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Patient Summary

A female in her 40s with no past medical history presented 6 years prior with acute onset dizziness, palpitations and fatigue without chest pain. She had no family history of arrythmias, SCD, or prior syncope. Her heart rate was 170 bpm and EKG showed wide complex, regular tachycardia felt to be VT. She underwent synchronized cardioversion to sinus rhythm. Her baseline EKG showed sinus bradycardia with low voltage, incomplete RBBB, and ventricular ectopy. Labs were unrevealing, and social history was negative for toxic insults or illicit substance abuse. TTE showed preserved LVEF and normal valves, but RV was dilated with decreased systolic function. LHC was without obstructive coronary disease. She was diagnosed with ARVC and received an ICD for secondary prevention. She was discharged on sotalol for arrythmia management. Her genetic testing later returned positive for uncertain significance in the DSP gene and JUP gene, both commonly implicated in ARVC. She was followed in the outpatient setting for 5 years with no apparent shocks. Six years later, she presented with acute onset dizziness and palpitations similar to her initial presentation. EKG showed a wide complex tachycardia at 170 bpm treated with amiodarone and cardioversion. On ICD interrogation, she was found to have had several episodes of VT, but at a rates below the VT detection zone programmed in the ICD. Subsequent RHC showed significantly depressed cardiac index and RV dysfunction. She underwent successful inpatient VT ablation. She was then discharged home with plans for close follow up; however, 2 days later, she started feeling nauseous with fatigue and abdominal pain. She was sent straight to the nearest transplant-capable hospital where she was found to be in cardiogenic shock. She was admitted to ICU and started on inotropes. Due to refractory shock, she was cannulated for VA ECMO and successfully underwent cardiac transplantation two days later.  

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Case Media

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Episode Schematics & Teaching

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The CardioNerds 5! – 5 major takeaways from the #CNCR case

1. What is ARVC? 

• Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is a heritable cardiac muscle disorder that classically involves the RV (though LV involvement is increasingly being recognized) marked by loss of healthy myocardium and replacement with fibrofatty tissue predominantly due to genetic defects in both desmosomal and non-desmosomal proteins. Clinical manifestations include RV dysfunction, ventricular arrhythmias, and sudden cardiac death (SCD). 
• This is a progressive disease that can affect the epicardium and/or mid-myocardium first and then move towards the sub-endocardium.  
• It affects approximately 1 in 5000 individuals and is an important cause of (SCD) in young patients. 50% of patients have a positive family history and it is thought to be inherit in an autosomal dominant fashion, however prevalence is underestimated due to incomplete penetrance. Interestingly, males are more affected than females possibly due to interaction of sex hormones with pathophysiology or historically different levels of participation in competitive sports among men and women. 
• The differential for ARVC should include Uhl’s anomaly, myocarditis, sarcoidosis, and Brugada syndrome among other considerations. 

2. What genes are implicated and what is the pathophysiology? 

• While 20-30% of ARVC is due to non-desmosomal gene variants (e.g., desmin, Titin) and non-genetic causes, 40-50% is due to autosomal dominant gene mutations that encode desmosomal proteins. These include plakophilin 2 PKP2 (in 10 to 45% of patients), followed by desmoplakin DSP (10 to 15%), desmoglein 2 DSG2 (7 to 10%), and desmocollin 2 DSC2 (2%).  Rarely, there can be an autosomal recessive inheritance pattern, including Naxos disease (first recognized in the Cycladian Islands in the Aegean Sea) characterized by ARVC along with “wooly hair” and palmoplantar hyperkeratosis. Our understanding of the genetic underpinnings of ARVC continues to evolve.  
• Desmosomes play a major role in intercellular adhesion and synchronized activation and signaling between myocytes. Defective desmosomes disrupt intercellular junctions which lead to myocyte detachment and myocyte death, and this process is especially exaggerated by mechanical stress like exercise. Athletes often have severe disease, possibly a result of high-intensity mechanical stress during exercise. Other resultant features of defective cardiac myocyte signaling is increased expression of adipogenic and fibrogeneic genes, resulting in the hallmark pathologic correlate of fibrofatty replacement of muscle tissue.  
• The fibrofatty scar tissue that replaces the myocardium slows conduction and allows for formation of macro-entry circuits that lead to the propagation of arrythmias. Furthermore, dysregulation of otherwise synchronized excitability due to abnormal cellular connections increase propensity for fatal arrhythmias. 

3. What EKG findings may be seen in ARVC? 

• EKG is an important tool in screening since 85-90% of patients will have at least one of the findings of ARVC. However, it is important to remember that the findings may evolve over time, including a normal ECG at presentation and thus serial re-assessment is crucial.  
• ECG changes include inverted T-waves in the right precordial leads, which have been correlated with RV enlargement and risk for ventricular arrhythmias. T wave inversions (TWI) are present in up to 87% of adult patients with ARVC, but can be especially challenging to interpret in athletes who may have TWIs as normal variants in 5% of white athletes and 25% of black athletes. The preceding ST-segment may provide a clue as to whether the TWI is abnormal, as ARVC patients with precordial TWI often have an isoelectric ST-segment while athletes have preceding convex ST-segment elevation.  
• Other findings include: 
  •  (1) prolonged S-wave upstroke (≥55 milliseconds) in the absence of a RBBB (~90% of patients w/o a RBBB) 
  • (2) Epsilon wave (~ 5 to 30% of patients) which is a distinct positive deflection at the end of the QRS complex best seen in V1 and/or V2 reflecting delayed activation of some parts to of the RV. Fontaine bipolar precordial leads (repositioning of the limb leads) may help increase the sensitivity for detecting epsilon waves.  
  • Isoproterenol infusion can be used to induce ventricular arrhythmias in suspected patients 

