Arrhythmogenic cardiomyopathy page Archivi - AF-ABLATION

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What is arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC)?

Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiac muscle disease, clinically characterized by potentially lethal ventricular arrhythmias. The prevalence is estimated at 1:2,000, although in some countries (Italy and Greece) the disease is particularly common (as much as 1:700). The disease consists of a degeneration of the ventricular myocardium, mainly localized to the right ventricle, but which may also involve the left ventricle. The cardiac muscle tissue (called myocardium) is replaced by a fibro-adipose tissue of such magnitude as to cause aneurysms (dilations) of the ventricle. It is not easy to estimate the true prevalence and incidence of ARVD because patients are not always easily identifiable from a diagnostic point of view. Furthermore, sometimes the first manifestation of the pathology is sudden cardiac death, and this complicates epidemiological investigations. The prevalence of the disease is similar in both sexes, although the majority of symptomatic patients are male.

What is the clinical presentation of ARVD?

ARVD is one of the major causes of sudden death in young adults and athletes. Its clinical presentation usually consists of arrhythmic phenomena ranging from more or less frequent isolated ventricular extrasystoles to tachycardia or ventricular fibrillation (VT/VF).

What are the genetic characteristics of ARVD? 

Based on current knowledge, ARVD has a genetic basis, and no acquired forms are known. Numerous genes have been described that, when mutated, cause ARVD. These include the genes PKP2, DSG2, DSC2, TGFB3, DSP, JUP, and TMEM43; more recently, the genes LDB3, LMNA, RYR2, TTN and CTNNA3 have also been added. The genes that cause the disease code for the proteins of mechanical cellular junctions (placoglobin, placofilina, desmoglein, desmocolina, desmoplakina).

A family history of ARVD is present in a percentage ranging from 30 to 50% of cases. The most common transmission pattern is autosomal dominant with variable penetrance and polymorphic phenotypic expression, although an autosomal recessive model has also been described. The most common hereditary modality of ARVD is of an autosomal dominant type: it is sufficient to possess a mutated single copy of a disease gene (mutation in heterozygosity) to be affected. In many families with a known ARVD genotype, incomplete penetrance (not all heterozygotes for causative mutations presenting clinical manifestations) and variable expressivity (the clinical picture may vary even between genetically related individuals and heterozygotes for the same causative mutation) were found. In addition to the typical form with autosomal dominant transmission and variable penetrance, recessive forms associated with palmo-plantar keratoderma and woolly hair have also been observed.

How is the ARVD diagnosis made?

The diagnosis of ARVD usually occurs during adolescence or adulthood. Because of the progressive evolution of the pathology, patients often present with a heterogeneous symptomatology. Palpitations, fatigue and syncope seem to be the most common symptoms, but sometimes there are non-specific symptoms, such as abdominal pain and mental confusion. In some cases, however, the first manifestation may be cardiac arrest in conjunction with intense physical effort, or at night. The main differential diagnoses are myocarditis, dilated cardiomyopathy, sarcoidosis and amyloidosis.

The diagnosis of ARVD begins with taking a good medical history. A personal history of palpitations (especially in young people), together with a family history of sudden death, should always lead to the suspicion of ARVD.

The tools of choice for diagnosis are imaging tests, including two-dimensional ultrasound, angiography and magnetic resonance imaging, which reveal structural and functional anomalies. The electroanatomical map enables the identification of the low voltage areas corresponding to myocardial atrophy, with fat-fibrous substitution.

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Figura 2. Displasia aritmogena biventricolare associata ad area di infiltrazione adiposa della parete  laterale distale e dell’apice del ventricolo sinistro.

What are the typical electrocardiographic abnormalities of ARVD?

50 to 90% of patients have electrocardiographic abnormalities, which include:

1) inversion of the T wave in precordial derivations, in subjects aged> 12 years and in the absence of RBBB

2) onda epsilon (low amplitude potentials located at the beginning of the ST segment – represent a delay in activation of right ventricular myocardium)

3) frequent ventricular extrasystoles (> 1000 BEV / 24 hours) with left bundle branch morphology,

4) unsupported ventricular tachycardias (NSVT) or sustained ventricular tachycardias (SVT) with left bundle branch morphology (although it is possible to find VT with different morphologies).

5) Late potentials on high resolution ECG

What are the risk factors for the ARVD prognosis?

The major risk factors for a poor prognosis are young age, family history of sudden juvenile death, a QRS greater than or equal to 140 ms, inversion of the T wave on the tracing, the extent of involvement of the right ventricle, the involvement of the left ventricle, the presence of ventricular tachycardias, the history of syncope or a previous cardiac arrest.

The endocavitary electrophysiological study (EES) is used for risk stratification in order to evaluate the susceptibility of the arrhythmogenic substrate. With the EES, it is possible to determine the type of inducible arrhythmia, as well as its morphology and hemodynamic tolerability.

What is the clinical evolution of ARVD?

