Article Text
Abstract
Dilated cardiomyopathy (DCM) is a common cardiac diagnosis that may result as a consequence of a variety of pathologies. The differential diagnosis remains quite broad since many pathologies can present as DCM, and as a result the approach to diagnosis may, at times, be quite difficult. This review article discusses genetic and acquired causes of DCM, pathophysiology of myocardial damage, pathology, and diagnostic criteria. An approach to management is also included, in the hope of informing physicians of a clinical entity that afflicts a substantial number of people worldwide.
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Dilated cardiomyopathy (DCM), the most common of the cardiomyopathies, is characterised by an increase in both myocardial mass and volume. The walls become thin and stretched, compromising cardiac contractility and ultimately resulting in poor left ventricular function. DCM may occur at any age, but is common in males between the ages of 20 and 50 years.1 Genetically inherited (familial) forms of DCM have been identified in 25–35% of patients presenting with this disease, but many other acquired conditions may result in an identical clinical presentation and pathological function. These conditions include alcohol-induced cardiomyopathy, peripartum cardiomyopathy, haemochromatosis, chronic anaemia, non-compaction cardiomyopathy, adriamycin toxicity, sarcoidosis and viral myocarditis. DCM may also occur secondary to ischaemic heart disease, valvular heart disease, hypertension and congenital heart disease.2 In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic dilated cardiomyopathy (iDCM). The 5 year survival after diagnosis is 50%, as patients often develop progressive congestive heart failure (CHF) and complications such as thromboembolic conditions and arrhythmias.3
AETIOLOGY
Genetics
Thirty per cent of patients with DCM either have a relative with the disease or show clinical evidence of left ventricular dysfunction or visible enlargement on two-dimensional echocardiography.4 Modes of inheritance include autosomal dominant (AD) with incomplete penetrance due to modifier genes and environmental factors, autosomal recessive (AR), and X-linked. These genes are summarised in table 1.5–17
Other genetic loci have been identified, but the specific genes are not yet known.17 Certain phenotypes have been identified for specific genes, but there is incomplete penetrance. Mutations in lamin A/C are often associated with conduction system disease; desmin and dystrophin with a skeletal myopathy; desmoplakin and plakoglobin are often associated with wooly hair and keratoderma. Mutations in δ-sarcoglycan have been found to cause loss of skeletal muscle and a form of muscular dystrophy. Patients with a mutation in the tafazzin loci may be neutropenic and short in stature. Lastly, arrhythmogenic right ventricle cardiomyopathy (ARVC) and exercise-induced ventricular tachycardias are commonly associated with mutations in the cardiac ryanodine receptor.18
Environmental
Myocarditis is responsible for a majority of DCM cases diagnosed in North America. Often a secondary complication to viral infections, myocarditis can progress to CHF in children and patients younger than 40 years of age.19 Common causative agents in North America and Europe include enteroviruses, coxsackie virus B3 and adenovirus. Parasitic infections with Trypanosoma cruzi (Chagas disease), which is endemic in South America, can cause DCM.20 Other inciting agents include cytomegalovirus, parvovirus, hepatitis C, HIV, Epstein-Barr virus, Chlamydia pneumoniae and Borrelia burgdorferi.21
Box 1: Diagnostic criteria for a patient suspected of a familial dilated cardiomyopathy with one affected first-degree relative
Diagnosis of familial dilated cardiomyopathy (DCM) if one of the following criteria is met
Presence of two or more affected first-degree relatives in a single family (to diagnose first-degree relatives, one of the following criteria must be met)
Diagnosis of DCM is already established
Unexplained sudden death or stroke <30 years
Two major two-dimensional echocardiographic (2DE) criteria:
Left ventricular end diastolic dimension (LVEDD) >117% of predicted value
Fractional shortening (FS) <25%
