Dilated cardiomyopathy

Dilated cardiomyopathy is a dysfunction of the myocardium leading to heart failure, in which ventricular dilation and systolic dysfunction predominate.

Symptoms of dilated cardiomyopathy include shortness of breath, fatigue, and peripheral edema. Diagnosis is based on clinical findings, chest X-ray, and echocardiography. Treatment of dilated cardiomyopathy is aimed at eliminating the cause, and heart transplantation may be necessary.

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Epidemiology of dilated cardiomyopathy

The incidence of dilated cardiomyopathy is 5-7.5 cases per 100,000 population per year. In men, it occurs 2-3 times more often, especially at the age of 30-50 years). This disease also causes chronic heart failure in 30% of cases. Among all types of cardiomyopathy, DCM accounts for 60%.

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Causes of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) has many known and probably many unrecognized causes. The most common cause is diffuse coronary artery disease (CAD) with widespread ischemic myopathy. More than 20 viruses can cause dilated cardiomyopathy. In temperate zones, coxsackievirus group B is the most common. In Central and South America, the most common cause is Chagas disease caused by Trypanosoma cruzi. Dilated cardiomyopathy is becoming increasingly common among patients with AIDS. Other causes include toxoplasmosis, thyrotoxicosis, and beriberi. Many toxic substances, especially alcohol, various organic solvents, and certain chemotherapeutic drugs (eg, doxorubicin), cause cardiac damage.

In most cases, the etiology of this disease is unknown, but in the development of primary dilated cardiomyopathy, much attention is currently paid to three points:

• family and genetic factors;
• transferred viral myocarditis;
• immunological disorders.

In genetic studies, in the development of idiopathic dilated cardiomyopathy, a familial predisposition has been identified in a third of cases, in which autosomal dominant inheritance (autosomal dominant DCM) is predominant. Along with autosomal dominant, autosomal recessive, X-linked and mitochondrial forms of dilated cardiomyopathy have also been described.

Autosomal dominant forms are characterized by clinical variability and genetic heterogeneity. They are associated with six different loci: simple dilated cardiomyopathy - with loci lq32, 2p31, 9ql3, 10q21-q23; DCM with conduction disturbances - with loci lql-lql, 3p22-3p25, and it is unknown for the synthesis of which cardiac proteins these loci are responsible.

Mitochondrial dilated cardiomyopathies are associated with abnormalities in mitochondrial structure and dysfunction of the oxidative phosphorylation process. As a result of mutation, energy metabolism of cardiomyocytes is disrupted, which leads to the development of DCM. Point mutations and multiple deletions in mitochondrial DNA have been described in both sporadic and familial cases of DCM. Many mitochondrial myopathies are associated with neurological disorders.

Currently, the molecular basis of X-linked DCM is being studied. Mutations in various parts of the gene responsible for the synthesis of the dystrophin protein (chromosome 21) have been described. Dystrophin is a myocardial protein that is part of a multiprotein complex that binds the muscle cytoskeleton of the cardiomyocyte to the extracellular matrix, thereby adhering the cardiomyocytes to the extracellular matrix. By binding to actin, dystrophin performs a number of important functions:

• membrane-stabilizing;
• transfers the contractile energy of the cardiomyocyte into the extracellular environment;
• ensures membrane differentiation, i.e. specificity of the cardiomyocyte membrane.

Mutations have been identified that involve nucleotide substitution, leading to amino acid substitution. This can cause a disruption in the polarity of the dystrophin molecule and change other properties of this protein, reducing its membrane-stabilizing property. As a result, cardiomyocyte dysfunction occurs. Dystrophin gene mutations have been described in DCM associated with Duchenne and Becker muscular dystrophies; deletions are most often found in these cases.

