Desmoplakin cardiomyopathy

Article written and reviewed by Dr Luca Moretti

Desmoplakin cardiomyopathy is a genetic myocardial disease associated with pathogenic or likely pathogenic variants in the DSP gene. Its distinguishing feature is not simply dilation of a chamber, but a variable combination of nonischemic scar, electrical instability, ventricular dysfunction and acute phases of myocardial injury. The left ventricle is often involved early and may be affected much more than the right, which is why the term DSP cardiomyopathy describes the disease biology better than its older automatic assimilation to arrhythmogenic right ventricular cardiomyopathy.

Presentation can be insidious. One carrier may have abnormal cardiac magnetic resonance with preserved ejection fraction, another may present with premature ventricular contractions or ventricular tachycardia, whereas a young person may come to medical attention because of chest pain and elevated troponin with an initial diagnosis of myocarditis. This clinical heterogeneity is not a collection of separate diseases, but different phases and directions of the same genetic process, modulated by age, variant type, sex, physical activity and factors that are not yet completely defined.

The term should not, however, be applied to everyone with a rare DSP variant. The gene is large, contains numerous population variants, and a variant of uncertain significance does not establish causality. Diagnosis requires genotype-phenotype integration including rigorous molecular classification, family history, electrocardiography, rhythm monitoring, biventricular imaging and assessment of alternative diagnoses. This caution prevents both missed diagnosis in a family at risk and unjustified medicalization of an uninterpretable genetic finding.

Population prevalence is not known precisely. The main cohorts come from inherited cardiomyopathy, arrhythmia and transplant centers and are therefore enriched for more severely affected probands compared with incidentally identified carriers. In the large international DSP-ERADOS network, a substantial proportion of individuals did not initially meet criteria for ARVC, dilated cardiomyopathy or nondilated left ventricular cardiomyopathy, showing that incomplete penetrance and the preclinical phase are central components of the disease. Event rates from specialist cohorts should therefore not be transferred without adjustment to every asymptomatic carrier.

Desmoplakin, desmosomes and mechanisms of disease

Desmoplakin is a desmosomal plaque protein located at intercalated discs, the junctions that allow cardiomyocytes to withstand the repetitive forces of contraction. Its amino-terminal portion interacts with plaque components including plakoglobin and plakophilins, whereas the carboxy-terminal region anchors the complex to desmin intermediate filaments. This mechanical bridge distributes tension across the tissue and also participates in cellular signaling; it is therefore not merely a passive rivet between adjacent cells.

Many causal heterozygous variants are nonsense, frameshift or splice-altering variants that introduce premature termination and reduce the amount of functional protein through nonsense-mediated RNA decay. Haploinsufficiency weakens the connection between the desmosome and cytoskeleton, but the phenotype cannot be explained simply as mechanical failure. Cellular models and human tissue show abnormalities in adhesion, proteostasis, intercalated-disc organization and stress-response pathways. Loss of function therefore creates a vulnerability involving structure, electrical behavior and immune response.

Focal cardiomyocyte death recruits inflammatory cells and is repaired with fibrosis. Over time, subepicardial foci may extend along the free wall and septum, producing an almost circumferential scar. Areas of viable myocardium separated by collagen slow and fragment conduction, providing a substrate for ventricular reentry; at the same time, cell loss reduces regional and then global function. This sequence links fibrosis and arrhythmias without requiring the ejection fraction to be severely impaired already.

Inflammation is not an incidental addition to scar. Clinical episodes with pain, troponin elevation, edema and new areas of late gadolinium enhancement suggest phases of active injury, whereas pathologic and clinical cohorts show that such episodes often precede electrical or functional progression. It remains uncertain to what extent immunity initiates, amplifies or responds to mechanical injury. The definition of a fibro-inflammatory disease recognizes this interaction but does not justify treating every troponin elevation as proven autoimmune disease.

