74. Case Report: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) – Summa Health

CardioNerds (Amit Goyal & Daniel Ambinder) join Summa Health cardiology fellows (Jack Hornick, Phoo Pwint Nandar, and Sideris Facaros) for a hike on the Towpath Trail at Cuyahoga Valley National Park in Akron, Ohio! They discuss an informative case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) complicated by ventricular tachycardia & cardiogenic shock. Dr. Kenneth Varian provides the E-CPR and program director, Dr. Marc Penn provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai.  

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CardioNerds (Amit Goyal & Daniel Ambinder) join Summa Health cardiology fellows (Jack Hornick, Phoo Pwint Nandar, and Sideris Facaros) for a hike through Cuyahoga Valley National Park in Akron, Ohio! They discuss an informative case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) complicated by ventricular tachycardia & cardiogenic shock. Dr. Kenneth Varian provides the E-CPR and program director, Dr. Marc Penn provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident, Eunice Dugan, with mentorship from University of Maryland cardiology fellow Karan Desai.
Episode graphic by Dr. Carine Hamo

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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.  


Case Media

A. Post cardioversion ECG: NSR, low voltage, incomplete RBBB, PVC
B. TTE: RV enlargement
C. TTE: Tissue Doppler velocity (S’) low

TEE

Episode Schematics & Teaching


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. 
  1. 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. 
  1. 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 
  1. 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. 
  1. 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.  

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. 


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.

Cardionerds Cardiology Podcast Presents CardioNerds Case Report Series

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56. Case Report: Arrhythmogenic Desmoplakin Cardiomyopathy – Northwestern University Feinberg School of Medicine

CardioNerds (Amit Goyal & Daniel Ambinder) join Northwestern University cardiology fellows (Sarah Hale, Sarah Chuzi, and Graham Lohrmann) for burgers and a great case by the Chicago River! They discuss a fascinating case of arrhythmogenic desmoplakin cardiomyopathy. Dr. Lisa Wilsbacher provides the E-CPR and program director Dr. Benjamin Freed provides a message for applicants.  Episode notes were developed by Johns Hopkins internal medicine resident Richard Ferraro with mentorship from University of Maryland cardiology fellow Karan Desai

Jump to: Patient summaryCase figures & mediaCase teachingReferencesProduction team


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.

CardioNerds Case Reports Page
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Patient Summary

A male in his early 40s presented for second opinion regarding multiple ICD shocks. 10 years prior he was diagnosed with a “weak heart,” thought secondary to a viral illness and a dual-chamber ICD was placed at that time. He noted shocks occurring for the first time 5 years prior, at which time amiodarone was started. They recurred two years prior, when he was diagnosed with paroxysmal atrial fibrillation. Finally, he was hospitalized one month before presentation with multiple ICD shocks and was found to have high defibrillation thresholds (DFTs) and amiodarone was stopped. He  then presented for a second opinion from the Northwestern CardioNerds! 

The patient had been doing well on GDMT and had NYHA Class I symptoms (Enjoy Ep #13 – Approach to GDMT). He did note a family history of a cousin with “cardiac issues” and did not know his father’s family history. Physical exam demonstrated bradycardia and ECG demonstrated an a-paced, v-sensed rhythm at 50 bpm. TTE demonstrated a moderately dilated LV with LVEF 30%, globally reduced LV function and multiple wall motion abnormalities without a vascular distribution.  PET-CT was performed which showed diffuse uptake and high-intensity signal at the inferolateral and basal anterior walls. Cardiac MRI showed diffuse circumferential epicardial delayed enhancement with associated diffuse, enhancing thickening of the pericardium favoring inflammatory versus fibrotic process. Patient was initially diagnosed with cardiac sarcoid and started on prednisone and weekly methotrexate.  

On return of genetic testing, patient found to have a pathogenic variant for desmoplakin gene, and it was felt his cardiomyopathy was secondary to desmoplakin Left Dominant Arrhythmogenic Cardiomyopathy (LDAC, or left-dominant ARVC) presenting with inflammatory myocardial injury. On follow up the patient remained listed for transplant, and DFTs improved off amiodarone.  