The natural history of ARVD depends both on the electrical instability of the substrate and on the progressive ventricular dysfunction. With the evolution of the pathology, there is an alteration of the ventricular contractility that results in heart failure in either the right ventricule, or in both ventricules. The involvement of the left ventricle, whether it is macroscopic or histological, affects about 70% of patients. This involvement appears to be dependent on age and intense exercise (for example in competitive athletes), which seems to worsen and accelerate the clinical evolution of the disease. It is therefore recommended to follow the clinical evolution with serial echocardiographic investigations. In the natural progression, however, the following phases could be considered:

1) initial or occult phase, characterized by minimal structural alterations, with or without minor ventricular arrhythmias, during which sudden death could occasionally be the first manifestation of disease (particularly during intense physical activity);

2) arrhythmogenic phase, during which ventricular arrhythmias originating from the right ventricle are symptomatic and can lead to cardiac arrest (whether or not there are functional anomalies of the ventricle);

3) right ventricular dysfunction phase, with the progressive appearance of right ventricular failure due to the progressive replacement of the muscle with fibroadipose tissue, with relatively conserved left ventricular function;

4) phase of biventricular dysfunction, in which there is progressive biventricular involvement and dysfunction. At this stage, the ARVD can mimic a different dilated cardiomyopathy and lead to congestive heart failure with all its related complications, such as atrial fibrillation and thromboembolic events.

What is the therapy for ARVD?

The main treatment of arrhythmogenic dysplasia is aimed at preventing sudden cardiac death. Although there is no way to cure ARVD, it is possible to control arrhythmic manifestations and ventricular dysfunction. Available therapies include lifestyle modifications, antiarrhythmic drugs, ablation of the arrhythmic substrate with radiofrequency, and implantation of an automatic defibrillator (ICD).

Although there is no definitive evidence regarding lifestyle changes, patients should avoid intense physical activity, both to avoid arrhythmias and to avoid ventricular overload that can promote ventricular dysfunction.

In the case of arrhythmias, antiarrhythmic drugs can be used, which have also shown limited efficacy. Amiodarone, administered intravenously, is effective in interrupting ventricular tachycardias. Other pharmacological regimens include beta-blockers, either alone or in combination with class Ia and Ic drugs, amiodarone in combination with class II or Ic drugs.

Radiofrequency ablation is used in the case of incessant or refractory well-localized ventricular tachycardias, after the defibrillator is implanted to reduce its intervention. The effectiveness of ablation varies from case to case, and sometimes more than one procedure is required. Recurrences are often due to the evolution of the pathology that creates new re-entry circuits.

The implantation of a defibrillator, generally, is recommended for patients with previous resuscitated cardiac arrest, or who have induced sustained ventricular arrhythmias during EES, or with unsupported ventricular arrhythmias and history family of sudden death at a young age, or when there is involvement of the left ventricle.



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What is Familial Dilated Cardiomyopathy (DCM)?

Familial dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilation and reduced systolic function. Patients have heart failure, arrhythmias, and an increased risk of sudden cardiac death (SCD). The prevalence of DCM is 1/2,500, with an incidence of 7/100,000 cases per year (although this incidence is probably underestimated). In many cases, the disease is inherited and is therefore referred to as familial DCM (FDCM). FDCM corresponds to about 20-48% of DCM cases, usually with autosomal dominant transmission. DCM is caused by mutations in the genes that code for cytoskeletal and sarcomeric proteins of cardiac muscle cells. One of the most important genes is LMNA, also responsible for other forms of arrhythmias (Bengala et al, 2019).

What is the clinical presentation of Dilated Cardiomyopathy (DCM)?

DCM is a progressive and usually irreversible pathology of the myocardial muscle, which leads to systolic and dilated dysfunction of the left ventricle. Clinically, it can occur with heart failure, supraventricular and ventricular arrhythmias, thromboembolism, and sudden death. DCM diagnosis requires the exclusion of a secondary cause, particularly ischemia. The mortality rate of the disease is high (12-20%), even in the population receiving optimal medical treatment, mainly due to heart failure and ventricular arrhythmias that result in SCD. The symptoms of DCM are those of heart failure (weakness, easy fatigue, labored breathing during sometimes even moderate effort, persistent dry cough, swelling of the abdomen and lower limbs, sudden weight gain caused by water retention, loss of appetite) and cardiac arrhythmias (palpitations, dizziness or fainting).

What are the diagnostic tests for Dilated Cardiomyopathy (DCM)?

The following tests are recommended for symptoms resulting in the suspicion of DCM:

Blood chemistry tests: A risk marker is the dosage of brain natriuretic peptide (BNP), which is elevated in the presence of heart failure. Changes in the liver and kidney function indices may also be present, an expression of the suffering of these organs due to heart failure. In severe cases, there is hyposodyemia, hypokalaemia and anemia.

Chest X-ray: provides information on the size of the heart and the presence and degree of lung congestion.

Basal ECG and dynamic Holter ECG: The electrocardiographic markers of arrhythmic risk may include the presence of fragmented QRS and the presence of micro-alternation of the T wave, even if these parameters have not yet been assessed prospectively. Other ECG markers are the recognition of supraventricular or ventricular arrhythmias, in particular unsustained ventricular tachycardias during Holter recording, usually detected by prolonged Holter monitoring.

