Genetic Arrhythmia Center: Caring for Patients and Families at Risk for Sudden Cardiac Death and Advancing the Understanding of Rare Cardiomyopathies and Channelopathies

Article Citation:

Miranda S. Kunz, Sajya M. Singh, Susan A. Casey, Katelyn M. Storey, William T. Katsiyiannis, Raed H. Abdelhadi, Allison A. Berg, Mosi K. Bennett, and Jay D. Sengupta (2018) Genetic Arrhythmia Center: Caring for Patients and Families at Risk for Sudden Cardiac Death and Advancing the Understanding of Rare Cardiomyopathies and Channelopathies. Journal of the Minneapolis Heart Institute Foundation: Fall/Winter 2018, Vol. 2, No. 2, pp. 26-30.

Original Article

Miranda S. Kunz, MPH

Sajya M. Singh, BS

Susan A. Casey, RN

Katelyn M. Storey, BA

William T. Katsiyiannis, MD, MS

Raed H. Abdelhadi, MD, FHRS

Allison A. Berg, MS

Mosi K. Bennett, MD, PhD

Jay D. Sengupta, MD, FHRS

Address for correspondence: Miranda Kunz, MPH, Minneapolis Heart Institute Foundation, 920 E 28 Street, Minneapolis, Minnesota 55407, Tel: 612-863-5505, Fax: 612-863-2490 E-mail: miranda.kunz@allina.com

ABSTRACT

Although rare in the general population, genetic arrhythmia syndromes have a significant public health impact due to their contribution to the incidence of sudden cardiac death, particularly in children and young adults. When sudden cardiac death occurs in the absence of ischemic heart disease, a genetic cardiac condition may be suspected and clinical and genetic screening of family members is recommended. The Genetic Arrhythmia Center at the Minneapolis Heart Institute collaborates with local partners in the Sudden Cardiac Arrest network to connect patients and their family members with interdisciplinary care for diagnosis and treatment of these conditions. The most common conditions seen in the Genetic Arrhythmia Center include arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, long QT syndrome, and Brugada syndrome. In addition to providing clinical care and genetic testing and counseling services, the Genetic Arrhythmia Center is working to advance the scientific understanding of the clinical presentation and natural history of these rare conditions.

Keywords: sudden cardiac death, channelopathy, arrhythmogenic right ventricular cardiomyopathy, genetic testing, long QT syndrome

INTRODUCTION

Inherited heart rhythm disorders have a considerable public health impact due to their contribution to the incidence of sudden cardiac death (SCD), particularly among children and young adults. Although ischemic heart disease is the most common cause of SCD, most cases of SCD under the age of 30 can be attributed to a genetic basis for arrhythmia with or without cardiomyopathy or remain unexplained.1–3 Genetic mutations that may contribute to the development of the substrate for malignant ventricular arrhythmias can be separated into two major categories: (1) cardiomyopathies with structural changes predisposing to arrhythmias and (2) channelopathies that can directly result in life-threatening arrhythmias despite being concealed on standard cardiac imaging (Table 1). Inherited cardiomyopathies account for an estimated 16% of SCDs in those 1 to 35 years of age.3 In 30% to 40% of SCDs among younger individuals, the cause of death is not identifiable at autopsy and is often thought to be the result of an unrecognized cardiac channelopathy.1–6 Overall, the annual incidence of SCD among those 1 to 35 years old is 1.3 deaths per 100,000 people.3

TABLE 1
Genetic arrhythmia conditions separated by channelopathies and cardiomyopathies. These diseases all have been found to be more prevalent in families and, therefore, have a genetic basis. Each of these conditions also carry a risk for premature sudden cardiac death through malignant ventricular arrhythmias.

To prevent disease progression and reduce the risk of SCD, patients can be managed using pharmacological therapies and implantable cardioverter defibrillators (ICDs).7However, identifying and then risk-stratifying patients with these rare conditions is challenging, and many go undiagnosed. Structural changes to the heart indicative of inherited cardiomyopathies can be discovered on autopsy, but channelopathies are not easily identified, often leading to no obvious cause of death with gross examination at autopsy.1,3–5,8 Studies have used postmortem genetic testing to identify pathogenic or likely pathogenic genetic mutations in approximately a quarter of unexplained SCDs. After subsequent screening of family members, 13% to 39% of cases had at least one family member clinically diagnosed with a genetic arrhythmia condition.3–4,8 Current guidelines for the management of inherited arrhythmias recommend that when an inherited cardiovascular disease is the suspected cause of SCD or sudden cardiac arrest (SCA), individuals and immediate family members should undergo multidisciplinary evaluation at a dedicated clinic.7

THE GENETIC ARRYTHMIA CENTER

The Genetic Arrhythmia Center (GAC) at the Minneapolis Heart Institute is a multidisciplinary group. This includes traditional cardiology subspecialty providers from cardiac electrophysiology (pediatric and adult), cardiac imaging, and advanced heart failure as well as genetic testing and counseling services along with clinical and research protocols (Figure 1).

