Cardiomegaly

Etiology

Several etiologies have been attributed to the development of cardiomegaly, resulting in either dilated or hypertrophic cardiomyopathy. These include the following:

• Coronary artery disease, including myocardial infarction and ischemia (most common cause)[2]
• Hypertensive heart disease[3]
• Valvular heart diseases, including stenosis or regurgitation of the aortic, mitral, pulmonary, or tricuspid valves and sub-acute bacterial endocarditis[4]
• Congenital heart disorders, including atrial septal defect, ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, Ebstein anomaly, and coarctation of the aorta
• Pulmonary diseases such as primary pulmonary hypertension, chronic obstructive pulmonary disease, obesity hypoventilation syndrome, and pulmonary embolism with cor-pulmonale[5]
• Infectious myocarditis secondary to viral infection (most common), HIV, Chaga disease[6]
• Infiltrative/deposition diseases, such as amyloidosis, sarcoidosis, hypothyroidism, acromegaly, and hemochromatosis[7]
• Toxin-induced cardiomyopathy (alcohol, cocaine, chemotherapeutic agents such as doxorubicin, cyclophosphamide, trastuzumab, and radiation)[8]
• Autoimmune cardiomyopathy, including eosinophilic myocarditis, idiopathic giant cell myocarditis, and collagen vascular disease
• Arrhythmia, including atrial fibrillation and flutter leading to tachycardia-induced cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy with the fibro-fatty replacement of RV
• Systemic diseases leading to a high output state, including anemia, hyperthyroidism, vitamin B1 deficiency (“beriberi”), and AV fistula[9]
• Physiologic conditions include stress cardiomyopathy, exercise-induced cardiomegaly or “athletic” heart, and pregnancy
• Familial cardiomyopathy, hypertrophic obstructive cardiomyopathy[10]
• Peripartum cardiomyopathy[11]
• Idiopathic cardiomyopathy[12][13][14] 

Epidemiology

Enlargement of the heart, both in the form of dilatation or hypertrophy, leads to a spectrum of clinical heart failure syndrome, with a prevalence of nearly 5.8 million people in the United States. Heart failure with preserved ejection fraction represents more than half of these cases. The incidence of heart failure increases with age, male gender, and African American race. About half of the people diagnosed with heart failure die within 5 years of diagnosis.[15] In adults, dilated cardiomyopathy is more prevalent in men than in women. In the pediatric population, the annual incidence is 0.57 cases per 100,000 per year (higher in boys than girls, in Blacks than Whites, and in babies less than 1 year than in children). Two-thirds of children have idiopathic disease.[16] Hypertrophic cardiomyopathy is a global disease, with cases in over 50 countries on all continents, affecting both sexes and of several ethnic and racial origins.[17] In diverse regions, such as the USA, Europe, China, Japan, and East Africa, hypertrophic cardiomyopathy is a common genetic cardiac disease, having a prevalence of around 1 in 500 in the general population.[18]

Pathophysiology

The development of cardiac remodeling and hypertrophy is complex, with genetic and non-genetic components. The most critical pathophysiological changes leading to cardiomegaly include dilated hypertrophy, fibrosis, and contractile malfunction. Contractile dysfunction and abnormal myocardial remodeling can lead to hypertrophic cardiomyopathy or dilated cardiomyopathy. Mechanical stretching, circulating neurohormones, and oxidative stress are significant stimuli for the signal transduction of inflammatory cytokines and MAP kinase in cardiomyocytes. Signal transduction leads to changes in structural proteins and proteins that regulate excitation-contraction. Dilated cardiomyopathy mutations result in a reduced force of the sarcomere contraction and a reduction in sarcomere content. Hypertrophic cardiomyopathy mutations result in a molecular phenotype of hyperdynamic contractility, poor relaxation, and increased energy consumption.[19][20]

Pathophysiological mechanisms can vary depending on the underlying cause of cardiomyopathy. For instance, in diabetic cardiomyopathy, fatty acid metabolism is enhanced, glucose oxidation is suppressed, and intracellular signaling is modified, causing impairment in multiple steps of inefficient energy production, excitation-contraction coupling, and increased potential for ischemia/reperfusion injury. In alcohol-induced cardiomyopathy, cell death due to apoptosis ultimately leads to changes in various aspects of myocyte function.[21] In mitochondrial cardiomyopathy, multiple biochemical pathways involving mitochondria impair oxidative phosphorylation.[22] Peripartum cardiomyopathy is associated with genetic alterations, angiogenic imbalance, oxidative stress, and the production of a prolactin fragment.[23] In hypertrophic cardiomyopathy, ventricular hypertrophy results in a dynamic pressure gradient across the left ventricular outflow tract, associated with further narrowing during systole. During this cardiac cycle, the mitral valve is pulled towards the septum by several proposed mechanisms: contraction of the papillary muscles, abnormal location in the outflow tract, and low pressure that occurs as blood is ejected at high velocity through a narrowed outflow tract (Venturi effect).[24]