Heterozygous variants responsible for adult forms generally follow autosomal dominant inheritance, with a 50% probability of transmitting the variant in each pregnancy. This probability is not equivalent to a 50% risk of severe cardiomyopathy because penetrance and expressivity vary. Biallelic variants can instead produce a broader recessive cardiocutaneous spectrum. Classic Carvajal syndrome is characterized mainly by early cardiac onset, woolly hair and palmoplantar keratoderma; skin fragility may occur in other biallelic DSP dermatoses but is not an obligatory feature of Carvajal syndrome. The inheritance pattern must be reconstructed from the specific variant and pedigree rather than inferred from the gene name.

Missense variants require particular caution because loss of function is the best-established mechanism for many dominant forms and a rare amino-acid substitution may be benign. Segregation with disease, population frequency, affected domain, functional data and independent observations all contribute to classification according to shared criteria. Even among truncating variants, position may modify the effect through transcript fate and the isoforms involved. Variant type adds information but does not replace individual phenotyping and cannot by itself predict age at onset.

Cutaneous signs are not exclusive to recessive forms. Curly or woolly hair, palmoplantar hyperkeratosis, early calluses and nail abnormalities have also been described with specific heterozygous variants, although they are not universal. A targeted dermatologic examination may become decisive when an adolescent has presumed recurrent myocarditis or when several relatives have characteristic hair and arrhythmias. These cardiocutaneous clues should be sought without using their absence to exclude the disease.

Phenotypic spectrum and hot phases

The most typical phenotype is left-sided or biventricular, but there is no mandatory configuration. Some patients meet criteria for arrhythmogenic right ventricular cardiomyopathy, others have nonischemic left ventricular scar with a nondilated chamber, and still others develop overt dilated cardiomyopathy. The 2023 ESC classification may place a phase with left ventricular scar and no dilation within nondilated left ventricular cardiomyopathy, whereas the Padua criteria and subsequent European Task Force consensus describe the corresponding phenotype as left-dominant arrhythmogenic cardiomyopathy. This nosologic overlap reflects different perspectives and should not obscure the DSP etiology.

Disease may begin with palpitations, premature ventricular contractions, nonsustained or sustained ventricular tachycardia, syncope or cardiac arrest. In other cases, dyspnea, fatigue and congestion from left-sided or biventricular dysfunction predominate. Absence of symptoms does not exclude scar, and the first finding may be an abnormal ECG or late gadolinium enhancement detected during family screening. The electrical phenotype may therefore precede pump failure and requires tools beyond echocardiography alone.

Hot phases are acute episodes typically characterized by chest pain, troponin elevation, ST-segment or T-wave changes, and signs of edema or nonischemic injury on cardiac magnetic resonance. Ventricular function may remain preserved, decline transiently or deteriorate persistently. Fever or a recent viral illness may be absent, and an episode may recur months or years later. The term hot phase describes clinical behavior but does not by itself identify a specific histologic or immunologic etiology.

The resemblance to myocarditis is real rather than merely semantic. A DSP carrier may meet clinical and CMR criteria compatible with acute myocarditis, and an infectious or immune-mediated cause can still coexist. The correct question is therefore not whether the episode is genetic or inflammatory in absolute terms, but whether a desmosomal vulnerability is producing or amplifying inflammatory injury and which treatable cause must be excluded. This dual perspective avoids both repeated diagnoses of idiopathic myocarditis and indiscriminate attribution of every episode of chest pain to the genotype.

Hot phases are particularly recognizable in adolescents and young adults and may precede chronic dysfunction by years. A history of recurrent episodes, scar more extensive than expected after a single event, ventricular arrhythmias, a family history of sudden death or cardiomyopathy, and cutaneous findings should prompt consideration of genetic testing. In acute myocarditis cohorts, desmosomal variants, particularly DSP, have identified a subgroup at greater risk of recurrence and complications. Recurrent myocarditis is therefore an important diagnostic gateway to inherited cardiomyopathy.

Each episode may leave new scar, but the course is not uniformly cumulative and some patients remain stable after a single phase. In large DSP cohorts, clinically documented myocardial injury is associated with a higher subsequent risk of sustained arrhythmias and heart failure, despite unavoidable selection and surveillance effects. The troponin history should therefore be reconstructed using reports and imaging, distinguishing mild nonspecific elevations from episodes coherent in symptoms, biomarkers and imaging.

