PKP2-related arrhythmogenic cardiomyopathy is the most common genetic form of arrhythmogenic right ventricular cardiomyopathy (ARVC), caused by loss-of-function mutations in PKP2 encoding the desmosomal protein plakophilin-2. PKP2 mutations account for approximately 40-50% of ARVC cases and up to 70% of familial ARVC. The disease is characterized by progressive fibrofatty replacement of right ventricular myocardium, ventricular arrhythmias, and risk of sudden cardiac death, particularly in young athletes. Inheritance is autosomal dominant with incomplete penetrance. While PKP2 variants have been reported in association with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and dilated cardiomyopathy phenotypes, these associations remain disputed and the definitive gene-disease relationship is with ARVC.
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name: PKP2_Cardiomyopathy
creation_date: '2026-04-04T00:00:00Z'
updated_date: '2026-04-07T02:27:09Z'
description: >-
PKP2-related arrhythmogenic cardiomyopathy is the most common genetic form of
arrhythmogenic right ventricular cardiomyopathy (ARVC), caused by loss-of-function
mutations in PKP2 encoding the desmosomal protein plakophilin-2. PKP2 mutations
account for approximately 40-50% of ARVC cases and up to 70% of familial ARVC.
The disease is characterized by progressive fibrofatty replacement of right
ventricular myocardium, ventricular arrhythmias, and risk of sudden cardiac death,
particularly in young athletes. Inheritance is autosomal dominant with incomplete
penetrance. While PKP2 variants have been reported in association with Brugada
syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and
dilated cardiomyopathy phenotypes, these associations remain disputed and the
definitive gene-disease relationship is with ARVC.
category: Genetic
synonyms:
- ARVC9
- arrhythmogenic right ventricular dysplasia 9
- PKP2-related ARVC
- plakophilin-2 cardiomyopathy
disease_term:
preferred_term: arrhythmogenic right ventricular dysplasia 9
term:
id: MONDO:0012180
label: arrhythmogenic right ventricular dysplasia 9
parents:
- Cardiovascular Disease
- Genetic Disorder
prevalence:
- population: Global
notes: >-
Estimated prevalence of ARVC overall is 1:2000 to 1:5000 globally.
PKP2 mutations account for approximately 40-50% of ARVC cases.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
description: >-
Incomplete penetrance is characteristic. In two kindreds with ARVC,
disease was incompletely penetrant in most carriers of PKP2 mutations.
genetic:
- name: PKP2 Loss-of-Function Variants
gene_term:
preferred_term: PKP2
term:
id: hgnc:9024
label: PKP2
association: Causative
inheritance:
- name: Autosomal dominant
features: >
Heterozygous loss-of-function mutations in PKP2 (plakophilin-2) are the
most common genetic cause of ARVC, identified in approximately 43-50% of
patients fulfilling Task Force Criteria. Mutation types include frameshift,
nonsense, splicing, and missense variants. The PKP2 C-terminus has been
identified as a potential functional domain. Truncating variants likely
cause disease irrespective of transcript position.
evidence:
- reference: PMID:15489853
reference_title: "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In 32 of 120 unrelated individuals with ARVC, we identified heterozygous
mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat
protein of the cardiac desmosome.
explanation: First identification of PKP2 mutations as a common cause of ARVC.
- reference: PMID:16567567
reference_title: "Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2
mutations were identified.
explanation: Establishes PKP2 mutations in 43% of ARVC patients fulfilling Task Force Criteria.
- reference: PMID:34120153
reference_title: "The genetic architecture of Plakophilin 2 cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identify the PKP2 C-terminus as a potential functional domain and find
that truncating variants likely cause disease irrespective of transcript
position.
explanation: Large multicohort study demonstrating near-complete specificity of PKP2 truncating variants for ARVC and identifying the C-terminus as a functional domain.
- reference: PMID:34191271
reference_title: "Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in
PKP2 were found in 28 (50%) cases.
explanation: Polish ARVC cohort confirming 50% prevalence of PKP2 variants with characterization of mutation types.
pathophysiology:
- name: Desmosomal Disruption
description: >-
Loss-of-function mutations in PKP2 destabilize the cardiac desmosome,
the principal cell-cell adhesion structure at cardiomyocyte intercalated
discs. Plakophilin-2 normally links desmosomal cadherins to the intermediate
filament cytoskeleton. Loss of PKP2 causes failure of mechanical coupling
between cardiomyocytes, particularly under conditions of hemodynamic stress.
genes:
- preferred_term: PKP2
term:
id: hgnc:9024
label: PKP2
molecular_functions:
- preferred_term: cadherin binding
term:
id: GO:0045296
label: cadherin binding
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: cell-cell adhesion
term:
id: GO:0098609
label: cell-cell adhesion
locations:
- preferred_term: heart right ventricle
term:
id: UBERON:0002080
label: heart right ventricle
evidence:
- reference: PMID:15489853
reference_title: "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In 32 of 120 unrelated individuals with ARVC, we identified heterozygous
mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat
protein of the cardiac desmosome.
explanation: Identifies PKP2 as an essential desmosomal protein whose mutations cause ARVC.
downstream:
- target: Wnt/Beta-Catenin Signaling Suppression
description: Disrupted desmosomes release plakoglobin to the nucleus where it competitively suppresses canonical Wnt signaling
- target: Gap Junction Remodeling
description: Loss of desmosomal integrity causes secondary loss of connexin43 gap junction plaques
- target: Fibrofatty Replacement
description: Mechanical uncoupling leads to cardiomyocyte detachment and death
- name: Wnt/Beta-Catenin Signaling Suppression
description: >-
Desmosomal disruption causes nuclear translocation of plakoglobin, which
competitively inhibits beta-catenin-mediated canonical Wnt signaling through
Tcf/Lef1 transcription factors. Suppression of Wnt signaling upregulates
adipogenic and fibrogenic gene expression programs, driving the characteristic
fibrofatty replacement of myocardium.
biological_processes:
- preferred_term: Wnt signaling pathway
term:
id: GO:0016055
label: Wnt signaling pathway
modifier: DECREASED
- preferred_term: fat cell differentiation
term:
id: GO:0045444
label: fat cell differentiation
modifier: INCREASED
evidence:
- reference: PMID:16823493
reference_title: "Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
suppression of DP expression leads to nuclear localization of the
desmosomal protein plakoglobin and a 2-fold reduction in canonical
Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The
ensuing phenotype is increased expression of adipogenic and fibrogenic
genes and accumulation of fat droplets.
explanation: Demonstrates that desmosomal disruption causes Wnt suppression via nuclear plakoglobin, leading to adipogenesis and fibrosis.
downstream:
- target: Fibrofatty Replacement
description: Suppressed Wnt signaling activates adipogenic transcription programs
- name: Gap Junction Remodeling
description: >-
Loss of PKP2 leads to secondary reduction in connexin43 (Cx43)
expression and abnormal localization at intercalated discs. Gap junction
loss impairs electrical coupling between cardiomyocytes, creating
the arrhythmogenic substrate that precedes structural disease.
biological_processes:
- preferred_term: gap junction assembly
term:
id: GO:0016264
label: gap junction assembly
modifier: DECREASED
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
evidence:
- reference: PMID:18662195
reference_title: "Abnormal connexin43 in arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Reduced connexin43 expression and localization to the intercalated disk
occurs in heterozygous human PKP-2 mutations, potentially explaining the
delayed conduction and propensity to develop arrhythmias seen in this disease.