4. How can we diagnose ARVC? 

• In the “concealed phase,” patients are often asymptomatic but are still at risk of sudden cardiac death, especially during exertion. Furthermore, in the early stages of disease, structural changes may be subtle (or even absent) and confined to a focal area of the RV. 
• In the “electrical phase,” patients can present with symptomatic ventricular arrhythmias and RV structural abnormalities that are detected by cardiac imaging. Sports and rigorous exercise increase risk of SCD and contribute to disease progression. Common first symptoms are palpitations and effort-induced syncope, though SCD can also be the first presentation. In the later stages, diffuse disease is possible with biventricular heart failure. 
• In patients in whom there is a clinical suspicion for ARVC (e.g., positive family history, exercise-induced palpitations, unexplained right precordial TWI, patients who present with unexplained ventricular arrhythmias, and/or SCD), the diagnosis frequently requires multiple diagnostic tests.  
• The 2010 revised Task Force Criteria is used to confirm the diagnosis of ARVC, though proposed changes continue to arise as our understanding of ARVC evolves. The criteria require a demonstration of structural, functional, and electrophysiological abnormalities that reflect underlying histological changes. Thus, the criteria include parameters defining  (1) global and/or regional dysfunction and structural changes; (2) tissue characterization of the walls; (3) repolarization abnormalities on ECG; (4) depolarization/conduction abnormalities on ECG; (5) arrhythmias; and (6) family history.  
• Criteria for diagnosis is based on meeting two major, one major and two minor, or four minor criteria. Cardiac MRI is the preferred imaging tool because it can quantitatively assess phenotypic structural and functional abnormalities such as global dilatation and/or systolic akinesia/dyskinesia. In suspected ARVC, late gadolinium enhancement can represent fibrofatty infiltration.  
• It is important to note that endomyocardial biopsy is not indicated as routine testing, but may be considered to aid in securing a diagnosis amongst competing diagnoses. 

5. How is ARVC managed? 

• In patients with suspected and/or confirmed ARVC, there are 5 pillars of management: 
  1. Prevent sudden cardiac death. 
  2. Reduce arrhythmia burden to improve quality of life. 
  3. Treat the ensuing heart failure. 
  4. Screen and protect the family members. 
  5. Develop disease modification therapies (stay tuned!) 
•  Patients with ARVC should not participate in competitive, endurance or high-intensity non-competitive sports due to the association with disease progression and ventricular arrhythmias.  
• Beta-blockers are a critical component of treatment for all symptomatic ARVC patients and is a Grade 2C recommendation to include them as part of treatment for patients without history of sudden cardiac arrest or documented ventricular arrhythmias, as well. There is unclear benefit in asymptomatic genetic carriers. 
• Patients who have suffered a sudden cardiac arrest (i.e., aborted sudden cardiac death) or who have experienced sustained VT which was hemodynamically unstable, secondary prevention ICD implantation is recommended in addition to medical therapy (Grade 1B recommendation). Further, in ARVC patients with suspected arrhythmogenic syncope, moderate to severe RV or LV dysfunction, frequent PVCs and/or NSVT, multiple disease-causing mutations, and/or inducible VT on EP study, ICD implantation for primary prevention is recommended (Grade 2C). For patients with frequent ICD discharges, antiarrhythmic medications are preferred initially over catheter radiofrequency ablation (RFA). RFA can be utilized but due to the patchy and progressive nature of the disease it is often unsuccessful in completely suppressing ventricular arrhythmias.  
• Patients with clinical right, left, or bi-ventricular failure are treated with standard guideline directed pharmacotherapy. For those with refractory arrythmias or end-stage heart failure, cardiac transplant is the curative treatment. Given the typical RV-predominant heart failure, options for durable mechanical circulatory support are limited. 
• Mutation-specific genetic testing is recommended for family members in order to identify and follow affected patients in the pre-clinical phase.  

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References

Corrado, Domenico, Mark S. Link, and Hugh Calkins. “Arrhythmogenic Right Ventricular Cardiomyopathy.” New England Journal of Medicine 376, no. 1 (January 5, 2017): 61–72. https://doi.org/10.1056/NEJMra1509267. 

Corrado, Domenico, Peter J. van Tintelen, William J. McKenna, Richard N. W. Hauer, Aris Anastastakis, Angeliki Asimaki, Cristina Basso, et al. “Arrhythmogenic Right Ventricular Cardiomyopathy: Evaluation of the Current Diagnostic Criteria and Differential Diagnosis.” European Heart Journal 41, no. 14 (April 7, 2020): 1414–29. https://doi.org/10.1093/eurheartj/ehz669. 

Gandjbakhch, Estelle, Alban Redheuil, Françoise Pousset, Philippe Charron, and Robert Frank. “Clinical Diagnosis, Imaging, and Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: JACC State-of-the-Art Review.” Journal of the American College of Cardiology 72, no. 7 (August 14, 2018): 784–804. https://doi.org/10.1016/j.jacc.2018.05.065. 

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The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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