Progression can also occur without clinically apparent hot phases. Subclinical injury, gradual fibrosis and arrhythmias may develop between apparently quiet follow-up visits, and normal troponin does not prove permanent quiescence. Conversely, persistently mild troponin elevation requires contextual assessment and does not by itself justify immunosuppression or repeated hospitalization. This silent disease explains why surveillance must combine rhythm, function and tissue rather than rely on a single biomarker.

Diagnostic pathway and multimodality characterization

Evaluation begins with a personal and family history extending for at least three generations. Cardiac arrests, sudden or unexplained deaths, unconfirmed epilepsy, incidents in water or during sports, defibrillators, transplantation, heart failure, recurrent myocarditis and cutaneous signs should be sought. Age and documentation of events matter more than a generic statement of heart disease. A dynamic pedigree is updated over time because a family that initially appears negative may become informative when relatives are examined.

A 12-lead ECG may show T-wave inversion in inferior or lateral leads, low limb-lead voltages, QRS fragmentation or less specific abnormalities. No finding is mandatory, and a normal ECG does not exclude scar. The number and distribution of negative T waves gain value when associated with imaging abnormalities or arrhythmias and may reflect more extensive left ventricular involvement. Serial ECG interpretation is more informative than a single snapshot, especially in young carriers.

Ambulatory monitoring quantifies premature ventricular contractions, morphologies, couplets and nonsustained ventricular tachycardias. A 24-hour Holter may underestimate intermittent arrhythmia, so monitoring duration and frequency should be adapted to symptoms and risk; an implantable loop recorder may be useful in selected patients with syncope. Ectopic morphology suggests the site of origin but does not establish etiology by itself. Arrhythmic burden is both a disease manifestation and a component of prognostic stratification and should be compared over time with therapy and activity.

Echocardiography assesses chamber dimensions, ejection fraction, right ventricular function, regional abnormalities and valves, while excluding alternative hemodynamic causes. In early phases it may be normal or show only regional hypokinesia and reduced longitudinal deformation, or strain, while subepicardial scar remains invisible. Apparently preserved right ventricular function does not contradict the diagnosis and may accompany a predominantly left-sided phenotype. Biventricular echocardiography remains essential for follow-up but does not replace tissue characterization.

Cardiac magnetic resonance is the reference examination for defining volumes, regional function and tissue. The most suggestive finding is nonischemic subepicardial late gadolinium enhancement, often inferior and inferolateral, which may extend across multiple segments to form an annular or ring-like distribution. Intramural or transmural areas, regional thinning and fatty replacement may coexist. The subepicardial pattern points toward DSP disease but also occurs in other cardiomyopathies and after myocarditis and is not by itself a genetic test.

Ring-like LGE is generally described as subepicardial or intramural involvement of at least three contiguous segments in the same short-axis slice, with a partially or nearly completely circumferential appearance. Some comparative studies, including the 2025 study by Laredo, used a more restrictive methodological definition limited to the basal slice; quantitative thresholds and definitions therefore vary among laboratories and sequences. Overall, cohorts show more extensive left ventricular scar and less right ventricular predominance in DSP cardiomyopathy than in classic desmosomal forms. The ring sign is highly suggestive in the appropriate context, not pathognomonic and not sufficient to classify an uncertain variant as causal.

During a hot phase, T1 and T2 mapping, extracellular volume and edema-sensitive sequences help distinguish recent activity from chronic scar. Increased T2 supports edema, whereas native T1, extracellular volume and LGE reflect injury with different temporal specificity. A late CMR may no longer show edema but may document residual scar; a very early or technically limited scan may be falsely reassuring. The timing of CMR should be recorded in relation to pain and troponin so that evolution can be interpreted correctly.

During an infarct-like presentation, an acute coronary syndrome must be excluded according to age, clinical probability and severity, using coronary computed tomography angiography or invasive coronary angiography when appropriate. Coronary dissection, vasospasm and embolism should also be considered, especially when imaging distribution is ischemic. Complete blood count, inflammatory markers, renal and hepatic function, electrolytes, natriuretic peptides and troponin define injury and consequences, whereas indiscriminate viral serology panels have low yield. Coronary exclusion precedes genetic attribution in acute presentations compatible with ischemia.