explanation: Direct human biopsy evidence of reduced Cx43 expression in PKP2 mutation carriers.
downstream:
- target: Ventricular Arrhythmias
description: Impaired electrical coupling creates slow conduction and re-entrant circuits
- name: Fibrofatty Replacement
description: >-
Progressive replacement of right ventricular myocardium with fibroadipocytic
tissue is the pathological hallmark of PKP2-related ARVC. This results
from cardiomyocyte death due to mechanical uncoupling, combined with
Wnt-suppression-driven adipogenic differentiation of cardiac progenitor
cells. The right ventricle is preferentially affected due to its thinner
wall and greater mechanical stress.
cell_types:
- preferred_term: fibroblast of cardiac tissue
term:
id: CL:0002548
label: fibroblast of cardiac tissue
- preferred_term: adipocyte
term:
id: CL:0000136
label: adipocyte
locations:
- preferred_term: heart right ventricle
term:
id: UBERON:0002080
label: heart right ventricle
- preferred_term: myocardium
term:
id: UBERON:0002349
label: myocardium
evidence:
- reference: PMID:16823493
reference_title: "Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis
in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and
ventricular arrhythmias, thus recapitulating the phenotype of human ARVC.
explanation: Mouse model demonstrates fibrofatty replacement and arrhythmias recapitulating human ARVC.
downstream:
- target: Ventricular Arrhythmias
description: Fibrofatty tissue creates substrate for re-entrant arrhythmias
- target: Right Ventricular Dysfunction
- name: Ventricular Arrhythmias
description: >-
Ventricular tachycardia and ventricular fibrillation arise from the
combined effects of gap junction remodeling (electrical uncoupling)
and fibrofatty replacement creating re-entrant circuits. Arrhythmias
may occur in the concealed phase before overt structural disease,
driven by electrical remodeling alone.
evidence:
- reference: PMID:15489853
reference_title: "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with
fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias
and sudden cardiac death.
explanation: Establishes the association of ARVC with ventricular tachyarrhythmias and sudden cardiac death.
downstream:
- target: Sudden Cardiac Death
- name: Right Ventricular Dysfunction
description: >-
Progressive fibrofatty replacement of the right ventricular wall leads to
right ventricular dilatation, wall motion abnormalities, and eventual
right heart failure. Some patients also develop left ventricular
involvement, though PKP2 mutation carriers are less likely to develop
left ventricular damage than non-PKP2 ARVC.
locations:
- preferred_term: heart right ventricle
term:
id: UBERON:0002080
label: heart right ventricle
evidence:
- reference: PMID:34191271
reference_title: "Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ARVC patients with PKP2 mutation are less likely to present left
ventricular involvement and heart failure symptoms.
explanation: PKP2 carriers show predominantly right ventricular phenotype with relative sparing of left ventricle.
- name: Sudden Cardiac Death
description: >-
Sudden cardiac death from ventricular fibrillation is the most feared
complication, particularly affecting young athletes. Exercise increases
right ventricular wall stress and accelerates disease progression, explaining
the strong association between vigorous exercise and sudden death in ARVC.
evidence:
- reference: PMID:15489853
reference_title: "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with
fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias
and sudden cardiac death.
explanation: ARVC is explicitly associated with sudden cardiac death.
phenotypes:
- category: Cardiovascular
name: Ventricular Tachycardia
description: >-
Monomorphic ventricular tachycardia, typically with left bundle branch
block morphology originating from the right ventricle, is a hallmark
presentation.
phenotype_term:
preferred_term: Ventricular tachycardia
term:
id: HP:0004756
label: Ventricular tachycardia
evidence:
- reference: PMID:15489853
reference_title: "Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with
fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias
and sudden cardiac death.
explanation: Directly establishes the association of PKP2-related ARVC with ventricular tachyarrhythmias.
- category: Cardiovascular
name: Right Ventricular Dilatation
description: >-
Progressive right ventricular dilatation with regional wall motion
abnormalities is a major diagnostic criterion for ARVC.
phenotype_term:
preferred_term: Right ventricular dilatation
term:
id: HP:0005133
label: Right ventricular dilatation
- category: Cardiovascular
name: Fibrofatty Replacement of RV Myocardium
description: >-
Histological hallmark of ARVC showing replacement of right ventricular
cardiomyocytes with fibroadipocytic tissue.
phenotype_term:
preferred_term: Fibrofatty replacement of right ventricular myocardium
term:
id: HP:0034364
label: Fibrofatty replacement of right ventricular myocardium
- category: Cardiovascular
name: Sudden Cardiac Death
description: >-
Leading cause of mortality, especially in young athletes during exercise.
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
- category: Cardiovascular
name: T-wave Inversion
description: >-
T-wave inversion in right precordial leads (V1-V3) is a major ECG
criterion and occurs more frequently in PKP2 mutation carriers.
phenotype_term:
preferred_term: T-wave inversion
term:
id: HP:0010872
label: T-wave inversion
evidence:
- reference: PMID:16567567
reference_title: "Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
negative T waves in V(2) and V(3) occurred more often in PKP2 mutation
carriers (P<0.05).
explanation: T-wave inversions in V2-V3 are significantly more common in PKP2 mutation carriers.
- category: Cardiovascular
name: Syncope
description: >-
Episodes of syncope due to ventricular arrhythmias are a common presenting
symptom.
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
- category: Cardiovascular
name: Palpitations
description: >-
Palpitations from ventricular ectopy or sustained tachycardia are frequent
symptoms.
phenotype_term:
preferred_term: Palpitations
term:
id: HP:0001962
label: Palpitations
- category: Cardiovascular
name: Congestive Heart Failure
description: >-
End-stage disease may progress to biventricular heart failure requiring
transplantation. PKP2 mutation carriers are less likely to develop heart
failure than non-PKP2 ARVC patients.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: PMID:34191271
reference_title: "Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003),
more often had negative T waves in V1-V3 (p = 0.01), had higher left
ventricular ejection fraction (p = 0.04), and were less likely to present
symptoms of heart failure (p = 0.01)
explanation: PKP2 carriers have better preserved LV function and lower heart failure rates.
- category: Cardiovascular
name: Right Ventricular Cardiomyopathy
description: >-
The primary structural phenotype affecting the right ventricle.
phenotype_term:
preferred_term: Right ventricular cardiomyopathy
term:
id: HP:0011663
label: Right ventricular cardiomyopathy
treatments:
- name: Beta-Blocker Therapy
description: >-
Beta-blockers (sotalol, metoprolol) are first-line antiarrhythmic therapy
to suppress ventricular arrhythmias and reduce adrenergic stimulation.
treatment_term:
preferred_term: beta-blocker pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Implantable Cardioverter-Defibrillator
description: >-
ICD implantation is the primary intervention for prevention of sudden
cardiac death in high-risk patients with ARVC, including those with
sustained ventricular arrhythmias, syncope, or significant RV dysfunction.
