Acute Myocardial Infarction-Like Events in Related Patients With a Desmoplakin-Associated Arrhythmogenic Cardiomyopathy

Singh, Siddharth; Sharkey, Scott W.; Casey, Susan A.; Harris, Kevin M.; Thaler, Christina; Chung, Mina K.; Berg, Allison; Bennett, Mosi K.; Ducanson, Emily R.; Mackey‐Bojack, Shannon; Sengupta, Jay

doi:10.1016/j.jaccas.2021.06.015

Cited by 4 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent examples of DSPtv presenting as recurrent myocarditis and acute myocardial infarctionlike events have also been reported. 23,24 Women were overrepresented in our population, but otherwise shared similar clinical characteristics compared with men, except reduced indexed right ventricular end diastolic diameter on CMR. This finding is in contrast to other reported inherited cardiomyopathy patient cohorts, where a higher prevalence of men is often reported.…”

Section: Discussionmentioning

confidence: 74%

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

Hoorntje

Burns

Marsili

et al. 2023

Circ: Genomic and Precision Medicine

View full text Add to dashboard Cite

BACKGROUND: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. METHODS: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions, resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%]; P <0.0001). CONCLUSIONS: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

show abstract

Section: Discussionmentioning

confidence: 74%

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

Hoorntje

Burns

Marsili

et al. 2023

Circ: Genomic and Precision Medicine

View full text Add to dashboard Cite

show abstract

“…Other studies have reported patients with pathogenic DSP variants presenting with inflammatory episodes. The initial suspicion of acute myocarditis or myocardial infarction has later led to a diagnosis of left-dominant or biventricular ACM ( 20 , 39 – 42 ). These episodes have sometimes been associated with exercise ( 18 , 19 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

DSP c.6310delA p.(Thr2104Glnfs*12) associates with arrhythmogenic cardiomyopathy, increased trabeculation, curly hair, and palmoplantar keratoderma

Heliö

Brandt

Vaara

et al. 2023

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

BackgroundPathogenic variants in DSP associate with cardiac and cutaneous manifestations including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, curly or wavy hair, and palmoplantar keratoderma (PPK). Episodes of myocardial inflammation associated with DSP cardiomyopathy might be confused in clinical work with myocarditis of other etiologies such as viral. Cardiac magnetic resonance imaging (CMR) may help in differential diagnosis.Methods and resultsThis study comprised 49 Finnish patients: 34 participants from families with suspected DSP cardiomyopathy (9 index patients and 25 family members) and 15 patients with myocarditis. All 34 participants underwent genetic testing and cardiac evaluation, and 29 of them also underwent CMR. Participants with the DSP variant, numbering 22, were dermatologically examined. The 15 patients with myocarditis underwent CMR and were evaluated during their hospitalization.A heterozygous truncating DSP c.6310delA p.(Thr2104Glnfs*12) variant was confirmed in 29 participants. Only participants with the DSP variant had pacemakers and life-threatening ventricular arrhythmias. Of the participants with the DSP variant, 24% fulfilled cardiomyopathy criteria, and the median age at diagnosis was 53. Upon CMR, myocardial edema was found to be more common in patients with myocarditis. Both groups had a substantial percentage of late gadolinium enhancement (LGE). A ring-like LGE and increased trabeculation were observed only in participants with the DSP variant. All the studied participants with the DSP variant had PPK and curly or wavy hair. Hyperkeratosis developed before the age of 20 in most patients.ConclusionsThe DSP c.6310delA p.(Thr2104Glnfs*12) variant associates with curly hair, PPK, and arrhythmogenic cardiomyopathy with increased trabeculation. Cutaneous symptoms developing in childhood and adolescence might help recognize these patients at an earlier stage. CMR, together with dermatologic characteristics, may help in diagnosis.

show abstract

“… 1 Mutations in desmosomes are implicated in approximately 50% of arrhythmogenic cardiomyopathy because of the loss of electromechanical coupling and subsequent lymphocyte infiltration and necrosis that lead to fibrofatty replacement of myocardium, arrhythmogenic potential, and left ventricular dysfunction. 1 , 3 , 5 , 7 Mutations include genes that encode components of desmosomes such as plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. 8 Genes encoding non desmosomal proteins such as ion channels or cytoskeleton-associated proteins (such as desmin, lamin, and myosin heavy and light chains) are also implicated in arrhythmogenic cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“… 1 , 7 Cold phases result in subclinical but continuous cell death and alternate with hot phases that result in episodes that mimic acute coronary syndrome or recurrent myocarditis. 1 , 3 …”

Section: Discussionmentioning

confidence: 99%

“… 1 , 2 Clinical presentation is highly variable and often includes ventricular arrhythmias, myocardial injury with left ventricular dysfunction, or recurrent myocarditis. 1 , 3 Patients are often misdiagnosed as having recurrent myocarditis because of alternating periods of the hot and cold phases of the disease. In the natural course of arrhythmogenic left ventricular cardiomyopathy, patients often cycle between the hot and cold phases, although not all patients will undergo both phases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy

Sanford,

Fan,

Hua

et al. 2023

TOJ

View full text Add to dashboard Cite

Background: Arrhythmogenic left ventricular cardiomyopathy is an increasingly recognized cause of recurrent myocarditis, a mimicker of acute coronary syndrome, and an important cause of malignant ventricular arrythmias and heart failure. Desmoplakin is a protein that is critical to maintaining the structural integrity of the myocardium. Disruption of desmoplakin leads to fibrofatty infiltration of the myocardium which leads to congestive heart failure, cardiac arrhythmias, and sudden cardiac death. However, desmoplakin cardiomyopathy is often misdiagnosed, resulting in significant morbidity and mortality. We report 2 contrasting cases illustrating the natural history—hot and cold phases—of arrhythmogenic left ventricular cardiomyopathy. Case Series: The first case demonstrates a common phenotypic presentation of desmoplakin cardiomyopathy manifested as recurrent myocarditis and myocardial injury representing the hot phase. The second case is an undulating course of chronic systolic heart failure and ventricular arrhythmias representing the cold phase. Conclusion: Arrhythmogenic cardiomyopathy manifests as a spectrum of disease processes that involve the right, left, or both ventricles. Mutations in the desmoplakin gene are often associated with a left dominant ventricular cardiomyopathy. Diagnosis remains difficult as the condition has no signature clinical presentation, and imaging findings are variable.

show abstract

Acute Myocardial Infarction-Like Events in Related Patients With a Desmoplakin-Associated Arrhythmogenic Cardiomyopathy

Cited by 4 publications

References 10 publications

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant

DSP c.6310delA p.(Thr2104Glnfs*12) associates with arrhythmogenic cardiomyopathy, increased trabeculation, curly hair, and palmoplantar keratoderma

Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy

Contact Info

Product

Resources

About