.
downstream:
- target: Mitral Regurgitation and Left Ventricular Volume Overload
causal_link_type: DIRECT
description: >-
Failure of leaflet coaptation permits systolic regurgitation into the left
atrium. This branch dominates in a minority of patients.
- target: Mechanical Traction on Papillary Muscles and Inferobasal Wall
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Excessive leaflet excursion transmits repetitive tension to the subvalvular
apparatus and adjacent myocardium. This branch does not require
haemodynamically significant regurgitation.
hypothesis_groups:
- mechanical_traction_arrhythmogenesis
- name: Mitral Annular Disjunction and Systolic Curling
biological_scale: TISSUE
description: >
A structural abnormality of the valve hinge rather than of the leaflet: the
atrial wall-mitral valve junction is displaced away from the ventricular
myocardium, so the annulus is not anchored where it should be. In systole the
disjointed posterior annulus curls toward the atrium instead of descending
with the ventricle. Disjunction is a constant feature of arrhythmic prolapse
with ventricular fibrosis - median 4.8 mm versus 1.8 mm in prolapse without
fibrosis - and the degree of disjunction correlates tightly with the degree
of curling. It is what converts leaflet excursion into myocardial traction,
and it can be measured directly.
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
evidence:
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mitral annulus disjunction is a constant feature of arrhythmic MVP with LV
fibrosis.
explanation: >-
States the central claim of this node in the authors' own terms.
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mitral annulus disjunction (median: 4.8 versus 1.8 mm; P<0.001)
explanation: >-
Quantifies the difference in disjunction between prolapse with and without
ventricular fibrosis.
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A linear correlation was found between mitral annulus disjunction and
curling (R=0.85).
explanation: >-
Links the anatomic abnormality to the abnormal systolic motion through
which it acts, which is what makes this a mechanism rather than an
association.
downstream:
- target: Mechanical Traction on Papillary Muscles and Inferobasal Wall
causal_link_type: DIRECT
description: >-
Curling of the unanchored annulus transmits leaflet excursion to the
inferobasal wall as repetitive stretch.
hypothesis_groups:
- mechanical_traction_arrhythmogenesis
- name: Mechanical Traction on Papillary Muscles and Inferobasal Wall
biological_scale: TISSUE
description: >
The mechanistic pivot of the arrhythmic phenotype. Excessive leaflet mobility
combined with an unanchored, curling annulus applies repetitive systolic
stretch to the inferobasal left ventricular wall and the papillary muscles.
The regional distribution of the resulting injury is the signature: fibrosis
appears exactly where the traction is applied, not diffusely, and not where
ischaemia or a cardiomyopathy would put it. Crucially, this operates in
patients with no or trivial mitral regurgitation, so it is not a consequence
of volume loading.
locations:
- preferred_term: papillary muscle of heart
term:
id: UBERON:0002494
label: papillary muscle of heart
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
cell_types:
- preferred_term: cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: cellular response to mechanical stimulus
term:
id: GO:0071260
label: cellular response to mechanical stimulus
modifier: INCREASED
evidence:
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The excessive mobility of the leaflets caused by posterior systolic curling
accounts for a mechanical stretch of the inferobasal wall and papillary
muscles, eventually leading to myocardial hypertrophy and scarring.
explanation: >-
States the traction-to-scarring mechanism this node encodes.
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
arrhythmic MVP patients with LV late gadolinium enhancement on cardiac
magnetic resonance and no or trivial mitral regurgitation
explanation: >-
The decisive control: the cohort in which this mechanism was demonstrated
had no haemodynamically significant regurgitation, so the myocardial injury
cannot be attributed to volume overload.
downstream:
- target: Regional Left Ventricular Fibrosis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Repetitive mechanical stretch drives regional myocardial hypertrophy and
replacement fibrosis.
hypothesis_groups:
- mechanical_traction_arrhythmogenesis
- name: Regional Left Ventricular Fibrosis
biological_scale: TISSUE
conforms_to: "fibrotic_response#Excessive ECM Deposition"
description: >
Fibrosis of the papillary muscles and the inferobasal left ventricular wall -
found at histology in every one of the sudden-death cases in which prolapse
was the only identified cause, and at the papillary muscles in all of them.