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: MAXO:0000004
label: surgical procedure
- name: Exercise Restriction
description: >-
Avoidance of competitive and high-intensity endurance exercise is recommended
as vigorous exercise accelerates disease progression by increasing right
ventricular wall stress and promoting desmosomal disruption.
treatment_term:
preferred_term: avoid excessive exercise
term:
id: MAXO:0000802
label: avoid excessive exercise
- name: Antiarrhythmic Drug Therapy
description: >-
Antiarrhythmic agents (amiodarone, flecainide) may be used adjunctively
for suppression of ventricular arrhythmias when beta-blockers are
insufficient.
treatment_term:
preferred_term: antiarrhythmic pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Heart Transplantation
description: >-
Cardiac transplantation is indicated for end-stage biventricular failure
refractory to medical therapy. Combined endpoint of death or heart
transplant was less frequent in PKP2 carriers than non-PKP2 ARVC patients.
treatment_term:
preferred_term: heart transplantation
term:
id: MAXO:0010039
label: organ transplantation
evidence:
- reference: PMID:34191271
reference_title: "Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Combined endpoint of death or heart transplant was more frequent in
subgroup without PKP2 mutation (p = 0.03).
explanation: PKP2 carriers have better survival and lower transplant rates.
notes: >-
This entry covers 4 Gene2Phenotype (G2P) rows for PKP2: the definitive
association with ARVC, and disputed associations with Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia (CPVT), and dilated
cardiomyopathy. PKP2 missense mutations have been reported to produce a
Brugada-syndrome-like phenotype via sodium channel dysfunction, but this
association remains controversial and is not considered a definitive
gene-disease relationship. Similarly, rare reports of PKP2 variants in
CPVT and DCM phenotypes exist but lack definitive evidence for causality.
PKP2 cardiomyopathy refers to arrhythmogenic cardiomyopathy (ACM) driven by pathogenic variants in PKP2 (plakophilin-2), the most commonly implicated desmosomal gene in classical right-dominant ACM/ARVC. Disease is characterized by ventricular arrhythmias and progressive fibro-fatty myocardial replacement, with highly variable penetrance influenced by sex and environmental factors (notably endurance/competitive exercise). 2023–2024 research emphasizes (i) refined phenotyping by CMR/strain/ECG, (ii) immune, metabolic, and mechanotransduction pathways beyond “desmosome failure,” and (iii) rapid translation of AAV-mediated PKP2 gene replacement from preclinical studies into first-in-human phase 1/2 trials. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2, bos2023thearrhythmogeniccardiomyopathy pages 4-6, chua2023understandingarrhythmogeniccardiomyopathy pages 6-8, mundisugih2024exploringthetherapeutic pages 2-4, NCT06976606 chunk 1)
Arrhythmogenic cardiomyopathy is a heart-muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by progressive dystrophy of ventricular myocardium with fibro-fatty replacement. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2)
Abstract quote (disease definition): “Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement.” (Pilichou et al., 2016) (pilichou2016arrhythmogeniccardiomyopathy pages 1-2)
PKP2 cardiomyopathy (often termed PKP2-ACM) is the desmosomal ACM subtype caused by pathogenic PKP2 variants, typically with right-ventricular predominance but with clinically relevant left-ventricular involvement in a subset. (bos2023thearrhythmogeniccardiomyopathy pages 1-3, bos2023thearrhythmogeniccardiomyopathy pages 4-6)
Primary cause: germline pathogenic variants in PKP2, which encodes plakophilin-2, an intercalated disc/desmosome component critical for cardiomyocyte mechanical and electrical coupling. Mechanism is frequently consistent with haploinsufficiency for truncating/splice variants. (hylind2022populationprevalenceof pages 5-7, vencato2024animalmodelsand pages 2-4)
No robust protective genetic variants or protective exposures were identified in the retrieved evidence set. Observationally, many PKP2 truncating-variant carriers in population cohorts do not develop clinically manifest ARVC, implying that additional protective or countervailing factors exist but are not yet well-defined. (hylind2022populationprevalenceof pages 5-7)
A key contemporary concept is that PKP2 loss-of-function creates susceptibility, while environmental stressors (notably endurance exercise) interact with the desmosome/intercalated disc to trigger arrhythmias and structural progression. (pilichou2016arrhythmogeniccardiomyopathy pages 2-3, hylind2022populationprevalenceof pages 5-7)
ACM may present from a concealed phase to overt electrical disorder to RV failure and ultimately biventricular failure; sudden death can occur at any stage. (pilichou2016arrhythmogeniccardiomyopathy pages 3-5)
Abstract quote (clinical variability): “Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation.” (Vencato et al., 2024) (vencato2024animalmodelsand pages 5-7)
A cross-study quantitative summary is provided below.
| Study (year, journal) | Population / variant | N | Key phenotype stats | Key diagnostic findings | Notes |
|---|---|---|---|---|---|
| Bos et al. (2023, Netherlands Heart Journal) | Heterozygous PKP2 c.1211dup (p.Val406Serfs*4) founder-variant carriers | 106 analyzed carriers | 44% diagnosed with ACM/ARVC at mean age 41 y; by end of follow-up 27% had sustained VA and 11% developed HF; 46% had RV dilatation/dysfunction and 37% had some LV involvement; by age 40, sustained VA in 33% of men vs 9% of women; HF by age 60 21% men vs 8% women; SCA mainly in males (7 males vs 1 female) (bos2023thearrhythmogeniccardiomyopathy pages 4-6, bos2023thearrhythmogeniccardiomyopathy pages 1-3) | Ambulatory monitoring: 34% had PVC burden >1% (median 2.6%); imaging showed RV involvement common, with LV LGE in ~33% of appropriately imaged carriers; probands vs relatives had more RV dilatation/dysfunction on CMR (e.g., RV dilatation 95% vs 38%, RV dysfunction 89% vs 32%) (bos2023thearrhythmogeniccardiomyopathy pages 4-6, bos2023thearrhythmogeniccardiomyopathy pages 3-4) | Typical right-dominant PKP2-ACM but with appreciable LV involvement; beta-blockers in 45%, ICD in 33%; ~60% remained asymptomatic by age 60 (bos2023thearrhythmogeniccardiomyopathy pages 4-6, bos2023thearrhythmogeniccardiomyopathy pages 1-3) |
| Hylind et al. (2022, Circulation: Genomic and Precision Medicine) | UK Biobank carriers of PKP2 truncating variants (PKP2tv) | 190 UKB carriers with PKP2tv | Manifest ARVC features in only 1.6%; cohort mean age 57 y vs symptomatic ARVC onset around 33 y in clinical cohorts; very low observed disease association overall (reported OR 0.047 for ARVC across PKP2tv seen in both cohorts) (hylind2022populationprevalenceof pages 5-7) | No detailed ECG/CMR rates in snippet; molecular evidence supports haploinsufficiency with plakophilin-2 reduced to ~50% in myocardium; AF noted as more common in UKB PKP2tv carriers (hylind2022populationprevalenceof pages 5-7) | Strong evidence for incomplete penetrance and need for additional genetic/environmental modifiers; example splice acceptor c.2146-1G>C seen in 46 UKB carriers but only 1 manifest ARVC case (hylind2022populationprevalenceof pages 5-7) |