Monomorphic ventricular tachycardia (13 sec) in patient with DCM (FEVS 25%)

Echocardiogram: It is the fundamental examination for the diagnosis and follow-up of DCM, as it allows to evaluate the size and thickness of the walls of the cardiac chambers, the contractile function (measured with a parameter called “left ventricular ejection fraction (LVEF)) and valve function, and to estimate lung pressure. The presence of a LVEF < 35% is considered a negative prognostic index, associated with a high risk of SCD.

Stress test with oxygen consumption: The exam consists of recording an electrocardiogram while the patient performs physical exercise, generally walking on a treadmill or pedaling on an exercise bike; a mouthpiece for the measurement of exhaled gas is also applied. The test allows to evaluate the subject’s resistance to exercise, the presence of desaturation during exercise, the appearance of signs of ischemia and arrhythmias under stress.

Coronary angiography: these tests serve to exclude the presence of significant coronary artery disease or the presence of congenital anomalies of the coronary artery.

Cardiac magnetic resonance imaging (cMRI) with contrast medium: The examination allows a better assessment of the right ventricle compared to the echocardiogram, and also assesses the structure of the myocardium, thus allowing to identify the presence of inflammatory processes and areas of intramyocardial fibrosis (scars). Myocardial fibrosis is a significant feature of dilated cardiomyopathy, and provides the substrate for ventricular arrhythmias, as it predisposes to the formation of re-entry circuits. Fibrosis is generally localized in the myocardial wall (mid-wall fibrosis).

Cardiac catheterization: is an invasive method that is based on the introduction of a catheter through a venous vessel up to the right cavities of the heart, which allows to acquire important information on the flow and oxygenation of the blood and on the pressure inside the right heart chambers and on the lung pressure. This is an examination reserved for the most serious forms in which it is necessary to verify the degree of increase in the ventricular filling pressures and the reduction in cardiac output (i.e. the amount of blood pumped by the heart) and pulmonary hypertension.

Endomyocardial biopsy: is performed during the execution of cardiac catheterization by using a tool called a biotome. Typically biopsies are performed on the right side of the interventricular septum. It is indicated in patients with recently found dilated cardiomyopathy and “fulminant” heart failure to identify the presence of myocarditis and, if necessary, identify the type of cells that support the inflammatory process, because this has an important prognostic value.

What are the treatments for Dilated Cardiomyopathy (DCM)?

The treatment of DCM is essentially therapy to treat and prevent heart failure and arrhythmias, to improve symptoms, and increase survival. Currently, heart failure therapy includes general measures (controlled intake of salt and liquids, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise), followed by the use of drugs and heart devices:

Drugs: ACE inhibitors, sartans, beta-blockers, anti-aldosterones, diuretics, digoxin.

Cardiac devices: pacemaker (PM), resynchronizers (CRT), intravenous cardiac defibrillators (ICD).

In cases refractory to medical and electrical treatments, the implantation of left ventricular assist devices (LVAD) and heart transplantation are indicated.

What are the current recommendations for the prevention of sudden death in dilated cardiomyopathy?

The current guidelines of the European Cardiology Society (ESC 2015) recommend the use of an implantable defibrillator (ICD) in primary prevention in patients with DCM in the New York Heart Association (NYHA) II and III class, and with a left ventricular ejection fraction (LVEF) less than or equal to 35%. LVEF is an important predictor of malignant ventricular arrhythmias in patients with DCM. The absolute risk of SCD increases with the worsening of LVEF. Even some recent trials (for example the DANISH study) have not shown a significant reduction in mortality in patients with ICD implantation in primary prevention, in comparison with only optimal medical therapy (OMT). In any case, current guidelines recommend ICD implantation after at least 3 months of optimal drug therapy with ACE inhibitors, beta-blockers and diuretics, since, in some patients, a more or less partial recovery of LVEF can be observed after at least 3 months of OMT.

What is the role of genetics in dilated cardiomyopathy?

DCM is associated with mutations in the genes that code for cytoskeletal and sarcomeric proteins of cardiac muscle cells. One of the most important genes is LMNA, which codes for Lamina A and C. Patients in whom the genetic mutation is identified appear to be at greater risk of SCD with a mortality of 40% at 5 years. Therefore, the earliest implantation of an ICD is recommended in patients with a genetic mutation of the LMNA gene.

In the case of familial dilated cardiomyopathy, the search for genetic mutations associated with the development of DCM is recommended. If a genetic mutation associated with the development of DCM is identified, the study of family members is naturally recommended, to identify other possible affected subjects within the family: those in whom the search for the mutation will be negative can be reassured that they will not develop the pathology, while the healthy carriers of a possible mutation must be followed over time (in particular with echocardiogram and ECG monitoring), to identify the possible clinical appearance of the disease.

To consult Orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=IT&Expert=154

For bibliographical references:

https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=Search&Term=cardiomyopathy,congestive%5Bmajr%5D+AND+familial

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