Three minor 2DE and/or ECG criteria:
LVEDD >112% of predicted value
FS <28%
Pericardial effusion
Unexplained conduction defects such as II° or III° atrioventricular block, bundle branch block or unexplained (supra-)ventricular arrhythmia <50 years)
OR
Presence of a first-degree relative of a DCM patient with a well-documented unexplained sudden cardiac death <35 years
Box 2: Diagnostic criteria for idiopathic dilated cardiomyopathy
Diagnosis if all of the following criteria are met
Criteria
Ejection fraction <0.45 and/or a fractional shortening of <25%
Left ventricle end diastolic diameter of >117% (corrected for age and body surface area using the formula = (45.3 × (body surface area)1/3− (0.03 × age)−7.2)±12%)
Exclusion criteria
Absence of systemic hypertension (>160/100 mmHg)
Coronary artery disease (50% in one or more branches)
Chronic excess alcohol (>40 g/day female, >80 g/day for male)
Systemic disease known to cause idiopathic dilated cardiomyopathy
Pericardial disease
Congenital heart disease
Cor pulmonale
CLINICAL PRESENTATION
Patients may present as early as childhood, though most present during the fourth and fifth decades of life. In general, symptoms are manifested when the disease has progressed to end-stage where significant myocardial (interstitial) fibrosis occurs. Symptoms related to CHF, such as dyspnoea, fatigue, angina, pulmonary congestion and low cardiac output may persist for months to years. Patients may also have complications related to DCM, including arrhythmias (atrial fibrillation, supraventricular and ventricular arrhythmias), and thromboembolic events due to dilated cardiac chambers and haemostasis. Disease severity and progression vary, as incomplete penetrance has been identified in families with familial DCM (fDCM) despite sharing identical mutations. At initial presentation, a thorough family history and pedigree should be recorded to identify any members who may have been diagnosed with DCM, or who have suffered from a thromboembolic event or sudden cardiac death before the age of 30 years.
A variety of physical findings may be evident if there is moderate-to-severe systolic dysfunction. If cardiac output is reduced, low arterial pressure, tachycardia and cool extremities would be evident. Pulmonary venous congestion may also occur with pulmonary fluid accumulation, which may be detected on auscultation. Upon palpation of the precordium, the apex beat may be displaced laterally due to a dilated left ventricle. Auscultation of the heart may reveal an S3 and/or a systolic murmur, suggestive of mitral regurgitation, secondary to left ventricular dilatation. If the right ventricle is involved, a murmur may be detected due to tricuspid regurgitation, and signs of diminished venous return such as elevated jugular venous pulse, hepatomegaly, ascites and pedal oedema would be evident.22
INVESTIGATIONS
Diagnosis of DCM in patients with one affected first-degree relative can be made with a complete history, alongside ECG and echocardiographic (two-dimensional) studies. The diagnostic criteria for fDCM can be found in box 1.23 24
If there is no history suggestive of fDCM or any secondary causes, iDCM may be considered a possible diagnosis. The diagnostic criteria for iDCM can be found in box 2.25 26
Echocardiography
2DE remains the mainstay of diagnosis, as it is able to measure the systolic and diastolic dimensions of the heart. The diagnostic criteria use parameters that are measured by 2DE, including left ventricular end diastolic dimension (LVEDD), fractional shortening (FS), and ejection fraction (EF). This modality is also able to assess valvular function and detect the severity of mitral or tricuspid regurgitation secondary to ventricular dilatation.
Electrocardiography
Given their non-invasive nature, ECG is the first test completed with any suspicion of underlying disease. ECG findings vary for each patient; some patients may be devoid of abnormalities while others may have isolated T wave changes, septal Q waves due to extensive fibrotic damage, prolonged atrioventricular conduction, bundle branch blocks, and/or atrial or ventricular tachyarrhythmias.26 The low specificity for DCM may warrant the need for additional investigations, including 2DE.
