Dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.

Fig. 1. Epidemiology of cardiomyopathy.

The map shows the annual percentage change in number of deaths (per 100,000 individuals) due to cardiomyopathy or myocarditis. Data include all ages and both sexes between 1990 and 2017. A decrease in deaths from cardiomyopathy is probably due to improvements in medication and health care; the reasons for the increase in deaths are less clear. Data from https://vizhub.healthdata.org/gbd-compare/. Accessed 21 February 2019.

Fig. 2. Genetic causes of dilated cardiomyopathy.

The ‘defective force transmission’ hypothesis postulates that the cytoskeleton provides an intracellular scaffolding that is important for transmission of force from the sarcomere to the extracellular matrix and for protection of the myocyte from external mechanical stress. Thus, defects in cytoskeletal proteins could predispose to dilated cardiomyopathy (DCM) by reducing force transmission and/or resistance to mechanical stress. Contractile dysfunction of myofibrils plays a central part in initiation and progression of DCM. The sarcomere is composed of numerous proteins, and mutations in several of them have been associated with DCM, including actin, α-cardiac muscle 1 (encoded by ACTC1), myosin-binding protein C, cardiac type (encoded by MYBPC3), myosin chains (encoded by MYL2, MYL3, MYH6 and MYH7) and tropomyosin-α1 chain (encoded by TPM1) (see Table 1). Mutations in genes encoding cardiac troponins (encoded by TNNT2, TNNC1 and TNNI3) are also linked directly to disordered force generation^,. MYH7 mutations have been predicted to disrupt the actin–myosin binding and crossbridge function, whereas mutations in TTN change viscoelasticity properties. Mutations in other non-contractile proteins (for example, a co-chaperone for heat shock protein 70 (HSP70) and heat shock cognate 70 chaperone proteins, encoded by BAG3) may induce defects in cell signalling pathways that modify cardiac response^,. Mutations in phospholamban (encoded by PLN), a key calcium signalling protein, have been directly linked to abnormal contractility. Variants in desmosomal proteins including desmin (encoded by DES) desmocollin 2 (encoded by DSC2), desmoglein 2 (encoded by DSG2), desmoplakin (encoded by DSP) and plakophilin 2 (encoded by PKP2) are most commonly associated with arrhythmogenic right ventricular cardiomyopathy, but mutations in these genes have also been implicated in DCM. In some patients with genetic DCM, a particular gene defect may be suggested by cardiac conduction abnormalities. For example, variants of lamin A/C (LMNA; which is part of a protein structure associated with the inner nuclear membrane) are associated with high rates of conduction system disease, ventricular arrhythmias and sudden cardiac death. However, in most cases of DCM, there are no specific distinguishing phenotype features. SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a. Adapted from ref., Springer Nature Limited.

Fig. 3. Echocardiography and endomyocardial biopsy in dilated cardiomyopathy.

a,b | Speckle-tracking echocardiographic images in a patient with active myocarditis show reduced global longitudinal strain at baseline (before treatment). Analysis of the left ventricular longitudinal strain from the left two chambers before immunosuppressive treatment. The value of the peak longitudinal systolic strain for each segment being examined is superimposed on the colour 2D image. The curves of longitudinal strain (%) as a function of time are also shown (part a). Peak systolic strain in each segment before immunosuppressive treatment (part b). c,d | Immunohistological staining of an endomyocardial biopsy sample from the same patient shows active myocarditis with evidence of massive enhanced CD3⁺ T cell infiltration at baseline (red-brown staining) (part c), myocytolysis and extensive infiltration of immunocompetent cells (purple staining) (part d). e,f | Speckle-tracking imaging of the same patient after 6 months of immunosuppressive treatment shows substantial increase in global longitudinal strain. g,h | After treatment, immunohistological staining showed reduced CD3⁺ T cell infiltration (absence of red-brown staining) (part g) and no active myocardial inflammation (reduced purple staining) (part h). ANT, anterior; ANT_SEPT, anteroseptal; INF, inferior; LAT, lateral; POST, posterior; SEPT, septal.

Fig. 4. Cardiac MRI.

Cardiac MRI of patients with endomyocardial-biopsy-proven active myocarditis shows evidence of late gadolinium enhancement (LGE) (white arrows), indicating fibrosis and oedema (red arrowheads). LV, left ventricle; RV, right ventricle.

Fig. 5. Differential diagnosis of the underlying causes of dilated cardiomyopathy.

Endomyocardial biopsy is important to determine the underlying cause of dilated cardiomyopathy. a | Active myocarditis with immune cell infiltration and myocytolysis (arrows), histological azan staining. b | Giant cell myocarditis with massive immune cell infiltration around multinuclear giant cells (arrows), histological haematoxylin and eosin (H&E) staining. c | Eosinophilic myocarditis with immune cell infiltration and eosinophils (arrows), histological H&E staining. d | Immunohistochemical staining depicting CD3⁺ T cells (red-brown staining) in a focal pattern in borderline myocarditis. e | Immunohistochemical staining of increased perforin-positive cytotoxic cells (arrows) in inflammatory cardiomyopathy. f | Immunohistochemical staining of increased cell-adhesion molecule HLA1 (red-brown staining) in inflammatory cardiomyopathy.

Fig. 6. Algorithm for the management of dilated cardiomyopathy.

Clinical management of a patient with symptomatic dilated cardiomyopathy starts with standard heart failure medications. If there is haemodynamic improvement, the treatment will be continued with careful follow-up to monitor for progressive left ventricular dysfunction. If left ventricular dysfunction is noted or there is a lack of haemodynamic improvement, an endomyocardial biopsy should be performed. If viral infection is detected by reverse transcriptase–PCR or immunohistochemistry staining, the patient may receive antiviral therapy. If certain inflammatory cells are discovered, a tailored immunosuppressive therapy may be administered. If there is no haemodynamic improvement, additional treatment options for heart failure should be explored.