In living patients with complex ventricular arrhythmia the same distribution
appears as late gadolinium enhancement in 93%, against 14% of prolapse
controls. The correspondence between the autopsy and imaging distributions is
what makes this a substrate rather than an epiphenomenon, and what makes it
detectable before the arrhythmia rather than after it.
This node conforms to the extracellular-matrix-deposition effector of the
`fibrotic_response` module with mechanical traction substituted for the
module's usual chemical or inflammatory tissue injury.
locations:
- preferred_term: papillary muscle of heart
term:
id: UBERON:0002494
label: papillary muscle of heart
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
cell_types:
- preferred_term: cardiac fibroblast
term:
id: CL:0002548
label: fibroblast of cardiac tissue
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: INCREASED
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Left ventricular fibrosis was detected at histology at the level of
papillary muscles in all patients, and inferobasal wall in 88%.
explanation: >-
Establishes the fibrosis and its regional distribution at autopsy in
sudden-death cases where prolapse was the only cause found.
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Left ventricular late enhancement was identified by contrast-enhanced
cardiac magnetic resonance in 93% of patients versus 14% of control
subjects (P<0.001), with a regional distribution overlapping the
histopathology findings in SCD cases.
explanation: >-
The in vivo counterpart with the same regional distribution, which is what
converts an autopsy finding into a detectable antemortem substrate.
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Fibrosis of the papillary muscles and inferobasal left ventricular wall,
suggesting a myocardial stretch by the prolapsing leaflet, is the
structural hallmark and correlates with ventricular arrhythmias origin.
explanation: >-
Directly attributes the fibrosis to leaflet-mediated myocardial stretch and
ties it to arrhythmia origin.
downstream:
- target: Ventricular Electrical Instability and Sudden Cardiac Death
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Regional scar and hypertrophy provide the reentrant substrate on which
triggered beats degenerate into malignant ventricular arrhythmia.
hypothesis_groups:
- mechanical_traction_arrhythmogenesis
- name: Ventricular Electrical Instability and Sudden Cardiac Death
biological_scale: ORGANISM
description: >
Malignant ventricular arrhythmia in prolapse appears to need both halves of
the classical substrate-plus-trigger pair. The substrate is the regional
hypertrophy and fibrosis together with surviving Purkinje tissue; the trigger
is mechanical stretch eliciting premature ventricular beats, documented
arising from Purkinje tissue in patients with aborted sudden death. Prolapse
accounts for 7% of sudden cardiac deaths in adults aged 40 or under and 13%
of those in young women, and the electrocardiographic signature points back
at the anatomy: inverted inferior T waves in 83% of cases with an available
tracing, and right bundle-branch block morphology arrhythmias in all of them,
consistent with a left ventricular inferobasal origin.
locations:
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
cell_types:
- preferred_term: Purkinje myocyte
term:
id: CL:0002068
label: Purkinje myocyte
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Forty-three patients with MVP (26 females; age range, 19-40 years; median,
32 years) were identified (7% of all SCD, 13% of women).
explanation: >-
Quantifies the contribution of prolapse to sudden cardiac death in a young
autopsy registry, and its striking female predominance.
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among 12 cases with available ECG, 10 (83%) had inverted T waves on
inferior leads, and all had right bundle-branch block ventricular
arrhythmias.
explanation: >-
The electrocardiographic signature localizing the arrhythmia to the same
inferobasal territory as the fibrosis.
- reference: PMID:31498700
reference_title: "Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The genesis of malignant ventricular arrhythmias in MVP probably recognizes
the combination of the substrate (regional myocardial hypertrophy and
fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting
premature ventricular beats because of a primary morphofunctional
abnormality of the mitral valve annulus.
explanation: >-
States the substrate-plus-trigger model this node encodes. Evidence source
is OTHER because this is a review.
- name: Mitral Regurgitation and Left Ventricular Volume Overload
biological_scale: ORGANISM
description: >
The haemodynamic route, and the one that dominates the surgical literature.