Exercise testing
Exercise testing with respiratory gas analysis is useful to assess disease severity and establish a baseline exercise capacity. It can be employed to monitor disease progression, assess prognosis, and plan for further treatments, including cardiac transplantation.26
Viral serology
Viral serology and culture should be done to rule out myocarditis. Neutralising antibody titres to circulating viruses are generally elevated four times above normal, over a period of 2–4 weeks.19 Virus-specific IgM class antibodies to enteroviruses such as coxsackie B virus may be measured and, if positive, are indicative of recent infection.26
Endomyocardial biopsy
Endomyocardial biopsy may be used to rule out pathologies with a similar clinical presentation as iDCM, but which may require different treatment. These conditions include haemochromatosis, sarcoidosis, storage diseases and malignant diseases. Though biopsies may lead to complications such as right pneumothorax, air embolism, atrial arrhythmias, transient nerve palsies and paralysis, cardiac perforation and tamponade,27 they should still be completed if there is any clinical suspicion of these other conditions following evaluation of the clinical history, physical examination, and preliminary non-invasive investigations. A recent retrospective analysis from our institution compared the pathological diagnosis post-transplantation with the clinical diagnosis, established by a variety of investigations, excluding endomyocardial biopsy. The authors found, excluding those with a pathological diagnosis of ischemic cardiomyopathy, 46% (n = 152) were misdiagnosed prior to transplant. A majority of these patients did not receive an endomyocardial biopsy as part of their management prior to orthotopic heart transplant.28
Coronary angiography
To rule out ischaemic cardiomyopathy, coronary angiography must be done to examine the patency of the coronary arteries. This test is done to determine the presence of coexistent coronary artery disease, which may contribute to systolic dysfunction. However, it should only be done if the patient shows clinical evidence of angina or has a history of myocardial infarction.22
PATHOLOGY
Gross
Hearts of DCM patients often weigh two to three times normal, and in certain cases, may exceed 1000 g, in which case they are known as “cor bovinum”. The heart is enlarged and the muscle fibres hypertrophied, but this may not be evident due to dilatation of the cardiac chambers. When cut in a sagittal section, the heart, if there is biventricular involvement, appears spherical, and the apex rounded rather than pointed. If the disease is predominately left-sided, the interventricular septum may be found bulging into the cavity of the right ventricle. The ventricular walls may also appear thin (fig 1). Moreover, the mitral and tricuspid valves may show changes consistent with regurgitation, as progressive dilatation stretches the annulus. The coronary arteries may be stenotic if suspicion of ischaemic damage is present. In cases of iDCM, the coronary arteries are often patent. With progressive dilatation, thinning and consequential fibrosis of the myocardial wall, there is decreased contractility, which is normally most evident in the apical region. With haemostasis during the cardiac cycle, there is formation of mural thrombi during the terminal stages of the disease, and subsequently can embolise leading to stroke or sudden cardiac death.
Histology
Microscopic findings are non-specific and do not necessarily identify the main aetiology causing DCM. As the myocardium is hypertrophied and dilated, findings consistent with hypertrophy are evident (fig 2A). Myocytes may appear thickened with enlarged nuclei. Interspersed with these hypertrophied myocytes, others may appear thinned and elongated, with the nucleus occupying the entire width of the myocyte (fig 2B). The total number of intracellular contractile myofibrils is diminished, and the myocyte may appear empty. Areas of myocyte death may be evident, which eventually get replaced with collagen and become fibrotic (fig 2C). Degenerative changes responsible for a bundle branch block pattern on ECG may also be seen on histological examination of dilated hearts (fig 2D). Patients with myocarditis may have lymphocytic infiltration surrounding the degenerating myocardial cells (fig 3). Multinucleated giant cells (granulomas) surrounded by a rim of mononuclear cells and macrophages may be found in a patient with sarcoidosis (fig 4). An area of intramyocellular iron deposition resulting in myocellular degeneration with iron staining is indicative of haemochromatosis. Areas of vacuolisation that occur in the perinuclear area and are seen pushing the contractile elements to the periphery of the muscle fibres may be seen in patients with Fabry disease.