Great importance is also attached to the role of enterovirus infection (in particular, Coxsackie B, hepatitis C, herpes, cytomegalovirus-y) in the development of DCM. Persistent viruses embed their RNA into the genetic apparatus of cardiomyocytes, damaging mitochondria and disrupting the energy metabolism of cells. There is evidence of the presence of cardiospecific autoantibodies, such as antimyosin, antiactin, antimyolemma, anti-alpha-myosin and anti-beta-myosin heavy chains. Anti-adenosine diphosphate-adenosine triphosphate, which is an antibody to the mitochondrial membrane of cardiomyocytes and has an adverse effect on the functioning of membrane calcium channels, which in turn leads to disruption of myocardial metabolism, was also detected. An increase in proinflammatory cytokines (IL-1, IL-6, TNF-a) in the blood was detected in some patients. It is likely that patients with underlying autoimmune deficiency are more susceptible to the damaging effects of viruses and the development of dilated cardiomyopathy.

In some patients, dilated cardiomyopathy is thought to begin with acute myocarditis (probably viral in most cases), followed by a variable latent phase during which widespread cardiomyocyte necrosis develops (due to an autoimmune reaction to virus-altered myocytes), followed by chronic fibrosis. Regardless of the cause, the remaining myocardium dilates, thins, and hypertrophies compensatorily, often leading to functional mitral or tricuspid regurgitation and atrial dilation.

In most patients, the disease affects both ventricles, in some only the left ventricle (LV), and much less commonly only the right ventricle (RV).

Once the dilation of the cardiac chambers reaches a significant size, especially during the acute phase of myocarditis, mural thrombi often form. Arrhythmias often complicate the course of acute myocarditis and the late phase of chronic dilation, and atrioventricular block (AV block) may also develop. Atrial fibrillation often occurs due to dilation of the left atrium.

Causes of cardiomyopathy

Form	Etiology
Dilated congestive cardiomyopathy (acute or chronic)	Chronic widespread myocardial ischemia (damage to the coronary arteries). Infections (acute or chronic) caused by bacteria, spirochetes, rickettsia, viruses (including HIV), fungi, protozoa, helminths. Granulomatous diseases: sarcoidosis, granulomatous or giant cell myocarditis, Wegener's granulomatosis. Metabolic disorders: nutritional disorders (beriberi, selenium deficiency, carnitine deficiency, kwashiorkor), familial storage diseases, uremia, hypokalemia, hypomagnesemia, hypophosphatemia, diabetes mellitus, thyrotoxicosis, hypothyroidism, pheochromocytoma, acromegaly, morbid obesity. Drugs and toxins: ethanol, cocaine, anthracyclines, cobalt, antipsychotics (tricyclic and quadricyclic antidepressants, phenothiazines), catecholamines, cyclophosphamide, radiation. Tumors. Systemic connective tissue diseases. Isolated familial syndrome (dominant according to Mendel). Hereditary neuromuscular and neurological diseases (Friedreich's ataxia). Pregnancy (postpartum period)
Hypertrophic cardiomyopathy	Autosomal dominant inheritance, pheochromocytoma, acromegaly, neurofibromatosis
Restrictive cardiomyopathy	Amyloidosis, systemic sclerosis, endocardial fibrosis, Fabry disease, fibroelastosis, Gaucher disease, hemochromatosis, hypereosinophilic Löffler syndrome, sarcoidosis, hypereosinophilic syndrome, tumors

About 75 etiological factors have been described in the formation of secondary/specific DCM.

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Main causes of secondary/specific dilated cardiomyopathy