| Robles-Mezcua et al. (2023, Genes) | Málaga founder cohort with PKP2 p.Glu259Glyfs*77 | 47 subjects total; 24 variant carriers and 8 index families described | Mean diagnosis age 48.9 ± 18.6 y; arrhythmic presentation 21.5% and arrhythmic events during follow-up 20.9%; HF onset in 25%; 8.3% underwent VT ablation; 8.3% received appropriate ICD therapy; 1 patient required heart transplant; no significant sex differences in follow-up events, though women diagnosed younger (48.4 ± 17.3 y) (roblesmezcua2023thenovelvariant pages 6-9) | Specific ECG/CMR metrics not provided in snippet; patients were followed in HF/ICD unit and diagnosed using NGS plus clinical ACM evaluation (roblesmezcua2023thenovelvariant pages 10-12, roblesmezcua2023thenovelvariant pages 6-9) | Variant interpreted as pathogenic truncating PKP2 change with incomplete penetrance, variable expressivity, and probable regional founder effect; most affected carriers reportedly >55 y (roblesmezcua2023thenovelvariant pages 10-12, roblesmezcua2023thenovelvariant pages 6-9) |
| Aljehani et al. (2023, BMC Cardiovascular Disorders) | Tertiary inherited-cardiac-clinic cohort with suspected ARVC; includes desmosomal-positive cases such as PKP2 | 165 at-risk; 60 definite ARVC; 105 non-definite | Definite ARVC patients more symptomatic: palpitations 57% vs 17%, syncope 35% vs 6%, dyspnea 28% vs 5%; sustained VT 27% vs 2%; VF 13% in definite group only; 38/60 (72%) definite cases carried a pathogenic variant (aljehani2023characterisationofpatients pages 1-2) | T-wave inversion V1–V3 and epsilon waves seen only in definite group; longer PR (170 ± 34 ms) and QRS (100 ± 19 ms) than non-definite (149 ± 25 ms, 91 ± 14 ms); larger RVEDA (27 ± 10 cm²), lower RVFAC (37 ± 11%) and LVEF (56 ± 12%) vs non-definite (18 ± 4 cm², 49 ± 6%, 64 ± 7%) (aljehani2023characterisationofpatients pages 1-2) | Not PKP2-specific, but useful clinical comparator for phenotype severity and diagnostic yield in real-world ARVC assessment (aljehani2023characterisationofpatients pages 1-2) |
| Casian et al. (2024, Polish Heart Journal) | Illustrative ARVC case with likely pathogenic PKP2 c.1034+1G>C plus DSP VUS | 1 case | Qualitative phenotype: definite ARVC supported by structural and electrical abnormalities; sustained/complex ventricular arrhythmias prompted primary-prevention ICD decision-making in narrative case (casian2024arrhythmogenicrightventricular pages 9-10, casian2024arrhythmogenicrightventricular pages 3-5) | ECG: anterior T-wave inversion V3–V4, epsilon waves V3–V4; Holter: frequent PVCs 3% / ~3,500 ectopics per 24 h; strain echo: RV free-wall strain −17.8% with abnormal post-systolic shortening; CMR: RVEDVi 110 mL/m², RVEF 44%, RV free-wall dyskinesia (casian2024arrhythmogenicrightventricular pages 9-10) | Highlights contemporary deep phenotyping, cascade testing, sports restriction, and serial follow-up for PKP2-associated disease with variable penetrance (casian2024arrhythmogenicrightventricular pages 9-10, casian2024arrhythmogenicrightventricular pages 3-5) |
Table: This table summarizes quantitative phenotype and diagnostic findings for PKP2-related arrhythmogenic cardiomyopathy across key recent cohorts and one illustrative case. It is useful for comparing penetrance, arrhythmic burden, heart failure risk, sex effects, and the ECG/CMR/Holter features most often reported.
Below are practical HPO mappings for a PKP2-ACM knowledge base (frequencies vary by cohort; use study-specific frequencies where given): * Ventricular tachycardia / ventricular fibrillation → HP:0001663 (Ventricular tachycardia), HP:0001662 (Ventricular fibrillation) (Bos: sustained VA 27%) (bos2023thearrhythmogeniccardiomyopathy pages 1-3) * Premature ventricular contractions (PVCs) → HP:0011705 (Premature ventricular contractions) (Bos: PVC burden >1% in 34%) (bos2023thearrhythmogeniccardiomyopathy pages 4-6) * Syncope → HP:0001279 (Syncope) (Aljehani: 35% definite ARVC; Bos: 12% at presentation) (aljehani2023characterisationofpatients pages 1-2, bos2023thearrhythmogeniccardiomyopathy pages 4-6) * Palpitations → HP:0001962 (Palpitations) (Aljehani: 57% definite ARVC) (aljehani2023characterisationofpatients pages 1-2) * Sudden cardiac arrest → HP:0001699 (Sudden death) / HP:0001645 (Sudden cardiac death) (Bos: SCA enriched in males) (bos2023thearrhythmogeniccardiomyopathy pages 4-6) * Right ventricular dilatation/dysfunction → HP:0001698 (Dilated right ventricle), HP:0033688 (Right ventricular systolic dysfunction) (Bos: 46% RV dilatation/dysfunction) (bos2023thearrhythmogeniccardiomyopathy pages 1-3) * Left ventricular involvement / fibrosis (CMR LGE) → HP:0005162 (Abnormal left ventricular function), HP:0034332 (Myocardial fibrosis) (Bos: LV involvement 37%; LV LGE ~33% among imaged) (bos2023thearrhythmogeniccardiomyopathy pages 4-6) * Heart failure → HP:0001635 (Congestive heart failure) (Bos: 11%; Robles-Mezcua: 25%) (bos2023thearrhythmogeniccardiomyopathy pages 1-3, roblesmezcua2023thenovelvariant pages 6-9) * ECG epsilon waves → (HPO does not consistently include epsilon wave as a standalone term; represent as ECG abnormality HP:0011712 with note) (Aljehani; Casian) (aljehani2023characterisationofpatients pages 1-2, casian2024arrhythmogenicrightventricular pages 9-10)
While disease-specific EQ-5D/SF-36 metrics were not retrieved here, clinical impacts are implied by syncope, ICD implantation, arrhythmia burden, and progression to HF/transplant in a subset. (bos2023thearrhythmogeniccardiomyopathy pages 4-6, roblesmezcua2023thenovelvariant pages 6-9)
Variant interpretation standards referenced in clinical genetics include ACMG/AMP variant classification and periodic re-evaluation of VUS. (roblesmezcua2023thenovelvariant pages 10-12, casian2024arrhythmogenicrightventricular pages 9-10)
In UK Biobank, PKP2 truncating variants were present in 193/200,643 (0.10%), but ARVC features were present in only ~1.6%, illustrating a major penetrance gap between population genomics and clinically ascertained cohorts. (hylind2022populationprevalenceof pages 5-7)
The strongest, repeatedly emphasized environmental factor in ACM is vigorous/endurance exercise, which can trigger electrical instability and accelerate phenotypic expression; therefore, sports restriction is commonly incorporated into management. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2, pilichou2016arrhythmogeniccardiomyopathy pages 2-3)
Infectious triggers are not established as primary causes, though myocarditis-like presentations and inflammatory infiltrates are reported in ACM and may be part of the pathobiology in subsets. (pilichou2016arrhythmogeniccardiomyopathy pages 2-3, pilichou2016arrhythmogeniccardiomyopathy pages 3-5)
A synthesis of recent mechanistic work supports a multi-axis causal chain:
Primary anatomical sites: * Heart (UBERON:0000948) * Right ventricle (UBERON:0002080) * Left ventricle (UBERON:0002084) * Intercalated disc (GO cellular component: intercalated disc; and desmosome GO:0030057)
Disease predominantly affects ventricular myocardium (classically RV), but biventricular and LV involvement are clinically relevant in PKP2 cohorts (e.g., LV involvement in 37% for PKP2 c.1211dup carriers). (bos2023thearrhythmogeniccardiomyopathy pages 1-3)
In a PKP2 founder cohort, ventricular arrhythmias were described as early manifestations “from 14 years of age onwards,” while heart failure was “uncommon before the age of 55 years,” supporting an age-dependent progression pattern with early electrical disease and later pump failure. (bos2023thearrhythmogeniccardiomyopathy pages 1-3)
ACM is most often familial with autosomal-dominant inheritance and incomplete penetrance, though recessive forms exist in ACM more broadly. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2, pilichou2016arrhythmogeniccardiomyopathy pages 3-5)