PATHOPHYSIOLOGY
Genetics
The pathophysiology of DCM has been identified in a majority of the genetic mutations, and may be separated into two categories: defects in force generation and defects in force transmission. The mechanism for DCM from mutations in tafazzin, lamin A/C and cardiac ryanodine receptor has not been identified.
Defects in force generation
Defects in generating force are typically due to a loss of integrity of the sarcomere unit. Mutations in the loci coding for β-cardiac myosin heavy chain and cardiac troponin T have been identified to disrupt force generation. Mutations in the β-cardiac myosin heavy chain have been found to disrupt either the site of actin–myosin binding29 or the site of flexible joints of the myosin protein that is responsible for its mobility during the contraction process. Mutations in cardiac troponin T disrupt the calcium-sensitive troponin C interactions. This interaction is important to generate ATP to drive actin–myosin contraction, and a lack of ATP decreases the amount of force that may be generated by the sarcomere.7
Defects in force transmission
As the actin–myosin contraction is completed, the force is transferred from the sarcomere to the extracellular matrix. This is completed by interactions between the actin subunit and certain cytoskeletal units. Mutations in cardiac actin, at the site of actin–cytoskeleton interaction, have been found to be associated with early disease onset.8 Two mutations coding for the surface of α-tropomyosin have been identified. It is suspected that these areas on the protein are responsible for α-tropomyosin–actin interactions.8 Mutations in dystrophin,30 desmin11 and δ-sarcoglycan31 have been found to diminish the maximum force of transmission as well. Plakoglobin and desmoplakin are involved with proper functioning at the desmosome and adherens junction. Mutations in these genes most likely contribute to impairment in the propagation of force from the sarcomere to the sarcolemma.18
Viral
Despite a number of different viral agents identified in causing cardiac myocarditis, it is hypothesised that these viruses function by directly damaging the myocyte and cleaving dystrophin, a cytoskeletal protein that maintains myocyte integrity.32 Loss of this structural component of the myocardium results in a progressively dilated heart. The exact mechanism of how the virus cleaves dystrophin has not been fully elucidated.
TREATMENT
The main goals of treatments include counselling, symptom management, and prevention of disease progression and complications, including congestive heart failure, sudden cardiac death and thromboembolic events. The treatment strategy is summarised in fig 5, after a review of the literature.
Counselling
Patient education is an important component of disease management. First, patient education and increasing treatment compliance is essential. Patient awareness of the associated symptoms, risk factors, different treatment methods and their respective side effects, exercise tolerance and rehabilitation, and dietary modifications is necessary to reduce symptoms, reduce disease progression and improve quality of life.
Pharmacological
Symptom management
ACE inhibitors remain the first line of treatment for symptoms related to CHF. They have been found to be beneficial in patients with reduced left ventricular systolic function and reduced ejection fraction.33 If side effects such as new onset cough, hypotension or deterioration of renal function occur, lowering the dose of the drug should be attempted in order to maximise therapeutic benefit and avoid the side effects. Diuretics may be added if there is excessive fluid retention (pulmonary congestion or peripheral oedema), but should not be used on its own as it may exacerbate neurohormonal activation and worsen disease progression.26 Beta blockers can also be used with both ACE inhibitors and diuretics for all patients with CHF and reduced LV ejection fraction.33 Digoxin and spironolactone may also be added for symptom management. A more thorough review of treatment of CHF can be found elsewhere.34
Prevention of disease progression
ACE inhibitors have also been found to prevent disease progression. Packer et al examined the long-term effects of low-dose and high-dose lisinopril. The authors found that a high dose of lisinopril (32.5–35 mg once daily) had a significant lower risk (12%) of death and hospitalisation and a significant decrease (24%) in hospitalisation for heart failure.35 Angiotensin II receptor antagonists have also been found to prevent disease progression. McKelvie et al investigated the effects of candesartan and enalapril, and both in combination, in patients with CHF. They found that the combination reduced disease progression by decreasing neurohormonal activation and preventing ventricular remodelling.36