Failure of coaptation regurgitates a fraction of stroke volume into the left
atrium; the ventricle compensates by dilating. Outcome is graded by the
effective regurgitant orifice area rather than by symptoms: in asymptomatic
patients followed for a median of 26 years, five-year survival under medical
management fell from 88% with an orifice below 20 mm2 to 55% at 40 mm2 or
above, with risk rising continuously rather than at a threshold. This is a
different disease from the arrhythmic one, in a different population, and it
is measured differently.
locations:
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
evidence:
- reference: PMID:42525396
reference_title: "Twenty-Five-Year Follow-Up of Quantified Mitral Regurgitation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Survival of medically treated patients declined progressively with
increasing ERO category (5-year rate: 88%
explanation: >-
Establishes regurgitant orifice area as the graded determinant of survival
under medical management.
- reference: PMID:42525396
reference_title: "Twenty-Five-Year Follow-Up of Quantified Mitral Regurgitation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
increasing ERO was associated with an increase in risk of mortality under
medical therapy.
explanation: >-
States the continuous relationship between regurgitation severity and
mortality.
- reference: PMID:26258302
reference_title: "Mutations in DCHS1 cause mitral valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It can manifest as mitral regurgitation and is the leading indication for
mitral valve surgery.
explanation: >-
Supports regurgitation as the manifestation that drives surgical
intervention.
downstream:
- target: Heart Failure
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Sustained volume overload eventually exceeds ventricular compensation.
- name: Heart Failure
biological_scale: ORGANISM
description: >
Decompensation of the volume-loaded ventricle. Notably absent from the
community phenotype: no subject with prolapse in the Framingham offspring
cohort had a history of heart failure, which is the clearest single statement
of how rarely uncomplicated prolapse progresses this far.
locations:
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
None of the subjects with prolapse had a history of heart failure
explanation: >-
Bounds the frequency of this outcome in a community population, which is
what keeps the entry honest about the benignity of the common phenotype.
phenotypes:
- category: Cardiovascular
name: Mitral Valve Prolapse
description: >
Systolic displacement of one or both mitral leaflets more than 2 mm above the
annular plane, the defining finding.
phenotype_term:
preferred_term: Mitral valve prolapse
term:
id: HP:0001634
label: Mitral valve prolapse
frequency: OBLIGATE
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A total of 84 subjects (2.4 percent) had mitral-valve prolapse: 47 (1.3
percent) had classic prolapse, and 37 (1.1 percent) had nonclassic
prolapse.
explanation: >-
Establishes the finding and its community prevalence with the
classic/non-classic split.
- category: Cardiovascular
name: Mitral Regurgitation
description: >
Systolic regurgitation into the left atrium. Usually trace or mild in the
community; severe in the minority who come to surgery.
phenotype_term:
preferred_term: Mitral regurgitation
term:
id: HP:0001653
label: Mitral regurgitation
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
had a greater degree of mitral regurgitation than those without prolapse,
but on average the regurgitation was classified as trace or mild.
explanation: >-
Establishes that regurgitation is greater in prolapse than without it, and
pins its usual severity as trace or mild. No proportion of affected
patients is reported, so no frequency band is asserted.
- category: Cardiovascular
name: Myocardial Fibrosis
description: >
Regional fibrosis of the papillary muscles and inferobasal left ventricular
wall, detectable as late gadolinium enhancement, marking the arrhythmic
phenotype.
phenotype_term:
preferred_term: Myocardial fibrosis
term:
id: HP:0001685
label: Myocardial fibrosis
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Left ventricular fibrosis was detected at histology at the level of
papillary muscles in all patients, and inferobasal wall in 88%.
explanation: >-
Histological documentation of the fibrosis phenotype and its distribution.
- category: Cardiovascular
name: Ventricular Arrhythmia
description: >
Complex ventricular arrhythmia, characteristically of right bundle-branch
block morphology consistent with a left ventricular inferobasal origin.
phenotype_term:
preferred_term: Ventricular arrhythmia
term:
id: HP:0004308
label: Ventricular arrhythmia
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all had right bundle-branch block ventricular arrhythmias.
explanation: >-
Documents the arrhythmia and its morphology in sudden-death cases with an
available tracing.
