Dilated cardiomyopathy

According to the European Society of Cardiology, dilated cardiomyopathy is defined as "the presence of dilation and systolic dysfunction of the left or both heart chambers in the absence of abnormal filling conditions (arterial hypertension, valvular defects) or coronary artery involvement sufficient to cause global systolic dysfunction". In other words, there is dilation of the left heart chamber, possibly other heart compartments, and systolic dysfunction of the chamber, which cannot be explained by other possible precipitating causes. Dilated cardiomyopathy is, together with hypertrophic cardiomyopathy, one of the most frequently diagnosed cardiomyopathies. Its etiopathogenesis is extremely broad. Etiology, or the phenotype of dilated cardiomyopathy includes genetic causes, infectious or post-infectious involvement (inflammatory cardiomyopathy after previous myocarditis), endocrine causes, pregnancy cardiomyopathy, cardiotoxic involvement of the myocardium (antitumor treatment, alcohol, cocaine), neuromuscular and autoimmune disorders. It is mainly manifested by left-sided heart failure, arrhythmias and thromboembolic complications. Diagnostics is based on non-invasive (EKG, echocardiography, magnetic resonance) and in some cases invasive examination methods (e.g. endomyocardial biopsy). Due to the wide etiology, the treatment of dilated cardiomyopathy is also very diverse. Both standard treatment of heart failure and, in indicated cases, resynchronization treatment of heart failure, ablation techniques or heart transplantation are applied. Specific treatment is also not a simple issue, however it is already available in many cases.

Etiopathogenesis and classification
The etiology of dilated cardiomyopathy, and the resulting pathophysiology and pathological changes, are very diverse. Macroscopically, a characteristic feature of the disease is the dilation of the heart compartments. Thrombi are often present in both the atria and ventricles. The microscopic picture is also diverse (again sometimes depending on the specific etiology – inflammatory cardiomyopathy, etc.), but it is rather non-specific. The cardiac muscle is histologically hypertrophic with concomitant atrophy and destruction of other cardiomyocytes. There are areas of interstitial fibrosis.

The pathophysiological basis is a primary malfunction of cardiomyocytes from various causes, which leads to a malfunction of the contractile function of the myocardium. Of course, there are many more pathophysiological mechanisms involved. There is an increased activation of the neurohumoral system (renin-angiotensin-aldosterone system, catecholamines, dysregulation of the adrenergic system), remodeling of the primarily left ventricle, changes in the proliferation of the extracellular matrix, acceleration of apoptosis, dyshomeostasis of calcium ions and their cycle in cardiomyocytes, oxidative stress and the formation of pro-inflammatory and profibrotic cytokines (TNF alpha, IL-1, IL-2, IL-6).

At the forefront of pathophysiological changes is the remodeling of the left ventricle with its hemodynamic effects. Many neuroendocrine and other humoral factors (including the renin-angiotensin-aldosterone axis) are involved in this. As a result of dilation and reduction of the systolic function of the left ventricle, there is an increase in end-diastolic volume (preload) and an increase in diastolic filling pressure . Ventricular dilatation is also accompanied by secondary mitral regurgitation. In addition, due to changes in the extracellular matrix, the myocardium becomes stiffer, which further complicates diastolic filling. As the preload reserve is depleted, the heart becomes increasingly sensitive to changes in afterload. At this point, it is necessary to mention Laplac's law, which says that the tension in the wall of a cylindrical organ (the so-called wall stress) is equal to the product of the pressure and the radius divided by twice the wall thickness, i.e. T = (P xr)/2h. Thus, when the heart dilates, the tension in the myocardial wall increases, leading to some compensatory cardiomyocyte hypertrophy that reduces afterload. On the other hand, this increases the energy demands of the myocardium, which is already increased by remodeling itself. In addition to the aforementioned, increased wall stress also leads to negative changes in the extracellular matrix and contributes to cardiomyocyte apoptosis. This again leads to the progression of left ventricular dilation and its further remodeling. This can be reversible in selected etiologies (alcoholic cardiomyopathy, tachycardia-induced cardiomyopathy, etc.). Decreased contractility of the myocardium leads, among other things, to blood stasis inside the heart, and thus to an increased risk of thrombus formation. Pathophysiology also varies depending on the precipitating cause of dilated cardiomyopathy. In 25-35% of cases, the basis of cardiomyopathy is genetic, most often with autosomal dominant inheritance, in some cases autosomal recessive or X-linked. The largest share of genetic alterations is titin (25% of mutations) and lamin A/C (6%), which also has an increased risk of malignant arrhythmias. More than 60 causal mutations with a dilated cardiomyopathy phenotype have already been identified. However, they can only be detected in about 30% of cases. The occurrence of dilated cardiomyopathy in patients with muscular dystrophies and mitochondrial disorders is also related to genetic disorders. Most dilated cardiomyopathies are therefore caused by external influences. Of these, myocardial involvement after previous myocarditis is very significant. Here, the simplified pathophysiological course is that viremia occurs leading to necrotic changes in the myocardium and host immune system response. In roughly 30% of cases, an autoimmune inflammatory response develops with the formation of the autoantibodies (e.g. based on the principle of molecular mimicry) against cardiomyocyte components, inflammatory damage to the myocardium, etc. All this with or without the presence of the most often viral causative agent. Dilated cardiomyopathy resulting from these changes is called inflammatory and accounts for 20-46% of all dilated cardiomyopathies. Toxic damage to the myocardium also plays a significant role in the etiology of the disease. This applies mainly to certain chemotherapy drugs and psychiatric drugs. Of the other toxic effects, the excessive use of alcohol (80g/day), which according to some sources is responsible for 20-30% of cases of dilated cardiomyopathies, is especially important. Other etiologies from the field of endocrine disorders, autoimmune diseases and others are summarized in the attached table.