There is no single gold standard; the 2010 Revised Task Force Criteria integrate imaging (echo/CMR), histology/biopsy, ECG, arrhythmias, and family history/genetics. (pilichou2016arrhythmogeniccardiomyopathy pages 3-5)
Key practical diagnostic markers in contemporary care include: * ECG: anterior T-wave inversion (V1–V3, or beyond), epsilon waves (minor criterion), conduction intervals (PR/QRS prolongation in definite cases) (aljehani2023characterisationofpatients pages 1-2, casian2024arrhythmogenicrightventricular pages 3-5) * Holter: frequent PVCs and VT burden (aljehani2023characterisationofpatients pages 1-2, casian2024arrhythmogenicrightventricular pages 9-10) * Imaging: CMR for RV volumes and function and tissue characterization (LGE) (casian2024arrhythmogenicrightventricular pages 3-5, mo2024describingandmapping pages 7-8) * Strain imaging: reduced RV free-wall strain can support disease detection (casian2024arrhythmogenicrightventricular pages 9-10) * Genetics: a pathogenic mutation is a major criterion in 2010 criteria, and genetic testing is embedded in modern diagnostic algorithms. (biernacka2021pathogenicvariantsin pages 1-2, mo2024describingandmapping pages 7-8)
Tables comparing diagnostic criteria frameworks and differential diagnosis ECG/imaging patterns were extracted from Casian et al. (2024). (casian2024arrhythmogenicrightventricular media 2c72158c, casian2024arrhythmogenicrightventricular media 7736dc34)
Genetic testing is used to confirm diagnosis and enable cascade screening; variant interpretation requires periodic re-evaluation (especially for VUS) and segregation analysis. (casian2024arrhythmogenicrightventricular pages 9-10, roblesmezcua2023thenovelvariant pages 10-12)
In PKP2 c.1211dup carriers, sustained ventricular arrhythmia occurred in 27% overall, with strong sex differences by age 40 (33% men vs 9% women). (bos2023thearrhythmogeniccardiomyopathy pages 4-6, bos2023thearrhythmogeniccardiomyopathy pages 1-3)
In affected adults with ACM broadly, a review cites sudden death incidence 0.08–3.6%/year. (pilichou2016arrhythmogeniccardiomyopathy pages 3-5)
In PKP2 c.1211dup carriers, HF developed in 11% overall and accumulated mostly at older ages; in the Málaga founder series HF onset was 25%, and transplant occurred in at least one case. (bos2023thearrhythmogeniccardiomyopathy pages 1-3, roblesmezcua2023thenovelvariant pages 6-9)
One cohort analysis suggests PKP2 pathogenic variants may associate with better survival compared with non-PKP2 ARVC genotypes (e.g., less LV progression and lower death/transplant composite). (biernacka2021pathogenicvariantsin pages 1-2)
Management is centered on preventing sudden cardiac death and managing arrhythmias and HF, including: * ICD therapy: a core therapy in risk-stratified patients; established for secondary prevention and used for selected primary-prevention cases. (pilichou2016arrhythmogeniccardiomyopathy pages 12-14, mo2024describingandmapping pages 7-8) * Antiarrhythmic drug therapy: used as part of symptomatic control and arrhythmia reduction; details vary by patient and were not fully extractable from the retrieved excerpts. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2) * Catheter ablation: used for VT control; in one PKP2 founder series, VT ablation occurred in 8.3% of patients. (roblesmezcua2023thenovelvariant pages 6-9) * Exercise restriction / sport disqualification: described as life-saving due to effort-triggered electrical instability and acceleration of disease onset/progression. (pilichou2016arrhythmogeniccardiomyopathy pages 1-2)
(Notes: MAXO IDs may vary by release; verify in your ontology build system.)
Primary prevention in genetically susceptible individuals is largely behavioral and surveillance-based: * Cascade genetic screening for at-risk relatives and periodic cardiac evaluation (ECG/Holter/imaging) (casian2024arrhythmogenicrightventricular pages 9-10, pilichou2016arrhythmogeniccardiomyopathy pages 1-2) * Restriction from high-intensity endurance/competitive sports in diagnosed individuals and (often) high-risk carriers (pilichou2016arrhythmogeniccardiomyopathy pages 1-2)
No naturally occurring veterinary PKP2-ACM evidence was retrieved in this tool run.
Human iPSC-derived cardiomyocytes and engineered myocardium reproduce PKP2 junctional, conduction, and contractile defects, and demonstrate molecular rescue via PKP2 gene replacement. (kyriakopoulou2023therapeuticefficacyof pages 1-2, mundisugih2024exploringthetherapeutic pages 2-4)
Abstract quote (hiPSC model value): “Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro…” (Chua et al., 2023) (chua2023understandingarrhythmogeniccardiomyopathy pages 31-33)
Several mouse models show severe arrhythmogenic phenotypes and enable gene-therapy testing: * Splice-site knock-in model with sudden death beginning at 4 weeks; AAV-PKP2 prevented and rescued disease with 100% survival in treated windows. (bradford2023plakophilin2gene pages 1-2) * Tamoxifen-inducible, cardiac-specific Pkp2 knockout used to test AAV9:PKP2 (TN‑401) with dose testing (e.g., 3E13–6E13 vg/kg preventive) and dramatic survival benefit in the model. (wu2024aav9pkp2improvesheart pages 13-14, wu2024aav9pkp2improvesheart pages 2-3)
AAV9-shRNA PKP2 knockdown in guinea pigs recapitulated RV enlargement, sudden death, and lipid accumulation; multi-omics implicated ECM remodeling and metabolic shifts (PI3K-Akt; lipid/TCA changes). (song2024multiomicsanalysisreveals pages 1-5, song2024multiomicsanalysisreveals pages 9-14)
Multiple independent studies show that AAV-mediated PKP2 replacement restores junctional proteins, improves conduction/contractility, reduces remodeling, and improves survival in PKP2-deficient models: * Kyriakopoulou et al. (2023-12; Nature Cardiovascular Research; https://doi.org/10.1038/s44161-023-00378-9): AAV6–PKP2 restored PKP2 and other junction proteins in PKP2c.2013delC/WT iPSC-CMs, improved sodium conduction, and improved engineered human myocardium; systemic AAV9–PKP2 prevented dysfunction in heterozygous knock-in mice at 12 months. (kyriakopoulou2023therapeuticefficacyof pages 1-2) * Bradford et al. (2023-12; Nature Cardiovascular Research; https://doi.org/10.1038/s44161-023-00370-3): neonatal gene therapy restored PKP2 and produced 100% survival up to 6 months; late-stage administration rescued desmosomal deficits and produced 100% survival up to 4 months in a severe splice-site model. (bradford2023plakophilin2gene pages 1-2) * Wu et al. (2024-03; Communications Medicine; https://doi.org/10.1038/s43856-024-00450-w): AAV9:PKP2 (TN‑401) prevented disease onset and attenuated established cardiomyopathy; preventive doses included 3E13–6E13 vg/kg in the mouse model. (wu2024aav9pkp2improvesheart pages 1-2, wu2024aav9pkp2improvesheart pages 13-14) * van Opbergen et al. (2024-02; Circulation: Genomic and Precision Medicine; https://doi.org/10.1161/circgen.123.004305): AAVrh.74-PKP2a arrested progression with survival benefit (100% survival in treated vs 100% mortality in untreated model). (opbergen2024aavmediateddeliveryof pages 7-9)
A 2024 review emphasizes PKP2 as a high-priority ARVC gene-therapy target and notes translational hurdles (vector dosing, immune barriers, cardiac specificity). (mundisugih2024exploringthetherapeutic pages 2-4)
Abstract quote (state of translation): “Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases.” (Mundisugih et al., 2024; Biomedicines; published 2024-06; https://doi.org/10.3390/biomedicines12061351) (mundisugih2024exploringthetherapeutic pages 2-4)
(These are identified by clinical trial search results in this run; detailed fields were not fully extractable for all NCTs in available excerpts.)
