Dilated cardiomyopathy

Genetics

About 25–35% of affected individuals have familial forms of the disease,^[13] with most mutations affecting genes encoding cytoskeletal proteins,^[13] while some affect other proteins involved in contraction.^[20] The disease is genetically heterogeneous, but the most common form of its transmission is an autosomal dominant pattern.^[13] Autosomal recessive (as found, for example, in Alström syndrome^[13]), X-linked (as in Duchenne muscular dystrophy), and mitochondrial inheritance of the disease is also found.^[21] Some relatives of those affected by dilated cardiomyopathy have preclinical, asymptomatic heart-muscle changes.^[22]

Other cytoskeletal proteins involved in DCM include α-cardiac actin, desmin, and the nuclear lamins A and C.^[13] Mitochondrial deletions and mutations presumably cause DCM by altering myocardial ATP generation.^[13]

Kayvanpour et al. performed 2016 a meta-analysis with the largest dataset available on genotype-phenotype associations in DCM and mutations in lamin (LMNA), phospholamban (PLN), RNA Binding Motif Protein 20 (RBM20), Cardiac Myosin Binding Protein C (MYBPC3), Myosin Heavy Chain 7 (MYH7), Cardiac Troponin T 2 (TNNT2), and Cardiac Troponin I (TNNI3). They also reviewed recent studies investigating genotype-phenotype associations in DCM patients with titin (TTN) mutations. LMNA and PLN mutation carriers showed a high prevalence of cardiac transplantation and ventricular arrhythmia. Dysrhythmias and sudden cardiac death (SCD) was shown to occur even before the manifestation of DCM and heart failure symptoms in LMNA mutation carriers.^[23]

Compensation effects

As DCM progresses, two compensatory mechanisms are activated in response to impaired myocyte contractility and reduced stroke volume:^[12]

• Frank-Starling law
• Neurohormonal feedback, via activation of the sympathetic nervous system and the renin-angiotensin system.

These responses initially compensate for decreased cardiac output and maintain those with DCM as asymptomatic. Eventually, however, these mechanisms become detrimental, intravascular volume becomes too great, and progressive dilatation leads to heart failure symptoms.

Computational models

Cardiac dilatation is a transversely isotropic, irreversible process resulting from excess strains on the myocardium.^[25] A computation model of volumetric, isotropic, and cardiac wall growth predicts the relationship between cardiac strains (e.g. volume overload after myocardial infarction) and dilation using the following governing equations:

${\displaystyle F=F^{e}\cdot F^{g}\,}$

where ${\displaystyle F^{e}}$ is elastic volume stretch that is reversible and ${\displaystyle F^{g}}$ is irreversible, isotropic volume growth described by:

${\displaystyle F^{g}=\mathbb {I} +[\lambda ^{g}-1]f_{0}\otimes f_{0}\,}$

where ${\displaystyle f_{0}}$ is a vector, which points along a cardiomyocyte's long axis and ${\displaystyle \lambda ^{g}}$ is the cardiomyocyte stretch due to growth. The total cardiomyocyte growth is given by:

${\displaystyle \lambda =\lambda ^{e}\cdot F\lambda ^{g}\,}$

The above model reveals a gradual dilation of the myocardium, especially the ventricular myocardium, to support the blood volume overload in the chambers. Dilation manifests itself in an increase in total cardiac mass and cardiac diameter. Cardiomyocytes reach their maximum length of 150 ${\displaystyle \mu }$m in the endocardium and 130 ${\displaystyle \mu }$m in the epicardium by the addition of sarcomeres.^[26] Due to the increase in diameter, the dilated heart appears spherical in shape, as opposed the elliptical shape of a healthy human heart. In addition, the ventricular walls maintain the same thickness, characteristic of pathophysiological cardiac dilation.

Valvular effects

As the ventricles enlarge, both the mitral and tricuspid valves may lose their ability to come together properly. This loss of coaptation may lead to mitral and tricuspid regurgitation. As a result, those with DCM are at increased risk of atrial fibrillation. Furthermore, stroke volume is decreased and a greater volume load is placed on the ventricle, thus increasing heart failure symptoms.^[12]

Medical therapy

Drug therapy can slow down progression and in some cases even improve the heart condition. Standard therapy may include salt restriction, ACE inhibitors, diuretics, and beta blockers.^[12] Anticoagulants may also be used for antithrombotic therapy. There is some evidence for the benefits of coenzyme Q10 in treating heart failure.^[31][32][33]

Electrical treatment

Artificial pacemakers may be used in patients with intraventricular conduction delay, and implantable cardioverter-defibrillators in those at risk of arrhythmia. These forms of treatment have been shown to prevent sudden cardiac death, improve symptoms, and reduce hospitalization in patients with systolic heart failure.^[34]

Surgical treatment

In patients with advanced disease who are refractory to medical therapy, heart transplantation may be considered. For these people 1-year survival approaches 90% and over 50% survive greater than 20 years.^[34]