Epidemiology
Dilated cardiomyopathy occurs at any age. The prevalence in the USA is estimated at 1:2500, or 36 cases per 100,000 population. The annual incidence is 5–8 cases per 100,000 inhabitants. In any case, dilated cardiomyopathy contributes significantly to the total number of patients with heart failure. According to some studies, the prevalence of dilated cardiomyopathy in patients with heart failure is around 30% (in some studies the proportion was even 47%). The incidence of heart failure in patients with dilated cardiomyopathy is also high, with over 60% of patients having at least one hospitalization for heart failure. Patients with dilated cardiomyopathy and advanced heart failure make up more than 40% of patients on mechanical cardiac support.  This diagnosis is also the most common indication for heart transplantation in the pediatric and adult population, accounting for 39% of all heart transplants (up to 50% in the Czech Republic). For patients under 40, this figure is even over 60%.

Clinical picture
Dilated cardiomyopathy most often manifests itself between the ages of 30 and 40. The predominant symptoms are fatigue, weakness and signs of left-sided heart failure, i.e. exertional, then dyspnea at rest, cough, paroxysmal nocturnal dyspnea and orthopnea. When the right ventricle is affected, patients have swelling of the lower limbs, hepatosplenomegaly and ascites. In addition to these symptoms, palpitations, chest pains, presyncope and syncope are described. On physical examination, the apex of the heart is displaced more caudal and lateral to the medioclavicular line. As a result of secondary mitral regurgitation, a systolic murmur can be heard with propagation to the axilla. With congestion in the small circulation, crunches are audible at the bases of the lungs.

In the case of specific etiologies, such as inflammatory cardiomyopathy, patients may have a history of infectious disease and flu-like symptoms. Infectious diseases, inflammation, reduction of medication and other influences can contribute to accentuate the symptoms of heart failure and even decompensate the patient.

Diagnostics
Diagnosing dilated cardiomyopathy and searching for its etiology is difficult. First of all, it is necessary to rule out whether the patient's problems are caused by ischemic heart disease, valvular defects or decorticated arterial hypertension. In the further investigation process, a detailed personal anamnesis is taken (family history of cardiomyopathies, infectious diseases, exposure to cardiotoxic substances), many non-invasive or invasive imaging methods and laboratory tests. In certain cases, an endomyocardial biopsy is indicated. Genetic testing is also important for many patients, when the causal mutation can only be detected in roughly 20-30% of cases. In the case of a positive mutation, a cascade screening of close relatives is in place.

ECG
ECG changes are nonspecific in dilated cardiomyopathy. Nonspecific changes in ST segments and T waves appear most often. Blockades of the left branch of Tawar are frequent, especially in more advanced stages of the disease. In general, any supraventricular and ventricular arrhythmias can occur in patients. The presence of persistent tachycardia is suspicious for tachycardia-induced cardiomyopathy.

Display methods
X-ray examination of the chest reveals varying degrees of pulmonary congestion (increased pulmonary vascular pattern) and cardiomegaly.

Echocardiography is a basic imaging and examination method. Among other things, the anatomy of the heart compartments (diastolic dimension of the left ventricle, thickness of its walls), morphology and function of the valves, as well as systolic and diastolic function of the ventricles and pressure ratios in the small circulation are evaluated. Both classic 2D and Doppler echocardiography, as well as newer techniques (e.g. deformation analysis of the myocardium) are used. The finding is very variable in patients with dilated cardiomyopathy. Typically, there is dilatation of the left ventricle, possibly other heart compartments, systolic dysfunction of the ventricles and dilatation of the annulus of the atrioventricular valves with secondary regurgitation. Diastolic function is also affected. Elevated pressures in the small circulation due to left heart failure may also be observed. Especially in patients with severe heart failure, thrombi can be trapped inside the ventricles.

Coronary angiography is used to rule out ischemic heart disease as the cause of complications. An alternative is a CT scan.

