Naxos Disease: Current Knowledge and Future Advances

Naxos disease is a genetic cardiocutaneous syndrome manifesting with a cardiomyopathy that belongs in the arrhythmogenic right ventricular cardiomyopathy (ARVC) spectrum and follows an autosomal recessive pattern. It manifests with wooly hair, keratosis of the extremities and right ventricular dysfunction. It is accompanied by risk of arrhythmias as well as sudden cardiac death (SCD), even at a young age. Furthermore, the disease often progresses to right ventricular heart failure, but can also affect the left ventricle. Patient management follows current guidelines on ARVC and principles for heart failure management. Bioengineering and research about pluripotent stem cells seem to have potential to improve future management of the disease. This chapter covers current knowledge on Naxos disease regarding clinical features, epidemiology, pathogenesis, guidelines on patient management and provides insights in research frontlines.


Introduction
Naxos disease is an arrhythmogenic cardiomyopathy, considered to represent a form of ARVC [1]. It is of genetic origin and two main proteins have been associated with the disease. The clinical manifestations include wooly hair, keratosis of the extremities, and right ventricular dysfunction. Albeit rare, the disease can cause advanced heart failure and life-threatening arrhythmias, even in the young [2]. Data on Naxos disease are limited, and current patient management follows the guidelines for heart failure and ARVC. In recent years, research has focused on the field of bioengineering, illuminating some of the aspects of the disease and cultivating future perspectives regarding its management. In this chapter we present current knowledge regarding the clinical presentation, epidemiology, genetic substrate, pathophysiology, current guidelines for patient management, and future paths for Naxos disease.

Clinical presentation of Naxos disease
Naxos disease manifests with a typical phenotype including both cardiac and extracardiac characteristics. The extracardiac manifestation of the disease involves

Pathophysiology and diagnostic criteria
Both plakoglobin (γ-catenin) and desmoplakin, that are linked with Naxos disease are associated with myocardial cell adhesion [3,25]. Plakoglobin has a two-fold role in both mechanical contraction and electrical signal conduction; it is a component of the desmosomes, interconnecting with the intermediate filaments of desmin, and constitutes a component of the adherens junctions where it is connected to the actin skeleton [3,26]. Similarly, desmoplakin is a cytoplasmic protein that links plakoglobin to the intermediate filaments of desmin [3]. The defective cell adhesion in the case of the truncated plakoglobin protein, also causes a reduction in the connexin-43 levels, a major gap junction protein. The associated myocardial gap-junction remodeling, creates a substrate for arrhythmogenic events [27]. Furthermore, the defective cell adhesion of the cardiomyocytes leads to their apoptosis which is then followed by fibrofatty replacement in the affected ventricles [18]. The associated conduction disturbances created can induce arrhythmogenic events and sustain re-entry circuits [3].
In the landmark paper Protonotarios et al., all patients were reported to have signs of intra-ventricular conduction delay ECG as well as echocardiographic findings of right-or bi-ventricular dysfunction. In more detail, the ECG abnormalities that were reported include a wide QRS ≥120 ms and abnormal T-wave inversions in seven out of nine patients [5]. The most common abnormalities documented Category Criteria Global or regional dysfunction and structural alterations

Minor
By 2-D echocardiography: • Regional RV akinesia or dyskinesia • and 1 of the following (measured in end diastole): in Naxos patients are wide QRS and inverted T-waves in V1-V3 or in all precordial leads, while epsilon waves may also be present [3]. An incomplete right bundle branch block may also be apparent, while the extrasystoles tend to manifest with an LBBB morphology [7]. Flattened T-waves appear in the case of biventricular involvement [3]. Late potentials in Naxos disease are more often abnormal than in

Major
Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads (V1 to V3) Minor other forms of cardiomyopathies [28]. In echocardiography, dysfunction, hypokinesia and aneurysms are prominent [3,7]. In histological specimens fibrofatty patterns are prominent, while focal myocarditis has also been reported in follow-up histology specimens [4]. Both the subepicardial and the mediomural myocardium of the involved ventricles is replaced by fibrofatty tissue, while healthy myocytes are surrounded by fatty tissue [3,29]. In immunohistochemical specimens the signal of plakoglobin and connexin-43 in the intracellular junctions is diminished [24,27].
Since the disease belongs in the ARVC spectrum and there are currently no specific diagnostic criteria for the cardiac manifestations of Naxos disease, the diagnostic criteria of ARVC are widely used [30,31]. However, while the specificity of the revised task force criteria is high, sensitivity has been shown to be as low as 13-20% [32]. Since then, progress has been made regarding tissue characterization through cardiac magnetic resonance (CMR), possibly providing a tool of higher diagnostic accuracy, high specificity and high sensitivity [32,33]. The revised task force criteria for ARVC are depicted in Table 1. In November 2020 the Padua criteria for the diagnosis of ACM was published. The Padua diagnostic criteria introduce tissue characterization by contrast enhanced cardiac magnetic resonance for detection of fibro-fatty myocardial replacement of both ventricles. It also adds new ECG criteria, including depolarization/ repolarization abnormalities and ventricular arrhythmias, specific for the LV involvement [34]. The proposed Padua diagnostic criteria need to be validated by further clinical studies in large cohorts of patients.