- category: Cardiovascular
name: Premature Ventricular Contraction
description: >
Premature ventricular beats, documented arising from Purkinje tissue and
acting as the trigger for ventricular fibrillation in patients with aborted
sudden death.
phenotype_term:
preferred_term: Premature ventricular contraction
term:
id: HP:0006682
label: Premature ventricular contraction
evidence:
- reference: PMID:31498700
reference_title: "Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
premature ventricular beats arising from the Purkinje tissue as ventricular
fibrillation triggers have been documented by electrophysiologic studies in
MVP patients with aborted sudden death.
explanation: >-
Documents the trigger and its Purkinje origin. Evidence source is OTHER
because this is a review.
- category: Cardiovascular
name: Sudden Cardiac Death
description: >
Arrhythmic sudden death, disproportionately affecting young women, and
occurring in patients whose valve lesion may be haemodynamically mild.
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MVP is an underestimated cause of arrhythmic SCD, mostly in young adult
women.
explanation: >-
States the outcome and its demographic skew.
- category: Cardiovascular
name: Syncope
description: >
Transient loss of consciousness, present in a small minority in the
community and of different significance when it accompanies documented
ventricular arrhythmia.
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
frequency: VERY_RARE
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
three (3.6 percent) had syncope, as compared with unadjusted prevalences of
these findings in the subjects without prolapse of 0.7, 1.7, 1.5, and 3.0
percent, respectively.
explanation: >-
Quantifies syncope in prolapse against the background rate in the same
cohort - the comparison is what shows it is barely raised.
- category: Cardiovascular
name: Congestive Heart Failure
description: >
End-stage consequence of chronic volume overload from severe regurgitation;
absent from the uncomplicated community phenotype.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
frequency: VERY_RARE
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
None of the subjects with prolapse had a history of heart failure
explanation: >-
None of the 84 community subjects with prolapse had heart failure, placing
it under the <5% VERY_RARE ceiling in unselected prolapse. The cases that
do occur come from the severe-regurgitation minority, not the community
phenotype this cohort samples.
mechanistic_hypotheses:
- hypothesis_group_id: mechanical_traction_arrhythmogenesis
hypothesis_label: Leaflet traction-induced myocardial fibrosis
status: CANONICAL
description: >
Arrhythmic risk in mitral valve prolapse is generated by mechanical traction
rather than by regurgitation. An unanchored, curling annulus converts
excessive leaflet excursion into repetitive stretch of the papillary muscles
and inferobasal wall, which scars; the scar plus surviving Purkinje tissue is
the substrate, and stretch-elicited premature beats are the trigger.
The hypothesis makes three predictions, all of which have been met: the
fibrosis should be regional and confined to the traction territory, it should
be present in patients with no significant regurgitation, and annular
disjunction should be measurable and should correlate with curling. Its most
important untested prediction is therapeutic - that abolishing the traction
should abolish the substrate's progression.
evidence:
- reference: PMID:27516479
reference_title: "Morphofunctional Abnormalities of Mitral Annulus and Arrhythmic Mitral Valve Prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The excessive mobility of the leaflets caused by posterior systolic curling
accounts for a mechanical stretch of the inferobasal wall and papillary
muscles, eventually leading to myocardial hypertrophy and scarring.
explanation: >-
States the hypothesis in the terms curated here.
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MVP may present with ventricular arrhythmias and sudden cardiac death (SCD)
even in the absence of hemodynamic impairment.
explanation: >-
The observation the hypothesis exists to explain, and the reason a
regurgitation-based account cannot be sufficient.
treatments:
- name: Mitral Valve Repair
description: >
Surgical reconstruction of the mitral valve and its annulus, the preferred
intervention for severe degenerative regurgitation and the operation the
surgical literature is built on. Whether it also abolishes arrhythmic risk in
prolapse without significant regurgitation is a separate and unresolved
question.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: mitral valve repair
term:
id: NCIT:C80449
label: Mitral Valve Repair
target_mechanisms:
- target: Mitral Regurgitation and Left Ventricular Volume Overload
treatment_effect: INHIBITS
description: >-
Restoring leaflet coaptation abolishes the regurgitant volume and the
ventricular volume load.
evidence:
- reference: PMID:42525396
reference_title: "Twenty-Five-Year Follow-Up of Quantified Mitral Regurgitation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients with upper-moderate MR (ERO 30-39 mm2) at baseline demonstrated a
significant association between surgical treatment and improved long-term
survival.
explanation: >-
Supports a survival benefit of surgery, and locates the severity threshold
at which it becomes demonstrable.
