**2.6 Mutations associated with SCD**

Regarding genetic factors, DCM patients who carry a desmosomal or LMNA (lamin A/C) mutation run a higher risk of life-threatening ventricular arrhythmias and SCD, regardless of their LVEF. Patients who carry the LMNA gene, which encodes the type V intermediate filament protein, tend to have more life-threatening arrhythmias compared to other variant carriers and variant-negative patients [21, 22]. LMNA mutations are associated with high morbidity and mortality and with a high clinical penetrance [23]. For the LMNA carriers, various risk factors have been identified. These include NSVT during electrocardiogram monitoring, truncating mutations, LVEF <45–50%, and male sex [24, 25]. More recently, 1st degree AV block has been identified as another risk factor in LMNA carriers [26]. Desmosomal gene mutations are present in around 3% of DCM patients. They are also frequent in ARVC patients, creating a genotype overlap between the two cardiomyopathies. They have been associated with a high risk of potentially fatal arrhythmias, independently from the LVEF [21]. The SCN5A (sodium voltage-gated channel alpha subunit 5) gene, which provides instructions for making sodium channels, is also associated with conduction defects and ventricular arrhythmias [10]. Also associated with a higher risk of arrhythmic events are mutations in the FLNC gene, which encodes filamin proteins; the RNA-binding motif protein 20 gene (RBM20 gene), which encodes a protein that regulates splicing and the phospholamban (PLN) gene, which encodes a protein that inhibits a sarcoplasmic ATPase [21, 27]. In a 2019 study, it was demonstrated that RBM20 mutation carriers were more likely to have NSVT and sustained VT than idiopathic DCM cohorts [28]. The AR-DCM phenotype is associated with a high risk of fatal arrhythmias. Spezzacatene et al. identified the AR-DCM phenotype as well as a family history of SCD or sustained VT/VF as the only early significant predictors for SCD or sustained VT/VF in the overall DCM population. Interestingly, the AR-DCM phenotype is associated with a higher risk of arrhythmias, irrespective of LV dilatation and dysfunction, which is in contradiction to the general DCM population, where a low LVEF is associated with a higher arrhythmic risk [14]. However, AR-DCM is not associated with a poorer prognosis due to non-arrhythmic events, including heart failure [14].

#### **2.7 Preventive management**

Most DCM patients present with heart failure and are at a high risk of death. The primary management of such patients lies in the stabilization of progressive heart failure. Drugs like renin-angiotensin-aldosterone system (RAAS) antagonists

**163**

guidelines [22, 33].

*Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy*

and beta-blockers are first-line management in patients with DCM and reduce the risk of SCD by preventing ventricular remodeling. Angiotensin converting enzyme inhibitors (ACEs)/angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers are recommended, unless contraindicated or not tolerated. Furthermore, the combination of sacubitril/valsartan has been shown to be superior to ACE inhibitors and tends to replace them in the treatment of patients who are still symptomatic patients despite optimal medical treatment [16]. The anti-diabetic drug, dapagliflozin, seems to reduce the risk of worsening heart failure and death in patients with a reduced LVEF as well, regardless of the presence of diabetes mellitus, as proven in Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) study [29]. In NYHA IV patients, asystolic arrest and pulseless electrical activity are a frequent cause of death [10]. Cardiac resynchronization therapy (CRT) and CRT with defibrillator (CRT-D) treatment also has a place in both symptomatic treatment and preventive

