Continuing Education Activity

Cardiomegaly is an umbrella designation for various conditions leading to enlargement of the heart, which usually remains undiagnosed until the symptoms ensue. It has become increasingly prevalent and carries a high mortality. Cardiomegaly means enlargement of the heart. The definition is when the transverse diameter of the cardiac silhouette is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography. This activity reviews the etiology, epidemiology, pathophysiology, signs and symptoms, evaluation, and management of cardiomegaly. It highlights the role of the interprofessional team in improving outcomes for patients with this condition.

Objectives:

• Review the risk factors for developing cardiomegaly.
• Describe the typical presentation of a patient with cardiomegaly.
• Summarize the treatment considerations in a patient with cardiomegaly.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance care delivery for patients affected by cardiomegaly.

Introduction

Cardiomegaly means enlargement of the heart. The definition is when the transverse diameter of the cardiac silhouette is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography. It should not be confused with an enlargement of the cardiomediastinal outline. Cardiomegaly is usually a manifestation of another pathologic process and presents with several forms of primary or acquired cardiomyopathies. It may involve enlargement of the right, left, or both ventricles or the atria. Many types of cardiomyopathy, such as dilated cardiomyopathy, are characterized by left ventricular dilation and systolic dysfunction, although right ventricular impairment and diastolic dysfunction can also develop.[1]

Etiology

Several etiologies have been attributed to the development of cardiomegaly resulting in either dilated or hypertrophic cardiomyopathy.[2][3][4] These include the following:

• Coronary artery disease, including myocardial infarction and ischemia (most common cause)[5]
• Hypertensive heart disease[6]
• Valvular heart diseases, including stenosis or regurgitation of the aortic, mitral, pulmonary, or tricuspid valves and sub-acute bacterial endocarditis[7]
• 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 (COPD), obesity hypoventilation syndrome, and pulmonary embolism with cor-pulmonale[8]
• Infectious myocarditis secondary to viral infection (most common), HIV, Chaga disease[9]
• Infiltrative/deposition diseases, such as amyloidosis, sarcoidosis, hypothyroidism, acromegaly, and hemochromatosis[10]
• Toxin-induced cardiomyopathy (alcohol, cocaine, chemotherapeutic agents such as doxorubicin, cyclophosphamide, trastuzumab, and radiation)[11]
• 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 (ARVC) 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[12]
• Physiologic conditions include stress cardiomyopathy, exercise-induced cardiomegaly or “athletic” heart, and pregnancy
• Familial cardiomyopathy, hypertrophic obstructive cardiomyopathy (HOCM)[13]
• Peripartum cardiomyopathy[14]
• Idiopathic cardiomyopathy

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 (HFpEF) 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 five 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 one 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 with 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 result in impaired 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 (LVOT), which is 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, and/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 on exertion only. 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 point of maximal impulse (PMI).[27] The precordial examination will reveal a displaced PMI, usually below the 5th intercostal space, lateral to the midclavicular line, and palpable across two 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 and/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 and/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 one 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 (LV) enlargement leads to a leftward displacement of the left heart border. Right atrial (RA) enlargement increases the right heart border convexity. Left atrial (LA) 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 be used to assess LV, RV, atrial size, and systolic/diastolic function. It can also determine valve structure and function and wall motion changes that suggest ischemia.
• Cardiac MRI is an emerging diagnostic modality for accurately evaluating LV and RV 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 LV/RV 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 (MI).
• 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 and/or coronary angiogram to evaluate for coronary artery disease.
• Often the etiology of cardiomegaly is unclear despite standard workup. In such cases, additional testing may be pursued to determine the underlying etiology.

Treatment / Management

Treatment of mild cardiomegaly centers upon the treatment of the underlying condition. Standard heart failure (HF) treatment guidelines also apply in 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 MI or reduced ejection fraction (EF).[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 EF. 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 EF, the addition of aldosterone antagonists further reduces mortality. A hydralazine/nitrate combination, when added to ACE inhibitor, beta blocker, and diuretics, improve 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 EF 35% or less to reduce mortality from sudden cardiac death. CRT (cardiac resynchronization) is performed with or without ICD in patients with EF 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] 

Of special consideration, no pharmacologic agent has shown benefit in HFpEF. The mainstay of treatment is controlling underlying conditions such as hypertension, heart rate in patients with atrial fibrillation, ischemia with medication and/or coronary intervention, and diuretics for fluid overload. Patients with asymptomatic HOCM (hypertrophic obstructive cardiomyopathy) can be safely monitored. Patients with symptoms of HF 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 HF. Roughly, 1-year mortality is 30%, while 5-year mortality is 50%. The severity of symptoms, advanced age, and HF hospitalization are significant predictors of mortality in HF.[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 five years. Mortality rates of 1% to 4% have been reported in patients with hypertrophic cardiomyopathy, but these numbers have greatly improved in the past two 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

Deterrence and Patient Education

Patient education regarding medication compliance, dietary restrictions, and regular follow-up is critical to achieving the best outcomes. In addition, families should go through an investigative procedure when someone is found to have hypertrophic obstructive cardiomyopathy.

Pearls and Other Issues

Cardiac transplantation is an emerging treatment for patients with refractory end-stage heart failure. Patients undergo cardiopulmonary assessment and prognostication using specific scoring systems to determine their candidacy for transplant. Patients with systemic illness, life expectancy under two years, active substance and alcohol abuse, and non-compliance with medical therapy are considered poor candidates for cardiac transplantation. Patients should have a robust psychosocial support system to qualify. A risk-benefit assessment is necessary before the patient is a candidate for the transplant list. Patients who are not candidates for a cardiac transplant can qualify for a durable ventricular assist device.[40]

Enhancing Healthcare Team Outcomes

Heart failure readmissions account for a majority of national healthcare expenditures. Support programs are operating nationwide to minimize the number of CHF-related hospitalizations and thereby reduce the economic strain. These programs utilize a collaborative approach with many integrated disciplines and providers. Some inpatient strategies include guideline-based care, discharge support by nurses, patient education, medication reconciliation by the pharmacist, and early post-discharge follow-up. A board-certified cardiology pharmacist can assist clinicians in selecting medications for blood pressure control and other factors where medication can provide ancillary benefits. Cardiology-specialized nurses are also valuable members of the interprofessional team, coordinating activities between various specialists and other clinicians and providing patient counseling. Promising outpatient strategies include interprofessional team engagement in HF clinics and disease management programs that make in-person contact with patients and provide individualized education.[41]

Cardiomegaly and HF require an interprofessional team approach that includes physicians and specialists, specialty-trained nurses, pharmacists, and therapists, all working collaboratively to bring about optimal therapeutic choices that lead to the best possible patient outcomes. This interprofessional approach requires open communication between all members of the care team and accurate, updated documentation to be effective. [Level 5]