Endomyocardial biopsy is not necessary for every DSP carrier and is not used routinely to confirm a typical CMR pattern. It becomes relevant in fulminant presentations, shock, threatening arrhythmias or conduction block, severe new-onset dysfunction, and when the result can identify giant-cell myocarditis, eosinophilic myocarditis, sarcoidosis or an infectious etiology capable of changing therapy. Sampling may miss a focal lesion and should be performed in experienced centers, preferably guided by imaging. Targeted biopsy is intended to answer a therapeutic question, not to replace an incomplete clinical pathway.

Genetic testing should be accompanied by pre- and post-test counseling and should analyze DSP within a panel of genes with validated cardiomyopathy associations. A pathogenic or likely pathogenic variant confirms etiology when the clinical picture is coherent and enables cascade testing; a variant of uncertain significance remains nonactionable. A negative result does not exclude an inherited basis, whereas a second variant can modify the phenotype only if it also has robust evidence. Molecular diagnosis requires a qualified laboratory, expert review and the possibility of reclassification over time.

Diagnostic criteria and differential diagnosis

The 2010 Task Force Criteria were designed for arrhythmogenic right ventricular cardiomyopathy and are less sensitive to left-sided phenotypes. The 2020 Padua criteria introduced structural, tissue, electrocardiographic and arrhythmic left ventricular abnormalities; the European Task Force consensus published in 2024 refined this framework and recognized ring-like scar as a characteristic finding of ALVC. Criteria-guided diagnosis protects against overdiagnosis, but a DSP carrier may be at a stage preceding attainment of a formal threshold.

The 2023 ESC classification instead adopts a phenotype-first, etiology-second pathway and includes nondilated left ventricular cardiomyopathy, defined by nonischemic scar or fatty replacement, with or without wall-motion abnormalities, or by isolated global hypokinesia without dilation. A patient with DSP disease may progress over time from this category to DCM or show biventricular involvement. The longitudinal phenotype should therefore be updated without arbitrarily changing the genetic cause and without treating the labels as mutually exclusive.

Infectious or immune-mediated myocarditis is the principal differential diagnosis during hot phases. A single episode after infection, with edema and limited LGE that regress without family history or persistent arrhythmias, may be acquired; recurrences, annular scar, persistent ventricular ectopy and affected relatives instead increase the probability of DSP disease. The distinction cannot depend on CMR appearance alone because both processes can produce subepicardial LGE. A diagnosis of myocarditis and genetic predisposition can also coexist in the same individual.

Cardiac sarcoidosis can produce conduction block, tachycardias, dysfunction and multifocal LGE, often involving the basal septum and right ventricle. Positron emission tomography, evaluation for extracardiac disease and biopsy of an accessible site become important when distribution, conduction abnormalities or systemic manifestations are atypical for DSP disease. Giant-cell and eosinophilic myocarditis should be considered in rapidly progressive presentations or those associated with eosinophilia and medications. These inflammatory phenocopies require urgency because treatment and prognosis differ radically.

Among genetic cardiomyopathies, truncating FLNC variants can produce a left-sided phenotype with ring-like LGE and very similar arrhythmias. LMNA more strongly suggests conduction disease and atrial arrhythmias, PLN may produce low voltages and fibrosis, whereas PKP2 more often retains classic right ventricular predominance. Dystrophinopathies and desmin diseases require attention to creatine kinase and neuromuscular signs. This genetic differential diagnosis shows why a curated panel and expert variant interpretation are superior to targeted DSP testing based on a suggestive image.

Ischemic cardiomyopathy produces subendocardial or transmural scar in a coronary territory, in contrast to the nonterritorial subepicardial predilection of DSP disease, although previous emboli or dual pathology may confound the picture. Tachycardia-induced cardiomyopathy requires a temporal relationship between high arrhythmic burden and dysfunction and tends to improve after rhythm control, without explaining extensive subepicardial scar. Alcohol, chemotherapeutic drugs and autoimmunity should also be assessed as causes or modifiers. A multiple-hit model is often more realistic than requiring a single exposure to explain the entire phenotype.

