*2.7.3 Arrhythmias*

The most common arrhythmia in DCM is AF, which increases the risk of thromboembolic complications, impairs cardiac function and worsening HF symptoms. Therefore, evaluation of rate control and anticoagulation in order to preserve LV-function and prevent thromboembolic events is crucial. In the acute setting betablockers, digoxin and their combination may be used to control ventricular rate. In the chronic stage, rhythm control has been shown to be superior to rate control alone in reducing mortality [85]. Because of the commonly reduced left ventricular function, the only therapeutic option is type III antiarrhythmic drug such as amiodarone. Alternatively, electrical cardioversion can be performed. Recently, the CASTLE-AF study demonstrated the superiority of AF catheter ablation in certain patients with HF as compared to medical therapy. The ablation was associated with a significantly lower rate of death and hospitalization for worsening HF [86]. DCM patients may suffer from ventricular arrhythmias (VA), which are mainly caused by myocardial damage, fibrosis and/or loss of cell-to-cell conjunctions, that are described by three mechanisms: reentry, trigger activity, and automatism [87]. Monomorphic ventricular tachycardias (VTs) are frequently induced by macro-reentry mechanism, which is best treated by ablation. The main trigger mechanisms are electrolyte imbalance, mostly secondary to diuretic treatment, antiarrhythmic drugs, and bradycardia. The therapeutic options are a combination of antiarrhythmic drugs like betablockers and type III antiarrhythmics and/or implantation of an implantable cardioverter defibrillator (ICD). The indications for ICD treatment are described later [4].

#### **2.8 Prognosis and risk stratification**

Although there has been a significant improvement in prognosis of DCM patients over the last decades, mortality is still high. The prognosis is mainly influenced by HF symptoms and more relevant by the appearance of VTs. Survival data of adults with DCM have shown a one-year mortality of 25–30% and a 50% survival at 5 years. Sustained VT or VF presents the main cause for SCD, which occurs in up to 12% of DCM patients [4, 88]. In general, the prevalence of sustained VT (monomorphic or polymorphic) is estimated as less than 5% [89]. Recently, the Pediatric Cardiomyopathy Registry presented a 5-year incidence rate of SCD in children with DCM of 3% [90]. An age at diagnosis below 14 years, LV dilation, and posterior wall thinning were identified as the most important risk factors. In contrast, the mortality in adults is mostly associated with age and male gender, reduced New York Heart Association (NYHA) functional class, impaired LVEF, and the presence of specific cardiac biomarkers as well as myocardial fibrosis in CMR [91–94]. Furthermore,

**53**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

genetic aspects play an important role for detection of high-risk patients. Most commonly the pathogenic mutation in the lamin A/C (LMNA) gene is associated with atrial and ventricular arrhythmias. LMNA mutation has been identified as the most malignant and penetrant condition with worse outcomes compared to other forms of DCM [95]. Beside risk models such as the Seattle Heart Failure Model for the prediction of prognosis in the general population of HF patients, there exist no specific risk tools for DCM patients [96]. For the identification of high-risk DCM patients, a personalized and precise approach is required (**Table 3**). This should include the personal and familial history, measurement of LVEF, detailed search for VA and proof of fibrosis using CMR. Other promising approaches are expected to be helpful in decision-making in high-risk DCM patients, determination of microvolt T-wave alternans analysis and detection of autonomic dysfunction using nuclear imaging. In addition, detection of LMNA gene mutation has been described to identify the high-risk DCM population. However, all these approaches need

The most effective therapy of malignant VTs and thus prevention of SCD in DCM patients is the implantation of an ICD. Current ESC guidelines recommend the implantation of a defibrillator in patients who experienced VT or VF (secondary prevention of sudden cardiac death), as well as in high risk patients for primary prevention. The latter are patients with symptomatic HF NYHA class II–III and LVEF ≤35% after ≥3 months of optimal medical therapy who are expected to survive for at least 1 year [97]. Similarly, the American College of Cardiology and American Heart Association guidelines recommend ICD therapy in patients with LVEF ≤35% due to prior myocardial infarction (MI), at least 40 days post-MI, or non-ischemic DCM and NYHA class II or III [98]. However, existing guidelines lack sensitivity and specificity for the selection of patients with DCM for primary prevention ICD implantation. A recently presented meta-analysis by Golwala et al. has demonstrated a 23% reduction in all-cause mortality with ICD therapy compared with optimal medical therapy alone (HR, 0.77; 95% CI, 0.64–0.91) [99]. Although ICD implantation seems to be the best possible option for SCD prevention in DCM, there remain potential complications. Inappropriate shocks, risk of infection, device or lead replacement have to be considered and discussed in detail

DCM includes a heterogeneous group of myocardial and systemic conditions

causing left ventricular dilatation and dysfunction. DCM is one of the most common cardiomyopathies worldwide. Yet, the real prevalence is unknown. The etiology contains non-genetic (e.g. myocarditis, peripartum, toxics, arrhythmia, infiltrative etiologies, endocrine, nutritional, and neuromuscular) and genetic causes. Literature on genetic mutations being responsible for DCM has increased exponentially. Today, up to 30% of the DCM cases are described to be caused by a gene mutation, the majority of which occur in autosomal genes that encode for a wide range of proteins of the cardiomyocyte's structural elements. Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM. However, the most common mutations occur in genes encoding sarcomeric proteins and in genes related to the nuclear envelope and the

*DOI: http://dx.doi.org/10.5772/intechopen.83567*

**2.9 Prevention of sudden cardiac death**

further research.

before an ICD is implanted.

**3. Conclusion**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83567*

genetic aspects play an important role for detection of high-risk patients. Most commonly the pathogenic mutation in the lamin A/C (LMNA) gene is associated with atrial and ventricular arrhythmias. LMNA mutation has been identified as the most malignant and penetrant condition with worse outcomes compared to other forms of DCM [95]. Beside risk models such as the Seattle Heart Failure Model for the prediction of prognosis in the general population of HF patients, there exist no specific risk tools for DCM patients [96]. For the identification of high-risk DCM patients, a personalized and precise approach is required (**Table 3**). This should include the personal and familial history, measurement of LVEF, detailed search for VA and proof of fibrosis using CMR. Other promising approaches are expected to be helpful in decision-making in high-risk DCM patients, determination of microvolt T-wave alternans analysis and detection of autonomic dysfunction using nuclear imaging. In addition, detection of LMNA gene mutation has been described to identify the high-risk DCM population. However, all these approaches need further research.

#### **2.9 Prevention of sudden cardiac death**

The most effective therapy of malignant VTs and thus prevention of SCD in DCM patients is the implantation of an ICD. Current ESC guidelines recommend the implantation of a defibrillator in patients who experienced VT or VF (secondary prevention of sudden cardiac death), as well as in high risk patients for primary prevention. The latter are patients with symptomatic HF NYHA class II–III and LVEF ≤35% after ≥3 months of optimal medical therapy who are expected to survive for at least 1 year [97]. Similarly, the American College of Cardiology and American Heart Association guidelines recommend ICD therapy in patients with LVEF ≤35% due to prior myocardial infarction (MI), at least 40 days post-MI, or non-ischemic DCM and NYHA class II or III [98]. However, existing guidelines lack sensitivity and specificity for the selection of patients with DCM for primary prevention ICD implantation. A recently presented meta-analysis by Golwala et al. has demonstrated a 23% reduction in all-cause mortality with ICD therapy compared with optimal medical therapy alone (HR, 0.77; 95% CI, 0.64–0.91) [99]. Although ICD implantation seems to be the best possible option for SCD prevention in DCM, there remain potential complications. Inappropriate shocks, risk of infection, device or lead replacement have to be considered and discussed in detail before an ICD is implanted.