References
(pilichou2016arrhythmogeniccardiomyopathy pages 1-2): Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Ilaria Rigato, Elisabetta Lazzarini, Federico Migliore, Martina Perazzolo Marra, Stefania Rizzo, Alessandro Zorzi, Luciano Daliento, Domenico Corrado, and Cristina Basso. Arrhythmogenic cardiomyopathy. Orphanet Journal of Rare Diseases, Apr 2016. URL: https://doi.org/10.1186/s13023-016-0407-1, doi:10.1186/s13023-016-0407-1. This article has 211 citations and is from a peer-reviewed journal.
(bos2023thearrhythmogeniccardiomyopathy pages 4-6): Thomas A. Bos, Sebastiaan R. D. Piers, Marja W. Wessels, Arjan C. Houweling, Regina Bökenkamp, Marianne Bootsma, Laurens P. Bosman, Reinder Evertz, Debby M. E. I. Hellebrekers, Yvonne M. Hoedemaekers, Jeroen Knijnenburg, Ronald Lekanne Deprez, Anneke M. van Mil, Anneline S. J. M. te Riele, Marjon A. van Slegtenhorst, Arthur A. M. Wilde, Sing-Chien Yap, Dennis Dooijes, Tamara T. Koopmann, J. Peter van Tintelen, Daniela Q. C. M. Barge-Schaapveld, Arjan C. Houweling, Ronald Lekanne Deprez, Anneline S. J. M. te Riele, Arthur A. M. Wilde, and J. Peter van Tintelen. The arrhythmogenic cardiomyopathy phenotype associated with pkp2 c.1211dup variant. Netherlands Heart Journal, 31:315-323, Jul 2023. URL: https://doi.org/10.1007/s12471-023-01791-2, doi:10.1007/s12471-023-01791-2. This article has 3 citations and is from a peer-reviewed journal.
(chua2023understandingarrhythmogeniccardiomyopathy pages 6-8): Christianne J. Chua, Justin Morrissette-McAlmon, Leslie Tung, and Kenneth R. Boheler. Understanding arrhythmogenic cardiomyopathy: advances through the use of human pluripotent stem cell models. Genes, 14:1864, Sep 2023. URL: https://doi.org/10.3390/genes14101864, doi:10.3390/genes14101864. This article has 19 citations.
(mundisugih2024exploringthetherapeutic pages 2-4): Juan Mundisugih, Dhanya Ravindran, and Eddy Kizana. Exploring the therapeutic potential of gene therapy in arrhythmogenic right ventricular cardiomyopathy. Biomedicines, 12:1351, Jun 2024. URL: https://doi.org/10.3390/biomedicines12061351, doi:10.3390/biomedicines12061351. This article has 12 citations.
(NCT06976606 chunk 1): A Study to Assess Real-world Patient Characteristics and Clinical Course for Symptomatic Patients With PKP2-ACM. Lexeo Therapeutics. 2024. ClinicalTrials.gov Identifier: NCT06976606
(bos2023thearrhythmogeniccardiomyopathy pages 1-3): Thomas A. Bos, Sebastiaan R. D. Piers, Marja W. Wessels, Arjan C. Houweling, Regina Bökenkamp, Marianne Bootsma, Laurens P. Bosman, Reinder Evertz, Debby M. E. I. Hellebrekers, Yvonne M. Hoedemaekers, Jeroen Knijnenburg, Ronald Lekanne Deprez, Anneke M. van Mil, Anneline S. J. M. te Riele, Marjon A. van Slegtenhorst, Arthur A. M. Wilde, Sing-Chien Yap, Dennis Dooijes, Tamara T. Koopmann, J. Peter van Tintelen, Daniela Q. C. M. Barge-Schaapveld, Arjan C. Houweling, Ronald Lekanne Deprez, Anneline S. J. M. te Riele, Arthur A. M. Wilde, and J. Peter van Tintelen. The arrhythmogenic cardiomyopathy phenotype associated with pkp2 c.1211dup variant. Netherlands Heart Journal, 31:315-323, Jul 2023. URL: https://doi.org/10.1007/s12471-023-01791-2, doi:10.1007/s12471-023-01791-2. This article has 3 citations and is from a peer-reviewed journal.
(pilichou2016arrhythmogeniccardiomyopathy pages 2-3): Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Ilaria Rigato, Elisabetta Lazzarini, Federico Migliore, Martina Perazzolo Marra, Stefania Rizzo, Alessandro Zorzi, Luciano Daliento, Domenico Corrado, and Cristina Basso. Arrhythmogenic cardiomyopathy. Orphanet Journal of Rare Diseases, Apr 2016. URL: https://doi.org/10.1186/s13023-016-0407-1, doi:10.1186/s13023-016-0407-1. This article has 211 citations and is from a peer-reviewed journal.
(pilichou2016arrhythmogeniccardiomyopathy pages 3-5): Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Ilaria Rigato, Elisabetta Lazzarini, Federico Migliore, Martina Perazzolo Marra, Stefania Rizzo, Alessandro Zorzi, Luciano Daliento, Domenico Corrado, and Cristina Basso. Arrhythmogenic cardiomyopathy. Orphanet Journal of Rare Diseases, Apr 2016. URL: https://doi.org/10.1186/s13023-016-0407-1, doi:10.1186/s13023-016-0407-1. This article has 211 citations and is from a peer-reviewed journal.
(chua2023understandingarrhythmogeniccardiomyopathy pages 31-33): Christianne J. Chua, Justin Morrissette-McAlmon, Leslie Tung, and Kenneth R. Boheler. Understanding arrhythmogenic cardiomyopathy: advances through the use of human pluripotent stem cell models. Genes, 14:1864, Sep 2023. URL: https://doi.org/10.3390/genes14101864, doi:10.3390/genes14101864. This article has 19 citations.
(opbergen2024aavmediateddeliveryof pages 7-9): Chantal J.M. van Opbergen, Bitha Narayanan, Chester B. Sacramento, Katie M. Stiles, Vartika Mishra, Esther Frenk, David Ricks, Grace Chen, Mingliang Zhang, Paul Yarabe, Jonathan Schwartz, Mario Delmar, Chris D. Herzog, and Marina Cerrone. Aav-mediated delivery of plakophilin-2a arrests progression of arrhythmogenic right ventricular cardiomyopathy in murine hearts: preclinical evidence supporting gene therapy in humans. Circulation: Genomic and Precision Medicine, Feb 2024. URL: https://doi.org/10.1161/circgen.123.004305, doi:10.1161/circgen.123.004305. This article has 55 citations.
