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Diseases of Conduction Block Conduction block can occur at any level of the cardiac conduction system (CCS) and can manifest as sinoatrial exit block, atrioventricular block, infra-Hisian block, or bundle branch block. Impaired conduction can be caused by ion channel defects that alter action potential shape or by defective coupling between cardiomyocytes. Inherited defects in cardiac conduction have been linked to mutations in SCN5A and SCN1B (both affect phase 0) and KCNJ2 (affects phase 3 and 4). 

The cardiac sodium channel consists of the pore-forming α-subunit (encoded by SCN5A) and a modulatory β-subunit (encoded by SCN1B). The α-subunit contains a voltage sensor that allows for rapid activation in response to membrane depolarization. After depolarization, the sodium channel undergoes a period of inactivation, in which it is refractory to further impulses. SCN5A requires membrane repolarization to relieve the inactivated state. The inward rectifier potassium channel, Kir2.1, encoded by KCNJ2, maintains the resting membrane potential. Therefore, proper functioning of Nav1.5 and Kir2.1 is necessary for normal cardiac excitability.

SCN5A

Progressive cardiac conduction defect, or Lev-Lenègre disease, is characterized by age-related, fibrosclerotic degeneration of the His-Purkinje system.⁶ Impulse propagation through the proximal ventricular conduction system progressively declines, resulting in bundle branch blocks and eventually complete atrioventricular block. An inherited form of Lev-Lenègre disease is associated with loss of function mutations in SCN5A and can exist alone or as overlap syndromes with Brugada or long QT syndrome 3.⁶ Inherited progressive cardiac conduction defect is associated with a high risk of complete atrioventricular block and Stoke-Adams syncope without ventricular dysrhythmia.⁷ Schott et al⁸ identified a mutation in SCN5A that cosegregates with Lenègre disease in a large French family. Affected individuals had variable degrees of conduction block requiring pacemaker implantation in 4 family members because of syncope or complete heart block. Linkage analysis and candidate gene sequencing identified a T>C substitution at position +2 of the donor splice site of intron 22 (IVS22+2 T>C), which results in a mutant lacking the voltage-sensitive segment.⁸ Functional analysis demonstrated no transient inward sodium current in response to depolarization, consistent with a loss-of-function mutation.⁶

SCN1B

The majority of patients with Brugada and conduction disease do not have SCN5Amutations. Therefore, modifiers of Nav1.5 expression or function have become the target of candidate gene sequencing approaches. Watanabe et al⁹ identified SCN1B mutations in 3 families with conduction disease with or without Brugada syndrome. Coexpression of mutant β-subunits with Nav1.5 resulted in diminished sodium current.

KCNJ2

Mutations in KCNJ2 have been found in a rare autosomal dominant condition called Andersen-Tawil syndrome, characterized by periodic paralysis, dysmorphic features, polymorphic ventricular tachycardia, and cardiac conduction disease.^10,11 ECG evaluation of 96 patients with Andersen-Tawil syndrome from 33 unrelated kindreds revealed conduction defects at multiple levels from the atrioventricular node to the distal conduction system.⁵⁵ Cardiomyocytes expressing a dominant-negative subunit of Kir2.1 exhibited a 95% reduction in I_K1, resulting in significant action potential prolongation. Mouse models of Andersen-Tawil syndrome exhibited a slower heart rate and significant slowing of conduction.^56,57

Therapeutic Strategies

The current standard of care for symptomatic bradycardia due to conduction system disease is the implantation of an electronic pacemaker. Despite their success, electronic pacemakers have limitations, which include lead complications, finite battery life, potential for infection, lack of autonomic responsiveness, and size restriction in younger patients. These limitations have spurred on the development of biological pacemakers, the premise of which is to restore pacemaking activity with the use of viral-based or stem cell–based gene delivery systems.⁹⁹ The identification and characterization of genes involved in generating pacemaker currents have allowed biological pacemaker technology to become a reality.