- name: Transcatheter Edge-to-Edge Repair
description: >
Catheter-delivered leaflet approximation, avoiding sternotomy and
cardiopulmonary bypass. In degenerative disease it achieves less complete
abolition of regurgitation than surgery and is associated with worse
long-term survival, so current evidence does not support it as a substitute
where surgery is feasible.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: transcatheter mitral valve repair
term:
id: NCIT:C158019
label: Transcatheter Mitral Valve Repair
target_mechanisms:
- target: Mitral Regurgitation and Left Ventricular Volume Overload
treatment_effect: INHIBITS
description: >-
Leaflet approximation reduces the regurgitant orifice, though less
completely than surgical repair.
evidence:
- reference: PMID:42008639
reference_title: "Comparative Outcomes of Transcatheter Edge-to-Edge Repair and Surgical Mitral Valve Repair or Replacement for Degenerative Mitral Regurgitation: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although TEER is associated with a lower risk of septicemia and may reduce
the risk of new-onset AF, hospital stay, and ICU stay, current evidence
doesn't support the use of TEER as a substitute for surgery
explanation: >-
Supports procedural advantages while explicitly declining to support
substitution for surgery, which is why this is graded PARTIAL rather than
SUPPORT.
- reference: PMID:42008639
reference_title: "Comparative Outcomes of Transcatheter Edge-to-Edge Repair and Surgical Mitral Valve Repair or Replacement for Degenerative Mitral Regurgitation: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
TEER was associated with a significantly lower rate of postoperative MR
grade 0 (RR 0.20, 95% CI: 0.08-0.49), and significantly higher rates of MR
grades 2 (RR 4.82, 95% CI: 1.87-12.40), 3 (RR 8.39, 95% CI: 3.69-19.09),
and 4 (RR 4.20, 95% CI: 1.45-12.18), indicating inferior MR resolution.
explanation: >-
Refutes equivalence of transcatheter repair to surgery on the
mechanistically relevant endpoint, abolition of the regurgitation, with the
grade-by-grade distribution that establishes it.
- reference: PMID:42008639
reference_title: "Comparative Outcomes of Transcatheter Edge-to-Edge Repair and Surgical Mitral Valve Repair or Replacement for Degenerative Mitral Regurgitation: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Survival at ≥ 2-year follow-up was significantly favored in the surgery
group (RR 0.72, 95%
explanation: >-
Refutes equivalence on survival at two years or more.
discussions:
- discussion_id: mvp_arrhythmic_risk_stratification
kind: KNOWLEDGE_GAP
attaches_to:
- "pathophysiology#Regional Left Ventricular Fibrosis"
- "pathophysiology#Ventricular Electrical Instability and Sudden Cardiac Death"
prompt: >
Which patients with mitral valve prolapse should be investigated for
arrhythmic risk, and what should be done for those found to be at risk?
rationale: >
The mechanism is now well enough characterized to name the features that
travel with arrhythmic prolapse - bileaflet involvement, annular disjunction,
systolic curling, inferobasal and papillary late gadolinium enhancement,
inverted inferior T waves, a midsystolic click. What is missing is anything
that turns those features into a decision. The absolute risk conferred by
each is unknown because the denominators come from autopsy series and
referral cohorts rather than from a population followed prospectively, and
prolapse is far too common - 2.4% of the population - for a feature with a
small positive predictive value to be actionable. Nor is it known whether
valve surgery, catheter ablation, or a defibrillator modifies the outcome.
The consequence is a mechanism understood well enough to worry patients and
not well enough to guide them.
proposed_experiments:
- experiment_id: exp_mvp_prospective_cmr_cohort
name: Prospective population-based cohort with cardiac magnetic resonance phenotyping
description: >-
Enrol an unselected population-based cohort with echocardiographic prolapse
and characterize annular disjunction, curling, leaflet involvement, and
late gadolinium enhancement at baseline, then follow prospectively for
arrhythmic events. This supplies the denominator that autopsy registries
and referral cohorts structurally cannot, and is the only design that can
convert the identified features into absolute risks.