FIGURE 1
The clinical and research flow of the Genetic Arrhythmia Center (GAC). Patients come for evaluation based on personal or family history. Different diagnostic tools are used based on the suspected condition. Genetic testing may be performed in the affected individual to aid with familial screening. Enrollment in the GAC research registry allows follow-up and better understanding of disease progression and medical interventions.

Referrals to the GAC come from primary care physicians, cardiovascular physicians, medical examiners, or self-referring individuals who have a family history of SCD. Patients who have a suspected genetic arrhythmia condition due to an incidental finding or symptoms, including unexplained syncope, ventricular arrhythmias, or out-of-hospital cardiac arrest (OOHCA), can be referred to the GAC clinic. Additionally, the partnership with medical examiners and pathologists via the Sudden Cardiac Arrest Network enables smooth transition of family members of victims of SCD into GAC clinical evaluation (Figure 2).9

FIGURE 2
The Sudden Cardiac Arrest (SCA) network in Minneapolis, MN. These partnerships connect those affected by rare genetic heart conditions with the Genetic Arrhythmia Center (GAC) through referrals from family members, physicians, and medical examiners. Collaboration with interdisciplinary cardiovascular subspecialties ensures patients receive the best diagnostic and treatment options.

Advancing the Understanding of Genetic Arrhythmia Syndromes

GAC patients are offered the option of enrolling in a research registry specific to the Center, which aims to better understand the clinical presentation and natural history of these conditions. Currently, the GAC registry includes 374 patients (male: 156, 42%). Of these, 174 patients (47%) have a family history of SCD, and 25 patients (7%) presented to the GAC after an OOHCA. Genetic testing for mutations in genes associated with genetic arrhythmia conditions has been performed for over a third of GAC patients (157, 42%). A pathogenic or likely pathogenic variant was identified in approximately half these individuals (86, 55%). Two hundred twenty-six patients (60%) in the GAC registry have been formally diagnosed with a genetic arrhythmia condition, including arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction (LVNC), long QT syndrome, and Brugada syndrome.Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The most common diagnosis in the GAC registry is ARVC, with 18% of patients diagnosed. ARVC is present in an estimated 1 in 5,000 live births and involves a process of fibrous or fibro-fatty replacement of myocardium.10 This progressive disease has been associated with regional right ventricle (RV) akinesia or dyskinesia, RV dilatation, reduced RV function, and repolarization and depolarization abnormalities.11 ICD implantation is often pursued for secondary prevention in individuals with ARVC; however, ICD implant for primary prevention in those at highest risk is based on consensus statements. The diagnostic criteria and the updated guidelines for ICD implant are from 2010 and 2017, respectively. Advanced RV involvement, quantified by RV volume size and RV ejection fraction, is associated with appropriate subsequent ICD therapy in ARVC patients with ICDs originally implanted for primary prevention.

ARVC typically follows autosomal-dominant inheritance, and seven genes have been associated with ARVC.11 In the GAC registry, 56% of ARVC patients with genetic testing have had a pathogenic or likely pathogenic variant identified. Of these, 6 patients had a novel pathogenic mutation in the desmoplakin (DSP) gene that was first described in association with ARVC at our center.12 In these patients and in a growing subset, we find that the term “ARVC” does not incorporate the degree to which the left ventricle is affected by the condition. The term “arrhythmogenic biventricular cardiomyopathy” may be a more apt description of the condition in a larger number of patients than previously recognized. We are working in conjunction with medical examiners to better understand the degree to which left ventricular involvement is underappreciated and determine the utility of further characterizing left ventricular involvement with cardiac magnetic resonance imaging (cMR) to correlate to long-term outcomes. Other researchers are also recognizing the higher incidence of left ventricular involvement than previously appreciated.13 Consensus documents state that advanced left ventricular involvement may be an independent risk factor for SCD.