Arrhythmia management in hereditary DCM patients follows the general recommendations as SCD prevention in patients with reduced LVEF (<35%) [7]. Thus, patients with diagnosed DCM must be carefully evaluated for ventricular arrhythmias. Regarding drug management, amiodarone has not been proven to further reduce overall mortality or arrhythmic risk in the Amiodarone versus Implantable Defibrillator (AMIOVIRT) study, which showed that DCM patients who were on amiodarone did not have a statistically significant difference in terms of survival, compared to patients who received an ICD [30]. However, in the Sudden Cardiac Death in Heart Failure trial (SCD-HeFT) which enrolled patients with an LVEF <35% and NYHA II or III despite optimal medical therapy and compared ICD insertion vs. amiodarone vs. placebo, ICD therapy conferred a significant benefit in patients in NYHA class II, but not in class III. Furthermore, amiodarone, when compared to placebo therapy, showed no benefit in NYHA Class II patients and decreased survival among NYHA Class III patients. Results varied among NYHA classes but did not vary between heart failure of ischemic or nonischemic origin [31]. The Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure (DANISH) trial concluded that prophylactic ICD implantation in symptomatic patients with nonischemic heart failure did not offer a significantly lower long-term rate of death from any cause when compared to standard clinical care but

ICD implantation remains the main therapy in preventive management for DCM patients with impaired LV function, who run a high risk of fatal arrhythmias. Guidelines, as well as the Expert Consensus Statement, recommend an ICD implantation in DCM patients with an LMNA gene mutation and risk factors such as NSVT observed during monitoring, male sex, truncating mutations (class IIa, level B), and an LVEF <45%, which is a higher cutoff value than used in heart failure population

In addition, a primary-prevention ICD should be considered in DCM patients with both an arrhythmogenic phenotype and a family history of SCD or ventricular arrhythmias, irrespective of their LVEF or LV end-diastolic diameter, as they compose a high-risk group for major arrhythmic events and SCD [14]. However, in individual cases, it can be challenging to determine in which particular patients the benefits of ICD implantation would outweigh the risks. The DEFINITE study (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) randomized 458 patients with nonischemic DCM (LVEF <36%) and premature ventricular complexes or nonsustained VT, between standard medical therapy and ICD implantation. SCD by arrhythmias during a mean follow-up of 29 months was far fewer in the ICD group, proving the efficacy of defibrillation [34]. Yet, the use of LVEF

*DOI: http://dx.doi.org/10.5772/intechopen.91702*

management of such patients.

decreased the incidence of SCD by 50% [32].

#### *Sudden Cardiac Death in Hereditary Dilated Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.91702*

and beta-blockers are first-line management in patients with DCM and reduce the risk of SCD by preventing ventricular remodeling. Angiotensin converting enzyme inhibitors (ACEs)/angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers are recommended, unless contraindicated or not tolerated. Furthermore, the combination of sacubitril/valsartan has been shown to be superior to ACE inhibitors and tends to replace them in the treatment of patients who are still symptomatic patients despite optimal medical treatment [16]. The anti-diabetic drug, dapagliflozin, seems to reduce the risk of worsening heart failure and death in patients with a reduced LVEF as well, regardless of the presence of diabetes mellitus, as proven in Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) study [29]. In NYHA IV patients, asystolic arrest and pulseless electrical activity are a frequent cause of death [10]. Cardiac resynchronization therapy (CRT) and CRT with defibrillator (CRT-D) treatment also has a place in both symptomatic treatment and preventive management of such patients.

Arrhythmia management in hereditary DCM patients follows the general recommendations as SCD prevention in patients with reduced LVEF (<35%) [7]. Thus, patients with diagnosed DCM must be carefully evaluated for ventricular arrhythmias. Regarding drug management, amiodarone has not been proven to further reduce overall mortality or arrhythmic risk in the Amiodarone versus Implantable Defibrillator (AMIOVIRT) study, which showed that DCM patients who were on amiodarone did not have a statistically significant difference in terms of survival, compared to patients who received an ICD [30]. However, in the Sudden Cardiac Death in Heart Failure trial (SCD-HeFT) which enrolled patients with an LVEF <35% and NYHA II or III despite optimal medical therapy and compared ICD insertion vs. amiodarone vs. placebo, ICD therapy conferred a significant benefit in patients in NYHA class II, but not in class III. Furthermore, amiodarone, when compared to placebo therapy, showed no benefit in NYHA Class II patients and decreased survival among NYHA Class III patients. Results varied among NYHA classes but did not vary between heart failure of ischemic or nonischemic origin [31]. The Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure (DANISH) trial concluded that prophylactic ICD implantation in symptomatic patients with nonischemic heart failure did not offer a significantly lower long-term rate of death from any cause when compared to standard clinical care but decreased the incidence of SCD by 50% [32].

