The cardiomyopathies represent an important group of heart muscle disorders that are all associated with significant morbidity and mortality. The most prevalent of these conditions is dilated cardiomyopathy (DCM), which accounts for more than half of all cases. A proportion of cases of DCM result from the progression of an initial inflammatory insult to the myocardium during an episode of acute myocarditis. Significant efforts have been made to further our understanding of the underlying disease pathophysiology, which in turn have led to refinements in diagnosis and management. In particular, novel imaging techniques have provided a new insight into risk stratification of DCM patients, who may consequently benefit from more aggressive therapy earlier on in the disease course. Genetic screening advances with the advent of next-generation parallel sequencing have heralded a new era of early detection and diagnosis of cardiomyopathy. In this chapter the diagnostic cascade, current management, and prognosis of DCM and myocarditis are reviewed.
Definition
DCM is characterized by enlargement and impaired contractility of the left ventricle in the absence of an ischemic etiology or abnormal loading conditions (hypertension or valve disease). The World Health Organization echocardiographic diagnostic criteria require a left ventricular end-diastolic value greater than 117% of predicted value (corrected for age and body surface area), associated with a fractional shortening of less than 25%. In up to one-third of cases the right ventricle may also be involved, resulting in biventricular systolic dysfunction.
The condition should not be considered a single disease entity but is more accurately regarded as the final common pathway for multiple heterogeneous disease processes affecting the myocardium. DCM has a familial etiology in up to 50% of cases, and many different genes have been implicated in its pathogenesis ( Table 60.1 ). In addition, a wide range of environmental factors and systemic disorders are also known to trigger the DCM phenotype ( Table 60.2 ). However, in approximately half of DCM patients an underlying cause is never identified, and these cases are often labeled as “idiopathic.” Idiopathic DCM may partially reflect undiagnosed factors, such as infectious, genetic, or toxic causes. The number of patients with idiopathic DCM is likely to diminish in the future as our understanding of the pathophysiologic mechanisms, specifically genetic-environmental interactions, is enhanced.
| Gene | Protein | Function | Estimated Contribution in DCM Patients |
|---|---|---|---|
| Sarcomeric | |||
| ACTC1 | Alpha cardiac actin | Muscle contraction | <1% |
| ACTN2 | Alpha actinin 2 | Anchor for myofibrillar actin | 1% |
| MYBPC3 | Cardiac type myosin binding protein C | Muscle contraction | 2% |
| MYH6 | Myosin-6 (alpha myosin heavy chain) | Muscle contraction | 4% |
| MYH7 | Myosin-7 (beta myosin heavy chain) | Muscle contraction | 4% |
| TNNC1 | Cardiac muscle troponin C | Muscle contraction | <1% |
| TNNI3 | Cardiac muscle troponin I | Muscle contraction | <1% |
| TNNT2 | Cardiac muscle troponin T | Muscle contraction | 3% |
| TTN | Titin | Extensible scaffold/Molecular spring | 25% |
| Cytoskeleton | |||
| DES | Desmin | Contractile force transduction | <1% |
| DMD | Dystrophin | Contractile force transduction | In patients with dystrophinopathies |
| Nuclear Envelope | |||
| LMNA | Lamin A/C | Nuclear membrane structure | 6% |
| Ion Channel | |||
| SCN5A | Sodium channel protein type 5 subunit alpha | Sodium influx into cells | 2%–3% |
| Mitochondrial | |||
| TAZ | Tafazzin | — | Syndromic DCM (eg, Barth syndrome) |
| Spliceosomal | |||
| RBM20 | RNA Binding protein 20 | Regulates splicing of cardiac genes | 2% |
| Sarcoplasmic Reticulum | |||
| PLN | Phospholamban | Sarcoplasmic reticulum calcium regulator; inhibits SERCA2a pump | <1% |
| Desomosomal | |||
| DSP | Desmoplakin | Desmosomal junction protein | Linked to arrhythmogenic right and left ventricular cardiomyopathy |
| Other | |||
| BAG3 | BAG family molecular chaperone regulator 3 | Inhibits apoptosis | — |
| Cause | Comment |