• Electrolyte disturbances.
  • Hypokalemia.
  • Hypophosphatemia.
  • Uremia.
• Endocrine disorders.
  • Itsenko-Cushing's disease.
  • Diabetes mellitus.
  • Acromegaly.
  • Hypothyroidism/hyperthyroidism.
  • Pheochromocytoma.
• Long-standing arterial hypertension.
• Ischemic heart disease.
• Infectious diseases.
  • Bacterial (brucellosis, diphtheria, typhoid fever, etc.).
  • Fungal.
  • Mycobacterial.
  • Parasitic (toxoplasmosis, Chagas disease, schistosomiasis).
  • Rickettsial.
  • Viral (Coxsackie virus A and B, HIV, adenovirus).
• Infiltrative diseases.
  • Amyloidosis.
  • Hemochromatosis.
  • Sarcoidosis.
• Neuromuscular pathology.
  • Myopathies.
  • Friedreich's ataxia.
  • Atrophic myotonia.
• Eating disorder.
  • Selenium deficiency.
  • Carnitine deficiency.
  • Thiamine deficiency.
• Rheumatic diseases.
  • Giant cell arteritis.
  • Systemic scleroderma.
  • Systemic lupus erythematosus.
• Exposure to toxins.
  • Amphetamines.
  • Antiviral drugs.
  • Carbon monoxide.
  • Radiation, chemotherapy drugs.
  • Chloroquine, phenothiazine.
  • Cobalt, lead, mercury.
  • Cocaine.
  • Ethanol.
• Tachyarrhythmia.
• Congenital and acquired heart defects.

Pathogenesis of dilated cardiomyopathy

As a result of the impact of etiological factors on the heart, damage to cardiomyocytes develops with a decrease in the number of functioning myofibrils.

This leads to progression of heart failure, expressed in a significant decrease in the contractility of the myocardium with rapid development of dilatation of the heart cavities. At the first stages, the sympathoadrenal system is activated compensatorily to maintain the stroke volume and ejection fraction, with the development of tachycardia. As a result, compensatory myocardial hypertrophy is formed, there is a significant increase in the myocardial oxygen demand with the appearance of signs of ischemia, the development of cardiac fibrosis and the progression of heart failure. As a result of the pathological process, there is a critical decrease in the pumping function of the heart, an increase in the end-diastolic pressure in the ventricles and the development of myogenic dilatation of the heart cavities with relative insufficiency of the mitral and tricuspid valves. Increased activation of the body's neurohormonal systems leads to greater damage to the myocardium, peripheral vasoconstriction, disorders of the coagulation and anticoagulation systems of the blood with the development of intracardiac thrombi and systemic thromboembolic complications.

Symptoms of dilated cardiomyopathy

The disease most often occurs in young and middle-aged people. The onset is usually gradual, except in cases of acute myocarditis. Symptoms depend on which ventricle is affected. LV dysfunction causes dyspnea during exercise, as well as fatigue due to increased LV diastolic pressure and low cardiac output. RV failure leads to peripheral edema and venous distension in the neck. Isolated RV involvement is characterized by the development of atrial arrhythmias and sudden death due to malignant ventricular tachyarrhythmias. Approximately 25% of all patients with dilated cardiomyopathy report atypical chest pain.

In the early stages, only individual symptoms of heart failure are determined, and cardiomegaly is detected by chest X-ray. As a result of progressive left ventricular failure, shortness of breath, attacks of suffocation, rapid fatigue, and muscle weakness are characteristic. Auscultation of the heart reveals tachycardia, and the third heart sound (the "gallop rhythm"), often the fifth heart sound, and the murmur of relative mitral regurgitation. In 40-50% of cases, the course of dilated cardiomyopathy is complicated by the appearance of ventricular arrhythmias, which are accompanied by syncope, and in 15-20% of cases, paroxysmal atrial fibrillation develops initially, turning into constant, which sharply increases the risk of thromboembolic complications against the background of existing systolic dysfunction of the myocardium. Signs of right ventricular failure (swelling of the legs, heaviness in the right hypochondrium, enlargement of the liver and abdomen due to ascites) appear later. Thus, the clinical symptoms of dilated cardiomyopathy vary from a low-symptom course to severe heart failure.

Classification of dilated cardiomyopathy

According to the existing WHO classification, the following forms are distinguished among DCM: idiopathic, familial/genetic, viral and/or immune, alcoholic/toxic, as well as “specific cardiomyopathies” in other heart diseases and systemic processes.

According to the classification of Maron et al. (2006), all cases of dilated cardiomyopathy are divided into two groups: primary (genetic, non-genetic, acquired), in which only the myocardium is predominantly affected, and secondary (in various systemic diseases).