Case Media


Episode Schematics & Teaching


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

  1. We started the case talking about DFTs. What are DFTs?! 
    • Defibrillation Thresholds (DFTs) are the minimal amount of energy required to return a patient to sinus rhythm that is in a cardiac dysrhythmia.  
    • Most modern ICD leads have thresholds less than 15 joules and typically less than 10 joules with biphasic shocks. High DFT thresholds tend to be defined as >25J or a safety margin of <10J. 
    • DFT testing is not routinely recommended during implantation of left-sided transvenous devices; however, in patients undergoing right-sided transvenous ICD or ICD pulse generator changes, DFT testing is a reasonable approach. Patients undergoing subcutaneous ICD placement should generally have DFT testing. 
    • Contraindications to DFT testing include acute LV thrombus, atrial fibrillation/flutter without adequate anticoagulation, severe aortic stenosis, recent stroke or TIA, or hemodynamic compromise as DFT itself can cause hypotension and/or CVA.   
  2. What are the major causes of high DFTs? 
    • First there are myocardial factors. This includes pathology that affects the current density through the myocardium. Conditions like hypertrophic cardiomyopathy, inflammatory cardiomyopathy, or significant LV dilation can lead to high DFTs.    
    • The second set of factors are extra-cardiac causes that lead to increased impedance or resistance in the counter coil, such as high BMI or medications that lead to electrical imbalances such as amiodarone, which is a common cause of increased DFTs. However, the increase in DFT caused by amiodarone can be small and routine DFT testing in patients is not recommended.   
    • The last cause is a device factor, such as a lead fracture or a mal-positioned lead.  
  3. In the case, we used MRI and PET. What are their role in Cardiomyopathy? 
    • Cardiac MRI (CMR) has transformed our ability to assess cardiomyopathies, specifically by accurately defining chamber size & function, characterizing myocardial tissue, and determining ischemia & viability. The specific pattern of late gadolinium enhancement (LGE) can help us differentiate between ischemic and non-ischemic etiologies and specific cardiomyopathies have characteristic patterns on MRI. Further, MRI can reliably identify edema, inflammation, and fatty replacement. CMR can provide a wealth of information in a variety of disease processes. Enjoy Ep #33 – CMR!
    • When evaluating an unexplained cardiomyopathy, FDG-PET can be useful in identifying active myocardial inflammation. 18F-FDG is a glucose analogue that can differentiate activated macrophages in areas of inflammation from normal myocytes if there is appropriate suppression of normal physiologic myocardial glucose uptake (I.e., Ketogenic Diet). This can be especially useful in Cardiac Sarcoidosis. Note, if there is global myocardial uptake, without diffuse perfusion defects, it may be a false positive scan in the setting of inadequate prep!  
    • For more on evaluation of heart failure, enjoy Ep #12 – Eval of New Onset HF & CPS Ep #48 – HFrEF
  4. When should we consider a genetic cause to cardiomyopathy? 
    • If a family history suggests a genetic predisposition to cardiomyopathy, a cardiomyopathy seems out of proportion to an identified ischemic or non-ischemic cause, a patients presents with a cardiomyopathy at a young age, or if multi-modal imaging has not revealed a clear cause of a cardiomyopathy, genetic testing would be appropriate. 
    • Various studies have indicated that 30 to 50% of unexplained cases of (DCM) may have a genetic component. A detailed, at least three-generation family history should be obtained when initially evaluating a dilated CM, as most genetic cardiomyopathies are autosomal dominant with variable penetrance.  
    • Genetic counseling is key prior to genetic testing given complexities including interpretation of potentially confounding results and contextualizing results for relatives. 
  5. Our patient’s final diagnosis was “Arrhythmogenic Desmoplakin Cardiomyopathy”…what’s that?! 
    • Arrhythmogenic RV Cardiomyopathy is a familial cardiomyopathy which usually affects the RV via fibrous or fibro-fatty replacement of normal myocardium. This predisposes patients to sudden cardiac death (SCD), ventricular arrhythmias, and heart failure.  
    • ARVC classically displays autosomal dominant inheritance from mutations in genes encoding desmosomal proteins affecting the cell-to-cell junction: desmoplakin (DSP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2). Rarely, genes unrelated to cell-to-cell junction may be involved.  
    • Clinically we have noted a “Left-Dominant Arrhythmogenic Cardiomyopathy” (LDAC), with similarities to classic ARVC, but affecting predominantly the LV.  
    • Genotype-phenotype studies are shedding light on these “Arrhythmogenic Cardiomyopathies”. DSP mutations affect predominantly the LV (causing LDAC) whereas PKP2 mutations affect predominantly the RV (causing ARVC); these are distinct entities with key differences in presentation, progression, and markers of SCD risk (see Smith et al., Circulation 2020 reference for more!). Pertinent to our case, a subset of patients with DSP cardiomyopathy will have evidence of myocardial inflammation on FDG-PET and will are initially misdiagnosed as a myocarditis or sarcoidosis. 

References


CardioNerds Case Reports: Recruitment Edition Series Production Team

35. Heart Failure with Preserved Ejection Fraction with Dr. Kavita Sharma

Heart Failure with Preserved Ejection Fraction with Dr. Kavita Sharma

We discuss Heart Failure with Preserved Ejection Fraction (HFpEF) with Dr. Kavita Sharma, director of the Heart Failure with Preserved Ejection Fraction Program and interim director of Advanced Heart Failure Transplant section at The Johns Hopkins Hospital. CardioNerds hosts Carine Hamo and Daniel Ambinder are joined by Dr. Beth Feldman (resident at The Johns Hopkins Hospital). Topics discussed include a definitions, diagnosis, phenotypic presentations, inpatient management of acute decompensated heart failure, role of dopamine, advanced therapies of HFpEF, and the Paraglide trial.

References mentioned in this episode can be found here

On the CardioNerds Heart Failure topic page you’ll podcast episodes, references, guest experts and contributors, and so much more.

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Acute Decompensated Heart Failure Primer – Youtube

Dr. Kavita Sharma graduated from the University of Virginia School of Medicine and completed her residency and served as the assistant chief of service, cardiology fellowship and advanced heart failure fellowship at the Johns Hopkins Hospital. She is the Director of the Johns Hopkins Heart Failure with Preserved Ejection Fraction Program and is currently the interim director of Advanced Heart Failure Transplant section at Hopkins. She has a specialized interest in heart failure with preserved ejection fraction (HFpEF), and directs one of the largest programs in the country dedicated to caring for patients with this condition. She is the principal investigator of numerous clinical and translational trials in HFpEF and leads a team of nurses, research coordinators, and fellows-in-training in this multifaceted program. She is an invited speaker at national meetings in topic areas covering advanced heart failure and HFpEF.

Dr. Beth Feldman graduated from Temple University School of Medicine and is currently on the Longcope Firm on the Osler Medical Service at Johns Hopkins University Hospital. Before pursuing a career in medicine, she worked in health care consulting focusing in health systems. She is passionate about health policy and health systems research. She is hoping to pursue a career in cardiology, with a particular interest in critical care.