A 68-year-old White woman is brought to the emergency department by ambulance after experiencing chest pain, palpitations, and shortness of breath for 1 hour prior to arrival. Vital signs recorded by emergency medical technicians on arrival at the patient’s home show a blood pressure of 200/100 mm Hg, pulse of 110 beats per minute, and oxygen saturation of 94% on room air. The patient has a single-lead electrocardiography recording from her smartwatch showing premature ventricular contractions (PVCs) occurring at a rate of 6 per minute (Figure).

Electrocardiography in the emergency department shows no evidence of acute coronary syndrome. Cardiac enzymes are negative. The patient has never used tobacco products and has well-controlled hypertension and hyperlipidemia. However, the patient reports a strong family history of sudden cardiac arrest and syncope with cardiac arrhythmias from arrhythmogenic right ventricular cardiomyopathy (ARVC). These family members all had a mutation in the desmosomal protein (DSP) gene that controls the interlinking of cardiac cells.

The patient previously tested negative for this gene mutation. Four out of 10 of her first- and second-degree relatives with the DSP gene mutation have been diagnosed with ARVC and have had implantable cardiac defibrillators (ICD) placed. The patient is admitted to the cardiac unit for further evaluation. Computed tomography angiography reveals abnormal wall movement in the left ventricle. Cardiac catheterization is performed the following day and shows a 50% blockage in the left anterior descending artery that does not require stenting. The hospital course is uneventful and the patient is discharged 1 day later with instructions to follow up with her cardiologist. The patient later sought a second opinion at the ARVD/C Program at Johns Hopkins University.


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Discussion

Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed cause of sudden cardiac arrest, especially in young, athletic adults; although people of all ages may be affected. An estimated one-fifth of cases of sudden cardiac death in people younger than 35 years of age are attributed to ARVC.1 The condition involves progressive remodeling of cardiac muscle with fat and fibrosis and affects primarily the right ventricle, although the left ventricle can also be affected, especially in those with the DSP gene mutation.2

Symptoms of Arrhythmogenic Right Ventricular Cardiomyopathy

Sudden cardiac death is often the first symptom of ARVC. However, many people with ARVC have subtle signs and symptoms of cardiac arrhythmias that go unreported and unrecognized until a syncopal event or sudden cardiac death occurs. Palpitations and severe tachycardia may occur with or without preceding exertion. Lightheadedness and dizziness often precede the syncopal event. Episodic anginal chest pain that resolves spontaneously may occur in the weeks and months prior to the sudden cardiac arrest. If untreated, ARVC may progress to heart failure and death.1

Family History

The index patient (proband) in this family was a 45-year-old first cousin once removed who experienced sudden cardiac arrest at her home after a vigorous exercise session. She was resuscitated after she collapsed in her front yard. The diagnosis of ARVC was delayed for over a year until her child’s pediatrician suggested genetic testing. Two family members (first cousin and aunt of the proband) subsequently experienced sudden cardiac arrests. The proband’s mother (the patient’s first cousin) experienced a severe cardiac arrhythmia during hospitalization for an unrelated illness prior to the proband’s cardiac event and had an ICD placed. Other family members who tested positive for the same DSP gene mutation included 2 of the proband’s 3 children as well as the proband’s brother and 1 of his 2 children. The proband’s 29-year-old first cousin once removed (the case patient’s great niece) was diagnosed with ARVC after a syncopal event of unknown etiology with elevated cardiac enzymes that was initially diagnosed as myocarditis. Genetic testing of this relative revealed the DSP mutation. Other family members declined testing.

The proband later had a heart transplant after she experienced rapid disease progression with severe heart failure. No deaths occurred in the case patient’s generation and subsequent generations, but the high incidence of past sudden premature deaths suggested that ARVC was present in the family for several generations. The case patient’s parents were second cousins and the incidents of sudden premature cardiac death occurred in both the paternal and maternal lines, including the patient’s father who died of a sudden cardiac arrest at the age of 56 years.

Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosis

A comprehensive workup for ARVC includes an exercise stress test, echocardiography, and 30-day trial with a Holter monitor. The definitive study for diagnosis of ARVC is cardiac magnetic resonance imaging, but such studies require interpretation by a radiologist with extensive experience with ARVC. Further testing may include an electrophysiology study and cardiac CT angiography. Genetic testing is important for diagnosing the disease, but not all gene mutations that cause ARVC have been identified. Currently, mutations in the following genes have been implicated in ARVC: plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2), desmoplakin (DSP), and plakoglobin (JUP).1 All mutations are dominant. The condition has incomplete penetrance as some people with a gene mutation do not show any signs or symptoms of the disorder. Negative genetic testing may not necessarily rule out the diagnosis as ARVC can occur in the absence of identifiable genetic mutations and, thus, may be a gene-elusive disease.3

Treatment

Arrhythmias can be controlled with appropriate medications, including β-blockers and antiarrhythmic agents. Many patients will require ICD. Cardiac catheter ablation may be necessary to eliminate irritable foci. Lifestyle changes are essential; patients who continue vigorous exercise or endurance sports participation will likely experience a rapid progression of the disease and increase their risk for sudden cardiac arrest. Arrhythmogenic right ventricular cardiomyopathy is progressive and incurable. Heart failure is common and must be treated aggressively to slow progression. When the heart becomes weakened and medical therapy is no longer effective in preventing heart failure, heart transplantation is an option for suitable candidates. Many patients are diagnosed in the second to fourth decades of life and may experience severe distress and disability.4 Family members should undergo genetic testing.5

Case Resolution

The patient in this case underwent a thorough workup at a local cardiac specialty center and the results were reviewed by the ARVD/C center at Johns Hopkins University. She did not have any of the pathologic changes that characterize ARVC, such as scarring of the ventricles. She was eventually diagnosed with a hiatal hernia that, once appropriately treated, resolved the episodic chest pain that she continued to experience after the initial hospitalization. The patient continued to do well with only minor episodes of palpitations, arrhythmias, and chest pain during the 18 months following hospitalization.

Conclusion

Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed genetic cardiomyopathy that causes significant disability and raises the risk for sudden cardiac death in those affected. Clinicians encountering unexplained sudden cardiac arrest, syncope, or arrhythmia in a patient with a strong family history of similar events or who carries the genetic mutation should suspect ARVC. The condition is treatable and, although progressive, patients can live a normal lifespan with frequent monitoring, medical management, and ICD placement. Heart transplantation may be required to extend life for appropriate candidates. Because of a lack of provider education about ARVC and related cardiomyopathies, evaluation of patients at a specialized ARVC center is recommended.6

Kathy Holmes Dexter, MLS, MHA, MPA, PA-C, CAQ-Psych, is an associate professor and assistant dean for Clinical Practice at Augusta University College of Allied Health Sciences in Augusta, Georgia.

References

  1. Smoot K. ARVD/C patient resources. Johns Hopkins Heart and Vascular Institute. Accessed September 22, 2022. https://www.hopkinsmedicine.org/heart_vascular_institute/centers_excellence/arvd/patient_resources.html
  2. Corrado D, Basso C. Arrhythmogenic left ventricular cardiomyopathy. Heart. 2022;108(9):733-743. doi:10.1136/heartjnl-2020-316944
  3. Gao C, Pan J, Li J. Refractory electrical storm in a 50-year-old man. Circ Cardiovasc Imaging. 2020;13(7):e010164. doi:10.1161/CIRCIMAGING.119.010164
  4. Peters MN, Katz MJ, Alkadri ME. Diagnosis of arrhythmogenic right ventricular cardiomyopathy. Proc (Bayl Univ Med Cent). 2012;25(4):349-53. doi:10.1080/08998280.2012.11928874
  5. Yuan ZY, Cheng LT, Wang ZF, Wu YQ. Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy. Chin Med J (Engl). 2021;134(15):1771-1779. doi:10.1097/CM9.0000000000001581
  6. Sharma A, Assis F, James CA, et al. Misdiagnosis of ARVC leading to inappropriate ICD implant and subsequent ICD removal – lessons learned. J Cardiovasc Electrophysiol. 2019;30(10):2020-2026. doi:10.1111/jce.14088.