Athlete’s heart may show balanced dilation, bradycardia and modest repolarization abnormalities but does not explain extensive subepicardial scar, complex ventricular tachycardia or recurrent hot phases. A period of detraining may help in selected cases but should not delay genetics and CMR when warning signs are present. In young people, syncope during exercise, chest pain with troponin elevation and a positive family history require temporary suspension of activity until evaluation is complete. Distinguishing disease from adaptation is particularly delicate because exercise can also accelerate expression of a desmosomal cardiomyopathy.

Natural history and risk stratification

Natural history does not follow an inevitable sequence from genotype positivity to scar, dilation, heart failure and sudden death. Some carriers remain phenotype-negative for decades, others develop early electrical abnormalities or a hot phase, and still others present directly with dysfunction. All of these trajectories may coexist within the same family. This nonlinear progression requires repeated follow-up and prevents using the proband’s age at onset as a calendar for other carriers.

Arrhythmic risk can be substantial with moderately reduced or even preserved ejection fraction. A history of nonsustained ventricular tachycardia, previous sustained arrhythmia, high premature ventricular contraction burden, reduced left ventricular function and right ventricular dysfunction are reproducible signals in contemporary cohorts. Scar provides a biologically plausible substrate, but its extent and distribution have not yet been standardized in every model. Ejection fraction alone is therefore insufficient for surveillance and sudden-death prevention decisions in DSP cardiomyopathy.

The large DSP-ERADOS cohort of 800 carriers documented sustained ventricular arrhythmias in 17.4% and heart failure hospitalizations in 9% during a median follow-up of 3.7 years, with the caution required by tertiary-center selection. In the multivariable model, previous arrhythmias, female sex and an ejection fraction no greater than 50% were associated with arrhythmic events, whereas negative T waves in at least three leads and reduced left ventricular function were associated with heart failure. These gene-specific data have moved beyond the assumption that DSP risk simply mirrors classic ARVC.

A dedicated model, the DSP risk score, estimates the 5-year probability of a first sustained ventricular arrhythmic event in carriers of pathogenic or likely pathogenic DSP variants who have not had sustained ventricular arrhythmias before or at initial assessment. It is therefore a primary-prevention tool and does not apply to variants of uncertain significance, secondary prevention or patients who have already presented with a sustained event. The model integrates sex, nonsustained ventricular tachycardia, the logarithm of the number of premature ventricular contractions over 24 hours, left ventricular ejection fraction below 50% and moderate or severe right ventricular dysfunction. The original external validation, performed in 86 individuals, showed a c-statistic of 0.791; an independent validation published in 2026 in 450 carriers not included in the original cohorts confirmed useful but more moderate discrimination, with a c-statistic of 0.719. These findings support generalizability without turning the model into an automatic rule. The DSP calculator can inform shared ICD decision-making, does not establish a universal mandatory threshold and should be reconsidered when rhythm or function changes.

Sex requires cautious interpretation. Some small historical series suggested a worse course in men, whereas larger cohorts and the recent model found a greater adjusted risk of sustained arrhythmia in women. Differences in selection, right- versus left-sided phenotype, exercise, pregnancy and hormones may contribute to this discrepancy. Sex-related risk should not be transferred from one cohort to another as a definitive biologic rule and should not automatically reassure either men or women.

Hot phases modify prognosis. In longitudinal analyses, an episode of myocardial injury is followed by a higher incidence of arrhythmias and heart failure, and recurrences identify a more unstable course. It is not yet possible to determine how much of the risk derives from the episode itself, from greater underlying genetic severity or from more intensive surveillance. A history of an inflammatory phase should nevertheless enter risk assessment together with scar and rhythm, even if function has normalized.

Heart failure risk depends on left ventricular function, disease extent and hot phases but does not coincide with arrhythmic risk. A patient may have many arrhythmias with relatively preserved pump function, or functional progression with less ectopy. Biventricular dysfunction, recurrent hospitalizations, hypotension, renal impairment, elevated natriuretic peptides and reduced functional capacity indicate the need for advanced evaluation. These dual arrhythmic and hemodynamic trajectories require parallel stratification and prevent an ICD from being considered a therapy for heart failure.