(chua2023understandingarrhythmogeniccardiomyopathy pages 17-19): Christianne J. Chua, Justin Morrissette-McAlmon, Leslie Tung, and Kenneth R. Boheler. Understanding arrhythmogenic cardiomyopathy: advances through the use of human pluripotent stem cell models. Genes, 14:1864, Sep 2023. URL: https://doi.org/10.3390/genes14101864, doi:10.3390/genes14101864. This article has 19 citations.
(vencato2024animalmodelsand pages 5-7): Sara Vencato, Chiara Romanato, Alessandra Rampazzo, and Martina Calore. Animal models and molecular pathogenesis of arrhythmogenic cardiomyopathy associated with pathogenic variants in intercalated disc genes. International Journal of Molecular Sciences, 25:6208, Jun 2024. URL: https://doi.org/10.3390/ijms25116208, doi:10.3390/ijms25116208. This article has 9 citations.
(aljehani2023characterisationofpatients pages 1-2): A. Aljehani, T. Kew, S. Baig, H. Cox, L. C. Sommerfeld, B. Ensam, M. Kalla, R. P. Steeds, and L. Fabritz. Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (arvc). BMC Cardiovascular Disorders, Jan 2023. URL: https://doi.org/10.1186/s12872-022-03021-w, doi:10.1186/s12872-022-03021-w. This article has 4 citations and is from a peer-reviewed journal.
(casian2024arrhythmogenicrightventricular pages 9-10): Mihnea Casian, Michael Papadakis, and Ruxandra Jurcut. Arrhythmogenic right ventricular cardiomyopathies (arvc): diagnostic challenges from imaging to genetics. Polish Heart Journal, Sep 2024. URL: https://doi.org/10.33963/v.phj.102391, doi:10.33963/v.phj.102391. This article has 4 citations.
(roblesmezcua2023thenovelvariant pages 6-9): Ainhoa Robles-Mezcua, Amalio Ruíz-Salas, Carmen Medina-Palomo, María Robles-Mezcua, Arancha Díaz-Expósito, María Victoria Ortega-Jiménez, Juan Ramón Gimeno-Blanes, Manuel F. Jiménez-Navarro, and José Manuel García-Pinilla. The novel variant np_00454563.2 (p.glu259glyfs*77) in gene pkp2 associated with arrhythmogenic cardiomyopathy in 8 families from malaga, spain. Genes, 14:1468, Jul 2023. URL: https://doi.org/10.3390/genes14071468, doi:10.3390/genes14071468. This article has 3 citations.
(hylind2022populationprevalenceof pages 5-7): Robyn J. Hylind, Alexandre C. Pereira, Daniel Quiat, Stephanie F. Chandler, Thomas M. Roston, William T. Pu, Vassilios J. Bezzerides, Jonathan G. Seidman, Christine E. Seidman, and Dominic J. Abrams. Population prevalence of premature truncating variants in plakophilin-2 and association with arrhythmogenic right ventricular cardiomyopathy: a uk biobank analysis. Circulation: Genomic and Precision Medicine, Jun 2022. URL: https://doi.org/10.1161/circgen.121.003507, doi:10.1161/circgen.121.003507. This article has 19 citations.
(kyriakopoulou2023therapeuticefficacyof pages 1-2): Eirini Kyriakopoulou, Danielle Versteeg, Hesther de Ruiter, Ilaria Perini, Fitzwilliam Seibertz, Yannic Döring, Lorena Zentilin, Hoyee Tsui, Sebastiaan J. van Kampen, Malte Tiburcy, Tim Meyer, Niels Voigt, van J. Peter Tintelen, Wolfram H. Zimmermann, Mauro Giacca, and Eva van Rooij. Therapeutic efficacy of aav-mediated restoration of pkp2 in arrhythmogenic cardiomyopathy. Nature Cardiovascular Research, 2:1262-1276, Dec 2023. URL: https://doi.org/10.1038/s44161-023-00378-9, doi:10.1038/s44161-023-00378-9. This article has 66 citations and is from a peer-reviewed journal.
(wu2024aav9pkp2improvesheart pages 13-14): Iris Wu, Aliya Zeng, Amara Greer-Short, J. Alex Aycinena, Anley E. Tefera, Reva Shenwai, Farshad Farshidfar, Melissa Van Pell, Emma Xu, Chris Reid, Neshel Rodriguez, Beatriz Lim, Tae Won Chung, Joseph Woods, Aquilla Scott, Samantha Jones, Cristina Dee-Hoskins, Carolina G. Gutierrez, Jessie Madariaga, Kevin Robinson, Yolanda Hatter, Renee Butler, Stephanie Steltzer, Jaclyn Ho, James R. Priest, Xiaomei Song, Frank Jing, Kristina Green, Kathryn N. Ivey, Timothy Hoey, Jin Yang, and Zhihong Jane Yang. Aav9:pkp2 improves heart function and survival in a pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy. Communications Medicine, Mar 2024. URL: https://doi.org/10.1038/s43856-024-00450-w, doi:10.1038/s43856-024-00450-w. This article has 50 citations and is from a peer-reviewed journal.
(song2024multiomicsanalysisreveals pages 1-5): Rui Song, Haiyan Wu, Lihui Yu, Jingning Yu, WenHui Yang, WenJun Wu, Fei Sun, and Haizhen Wang. Multiomics analysis reveals extensive remodeling of the extracellular matrix and cellular metabolism due to plakophilin-2 knockdown in guinea pigs. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.11.584401, doi:10.1101/2024.03.11.584401. This article has 1 citations.
(vencato2024animalmodelsand pages 2-4): Sara Vencato, Chiara Romanato, Alessandra Rampazzo, and Martina Calore. Animal models and molecular pathogenesis of arrhythmogenic cardiomyopathy associated with pathogenic variants in intercalated disc genes. International Journal of Molecular Sciences, 25:6208, Jun 2024. URL: https://doi.org/10.3390/ijms25116208, doi:10.3390/ijms25116208. This article has 9 citations.
(biernacka2021pathogenicvariantsin pages 1-2): Elżbieta K. Biernacka, Karolina Borowiec, Maria Franaszczyk, Małgorzata Szperl, Alessandra Rampazzo, Olgierd Woźniak, Marta Roszczynko, Witold Śmigielski, Anna Lutyńska, and Piotr Hoffman. Pathogenic variants in plakophilin-2 gene (pkp2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy. Journal of Applied Genetics, 62:613-620, Jun 2021. URL: https://doi.org/10.1007/s13353-021-00647-y, doi:10.1007/s13353-021-00647-y. This article has 25 citations and is from a peer-reviewed journal.
(bos2023thearrhythmogeniccardiomyopathy pages 3-4): Thomas A. Bos, Sebastiaan R. D. Piers, Marja W. Wessels, Arjan C. Houweling, Regina Bökenkamp, Marianne Bootsma, Laurens P. Bosman, Reinder Evertz, Debby M. E. I. Hellebrekers, Yvonne M. Hoedemaekers, Jeroen Knijnenburg, Ronald Lekanne Deprez, Anneke M. van Mil, Anneline S. J. M. te Riele, Marjon A. van Slegtenhorst, Arthur A. M. Wilde, Sing-Chien Yap, Dennis Dooijes, Tamara T. Koopmann, J. Peter van Tintelen, Daniela Q. C. M. Barge-Schaapveld, Arjan C. Houweling, Ronald Lekanne Deprez, Anneline S. J. M. te Riele, Arthur A. M. Wilde, and J. Peter van Tintelen. The arrhythmogenic cardiomyopathy phenotype associated with pkp2 c.1211dup variant. Netherlands Heart Journal, 31:315-323, Jul 2023. URL: https://doi.org/10.1007/s12471-023-01791-2, doi:10.1007/s12471-023-01791-2. This article has 3 citations and is from a peer-reviewed journal.