Heart failure
Naxos disease is predominantly a condition affecting the right ventricle, causing right ventricular failure. Unlike for LV failure, less is known regarding the optimal pharmacological therapy. However, the expert consensus regarding the management of ACMs suggests that when treating left or right ventricular dysfunction, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and diuretics, in the case of fluid overload, should be considered [35]. Despite the lack of Naxosspecific guidelines, ACE inhibitors, betablockers, and diuretics are reasonable prescribing choices [2]. Dapagliflozine and empagliflozine have been introduced in the treatment of heart failure, even in non-diabetic patients [36,37], while sacubitril/valsartan is indicated for patients with left ventricular ejection fraction (EF) ≤35% [38]. Anticoagulation treatment is indicated in the case of atrial fibrillation/flutter, in the event of intra-cardiac thrombi and can also be considered in patients with ventricular aneurysms, either left or right [35,39]. In the case of advanced heart failure, patients may benefit from devices such as cardiac resynchronization therapy (CRT), often combined with an implantable cardioverter-defibrillator (ICD), left ventricular assist devices (LVAD) and assist devices for the right ventricle (RVAD or BiVAD) in the setting of an LVAD implantation and considered as bridge to transplant [38].

Arrhythmias and sudden cardiac death
The prognosis of the disease is adverse, especially in the young and annual SCD mortality is 2.3% [7,8]. As risk factors for SCD, the following have been identified: history of syncope, onset of symptoms before the age of 35, structural progression DOI: http://dx.doi.org/10.5772/intechopen.96020 before the age of 35, and left-ventricular involvement [7]. However, risk stratification of SCD constitutes a challenge. ARVC guidelines and position papers on ICD implantation, guide the same decisions in the management of Naxos disease [35,40]. Criteria for risk stratification for SCD is presented in Table 2. A clear indication for an ICD implantation is aborted SCD and VT with haemodynamic instability, while in the case of VT without haemodynamic compromise it should also be considered [35,40]. An ICD protects from SCD in ARVC either in secondary prevention or is justified as primary prevention based on careful judgment of risk factors [40][41][42]. However, the clinical presentation should play a major part in the decision making; unexplained syncope, risk markers associated with medical history, family history and severity of clinical presentation and deterioration should be considered [40]. An ICD is indicated for ACM patients with low ejection fraction ≤35% and New York Heart Association (NYHA) class II or III, provided that the patient's estimated survival exceeds one year [35]. The same guidelines apply for Naxos patients. The first implantation of an ICD in a Naxos patient was reported in 2000 [43]. Naxos-specific guidelines are rare. Among those, an ICD is indicated for patients who are symptomatic or present structural progression especially before the age of 35 [8,44]. Naxos patients, like ARVC patients, should abstain from competitive sports as myocardial stress can exacerbate the dysplasia [40]. Regarding drug therapy, beta-blockers (Class I), and possibly amiodarone (Class IIb) and sotalol (Class IIb) in special cases have been suggested for patients with ACMs for the control of arrhythmias and the reduction of ICD shocks [35,45]. Specifically for Naxos patients with recurrent sustained VTs, anti-arrhythmic drugs should be prescribed as per the general guidelines of arrhythmias, while amiodarone or sotalol alone or in combination with beta-blockers have been suggested [8,40,45]. As far as catheter ablation is concerned, it should be considered in ACM cases with amiodaronerefractory recurrent monomorphic VT, recurrent symptomatic drug-refractory  sustained VT, symptomatic nonsustained VT or a high ectopic burden (≥1000 premature ventricular contractions/day) refractory to beta-blockers [35]. Beta-blockers are also recommended for patients without an ICD (Class IIa) [35].

Bioengineering
On the front of cellular and molecular engineering, advances have been made that may create a substrate with therapeutic potentials in the future. The pharmaceutical substance SB216763 (SB21) (an inhibitor of the glycogen synthase kinase GSK-3β) prevented heart failure and reduced mortality when administered early on to zebrafish models with induced plakoglobin mutations that resulted in Naxos disease. The effect could possibly be attributed to the prevention of the formation of an arrhythmic substrate on the intercalated disk level [47]. Further data on mammalian models are, however, needed [2,48].
On the front of induced pluripotent stem cells (iPSCs) that enable the in-vitro study of human genetic disorders like ARVC through the induction of mutant cardiomyocytes, albeit a challenging field, promising results have been reported [49][50][51]. Researchers have been able to re-create the ARVC phenotype using adultlike metabolic energetics, proving that adultlike metabolism plays a crucial role in establishing ARVC models through iPSCs [49]. Furthermore, cultured ARVC cardiomyocytes manifest with adipogenic phenotype and reduced cell surface localization of desmosomal proteins, characteristic features of ARVC [50]. Also Naxos-ARVC has been created in mice models through a homozygous mutation of the plakoglobin gene [52] and of the desmoplakin gene, the latter causing humanlike cardiac arrhythmias, palmoplantar keratosis, and alopecia [53]. Interestingly, cardiac function was restored in mice through the normalization of Naxos plakoglobin levels, indicating that it is the downregulation of the protein that causes the cardiac dysfunction, rather than the mutation itself [54]. This conclusion, if further supported, could have clinical applications in Naxos disease [2]. The article suggests that an approach to this would be to use antisense technology to specifically block nonsense-mediated decay of mutant plakoglobin mRNA, enabling the expression of the truncated protein at increased levels [54,55].

Conclusion
In this chapter key aspects of Naxos disease are presented. Due to its rarity, the condition follows the general guidelines for arrhythmias and heart failure, as disease-specific criteria is lacking. However, due to its uniqueness, larger Naxos registries are needed, as they would illuminate the individual characteristics of the disease as well as guide the way to designated guidelines for the management of Naxos patients. Possibly, the thorough study of the origins of the disease, the genetic substrate and pathogenesis, can offer insights with therapeutic potential.

Conflict of interest
IK and ML reports no conflicts of interest. GM has received speaker's fee from Alnylam, MSD, and Internetmedicin. PM is on the advisory board of Coala Life and has received speaker's fees or grants from Abbott, Alnylam, Amicus Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Internetmedicin, Lilly, MSD, Novo Nordisk, Octopus Medical, OrionPharma, Pfizer, Vifor Pharma, and Zoll.