The restoration of sinus pacing rates can be achieved by modulating inward and outward currents to establish or increase the slope of diastolic depolarization in cardiac tissue. Increasing inward currents and/or decreasing outward currents increase the slope of diastolic depolarization and therefore the pacing rate. Genes that have been investigated or are under current investigation include the following: (1) β₂-adrenergic receptor,^100,101(2) dominant-negative Kir2.1 mutants,¹⁰² (3) adenylate cyclase type VI (ACVI),^103,104and (4) HCN channels.¹⁰⁵ The β₂-adrenergic receptor and adenylate cyclase type VI both increase cAMP levels, leading to activation of endogenous HCN channels and calcium clock mechanisms. Although initial animal models using the β₂-adrenergic receptor showed promise with transient increases in heart rate, the potential for proarrhythmia and the inability of this approach to establish de novo pacemaker activity limited its efficacy.¹⁰¹

Another approach focused on modifying ionic currents that convert working myocardial cells, which have relatively stable diastolic potentials, into cells with phase 4 diastolic depolarization. It was postulated that atrial and ventricular myocytes have the potential for automaticity, but that hyperpolarizing currents, such as I_K1, prevent diastolic depolarization by stabilizing the resting membrane potential. Miake et al¹⁰² confirmed this hypothesis when they demonstrated that adenoviral delivery of a dominant-negative Kir2.1 construct into the left ventricle of guinea pigs resulted in conversion of quiescent myocytes into pacemaker cells. Unfortunately, significant action potential prolongation limited the clinical utility of this treatment strategy.¹⁰²

Rosen and colleagues^105,106 demonstrated that automaticity could be induced in quiescent myocardium with the use of heterologous expression of HCN channels that produce the pacemaker current I_f. Qu and Plotnikov et al demonstrated that stable autonomous rhythms could be generated when adenovirus encoding HCN2 was injected into the left atrium¹⁰⁵ or left bundle branch¹⁰⁶ of a canine heart. To bypass the limitations of viral-based systems, such as host immune response, several groups reported the successful use of cell-based delivery systems. Plotnikov et al¹⁰⁷ reported the successful implantation of human mesenchymal stem cells expressing HCN2 in the left ventricle of a canine model of atrioventricular block. Dogs maintained stable ectopic pacemaker activity for >6 weeks without the use of immunosuppression.¹⁰⁷ Human mesenchymal stem cells electronically couple to host myocardium through gap junctions; therefore, conditions with significant gap junction remodeling may affect the efficacy of this method.

Although standalone biological pacemakers may be far into the future, adjuvant biological pacemakers may find real-world utility for current deficiencies of electronic pacemakers, such as limited battery life and device infections. For example, biological preparations used in conjunction with device therapy may be used to extend battery life, decreasing the frequency of generator changes. Transient injectable pacemakers may also function as bridge therapy after lead extraction of an infected device. The need for adjuvant biological pacemakers is clear, but continued refinement of gene- and cell-based delivery systems will be necessary to make this technology a reality.⁹⁹

Conclusion

Although rare, inherited arrhythmias have become an invaluable tool in identifying the genetic determinants of CCS function. Each new mutation enhances our understanding and appreciation of the biochemical and structural complexity needed for cardiac impulse generation and propagation. This methodology is hampered, however, by the relative scarcity of inherited conditions affecting the CCS. The addition of genome-wide association studies has broadened this search for novel genes beyond rare familial afflictions to include common, multifactorial conditions. It is hoped that this exciting new frontier will bring to light the complex interplay of genes and genetic/epigenetic modifiers that influence the prevalence of common diseases. These genetic screens will ultimately yield a bevy of new gene targets for pharmaceutical or gene-based therapeutics of the future.

REFERENCES

• The Cardiac Conduction System

  1. David S. Park, MD, PhD;
  2. Glenn I. Fishman, MD

http://circ.ahajournals.org/content/123/8/904 [Circulation.2011; 123: 904-915 doi: 10.1161/​CIRCULATIONAHA.110.942284]

• Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis by Aviva Lev-Ari, PhD, RN 

• Benson DW Genetics of atrioventricular conduction disease in humans. Anat Rec A Discov Mol Cell Evol Biol. 2004 Oct;280(2):934-9.

http://www.ncbi.nlm.nih.gov/pubmed/15372490

• N Engl J Med 2013; 368:2335-2337 June 13, 2013DOI: 10.1056/NEJMc1300484

• Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013 Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP