Familial cardiomyopathy I42.9

A spongy appearance of the myocardium, the typical appearance of non-compaction cardiomyopathy, was described by Grant as early as 1926 (Oechslin 2011).

The first classification of myopathies was made in 1980 by the WHO / ISFC (Pankuweit 2009).

Fritzpatrick was the first to describe familial restrictive cardiomyopathy (RCM) over 5 generations in 1990 (Meder 2017).

One year later, in 1991, the genetic cause of ion channel disease was demonstrated with alterations in the HERG- gene (Schimpf 2013).

The WHO describes cardiomyopathy as "disease of the myocardium with cardiac dysfunction" (Kaltenbach 2013).

In the latest European classification, cardiomyopathies are described as a cardiac disease that results in structurally and functionally altered myocardium without the presence of CHD, arterial hypertension, congenital heart disease, or valvular heart disease (Pankuweit 2009).

The group of familial cardiomyopathies is one of the primary cardiomyopathies (Brieler 2017).

Familial cardiomyopathies include:

- 1. hypertrophic cardiomyopathy (HCM).

HCM represents the most common familial cardiomyopathy with an incidence of 1: 500 (Stiefelhagen 2020). It is familial in approximately 50% and is inherited in an autosomal dominant manner (Kaltenbach 2013). It is a disease of the sarcomere, resulting in concentric, asymmetric, and apical myocardial hypertrophy (Sieverding 2020).

Deaths have been described in sports starting at 10 years of age (Moog 2014).

- 2. arrhythmogenic (right) ventricular cardiomyopathy (A[R]VC):

A(R)VC was originally described as a disease of the right ventricle. However, it has since been shown that one or both ventricles can be affected (Kasper 2015).

The disease is rather rare with an incidence of 1: 5,000 (Stiefelhagen 2020). A(R)VC shows a familial clustering in about 30% (Kaltenbach 2013).

The mode of inheritance is predominantly autosomal dominant with genetic heterogeneity and variable clinical expression (Greten 2010). The mutation affects cell contact proteins (Stiefelhagen 2020). This results in electroanatomical abnormalities (Sieverding 2020). Deaths in sports have also been described from the age of 10 (Moog 2014).

- 3. long QT syndrome (LQT):

An autosomal dominant inheritance is found in the more common form, also known as Romano-Ward syndrome, and an autosomal recessive inheritance in the rarer variant, Jervell and Lange-Nielsen syndrome (Greten 2010).

The disease usually occurs in late childhood or early adolescence. Girls are more frequently affected (Greten 2010).

The syndrome is blamed for drowning accidents in children (Moog 2014).

- 4. brugada syndrome:

Brugada- syndrome is a genetically heterogeneous disorder. Approximately 20 % of the patients have a defect in the ion channel (Greten 2010).

This can lead to life-threatening arrhythmias, particularly in the context of high-fever infections (Moog 2014).

- 5. dilated cardiomyopathy (DCM):

DCM is the most common form of all cardiomyopathies and is familial in 25% (Stiefelhagen 2020 / Wappler 2011). Kasper (2015) reports familial involvement at 30%, and the incidence is 1: 2,500 (Kaltenbach 2013).

There is a predominantly autosomal dominant inheritance, more rarely an autosomal recessive, X chromosomal (Kaltenbach 2013) or mitochondrial. So far, > 40 genes have been identified as carriers of the mutation (Soares 2017). Men usually develop cardiomyopathy 10 years earlier than women, albeit asymptomatically (Kasper 2015).

Approximately 30% have a mutation of DCM-associated genes (Meder 2017).

- 6. restrictive cardiomyopathy (RCM):

This is a rare disease that can occur in association with scleroderma, sarcoidosis, Fabry disease, Gaucher disease, Hurler disease, etc (Greten 2010). In this case, there is a reduced distensibility of the myocardium and mutations of troponin I (Sieverding 2020).

RCM manifests itself predominantly in conduction disorders (Meder 2017).

- 7. noncompaction cardiomyopathy (NCCM), also known as left ventricular noncompaction cardiomyopathy (LVNC):

The incidence of NCCM is 1: 1,000 and the disease is inherited in an autosomal dominant manner. NCCM shows genetic and phenotypic overlap with hypertrophic cardiomyopathy and dilated cardiomyopathy (Stiefelhagen 2020).

Approximately 5% of cardiomyopathies in children are due to NCCM. The disease leads to an increased risk of thromboembolic events and arrhythmias (Hänselmann 2020).

- 8. ion channel diseases/primary arrhythmia syndromes:

These include, for example, long Q syndrome, Brugada syndrome (Schimpf 2013).

Mostly, these are mutated sodium and potassium ion channels (Engelhardt 2022).

With regard to ion channel diseases, no other field has so many findings on direct correlations between genetic cause and clinical phenomenon. Nevertheless, due to the large number of changes in the ECG, there is still uncertainty regarding the relevance of the findings (Ziakos 2019).

The mode of inheritance is autosomal dominant in the majority of cases (Beckmann 2011).

Before the age of 40, 3 in 100,000 individuals experience sudden cardiac death. In more than half, a hereditary arrhythmia syndrome can be identified retrospectively (Schaaf 2018).

- 9. mitochondrial cardiomyopathies:

Mitochondrial diseases represent a heterogeneous group of multisystemic diseases.

In mitochondrial cardiomyopathy, there is a disruption of mitochondrial protein import into the inner mitochondrial mambrane (Wachoski- Dark 2022). This disrupts cardiac structure and/or function and manifests as hypertrophicor dilated cardiomyopathy, heart failure, arrhythmias, and left ventricular myocardial noncompaction (Meyers 2013).

The mutations affect the mtDNA and nDNA, respectively. The incidence of mitochondrial disease is 1: 10,000, and there is an inheritance pattern with autosomal dominant, recessive, and X chromosomal inheritance (Meyers 2013). This mitochondrial cardiomyopathy is one of the rare forms of cardiomyopathy (Gerok 2007).

- 10. syndromic cardiomyopathies:

The syndromic cardiomyopathies may occur in the context of the following diseases such as Fabry disease or Danon disease. There is an X- chromosomal inheritance (Meder 2017). This form of cardiomyopathy results in dilatation with defects in conduction of excitation (Meder 2017).

- 11. familial amyloid cardiomyopathy.

This is inherited in an autosomal dominant manner. In this case, there are mutations of transthyretin. The conduction system is often affected (Erdmann 2009).

Clinically, a restrictive cardiomyopathy is found due to amyloid deposits (Roskamm 2013). In this disease, monoclonal proteins are found in the urine (Caspary 2013).

The symptoms of cardiomyopathy - depending on the cause - can be very different. These include:

- Partially asymptomatic course

- cardiac arrhythmias of any kind

- sudden cardiac death

- signs of heart failure

- Thrombus in the left-sided cardiac cavities with the risk of embolic apoplexy (Moog 2014).

In patients with a history of cardiomyopathy , the following examinations should be performed:

- physical examination

- ECG

The ECG should also be checked for subtle changes because of possible ion channel disease.

- echocardiography

- Family history with pedigree over 3 generations

and, if necessary, optional examinations such as:

- Stress ECG

A stress ECG should be performed especially in cases of suspected ion channel disease, since arrhythmias are triggered by physical stress.

- Cardio- MRI for more precise measurement of wall thickness and function as well as detection of fibrosis or myocardial edema.

- blood sampling

- invasive diagnostics of the coronary arteries

- Myocardial biopsy (Moog 2014).

To date, the significance of cardiac biomarkers such as troponins and NT- proBNP has not been established for screening purposes (Moog 2014)

Family screening should always be performed in patients with cardiomyopathy. Because of the different modes of inheritance, not only first-degree relatives should be examined, but also second-degree relatives (Moog 2014).

It is recommended that family screening for cardiomyopathies manifesting in adulthood begin at approximately 16 years of age. However, because some cardiomyopathies manifest in childhood, the start of examinations should be determined on an individual basis.

Examinations should be repeated regularly, as the penetrance of cardiomyopathies increases with age. In children and adolescents, 1 - 2 examinations per year should be performed until 23 years of age; in adulthood, a 5-year interval of examinations is sufficient until approximately 70 years of age, since after that time initial manifestation is unlikely or clinically irrelevant (Moog 2014).

The familial examination should include:

- physical examination

- ECG

- echocardiography

- family history with pedigree over 3 generations

As well as optional examinations, if necessary, such as:

- stress ECG

- Cardio- MRI (Moog 2014).

Familial cardiomyopathy is considered confirmed if

- a family has 2 or more affected persons

- A first-degree relative aged < 35 years has died of a sudden death of unknown etiology and well-documented records are available (Moog 2014).

Familial cardiomyopathy is suspected when

- A first-degree relative aged < 65 years:

- died from a death due to heart failure

- has died of an unexplained sudden death

- This person has impaired left ventricular function (Moog 2014).

Currently, therapy is based on phenotype rather than genotype (Kasper 2015) and consists - in addition to treatment of the underlying condition - of e.g. (Stiefelhagen 2020):

- Implanted defibrillator / cardioverter (ICD):

In many familial cardiomyopathies, implantation of a defibrillator is required e.g. dilated cardiomyopathy, arrhythmogenic (right) ventricular cardiomyopathy, non-compaction cardiomyopathy (Kasper 2015), long QT syndrome (Beckmann 2011), hypertrophic cardiomyopathy after resuscitation (Greten 2010).

- Anticoagulation:

Depending on the course of the disease, this may be necessary in non-compaction cardiomyopathy (Kasper 2015) from an LVEF < 40% with an INR target of 2.0 - 3.0, taking into account the benefit-risk balance (Oechslin 2011), as well as in the presence of atrial fibrillation, such as in the context of hypertrophic cardiomyopathy (Sauerbruch 2018).

- Therapy of heart failure:

This is particularly indicated in noncompaction cardiomyopathy according to guidelines (Oechslin 2011).

- Cardiac rechronization therapy (CRT):

This may be indicated, for example, in dilated cardiomyopathy (Beckmann 2011).

- Pacemaker implantation:

Pacemaker implantation may be considered, for example, in hypertrophic cardiomyopathy to improve clinical symptoms and diastolic function and to reduce any mitral regurgitation and intraventricular pressure gradient (Steinbeck 2005).

- Ablation:

If arrhythmogenic (right) ventricular cardiomyopathy results in the occurrence of ventricular tachycardia, ablation may be required (Stiefelhagen 2020).

- Heart Transplantation:

Evaluation for heart transplantation should be considered in refractory cardiomyopathies (Beckmann 2011).

- Beta blockers:

These are an integral part of the treatment of long QT syndrome (Beckmann 2011). They are also used in hypertrophic cardiomyopathy (Sauerbruch 2018) and arrhythmogenic (right) ventricular cardiomyopathy (Stiefelhagen 2020).

- 1. hypertrophic cardiomyopathy (HCM).

Because the disease shows extreme heterogeneity, it is difficult to provide a general prognosis. Overall, however, HCM tends to be considered a benign disease (Mewis 2006).

- 2. arrhythmogenic (right) ventricular cardiomyopathy (A[R]VC):

There are approximately 20% of all sudden cardiac deaths at a young age caused by A(R)VC (Stiefelhagen 2020).

- 3. long QT syndrome (LQT):

The 10- year survival rate is 50% if untreated, and mortality to age 40 is 6% (Zerkowski 2006).

- 4. brugada syndrome:

The initial manifestation is often cardiac arrest. After implantation of an ICD, regular follow-up should be performed (Schölmerich 2003).

- 5. dilated cardiomyopathy (DCM):

The 5-year mortality rate is between 10-20%. Cause of death is usually sudden cardiac death and progressive heart failure (Greten 2010).

- 6. restrictive cardiomyopathy (RCM):

RCM has a poor prognosis. Approximately 70% of patients die within 5 years (Greten 2010).

- 7. non-compaction cardiomyopathy (NCCM), also called left ventricular non-compaction cardiomyopathy (LVNC):

Prognosis is rather poor. Patients die of arrhythmias, left ventricular dysfunction or thromboembolic events (Singh 2022).

- 8. mitochondrial cardiomyopathies:

Patients with mitochondrial disease in crisis show high lethality. The causes of death are cardiogenic shock, dilated cardiomyopathy, atrial and ventricular arrhythmias, sudden cardiac death (Meyers 2013).

- 9. familial amyloid cardiomyopathy:

The prognosis of primary amyloidosis has a median survival of 6 months after the onset of heart failure (Mewis 2006).

Molecular diagnostics are currently recommended by the DGK and DGPK:

- Recommendation Council I in:

- Hypertrophic cardiomyopathy

- Arrhythmogenic (right) ventricular cardiomyopathy

- Syndromal cardiomyopathies (Meder 2017).

- Grade of Recommendation IIA:

- Noncompaction cardiomyopathy

- Familial dilated cardiomyopathy

- Dilated cardiomyopathy with conduction disturbance (Meder 2017)

Patients with arrhythmogenic (right) ventricular cardiomyopathy (A[R]VC) should not undergo any physical exertion (Stiefelhagen 2020).

In mitochondrial cardiomyopathies, the following drugs that impair mitochondrial function should be avoided or a crisis state may result:

- Metformin

- propofol

- streptomycin

- tetracyclines

- erythromycin

- azithromycin

- chloramphenicol

- statins

- Aminoglycosides (Meyers 2013)

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