|---|---|
| Drugs and toxins | Ethanol, ∗ cocaine, ∗ doxorubicin, clozapine, cyclophosphamide, phenothiazines, ∗ zidovudine, didanosine, cobalt, ∗ mercury ∗ |
| Infectious | Viruses (coxsackie, HIV, adenovirus, cytomegalovirus) Parasites ( Trypanosoma cruzi , toxoplasmosis, ∗ trichinosis) Bacteria (diphtheria) |
| Genetic | Muscular dystrophy (Duchenne, Becker, fascioscapulohumeral, myotonic) Friedreich ataxia Familial cardiomyopathy (see Table 60.1 ) Mitochondrial myopathies |
| Immunologic | Systemic lupus erythematosus, scleroderma, dermatomyositis Kawasaki disease Sarcoidosis ∗ Hypersensitivity myocarditis ∗ |
| Arrhythmias | Tachycardias, ∗ congenital complete heart block |
| Metabolic | Iron overload (hemochromatosis, multiple blood transfusions ∗ ) Endocrine ∗ (hypothyroidism, hyperthyroidism, acromegaly, pheochromocytoma, Cushing syndrome) Electrolyte disorder ∗ (hypocalcemia, hypophosphatemia) Nutritional deficiency (thiamine, selenium) Congenital metabolic defects (carnitine) |
| Peripartum ∗ | — |
Myocarditis is defined histologically by myocardial inflammation and myocyte necrosis. The condition typically presents acutely and may be associated with transient ventricular impairment, followed by complete or partial ventricular recovery in 50% of patients. Twenty-five percent of patients who fail to recover ventricular function develop chronic systolic impairment, and a further 25% progress to end-stage DCM.
Epidemiology and Etiology
DCM has an annual incidence of 4.8/100,000 in infancy, 0.7/100,000 in early childhood (birth to age 10 years), and 5 to 8 out of 100,000 in adulthood and is associated with a 20% 5-year mortality. Although previously regarded as relatively uncommon (1 in 3000 individuals), advances in imaging and screening have refined these estimates such that the prevalence of DCM is now thought to be up to 1:250. Although most cases of clinically apparent myocarditis have an infectious trigger, a vast array of etiologies may give rise to DCM. Identification of the precise underlying etiology in DCM and myocarditis is critical in targeting appropriate therapy. There is a familial basis to up to 50% of cases, although a clear genetic cause is not always identified. Genes that have been linked to DCM are presented in Table 60.1 , although it is noted that this is a rapidly evolving field.
When alcohol, drugs, or toxins are implicated, cessation of exposure to the responsible agent may yield dramatic improvement in ventricular function. Chemotherapeutic agents such as anthracyclines can also cause DCM and are estimated to affect up to 26% of patients receiving such therapies. Acute cardiotoxicity can develop immediately after infusion, early- and late-onset chronic progressive forms can develop within or after the first year of treatment, respectively, and late-occurring cardiotoxicity may develop 20 years after original treatment. The risk of cardiotoxicity is dose dependent; therefore the maximum lifetime cumulative dose of doxorubicin is limited to 400 to 550 g/m 2 .
Peripartum cardiomyopathy has an incidence of 1 in 2000 live births. In this condition, cardiomyopathy typically develops in the last month of pregnancy or in the first 5 months postpartum and is a diagnosis of exclusion.
A proportion of cases of idiopathic DCM are likely to be the result of an initial viral myocarditis that may have been clinically silent in its acute phase. Symptoms may develop insidiously, by which point a DCM phenotype has fully evolved. Cardiotropic viruses, such as enteroviruses (eg, coxsackievirus group B serotypes), are the most commonly implicated viruses in the pathogenesis of DCM. However, parvovirus B19, human herpesvirus 6, and adenovirus have also been identified.
Myocarditis can also be caused by human immunodeficiency virus (HIV), toxins, and autoimmune disease. Giant cell myocarditis is a poorly understood but clinically devastating variant of uncertain etiology. It is characterized by the presence of multinucleated giant cells on biopsy, most likely the result of an autoimmune process, which results in an acute and potentially lethal presentation of heart failure.