Individual prognosis should be reassessed after every clinical change, new arrhythmia, hot phase or change in ventricular function. Risk estimated at the first visit does not remain valid for life, and an apparently low-risk carrier may acquire markers over time. Conversely, persistent absence of a phenotype in a relative identified through cascade testing carries lower risk than in a symptomatic proband. Dynamic stratification is therefore more accurate than a permanent high- or low-risk label based on the gene alone.

Management of hot phases and chronic therapy

A hot phase with chest pain and troponin elevation initially requires the same seriousness as any suspected myocarditis or acute coronary syndrome. Hemodynamic stability, arrhythmias, ventricular function and signs of heart failure determine hospitalization, monitoring intensity and the need for intensive care. Serial ECGs and troponin, echocardiography and CMR are integrated with coronary assessment and evaluation for specific causes. The acute priority is to recognize ischemia, shock, malignant arrhythmias and treatable myocarditis rather than rapidly confirm an already known genetic explanation.

In fulminant presentations, principles of cardiogenic shock management apply, including inotropic and mechanical support in experienced centers when needed. Sustained arrhythmias are treated according to stability with cardioversion or defibrillation and correction of precipitating factors. Biopsy gains greater value if it can identify a histologic form requiring urgent immunosuppression. Support of vital functions precedes any discussion of the DSP mechanism and may bridge to recovery, durable mechanical support or transplantation.

There is still no universally validated drug protocol for DSP hot phases. NSAIDs and colchicine treat a pericarditic component when indicated but have not been shown to prevent fibrosis or arrhythmias in desmoplakin cardiomyopathy. A large 2025 observational study associated immunosuppression of the first episode with fewer arrhythmic and heart failure events, without clearly reducing recurrences; however, the nonrandomized design is vulnerable to confounding by indication and treatment differences. This emerging immunosuppression strategy warrants prospective evaluation, not automatic prescription.

When immunomodulatory treatment is considered, the decision should be multidisciplinary and based on severity, inflammatory activity, exclusion of relevant infections and, in appropriate cases, biopsy with immunohistochemistry and molecular testing for viral genomes. Dose, duration and combination with other immunosuppressive agents have not been standardized for DSP disease. Experience from virus-negative myocarditis may guide selected cases but remains an extrapolation. This therapeutic uncertainty should be communicated clearly because a favorable observational association is not equivalent to causal evidence of efficacy.

Chronic therapy for systolic dysfunction follows heart failure guidelines: renin-angiotensin system inhibition with ARNI when appropriate, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor, with diuretics for congestion. Initiation and titration depend on blood pressure, renal function, potassium and tolerance. Recovery of ejection fraction does not remove the genetic substrate or scar and does not justify routine treatment withdrawal. Pump-directed therapy reduces progression and hospitalizations even though it is not DSP-specific.

Beta-blockers are useful when dysfunction, arrhythmias or conventional indications are present, but they do not eliminate sudden-death risk. Antiarrhythmic drugs may reduce tachycardias and device therapies; selection considers ventricular function, proarrhythmia, target-organ toxicity and possible long-term effects. No antiarrhythmic drug replaces an ICD in a patient with an indication for sudden-death prevention. Rhythm control aims to reduce symptoms and arrhythmic burden while keeping protection from lethal events conceptually separate.

An ICD is indicated for secondary prevention after cardiac arrest or sustained ventricular arrhythmia not attributable to a completely reversible cause, according to general guidelines. For primary prevention, the decision integrates DSP genotype, ejection fraction, right ventricular dysfunction, nonsustained tachycardia, premature ventricular contractions, likely arrhythmic syncope, scar, hot phases and life expectancy. ESC guidelines recognize DSP among high-risk genotypes in DCM and NDLVC phenotypes and allow consideration of an ICD beyond the traditional 35% threshold when additional risk factors are present. Primary prevention remains individualized and shared.