We identified a unique subset of ARVC patients with varying DSP mutations who presented with acute myocardial infarction-like presentations, including acute chest pain and marked troponin I elevation, despite normal coronary arteries on evaluation. This may be a rare glimpse of the natural history of stepwise disease progression albeit to a more severe degree than what may be otherwise subclinical in nature. This atypical “hot phase” may represent acute disease progression with myocardial injury that likely has a genetic basis with some unknown trigger, resulting in cell death. One such trigger may be physical stress14; thus, our recommendations are to limit moderate to severe intensity exercise to help not only prevent arrhythmias but also progression of disease. The degree of disease progression in the myocardium is characterized best with detailed imaging on cMR. We continue to identify additional morphological characteristics that may help further risk-stratify patients with arrhythmogenic biventricular cardiomyopathy.Left Ventricular Noncompaction (LVNC)

LVNC is characterized by the presence of prominent trabeculations in the left ventricle, thought to be the result of an interruption in the normal process of myocardial compaction during embryologic development. Estimates of the prevalence of LVNC vary widely. Among patients referred for cMR, LVNC has been found on 3% to 39% of cMR studies, depending on the criteria.15 The association between LVNC and adverse clinical events has been debated, with some studies finding associations with ventricular arrhythmias, thromboembolism, heart failure, and SCD, and other studies finding no increased risk of adverse clinical events in LVNC patients.15–16

In the GAC registry, 17% of patients have been diagnosed with LVNC, and a disease causing mutation has been identified in 3 out of 9 patients genetically tested. There is a subset of patients with LVNC at high risk for SCD, and we have a substantial proportion of patients with LVNC and ICDs who have benefitted from their devices. We are attempting to determine predictors of ICD use and identify characteristics that may be used to help identify patients who may benefit from early ICD implant for primary prevention.Long QT Syndrome

Long QT syndrome is present in approximately 1 in 2,000 live births.17 This disease is characterized by an abnormally long QT interval on EKG at rest or during recovery after an exercise stress test. Many patients present with a history of syncope, seizures, or Torsade de pointes.18 In the GAC registry, 14% of patients have been diagnosed with long QT. Of the diseases evaluated in the GAC, long QT syndromes have the highest yield from genetic testing, with 82% having a disease-causing mutation identified. We have also seen rare subtypes of long QT syndrome and mutations causing channelopathies with crossover phenotypic manifestations, including long QT 7 and catecholaminergic polymorphic ventricular tachycardia (CPVT).Brugada Syndrome

Accurate estimates of the prevalence of Brugada syndrome are not available.7 Patients with the diagnosis of Brugada syndrome comprise 5% of the GAC registry. Brugada syndrome is characterized by a unique pattern on EKG that may be present at rest or be provoked during an acute illness, electrophysiology (EP) study, or pharmacologic provocative testing. Risk-stratification in patients with Brugada syndrome is especially complex. One large Minnesota family with a history of Brugada syndrome had 3 instances of SCD. The only patient to benefit from appropriate ICD therapy when implanted for primary prevention demonstrated a type I Brugada pattern during a procainamide challenge but no malignant ventricular arrhythmias or Brugada pattern during EP study. However, several other family members had ventricular arrhythmias on EP study or a type I Brugada pattern induced after ventricular pacing but never benefitted from appropriate therapy from their ICDs.Variants of Unknown Significance

We find that many patients with aborted SCA or family history of SCD either have no identifiable genetic mutations or have mutations with unknown pathological significance. Many of these patients may have phenotypes, characterized through clinical and family history, cardiac imaging (especially echocardiography and cMR), or clinical evaluation with cardiac rhythm monitoring that could result from a channelopathy or a variant of ARVC. With extensive pedigrees and segregation analysis as well as genetic whole exome sequencing, we hope to identify potential pathogenic mutations that may be useful for screening family members and populations in the future. Currently, a diagnosis is still analogous to putting the pieces of a puzzle together. Its accuracy still depends heavily on careful medical and family history taking as well as clinical data collection to understand the phenotype. Available genetic testing may or may not provide supplemental information to reach a conclusion regarding the diagnosis.

CONCLUSION

A multidisciplinary approach is needed to identify and treat patients at high risk of SCD due to genetic arrhythmia conditions. The Genetic Arrhythmia Center has created a model for addressing these conditions by bringing together a team of cardiovascular specialists, genetic counselors, researchers, and referring providers (the Sudden Cardiac Arrest Network). Through this model, GAC aims to not only provide comprehensive clinical care and genetic counseling for patients and families but to advance the scientific understanding of the clinical presentation, natural history, and treatment outcomes of these rare conditions.

ACKNOWLEDGMENTS

The authors would like to thank Minneapolis Heart Institute Foundation for its support. This research is supported in part by a grant from Medtronic, Inc.

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Disclosures: None.

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