Prevention of complications
Beta blockers have been found to decrease the risk for SCD or death from progressively worsening disease. Studies including US carvedilol studies (n = 1094),37 CIBIS II (bisoprolol, n = 2467)38 and MERIT-HF (metoprolol, n = 3991)39 examined survival in patients with progressive CHF. All studies were terminated early due to a significant reduction in the risk of SCD and risk of hospitalisation in patients treated with beta blockers. The RALES study40 concluded that the use of 25 mg spironolactone in patients with an ejection fraction <35% with NYHA IV status is associated with a 30% decrease in the risk of death, and it is therefore indicated in patients with diminishing ejection fraction as well.34
Complications such as arrhythmias and thromboembolic events can be reduced with prophylactic medications. Dofetilide has been found to decrease the incidence of atrial fibrillation in a double-blind study of 1518 patients with CHF and left ventricular dysfunction.41 Amiodarone is another medication that clinicians may use to treat arrhythmias, such as atrial fibrillation and supraventricular arrhythmias, there is no benefit in mortality in patients with ventricular arrhythmias.22 Reduction of thrombus formation within the dilated chambers may be necessary to prevent thromboembolic events. Anticoagulants, such as warfarin, are indicated for patients with a history of previous thromboembolic events, severe systolic dysfunction or ventricular dilatation, though the benefits for warfarin treatment must outweigh the risks.
Take-home messages
Though most patients have acquired causes of dilated cardiomyopathy (DCM), 25–35% of all patients have a genetically inherited (familial) form.
Biventricular involvement may occur which cause a spherical shape, while others may affect the left side only.
Microscopic findings are non-specific and do not necessarily identify the main aetiology causing DCM.
Microscopic findings include interspersed thick and thin myocytes with variable sized nuclei, and at times, may be surrounded by areas of fibrosis due to myocyte death.
Non-pharmacological
More recently, cardiac resynchronisation therapy (CRT) using biventricular pacing has been used to treat patients with heart-failure-induced conduction disturbances, including ventricular arrhythmias. Patients with moderate–severe symptoms of heart failure (ejection fraction <35%) and a QRS complex >130 ms who received CRT had improved New York Heart Association functional class, quality of life, and ejection fraction at 6 months postimplantation.42
Patients who are unresponsive to medications and have progressed to end-stage disease can be treated with an orthotopic heart transplant. With increasing wait times for donor hearts due to the scarcity of viable organs, this treatment modality remains limited. Patients awaiting heart transplantation may have a left ventricular assist device (LVAD, or even an LVAD and RVAD) implanted as a bridge to transplantation for a short period of time until an organ becomes available. Studies have found that the LVAD normalises haemodynamics, improves progressive dysfunction of the heart, improves exercise tolerance, and allows patients to become outpatients.43
Patients who are not eligible for heart transplantation may receive a LVAD to optimise medical management and improve quality of life. Rose et al43 studied 129 patients with end-stage CHF and compared those receiving a LVAD with those remaining on medical treatment alone. The authors found a 48% reduction in the risk of death in the patients receiving a LVAD. Although there was increased occurrences of complications related to the LVAD such as infection, device failure and bleeding, the survival rates at 2 years postimplantation were significantly higher in the LVAD group.43
CONCLUSIONS
DCM is the most common cardiomyopathy, occurring primarily due to genetic defects or secondarily as a consequence of multiple factors, including long-standing hypertension, ischaemic heart disease, infection, sarcoidosis and ARVC. For a practising clinician, it remains important to differentiate between fDCM, iDCM and the other aetiologies, since management differs for each. Because of this, the role of the pathologist is essential for timely diagnosis. Early intervention and accurate diagnosis remains the mainstay of treatment since it may prevent disease progression and its complications.
REFERENCES
Footnotes
Competing interests: None.