- experiment_id: exp_mvp_intervention_on_traction
name: Test whether abolishing leaflet traction halts progression of the arrhythmic substrate
description: >-
In patients with arrhythmic prolapse undergoing mitral valve surgery for an
independent indication, measure late gadolinium enhancement burden and
arrhythmia before and serially after operation. If the traction hypothesis
is correct, correcting annular and leaflet mechanics should arrest
progression of the fibrotic substrate; no change would indicate the scar,
once established, is autonomous.
- discussion_id: mvp_two_diseases_one_finding
kind: OPEN_QUESTION
attaches_to:
- "pathophysiology#Systolic Leaflet Prolapse"
prompt: >
Are haemodynamic and arrhythmic mitral valve prolapse one disease with two
outcomes, or two diseases sharing an echocardiographic finding?
rationale: >
They differ in almost everything measurable. The arrhythmic phenotype is
female-predominant, presents in the third and fourth decades, and occurs with
no or trivial regurgitation; the haemodynamic phenotype in the quantified
surgical cohorts is male-predominant, presents decades later, and is graded
entirely by regurgitant orifice area. The structural correlates differ too -
annular disjunction and curling versus leaflet flail and coaptation failure.
Whether a single myxomatous process yields both depending on where the
remodeling falls, or whether annular disjunction is a distinct developmental
abnormality that merely co-occurs with prolapse, is unsettled, and it
determines whether an entry like this one should eventually be split.
genetic:
- name: FLNA
gene_term:
preferred_term: FLNA
term:
id: hgnc:3754
label: FLNA
relationship_type: CAUSATIVE
notes: >
Missense mutations and an exon 16-19 deletion in FLNA cause X-linked
myxomatous valvular dystrophy, with complete penetrance in men and incomplete,
variable expression in women.
evidence:
- reference: PMID:17190868
reference_title: "Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among carriers of FLNA mutation, the penetrance of the disease was complete
in men and incomplete in women.
explanation: >-
Documents the X-linked penetrance pattern, which is what distinguishes this
from the autosomal forms.
- name: DCHS1
gene_term:
preferred_term: DCHS1
term:
id: hgnc:13681
label: DCHS1
relationship_type: CAUSATIVE
notes: >
Deleterious DCHS1 mutations segregate with non-syndromic prolapse in three
families and reduce protein stability in zebrafish, cultured cells, and
patient-derived mitral valve interstitial cells.
evidence:
- reference: PMID:26258302
reference_title: "Mutations in DCHS1 cause mitral valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Further genetic studies identified two additional families in which a second
deleterious DCHS1 mutation segregates with MVP.
explanation: >-
Independent segregation in additional families, which is what raises DCHS1
from a single-family finding to a causal gene.
epidemiology:
- name: Community prevalence of mitral valve prolapse
description: >
In the Framingham offspring cohort assessed by two-dimensional
echocardiography, 2.4% had prolapse - lower than earlier reports - with 1.3%
classic and 1.1% non-classic.
evidence:
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In a community based sample of the population, the prevalence of
mitral-valve prolapse was lower than previously reported.
explanation: >-
States the community prevalence finding and its correction of earlier
referral-based estimates.
- reference: PMID:10387935
reference_title: "Prevalence and clinical outcome of mitral-valve prolapse."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The prevalence of adverse sequelae commonly associated with mitral-valve
prolapse in studies of patients referred for that diagnosis was also low.
explanation: >-
The referral-bias correction that underlies this entry's separation of the
benign community phenotype from the arrhythmic one.
- name: Contribution to sudden cardiac death in young adults
description: >
In a cardiac pathology registry of 650 sudden cardiac deaths in adults aged
40 or under, prolapse was the only identified cause in 7% overall and 13% of
women.
evidence:
- reference: PMID:26160859
reference_title: "Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The cardiac pathology registry of 650 young adults (≤40 years of age) with
SCD was reviewed, and cases with MVP as the only cause of SCD were
re-examined.
explanation: >-
Describes the registry and the exclusion criterion that makes the 7% and
13% figures attributable to prolapse rather than merely co-occurring
with it.