ICD implantation remains the main therapy in preventive management for DCM patients with impaired LV function, who run a high risk of fatal arrhythmias. Guidelines, as well as the Expert Consensus Statement, recommend an ICD implantation in DCM patients with an LMNA gene mutation and risk factors such as NSVT observed during monitoring, male sex, truncating mutations (class IIa, level B), and an LVEF <45%, which is a higher cutoff value than used in heart failure population guidelines [22, 33].

In addition, a primary-prevention ICD should be considered in DCM patients with both an arrhythmogenic phenotype and a family history of SCD or ventricular arrhythmias, irrespective of their LVEF or LV end-diastolic diameter, as they compose a high-risk group for major arrhythmic events and SCD [14]. However, in individual cases, it can be challenging to determine in which particular patients the benefits of ICD implantation would outweigh the risks. The DEFINITE study (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) randomized 458 patients with nonischemic DCM (LVEF <36%) and premature ventricular complexes or nonsustained VT, between standard medical therapy and ICD implantation. SCD by arrhythmias during a mean follow-up of 29 months was far fewer in the ICD group, proving the efficacy of defibrillation [34]. Yet, the use of LVEF

alone is not always helpful in determining which patients would most benefit from an ICD. This was made clear in the Oregon and Maastricht Registries, in which 80% of SCD victims had an LVEF >35% [35, 36].

CRT is recommended in patients with sinus rhythm, NYHA class III/IV heart failure, LVEF ≤35%, and QRS >120 ms and/or evidence of mechanical dyssynchrony. It has been shown to offer great survival benefits as well as improvement of LV function in DCM patients [37]. This has been observed especially in women, who seem to benefit more than men from CRT [38]. Furthermore, it has been proven that in patients with nonischemic DCM with an LVEF ≤30%, NYHA class II, and QRS duration ≥130 ms, CRT-D device implantation was also beneficial in reducing the risk of death or heart failure when compared with defibrillation only [39]. On the other hand, patients with low LVEF heart failure and permanent atrial fibrillation do not seem to derive extra benefit from a CRT-D device compared with standard ICD treatment, as suggested by the Resynchronization for Ambulatory Heart Failure Trial (RAFT) trial [40]. Of interest in DCM patients, LGE was proven to be a strong, independent predictor of arrhythmic events and was suggested to improve risk stratification for SCD and better identify the need for ICD therapy [41].

Decisions about ICD therapy should incorporate genetic factors. In patients with mutations, i.e. LMNA mutations, the conventional LVEF-threshold based guidelines for ICD do not apply. In fact, an ICD may be considered for a patient with higher LVEF thresholds [26, 42]. Regarding FLNC mutations, 20% of patients with a primary-prevention ICD who carry the mutation had an appropriate ICD shock, much higher than in unselected DCM populations [43]. Appropriate ICD shocks are also more likely in PLN carriers, especially in R14del variant, along with a family history of SCD before the age of 50 years compared to those who do not carry the mutation [44]. These findings support the hypothesis that genetic factors should be considered early in the disease progression.

The CMR-Guide (Cardiac Magnetic Resonance Guided Management of Mild-Moderate Left Ventricular Systolic Dysfunction) trial, which is expected to be completed in 2020, is randomizing ischemic and nonischemic cardiomyopathy patients with an LVEF between 36 and 50% and presence of LGE to either an ICD or an implantable loop recorder in an attempt to determine whether LGE is a sufficient marker alone or whether genetic characterization is also necessary in risk stratification. In general, a polyparametric integration is being introduced in the primary prevention of SCD through ICD implantation in DCM patients that includes family history of SCD, LVEF, late gadolinium enhancement, and possibly genetic parameters [45].