The ESC Working Group (2008) proposed a new classification of cardiomyopathy, which essentially returns us to the Goodwin definition and excludes the presence of such DCM as ischemic, valvular, and hypertensive.

Classification of dilated cardiomyopathy includes familial/genetic and non-familial/non-genetic forms.

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Diagnosis of dilated cardiomyopathy

The diagnosis of dilated cardiomyopathy is based on the history, physical examination, and exclusion of other causes of ventricular failure (eg, systemic hypertension, primary valvular disorders). Therefore, chest radiography, ECG, and echocardiography should be performed. In the presence of acute symptoms or chest pain, cardiac-specific markers should be measured. An elevated troponin is typical of coronary artery disease but may occur in heart failure, particularly with decreased renal function. Potential specific causes are identified (see other sections of the Manual). In the absence of a specific cause, serum ferritin and iron-binding capacity should be measured, thyroid-stimulating hormone levels should be determined, and serologic tests for toxoplasma, coxsackievirus, and ECHO should be performed to identify treatable causes.

ECG may reveal sinus tachycardia, low-voltage QRS complexes, non-specific ST segment depression, and inverted R wave. Sometimes abnormal Q waves may be present in the chest leads, simulating a previous myocardial infarction. Left bundle branch block is often detected.

Chest radiographs show cardiomegaly, usually with enlargement of all chambers. Pleural effusion, especially on the right, is often accompanied by increased pulmonary pressures and interstitial edema. Echocardiography shows chamber dilation and hypokinesis and excludes primary valvular disorders. Focal wall motion abnormalities typical of myocardial infarction are also possible in DCM, since the process may be focal. Echocardiography may also demonstrate the presence of a thrombus within the chambers. MRI is not routinely performed, but it can be used to show detailed myocardial structure and function. In cardiomyopathy, MRI can reveal abnormal myocardial tissue structure.

Coronary angiography is indicated if the diagnosis is in doubt after noninvasive testing, especially in patients with chest pain or in the elderly in whom coronary artery disease is likely. However, nonobstructive coronary artery changes seen on angiography may not be the cause of DCM. A biopsy of either ventricle can be performed during catheterization but is not routinely performed because the yield is often low, the disease may be focal, and the results are unlikely to change treatment.

Diagnosis and treatment of cardiomyopathies

Sign or method	Dilated congestive cardiomyopathy	Hypertrophic cardiomyopathy	Restrictive cardiomyopathy
Pathophysiological features	Systolic dysfunction	Diastolic dysfunction ejection obstruction	Diastolic dysfunction
Clinical examination	Failure RV and LV. Cardiomegaly. Functional regurgitation on the atrioventricular valves, S 3 and S	Angina pectoris, dyspnea on exertion, syncope, sudden death, mitral regurgitation ejection murmurs, biphasic carotid pulse with rapid rise and fall	Dyspnea and weakness on exertion, LV insufficiency, functional regurgitation of the atrioventricular valves
ECG	Non-specific ST-T changes.	Ischemia and hypertrophy of the LV. Deep teeth in the leads from the septal region	LV hypertrophy or low voltage
Echocardiography	Dilated hypokinetic ventricles thrombi in the heart cavities. Low EF	Ventricular hypertrophy mitral systolic forward motion asymmetric hypertrophy LV deformation	Increasing wall thickness, decreasing cavity size. LV diastolic dysfunction
X-ray examination	Cardiomegaly. Pulmonary vein congestion	No cardiomegaly	Absence or slight cardiomegaly
Hemodynamic features	Normal or increased EDP. Low EF. Diffusely dilated hypokinetic ventricles. Regurgitation on the atrioventricular valves.	High EDP, high EF, large subvalvular pressure gradient, mitral regurgitation. Normal or decreased CO	High EDP, deep and flat LV diastolic pressure wave. Normal or reduced SV
Forecast	70% mortality within 5 years	4% mortality rate per year	70% mortality within 5 years
Treatment	Diuretics, ACE inhibitors, ARBs, beta-blockers, spironolactone or eplerenone, implantable cardioverter-defibrillator, biventricular pacemaker, inotropic drugs, anticoagulants	Decreased contractility by the administration of beta-blockers verapamil disopyramide septal myotomy catheter ablation with alcohol. Atrioventricular pacemaker	Phlebotomy for hemochromatosis. Endocardial resection. Hydroxyurea in hypereosinophilia

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Treatment of dilated cardiomyopathy

Treatable underlying causes (eg, toxoplasmosis, hemochromatosis, thyrotoxicosis, beriberi) should be corrected. Otherwise, treatment is the same as for heart failure: ACE inhibitors, beta-blockers, aldosterone receptor blockers, angiotensin II receptor blockers, diuretics, digoxin, and nitrates. Glucocorticoids, azathioprine, and equine antithymocyte globulin are no longer used: although these drugs may shorten the acute phase of some inflammatory cardiomyopathies (eg, acute viral myocarditis or myocarditis in sarcoidosis), they do not improve the long-term outcome. Antiviral drugs are ineffective.

Because intracavitary thrombi may form, prophylactic oral anticoagulation is used to prevent systemic or pulmonary emboli, although there are no controlled studies to support the efficacy of this treatment. Significant arrhythmias are treated with antiarrhythmic drugs, although aggressive treatment of heart failure reduces the risk of arrhythmia. A permanent pacemaker may be required when AV block progresses to the chronic dilated phase, but AV block occurring during the acute myocarditis phase often resolves, so permanent pacemakers are usually unnecessary. If the patient has a widened QRS complex and severe clinical manifestations, biventricular pacing may be considered.

Prevention of dilated cardiomyopathy

Patients at risk for developing dilated cardiomyopathy (family history of this disease, relatives with the development of severe heart failure at a young age) should avoid professional sports and choosing professions associated with overwork.

When dilated cardiomyopathy is detected in a patient, the main goal is to prevent the progression of heart failure,

The main directions of assessment of risk factors for dilated cardiomyopathy, heart failure and the indicators used:

• questionnaires;
• psychological testing (anxiety level);
• assessment of health status in connection with functional status and clinical manifestations, prognosis of complications (distribution into risk groups; identification of a “high risk” group);
• monitoring of risks affecting health (exposure monitoring and control);
• assessment of the effectiveness of preventive interventions and treatment (recovery methods; compliance with medical recommendations and prescriptions, motivation, training in recovery techniques and their comparative characteristics).

Forecast

Because the prognosis is pessimistic, patients with dilated cardiomyopathy are often candidates for heart transplantation. Selection criteria include the absence of associated systemic diseases, psychiatric disorders, and irreversibly high pulmonary vascular resistance. Because hearts for transplantation are scarce, priority is given to younger patients (usually under 60 years of age).

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History of the issue

The term "dilated cardiomyopathy" appeared relatively recently (1957). Nevertheless, one of the first detailed reports by the Russian scientist S.S. Abramov (1897) about an isolated myocardial disease with a subacute course in a previously healthy 28-year-old peasant, which ended fatally 4 months after the onset of the first manifestations of congestive heart failure, is of great interest. S.S. Abramov noted, first of all, a sharp dilation of all parts of the heart, while "... the left ventricle is stretched so much that its capacity alone exceeds the capacity of the other three cavities of the heart taken together. Its wall is somewhat thinned, the fleshy crossbars and papillary muscles seem thin due to excessive stretching of the ventricles." According to Yu.I. Novikov and M.A. Stulova, it was S.S. Abramov who wrote one of the first descriptions of DCM. The definition of the concept of “cardiomyopathy”, its classification and terminology have been repeatedly considered both in domestic (Vinogradov AV et al., Mukharlyamov NM, Sumarokov AB, Moiseev VS, Storozhakov GI, Dzhanashia PH et al.) and foreign (Goodwin JF, Elliot P., Maron B. et al.) literature and continue to be studied at the present time.

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