History and Physical

Many patients with cardiomegaly are asymptomatic, and the presence of symptoms alone is neither sensitive nor specific to diagnosis. The diagnosis of cardiomegaly is based on imaging, and history is only helpful in determining the cause of heart failure symptoms, resulting in systemic congestion and impaired organ perfusion.[25] A detailed history should elicit the presence or absence of the following:

• Shortness of breath on exertion or rest, orthopnea, and paroxysmal nocturnal dyspnea
• Peripheral edema and abdominal distension
• Fatigue and poor exercise tolerance
• Palpitations, lightheadedness, or syncope[26]
• Angina
• Anorexia, nausea, and early satiety
• Family history of cardiomyopathy
• Recent pregnancy/childbirth
• Comorbid illnesses, such as hypertension and diabetes mellitus

It is worth mentioning that cardiac function is adequate during rest and may become inadequate with exertion. Hence, it is not uncommon for patients to be asymptomatic at rest and experience symptoms only on exertion. The New York Heart Association classifies the severity of disease based on symptoms, where class I disease is asymptomatic with ordinary physical activity, and class IV denotes symptoms with rest. Perhaps the most specific sign of cardiomegaly is a displaced maximal impulse (PMI) point.[27] The precordial examination reveals a displaced PMI, usually below the 5th intercostal space, lateral to the midclavicular line, and palpable across 2 intercostal spaces. Sustained PMI is a sign of severe left ventricular hypertrophy. A sustained and prolonged left parasternal heave is indicative of right ventricular hypertrophy. Another physical finding observed in cardiomegaly is the holosystolic murmur of mitral or tricuspid regurgitation resulting from dilatation of the mitral annulus and displacement of papillary muscles with abnormal myocardial remodeling. Other exam findings may be seen depending on the presence or absence of decompensated heart failure. In such cases, a detailed physical exam may reveal the following abnormalities: 

• Sinus tachycardia resulting from increased sympathetic drive
• Diminished pulse pressure reflecting reduced stroke volume
• Varying degrees of respiratory distress based on the severity of the disease
• Cool, cyanotic extremities secondary to peripheral vasoconstriction
• Jugular venous distension or positive abdominojugular reflex indicating elevated right-sided filling pressures
• Ascites, hepatomegaly, and peripheral edema result from increased pressure in the hepatic veins and systemic veins[28]
• Pulmonary crackles resulting from elevated left-sided filling pressure and transudation of fluid into alveoli
• S3 gallop in early diastole resulting from volume overload and systolic dysfunction; S4 gallop in late diastole resulting from diastolic dysfunction

Evaluation

Diagnosis of cardiomegaly is primarily through imaging techniques that assess the heart's size and function. Diagnostic testing includes 1 of the following:

• A chest X-ray with an enlarged cardiac silhouette and a cardiothoracic ratio of more than 50% suggests cardiomegaly.[29] Further delineation of specific chamber enlargement is also possible. Right ventricle (RV) enlargement produces an upward deviation of the left apical margin, while left ventricle enlargement leads to a leftward displacement of the left heart border. Right atrial (RA) enlargement increases the right heart border convexity. Left atrial enlargement and its extension to the right leads to a "double density" sign.[30] Also, in heart failure, cephalization of the pulmonary vessels, Kerley B-lines, pulmonary edema, and pleural effusions are present.
• A transthoracic echocardiogram can assess the left ventricle, right ventricle, atrial size, and systolic/diastolic function. It can also determine valve structure and function and detect wall motion changes that suggest ischemia.
• Cardiac MRI is an emerging diagnostic modality for accurately evaluating left and right ventricle mass, size, and function. It can also characterize ischemic and non-ischemic causes such as myocarditis.
• An electrocardiogram (ECG) can reveal non-specific changes, including left ventricle/right ventricle hypertrophy, low voltage QRS in case of fibrosis/dilated cardiomyopathy, conduction abnormality, arrhythmia, premature ventricular complexes (PVCs), ST-T wave changes, and Q waves suggestive of prior myocardial infarction.
• Serum levels of brain natriuretic peptide (pro-BNP), troponin I and T, renal function, and liver function tests are helpful in the setting of heart failure.[31]
• Stress test or coronary angiogram to evaluate for coronary artery disease.
• Despite standard workup, the etiology of cardiomegaly is often unclear. In such cases, additional testing may be pursued to determine the underlying etiology.