The choice between transvenous and subcutaneous systems considers pacing requirements, the likelihood of tachycardias treatable with antitachycardia pacing, anatomy, age and cumulative complication risk. A subcutaneous device avoids endovascular leads but does not provide chronic or antitachycardia pacing; a transvenous system provides these functions at the cost of lead-related risks. The type of ICD is selected according to the expected arrhythmic profile and not solely according to young age or a center’s technical preference.

Catheter ablation is indicated for recurrent tachycardias that are symptomatic or responsible for ICD therapies and are not adequately controlled by medication. The DSP substrate is often subepicardial and may require epicardial mapping in experienced centers after assessment of procedural risks. Recurrences are possible because disease evolves and new scar areas may develop. Tachycardia ablation reduces arrhythmic burden but does not cure the cardiomyopathy, eliminate hot phases or replace defibrillator protection when indicated.

In patients with advanced heart failure, evaluation for ventricular assist support or transplantation should not be postponed until multiorgan collapse. Right ventricular involvement, refractory arrhythmias and extracardiac frailty influence the strategy, whereas cardiocutaneous forms may require dermatologic and nutritional expertise. Transplantation removes the diseased heart but does not automatically correct cutaneous manifestations of biallelic variants. Advanced care should begin when the functional trajectory, hospitalizations and treatment tolerance indicate rapidly diminishing reserve.

Exercise, pregnancy and daily life

Intense exercise increases mechanical stress on desmosomal junctions and is a recognized modifier of arrhythmogenic cardiomyopathies, but DSP-specific data are more recent than those for PKP2-related ARVC. In a cohort of adults with DSP variants, endurance activity was associated with a higher risk of myocardial injury episodes, whereas a direct association with sustained arrhythmias and heart failure was not demonstrated. This endurance signal supports caution without allowing a universal safe dose to be quantified precisely.

In DSP carriers with a phenotype, scar, arrhythmias or previous hot phases, competitive sports, high-intensity activity and prolonged endurance exercise are generally discouraged. Even a carrier of a pathogenic or likely pathogenic variant who remains phenotype-negative should receive explicit counseling against competitive sports and frequent high-intensity endurance exercise: this is a precautionary approach from arrhythmogenic cardiomyopathy consensus documents, whose historical evidence derives mainly from ARVC and PKP2, while direct DSP data remain more limited and relate particularly to myocardial injury episodes. Low- or moderate-intensity recreational activity can be maintained or prescribed individually because sedentary behavior and isolation have their own consequences. Type of sport, dynamic and static components, environment, availability of rescue and presence of an ICD enter the discussion. Exercise prescription should be updated when rhythm, function or imaging changes.

After a hot phase, exercise is suspended during the active phase and resumption requires resolution of symptoms, normalization or stabilization of biomarkers, functional recovery and absence of relevant arrhythmias on assessment. Scar may persist even when edema and troponin normalize, so return to activity does not erase genetic risk. Timing and intensity should follow myocarditis recommendations adapted to the underlying cardiomyopathy. Return to activity is a progressive clinical decision, not an automatic calendar deadline.

Pregnancy entails increased volume, heart rate and hemodynamic stress and may coincide with expression or worsening of a cardiomyopathy, but DSP-specific data are limited. Before conception, function of both ventricles, arrhythmias, scar, medications and history of hot phases should be reassessed; severe dysfunction or advanced heart failure may make maternal risk very high. Preconception assessment separates the mother’s clinical risk from the probability of transmitting the variant and involves cardiology, high-risk obstetrics and genetics.

During pregnancy and breastfeeding, therapy must be reviewed because some heart failure drugs are contraindicated, whereas selected beta-blockers may be continued when indicated with maternal and fetal monitoring. Palpitations, syncope, chest pain or new dyspnea require prompt evaluation and should not automatically be attributed to physiologic changes. The postpartum period warrants surveillance because of rapid hemodynamic changes. Peripartum management should be planned before labor, including device considerations, analgesia and place of delivery.

Fever, dehydration, electrolyte abnormalities, stimulants and drugs with proarrhythmic potential can increase electrical instability and should be managed promptly. Alcohol consumption is not a cause of DSP disease but may worsen function, arrhythmias and adherence, particularly when excessive. Patients should know which symptoms require urgent assessment, how the ICD functions and driving restrictions after events or device therapies according to local regulations. Daily prevention is concrete and individualized without becoming a set of prohibitions unsupported by evidence.