(roblesmezcua2023thenovelvariant pages 10-12): Ainhoa Robles-Mezcua, Amalio Ruíz-Salas, Carmen Medina-Palomo, María Robles-Mezcua, Arancha Díaz-Expósito, María Victoria Ortega-Jiménez, Juan Ramón Gimeno-Blanes, Manuel F. Jiménez-Navarro, and José Manuel García-Pinilla. The novel variant np_00454563.2 (p.glu259glyfs*77) in gene pkp2 associated with arrhythmogenic cardiomyopathy in 8 families from malaga, spain. Genes, 14:1468, Jul 2023. URL: https://doi.org/10.3390/genes14071468, doi:10.3390/genes14071468. This article has 3 citations.
(casian2024arrhythmogenicrightventricular pages 3-5): Mihnea Casian, Michael Papadakis, and Ruxandra Jurcut. Arrhythmogenic right ventricular cardiomyopathies (arvc): diagnostic challenges from imaging to genetics. Polish Heart Journal, Sep 2024. URL: https://doi.org/10.33963/v.phj.102391, doi:10.33963/v.phj.102391. This article has 4 citations.
(pilichou2016arrhythmogeniccardiomyopathy pages 12-14): Kalliopi Pilichou, Gaetano Thiene, Barbara Bauce, Ilaria Rigato, Elisabetta Lazzarini, Federico Migliore, Martina Perazzolo Marra, Stefania Rizzo, Alessandro Zorzi, Luciano Daliento, Domenico Corrado, and Cristina Basso. Arrhythmogenic cardiomyopathy. Orphanet Journal of Rare Diseases, Apr 2016. URL: https://doi.org/10.1186/s13023-016-0407-1, doi:10.1186/s13023-016-0407-1. This article has 211 citations and is from a peer-reviewed journal.
(vencato2024animalmodelsand pages 4-5): Sara Vencato, Chiara Romanato, Alessandra Rampazzo, and Martina Calore. Animal models and molecular pathogenesis of arrhythmogenic cardiomyopathy associated with pathogenic variants in intercalated disc genes. International Journal of Molecular Sciences, 25:6208, Jun 2024. URL: https://doi.org/10.3390/ijms25116208, doi:10.3390/ijms25116208. This article has 9 citations.
(mo2024describingandmapping pages 7-8): Leitong Mo, Ching‐Hui Sia, Weiqin Lin, Xifeng Zheng, and Kaiyi Peng. Describing and mapping the research trend of scientific publications on arrhythmogenic right ventricular cardiomyopathy across four decades: a bibliometric analysis. Clinical Cardiology, Nov 2024. URL: https://doi.org/10.1002/clc.70051, doi:10.1002/clc.70051. This article has 2 citations and is from a peer-reviewed journal.
(casian2024arrhythmogenicrightventricular media 2c72158c): Mihnea Casian, Michael Papadakis, and Ruxandra Jurcut. Arrhythmogenic right ventricular cardiomyopathies (arvc): diagnostic challenges from imaging to genetics. Polish Heart Journal, Sep 2024. URL: https://doi.org/10.33963/v.phj.102391, doi:10.33963/v.phj.102391. This article has 4 citations.
(casian2024arrhythmogenicrightventricular media 7736dc34): Mihnea Casian, Michael Papadakis, and Ruxandra Jurcut. Arrhythmogenic right ventricular cardiomyopathies (arvc): diagnostic challenges from imaging to genetics. Polish Heart Journal, Sep 2024. URL: https://doi.org/10.33963/v.phj.102391, doi:10.33963/v.phj.102391. This article has 4 citations.
(bradford2023plakophilin2gene pages 1-2): William H. Bradford, Jing Zhang, Erika J. Gutierrez-Lara, Yan Liang, Aryanne Do, Tsui-Min Wang, Lena Nguyen, Nirosh Mataraarachchi, Jie Wang, Yusu Gu, Andrew McCulloch, Kirk L. Peterson, and Farah Sheikh. Plakophilin 2 gene therapy prevents and rescues arrhythmogenic right ventricular cardiomyopathy in a mouse model harboring patient genetics. Nature Cardiovascular Research, 2:1246-1261, Dec 2023. URL: https://doi.org/10.1038/s44161-023-00370-3, doi:10.1038/s44161-023-00370-3. This article has 67 citations and is from a peer-reviewed journal.
(wu2024aav9pkp2improvesheart pages 2-3): Iris Wu, Aliya Zeng, Amara Greer-Short, J. Alex Aycinena, Anley E. Tefera, Reva Shenwai, Farshad Farshidfar, Melissa Van Pell, Emma Xu, Chris Reid, Neshel Rodriguez, Beatriz Lim, Tae Won Chung, Joseph Woods, Aquilla Scott, Samantha Jones, Cristina Dee-Hoskins, Carolina G. Gutierrez, Jessie Madariaga, Kevin Robinson, Yolanda Hatter, Renee Butler, Stephanie Steltzer, Jaclyn Ho, James R. Priest, Xiaomei Song, Frank Jing, Kristina Green, Kathryn N. Ivey, Timothy Hoey, Jin Yang, and Zhihong Jane Yang. Aav9:pkp2 improves heart function and survival in a pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy. Communications Medicine, Mar 2024. URL: https://doi.org/10.1038/s43856-024-00450-w, doi:10.1038/s43856-024-00450-w. This article has 50 citations and is from a peer-reviewed journal.
(song2024multiomicsanalysisreveals pages 9-14): Rui Song, Haiyan Wu, Lihui Yu, Jingning Yu, WenHui Yang, WenJun Wu, Fei Sun, and Haizhen Wang. Multiomics analysis reveals extensive remodeling of the extracellular matrix and cellular metabolism due to plakophilin-2 knockdown in guinea pigs. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.11.584401, doi:10.1101/2024.03.11.584401. This article has 1 citations.
(wu2024aav9pkp2improvesheart pages 1-2): Iris Wu, Aliya Zeng, Amara Greer-Short, J. Alex Aycinena, Anley E. Tefera, Reva Shenwai, Farshad Farshidfar, Melissa Van Pell, Emma Xu, Chris Reid, Neshel Rodriguez, Beatriz Lim, Tae Won Chung, Joseph Woods, Aquilla Scott, Samantha Jones, Cristina Dee-Hoskins, Carolina G. Gutierrez, Jessie Madariaga, Kevin Robinson, Yolanda Hatter, Renee Butler, Stephanie Steltzer, Jaclyn Ho, James R. Priest, Xiaomei Song, Frank Jing, Kristina Green, Kathryn N. Ivey, Timothy Hoey, Jin Yang, and Zhihong Jane Yang. Aav9:pkp2 improves heart function and survival in a pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy. Communications Medicine, Mar 2024. URL: https://doi.org/10.1038/s43856-024-00450-w, doi:10.1038/s43856-024-00450-w. This article has 50 citations and is from a peer-reviewed journal.
(NCT07050160 chunk 1): Long-term Follow-up Study of Gene Therapy for Arrhythmogenic Cardiomyopathy Due to a Plakophilin-2 Pathogenic Variant. Lexeo Therapeutics. 2025. ClinicalTrials.gov Identifier: NCT07050160