Treatment / Management

The treatment of mild cardiomegaly centers on the treatment of the underlying condition. Standard heart failure treatment guidelines also apply to moderate to severe cardiomegaly associated with heart failure. 

• Patients at risk of cardiomyopathy benefit from risk factor modification such as smoking cessation, limiting alcohol intake, weight loss, exercise, and consuming a healthy diet. Recommendations include treating underlying risk factors such as hypertension, dyslipidemia, and diabetes. Other underlying conditions, including obstructive sleep apnea, arrhythmias, anemia, and thyroid disorders, also require treatment.[32]
• Patients with early onset cardiomyopathy who are asymptomatic are managed with risk factor modification and the addition of an angiotensin-converting enzyme (ACE) inhibitor or ARB (if intolerant to ACE) and beta-blocker if there is a history of myocardial infarction or reduced ejection fraction.[33]
• Patients with cardiomyopathy and symptoms of heart failure are managed with diuretics and salt restriction in addition to the above therapies.[34] All such patients should receive an ACE inhibitor or ARB (if intolerant to ACE) and a beta-blocker if they have reduced ejection fraction. An ARNI (ARB plus neprilysin inhibitor) is occasionally used instead of ACE/ARB to reduce hospitalization in heart failure and mortality. For patients with moderate to severe symptoms and reduced ejection fraction, the addition of aldosterone antagonists further reduces mortality. A hydralazine/nitrate combination, when added to ACE inhibitor, beta blocker, and diuretics, improves outcomes in Black patients. Digoxin is added in some patients to reduce the rate of hospitalization with heart failure; however, it does not impact outcomes. An ICD (implantable cardioverter defibrillator) is placed in patients with an ejection fraction of 35% or less to reduce mortality from sudden cardiac death. Cardiac resynchronization is performed with or without ICD in patients with an ejection fraction of 35% or less and moderate to severe symptoms with evidence of left bundle branch block.
• Patients with refractory heart failure should receive optimal medical management. Also, eligible patients can be considered for cardiac transplantation and bridge therapy, such as ventricle assist devices.[35] 
(A1)

Of special consideration is that no pharmacologic agent has shown benefits in heart failure with preserved ejection fraction. The mainstay of treatment is controlling underlying conditions such as hypertension, heart rate in patients with atrial fibrillation, ischemia with medication or coronary intervention, and diuretics for fluid overload. Patients with asymptomatic hypertrophic obstructive cardiomyopathy can be safely monitored. Patients with symptoms of heart failure and left ventricular outflow tract obstruction may benefit from negative inotropes such as beta-blockers, calcium channel blockers, or dipyridamole. Vasodilators and diuretics should be avoided in such patients. Some novel treatment strategies are being studied through recent evidence favoring the supplementation of endogenous antioxidants for managing diabetic cardiomyopathy. These strategies include gene therapy targeting the phosphoinositide 3-kinase signaling pathway and miRNA dysregulation. A future strategy could be to target redox stress and protective protein signaling pathways for combating the ever-rising incidence of heart failure in patients with diabetes.[36]

Differential Diagnosis

Differentials of cardiomegaly include disorders that can result in an enlarged cardiomediastinal silhouette on a frontal (or posteroanterior) chest X-ray. These include: 

• Pericardial effusion
• Anterior mediastinal mass
• Prominent epicardial fat pad
• Mediastinal widening secondary to pulmonary/aortic pathology
• Expiratory radiograph
• AP projection
• Thymus tumor[37]
• Cardiac neoplasms
• Myocarditis

Prognosis

Despite the advent of new therapies, mortality remains high in patients with symptomatic heart failure. Roughly, 1-year mortality is 30%, while 5-year mortality is 50%. The severity of symptoms, advanced age, and heart failure hospitalization are significant predictors of mortality in heart failure.[38] Overall, the prognosis of patients with dilated cardiomyopathy is guarded. Most patients eventually end up with chronic heart failure. Many become candidates for a heart transplant or an assist device, which also adds morbidity. Almost 50% of patients are dead within 5 years. Mortality rates of 1% to 4% have been reported in patients with hypertrophic cardiomyopathy, but these numbers have greatly improved in the past 2 decades. Even though most patients have no symptoms, the first clinical presentation is often sudden death from malignant arrhythmias. The highest mortality is in young people.

Complications

As cardiomegaly can be secondary to various underlying pathologies, resulting complications tend to vary a great deal as well. The following are a few important complications to be aware of:

• Decompensated heart failure
• Sudden cardiac death and malignant ventricular arrhythmias[39]
• Thromboembolism secondary to mural thrombi