Magnetic resonance imaging of the heart serves both to differentiate between ischemic and non-ischemic etiology of left ventricular dilatation, and on the other hand it provides the possibility of a better visualization of the anatomy and function of the heart and the possibility of tissue characteristics of the myocardium. This is done using late gadolinium enhancement (LGE). This reveals necrosis of the myocardium or its fibrotization. Thanks to this examination, the ischemic/non-ischemic etiology of the disease is distinguished, in some cases even a more precise etiology, i.e. whether it is an inflammatory involvement of the myocardium (inflammatory cardiomyopathy) or an alternating disease affecting the heart. Nonischemic LGE is usually distributed midmyocardially or subepicardially with distribution outside the coronary basin. This examination is also important for evaluating the patient's prognosis.

Laboratory methods
Patients are routinely screened for heart failure parameters such as NT-proBNP. The examination of myoglobin and creatine kinase, which may be elevated in patients with muscular dystrophy, is also important. It is also possible to determine parameters of iron metabolism (hemochromatosis), parameters of the thyroid gland, electrolytes, urea, glucose level, hormone metabolites (metabolic disorders), liver enzymes (toxic damage) and parameters of infectious and autoimmune damage to the myocardium (troponins, CRP, blood sedimentation, serology of selected agents, etc.).

Endomyocardial biopsy
Examination of endomyocardial biopsies is important in patients unresponsive to heart failure treatment, in whom inflammatory or post-inflammatory/autoimmune involvement of the heart muscle, where patients could benefit from specific or immunosuppressive treatment. In addition to histological and immunohistochemical examination of myocardial tissue, the presence of selected, mainly viral agents in the myocardium is also determined.

Treatment of heart failure, thromboembolism and arrhythmias
Strict abstinence from alcohol (especially in those with alcohol-induced cardiomyopathy) and a certain restriction of physical activities depending on the patient's condition are required as part of the regimen. Adequate physical activity is also beneficial for patients with heart failure. Other measures include restriction of salt in food.

The treatment of heart failure is guided by general recommendations. The basis is therapy with ACE inhibitors (in case of sartan intolerance) and beta blockers (in patients with stabilized heart failure). In case of constipation, diuretics are used. Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are added to the pharmacological treatment according to the ejection fraction and NYHA class. Ivabradine can be added to the medication in patients with sinus rhythm and a frequency above 70 beats per minute with persistent shortness of breath. Of the newer drugs, the preparation has very good results in selected groups of patients sacubitril/valsartan (Entresto) combining a sartan and a neprilysin inhibitor (an enzyme that inactivates, for example, natriuretic peptides and bradykinin). Some preparations interfering with the functioning of sarcomeres and gene repair methods (mainly in the area of ​​muscular dystrophies) based on CRISPR are in the research or clinical testing phase.

Amiodarone or digoxin is mainly used as an antiarrhythmic treatment for atrial fibrillation. Anticoagulation treatment is used when atrial fibrillation is detected or after a thromboembolic event. It may be considered in patients with severely reduced left ventricular systolic function.

Device treatment and heart transplantation
Resynchronization treatment is indicated in patients with severe systolic dysfunction with an extension of the QRS complex above 120 ms, typically with blockade of the left Tawar arm, and with maximally optimized treatment. This positively influences the dyssynchrony of myocardial contraction during bundle branch block and has a positive effect on morbidity and mortality. In some patients, an implantable cardioverter-defibrillator (ICD) is indicated for primary or secondary prevention, which according to recent studies reduces the risk of sudden cardiac death, but not total mortality (except for selected groups of patients).

In patients with terminal heart failure unresponsive to treatment, mechanical cardiac support is indicated as a "bridge to recovery or bridge to transplantation". Five-year survival after heart transplantation is around 80% in adult patients with a history of familial dilated cardiomyopathy.

Some patients with significant functional mitral regurgitation may benefit from percutaneous intervention on this valve. This issue is still the subject of clinical studies.

Immunological treatment
Immunological and immunomodulating treatment is mainly considered for inflammatory cardiomyopathies and cardiomyopathies with an autoimmune background. One of the possibilities is treatment with antiviral drugs in case of evidence of persistence of the causative agent in the myocardium. In the case of enteroviruses, adenoviruses and parvovirus B19, interferon beta therapy can be considered, which reduces the viral load in the myocardium. Patients with inflammatory cardiomyopathy without the presence of an infectious agent are often indicated for immunosuppressive therapy, which also has a positive effect on cardiac remodeling. An alternative that is still under clinical investigation is immunoadsorption or immunoglobulin treatment.

Prognosis
The prognosis of patients has significantly improved with the development of pharmacological and non-pharmacological approaches in the treatment of heart failure. The four-year survival rate of patients with dilated cardiomyopathy is approximately 88%. Overall, the prognosis of patients depends on many factors - the possibility of reverse remodeling of heart compartments, the severity of systolic dysfunction and symptoms of heart failure, the degree of myocardial fibrosis detected on magnetic resonance imaging, complications of the disease (atrial fibrillation, thromboembolism, secondary mitral regurgitation). Despite major advances in treatment, heart failure remains the leading cause of death in patients with dilated cardiomyopathy. Ad integrum recovery is possible only if there has been no significant damage to the myocardium and the provoking cause is removed (e.g. alcoholic cardiomyopathy). In general, however, ad integrum healing is less common.

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