The psychological impact of a potentially arrhythmic inherited disease is substantial. Anxiety after a shock, fear of exercise, guilt about transmission to children and uncertainty in phenotype-negative carriers can reduce quality of life and adherence. Consistent information, adapted rehabilitation and psychological support are part of care, especially in young people excluded from competitive sports. Risk communication should use probabilities and modifiable scenarios, avoiding both absolute reassurance and the idea of an inevitable sudden fate.

Family screening and longitudinal surveillance

First-degree relatives of an affected patient should receive clinical evaluation even while testing of the proband is still in progress. History, physical examination, ECG, ambulatory monitoring and echocardiography form the foundation; CMR is particularly useful when ECG or echocardiography is equivocal, when the family has a left-sided phenotype or when prefunctional scar is being sought. Initial family screening may identify a relative who immediately needs treatment even before the variant is defined.

When a pathogenic or likely pathogenic variant has been identified in the proband, targeted cascade testing distinguishes carriers from noncarriers. A relative who tests negative for the causal variant can generally be discharged from disease-specific surveillance if the variant and segregation robustly explain the family and no other causes exist. A VUS should not be used this way: negative or positive status for an uncertain variant does not alter phenotype-based follow-up. Cascade testing is powerful precisely because it answers an already defined molecular question.

Phenotype-negative carriers do not automatically receive medications or an ICD but enter periodic surveillance based on age, family history, variant and activity. ECG and echocardiography are repeated at intervals, with Holter monitoring and CMR according to the profile and new symptoms; in children, intervals may shorten during growth, puberty or sports participation. Initial normality does not equal permanent nonpenetrance. The preclinical phase is the time when avoiding adverse exposures and recognizing changes early may offer the greatest benefit.

In minors, predictive testing is justified because the result can modify surveillance and activities during childhood and adolescence. Parental consent, the child’s assent and age-appropriate communication reduce the impact of a genetic label. Woolly hair, hyperkeratosis, syncope, chest pain with troponin elevation or arrhythmias require expert pediatric assessment even without a known family history. Pediatric surveillance should accompany transition to adult services without losing previous genetic reports and CMR studies.

Reproductive counseling explains transmission, penetrance and variability, clearly distinguishing the probability of inheriting the variant from the probability of severe disease. Natural conception, prenatal diagnosis and preimplantation genetic testing are options to present nondirectively when the familial variant is defined. In rare biallelic forms, both partners should be tested and interpreted according to the family context. The reproductive choice belongs to the individual or couple and requires accurate data rather than predictions of severity that genetics cannot provide.

Follow-up of a patient with a phenotype includes symptoms, functional class, blood pressure, signs of congestion, ECG, arrhythmic burden and imaging. Troponin and natriuretic peptides are useful in defined contexts but do not replace structural and electrical data. CMR is repeated after new hot phases, clinical changes or at selected intervals to assess scar and function, avoiding a rigid identical schedule for everyone. Multimodal surveillance should generate decisions, not merely accumulate tests.

Every new episode of syncope, nonsustained tachycardia, increase in premature ventricular contractions, reduction in ejection fraction or extension of scar reopens discussion of ICD therapy and follow-up intensity. Similarly, prolonged stability and absence of a phenotype in relatives identified through cascade testing allow personalized intervals without abandoning surveillance. Genetic reports should be reassessed when classifications change, and the family should be informed if a reclassification alters management. Longitudinal care links laboratory, imaging, electrophysiology, heart failure and genetics within a single pathway.

Desmoplakin cardiomyopathy shows that scar, inflammation and electrical abnormalities may precede dilation and that presumed recurrent myocarditis may be the first expression of a familial disease. Recognizing it requires CMR interpreted in context, rigorous genetics and attention to history over time. Therapy must protect against sudden death, treat dysfunction and address hot phases cautiously while distinguishing established evidence from still-experimental strategies. This gene-specific perspective allows earlier prevention without reducing every carrier to the molecular test result.