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PKP2_Cardiomyopathy

PKP2 Cardiomyopathy (PKP2-ACM): Comprehensive Disease Characteristics Report

2026-04-04
Falcon MONDO:0012180 Model: Edison Scientific Literature 52 citations

PKP2 Cardiomyopathy (PKP2-ACM): Comprehensive Disease Characteristics Report

Executive summary

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)

1. Disease information

1.1 What is PKP2 cardiomyopathy?

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)

1.2 Key identifiers

1.3 Synonyms / alternative names

1.4 Evidence sources represented in this report

2. Etiology

2.1 Disease causal factors

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)

2.2 Risk factors

Genetic risk factors

Environmental and demographic risk factors

2.3 Protective factors

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)

2.4 Gene–environment interactions

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)

3. Phenotypes (clinical features)

3.1 Core phenotype domains

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)

3.2 Quantitative phenotype statistics (key recent cohorts)

A cross-study quantitative summary is provided below.

Table (click to expand)
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.

3.3 Phenotype-to-ontology mapping (HPO suggestions)

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)

3.4 Quality of life impact

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)

4. Genetic/molecular information

4.1 Causal gene

4.2 Pathogenic variant classes (examples from recent cohorts)

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)

4.3 Population frequency and penetrance considerations

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)

5. Environmental information

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)

6. Mechanism / pathophysiology

6.1 Current mechanistic model (causal chain)

A synthesis of recent mechanistic work supports a multi-axis causal chain:

  1. PKP2 haploinsufficiency or loss → impaired intercalated disc/desmosome structure (widened intercalated discs; reduced junctional proteins) (vencato2024animalmodelsand pages 5-7, vencato2024animalmodelsand pages 2-4)
  2. Mechanical uncoupling and mechanosensing defects → altered actin remodeling (RhoA–ROCK) and reduced MRTF/SRF transcriptional activity, facilitating adipogenic programs (chua2023understandingarrhythmogeniccardiomyopathy pages 17-19)
  3. Electrical remodeling via “functional triad” disruption (desmosomes–gap junctions–Na channels): reduced Cx43 and NaV1.5 mislocalization/INa reduction → slowed conduction and re-entry propensity (pilichou2016arrhythmogeniccardiomyopathy pages 12-14, vencato2024animalmodelsand pages 5-7)
  4. Signal pathway reprogramming: plakoglobin nuclear translocation suppresses canonical Wnt/β-catenin, and Hippo/YAP activation contributes to fibrofatty remodeling (chua2023understandingarrhythmogeniccardiomyopathy pages 6-8, vencato2024animalmodelsand pages 2-4)
  5. Fibrosis and inflammation: PKP2 deficiency links to TGF-β1/p38 MAPK profibrotic signaling and transcriptomic immune/inflammatory signatures (chua2023understandingarrhythmogeniccardiomyopathy pages 31-33, vencato2024animalmodelsand pages 4-5)
  6. Metabolic remodeling/adipogenesis: PPARα/PPARG programs, lipogenesis/fatty-acid oxidation shifts, ROS and apoptosis (chua2023understandingarrhythmogeniccardiomyopathy pages 17-19, song2024multiomicsanalysisreveals pages 1-5)

6.2 Pathways and ontology suggestions

6.3 Cell types and anatomical structures (CL/UBERON suggestions)

  • Cardiomyocyte (CL:0000746)
  • Cardiac fibroblast (CL:0002548)
  • Monocyte-derived macrophage (CL:0001054; in broader ACM immune literature, not PKP2-specific in our excerpts)

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)

7. Anatomical structures affected

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)

8. Temporal development

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)

9. Inheritance and population

9.1 Inheritance

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)

9.2 Epidemiology

10. Diagnostics

10.1 Clinical criteria and diagnostic workup

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)

10.2 Visual evidence: diagnostic criteria tables

Tables comparing diagnostic criteria frameworks and differential diagnosis ECG/imaging patterns were extracted from Casian et al. (2024). (casian2024arrhythmogenicrightventricular media 2c72158c, casian2024arrhythmogenicrightventricular media 7736dc34)

10.3 Genetic testing approach

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)

11. Outcomes / prognosis

11.1 Arrhythmic outcomes

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)

11.2 Heart failure and transplant

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)

11.3 Genotype-informed prognosis

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)

12. Treatment

12.1 Current applications / real-world implementations

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)

12.2 MAXO suggestions (interventions)

  • Implantation of cardioverter-defibrillator → MAXO:0000508 (implantable cardioverter defibrillator implantation)
  • Catheter ablation for VT → MAXO:0000479 (cardiac ablation procedure; map to local MAXO in implementation)
  • Beta-blocker therapy → MAXO:0000511 (beta-adrenergic antagonist therapy)
  • Exercise restriction / activity modification → MAXO:0000915 (lifestyle modification; use appropriate child term)

(Notes: MAXO IDs may vary by release; verify in your ontology build system.)

13. Prevention

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)

14. Other species / natural disease

No naturally occurring veterinary PKP2-ACM evidence was retrieved in this tool run.

15. Model organisms and experimental systems

15.1 In vitro (human)

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)

15.2 In vivo (mouse)

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)

15.3 In vivo (guinea pig)

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)

16. Recent developments (2023–2024): gene therapy and translational pipeline

16.1 Preclinical gene replacement (key 2023–2024 findings)

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)

16.2 Expert synthesis (2024 review)

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)

17. Clinical trials and real-world implementations (2024–2025)

17.1 PKP2 gene therapy interventional trials (Phase 1/2)

  • TN‑401 (Tenaya Therapeutics) – Phase 1, open-label dose escalation in adults with PKP2 mutation-associated ARVC: NCT06228924 (Recruiting). (ClinicalTrials.gov) (trial metadata retrieved; details beyond NCT listing not shown in excerpts).
  • RP‑A601 (Rocket Pharmaceuticals) – Phase 1 dose escalation in PKP2 variant-mediated arrhythmogenic cardiomyopathy: NCT05885412 (Recruiting).
  • LX2020 (Lexeo Therapeutics) – Phase 1/2 gene therapy for ACM due to a PKP2 pathogenic variant: NCT06109181 (Active, not recruiting).

(These are identified by clinical trial search results in this run; detailed fields were not fully extractable for all NCTs in available excerpts.)

17.2 Observational trials/registries supporting implementation

  • SNAPSHOT‑PKP2 (Lexeo) – real-world symptomatic PKP2-ACM registry with AAVrh.10 antibody testing, biomarkers, imaging/ECG, and PVC endpoint. NCT06976606; start 2024-01-23; enrollment 40; recruiting. (NCT06976606 chunk 1)
  • GRIT‑PKP2 / LX2020-02 – long-term follow-up after receiving LX2020 parent study, safety TEAE/TESAE over 4 years; start 2025-08-29; enrollment 10; enrolling by invitation. NCT07050160. (NCT07050160 chunk 1)

Data gaps / limitations in this evidence set

  • MONDO/ICD/MeSH identifiers were not extractable from retrieved sources in this run.
  • Several sections (epigenetics, protective genetic variants, validated QoL scales) are incompletely supported by the retrieved full-text excerpts.
  • Some clinical-trial vector/construct details (e.g., exact capsid/promoter) were not present in the extracted NCT excerpts.

Key references (URLs and publication dates)

References

  1. (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.

  2. (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.

  3. (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.

  4. (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.

  5. (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

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