Genetics of Dilated Cardiomyopathy
Pathogenic mutations in more than 100 genes have been linked to DCM, although the evidence is strongest for 40 of these. Inheritance is predominantly autosomal dominant, although autosomal recessive, mitochondrial, and X-linked forms occur. Next-generation sequencing technologies have enabled the rapid assessment of many genes in many patients. The major challenge in the field is now variant interpretation and assigning pathogenicity to novel variants in the presence of limited segregation or functional data. Interpreting the significance of variants is further complicated by age-dependent penetrance (the development of any phenotype) and variable expressivity (the severity of the resulting phenotype), common to many DCM genes.
Truncating variants (nonsense mutations resulting in a truncated, incomplete protein) in the giant sarcomeric gene titin (TTN) account for up to 20% of DCM genetic variants. At present, clinical management of the proband does not change if TTN truncating variants are detected.
Variants (both truncating and nontruncating) in the nuclear envelope protein lamin A/C gene (LMNA) occur in up to 5% of patients and are clinically actionable. In the presence of conduction disease and an LMNA variant, guidelines recommend implantable cardiac defibrillator instead of pacemaker implantation, due to the high rate of malignant ventricular arrhythmias.
At present, genetic testing is of most utility for family screening. The absence of the pathogenic variant detected in a proband in relatives would permit the discharge of the relative from ongoing clinical screening.
Pathogenesis
Current understanding of the pathophysiologic processes underpinning myocarditis is predominantly derived from rodent enteroviral models. Enteroviruses and some adenoviruses are cardiotropic, gaining myocyte entry via a common transmembrane receptor. Both humoral and cellular immune responses are thought to play important roles. The process is initially triggered by myocyte invasion by a cardiotropic virus that itself may cause direct cytotoxicity in the acute phase. This invasion triggers a secondary immunologic cascade with CD8 + T lymphocyte–mediated eradication of virus-infected cells. Inadequate negative modulation results in an excessive inflammatory response with release of cytokines (eg, tumor necrosis factor-α) and activation of enzymes (eg, nitric oxide synthase) that cause further myocardial damage.
The virus itself uses elaborate systems to escape immunologic detection, and its persistence in myocytes stimulates a chronic immune response. The resulting expansion of CD4 + – activated cells results in autoimmune myocytolysis by cardiac-specific autoantibodies. The ensuing vicious cycle of myocardial injury and repair may lead to adverse cardiac remodeling and fibrosis, eventually culminating in significant ventricular dysfunction. In contrast, parvovirus affects cardiac damage through the downstream effects of endothelial cell (not myocyte) infection.
The pathogenesis of DCM remains largely unresolved, hindered by the fact that most patients present at a stage when the pathogenesis is complete. Histologic findings are nonspecific and not suggestive of any particular pathogenesis. The typical microscopic appearance is consistent with a healed myocarditis, with patchy perimyocyte and interstitial fibrosis, myocyte death and hypertrophy, and occasional scattered inflammatory cells. However, novel insights are being gained from genetic advances, from both human in vivo sequencing data and functional models. This has thrown light on the range of cellular structures and processes involved in the pathogenesis of DCM, including but not limited to the sarcomere, nuclear envelope, cytoskeleton, mitochondria, sarcoplasmic reticulum, and ion channels (see Table 60.1 ). A unifying final common pathway to phenotype remains to be established.
Clinical Presentation and Assessment
Clinical presentation can vary from the asymptomatic individual with electrocardiographic abnormalities through to heart failure (the most common presentation), arrhythmia, chest pain mimicking an acute coronary syndrome, embolic stroke, and rarely sudden cardiac death. A careful history to ascertain the aforementioned symptoms and any features of a viral prodrome, coupled with findings observed on abnormal electrocardiographic recordings and a chest radiograph, may alert the physician to the possibility of DCM and/or myocarditis. The history should also focus on uncovering the etiology of the ventricular dysfunction, including careful questioning regarding drug and alcohol use, as well as a detailed family history (to cover history of cardiomyopathies, deafness, pacemakers, musculoskeletal abnormalities, and sudden or unexplained death). In patients in whom chest pain is associated with electrocardiographic changes consistent with acute ischemia, prompt coronary angiography is advisable to exclude clinically significant coronary artery disease.
Recommended initial clinical investigations are outlined in Box 60.1 . B-natriuretic peptide (BNP) and its precursor N-terminal pro-BNP are useful for both screening in the initial presentation phase and may have value in monitoring disease progress.
