Restrictive Cardiomyopathy

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Background

Restrictive cardiomyopathy (RCM) is a rare disease of the myocardium and is the least common of the 3 clinically recognized and described cardiomyopathies.[1] Its principal abnormality is diastolic dysfunction—specifically, restricted ventricular filling. RCM accounts for approximately 5% of all cases of primary heart muscle disease.

The World Health Organization (WHO) defines RCM as a myocardial disease characterized by restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function and wall thickness. Increased interstitial fibrosis may be present. This disease may be idiopathic or associated with other diseases (eg, amyloidosis and endomyocardial disease with or without hypereosinophilia). The course of RCM varies, depending on the pathology and treatment, but is often unsatisfactory.

The importance of an accurate diagnosis of RCM is to distinguish this condition from constrictive pericarditis, a clinically and hemodynamically similar entity that also presents with restrictive physiology but is frequently curable by surgical intervention. This distinction is difficult to make but crucial because the treatment options and prognoses for the 2 conditions differ drastically.[2]

In the past, the correct diagnosis of RCM was frequently not made until surgical inspection demonstrated the pericardium of normal thickness and appearing normal. A subsequent myocardial biopsy would prove the diagnosis of RCM. With the improvement in diagnostic imaging, the necessity of progressing to surgical intervention to confirm the diagnosis of RCM (or constrictive pericarditis) should decrease.

Pathophysiology

RCM can be idiopathic or secondary to a heart muscle disease that manifests as restrictive physiology.[1, 3] The disease creates increased stiffness of the myocardium, which causes pressure within the ventricles to rise precipitously with small increases in volume. Thus, accentuated filling occurs in early diastole, which terminates abruptly at the end of the rapid filling phase. When pressure tracings are taken at this point, they show a characteristic diastolic “dip-and-plateau” or “square-root” pattern, both similar to constrictive pericarditis.[4]

Patients typically have diastolic heart failure, meaning that systolic function is normal but the left ventricle has increased diastolic stiffness (reduced compliance) and cannot fill adequately at normal diastolic pressures, leading to reduced cardiac output as a result of reduced left ventricular filling volume. Systolic function usually remains normal, at least early in the disease; wall thickness is typically increased secondary to myocardial infiltration with amyloidosis, but the increase is usually not as pronounced as that observed in hypertrophic cardiomyopathy.

A variable reduction in systolic function may be present as the disease progresses. Reduced left ventricular filling volume leads to reduced stroke volume and low cardiac output symptoms (eg, fatigue, lethargy), whereas increased filling pressures cause pulmonary and systemic congestion. Thus, RCM causes symptoms and signs of left-side failure, right-side failure, or both because it affects both ventricles, but amyloidosis typically presents with dominant right-side fluid retention.

Some patients may have complete heart block as a consequence of fibrosis encasing the sinoatrial or the atrioventricular nodes. Interestingly, amyloid deposition in the bundle branches is rare.

On the basis of pathology, RCM can be classified as obliterative (ie, thrombus-filled ventricles) or nonobliterative/idiopathic.

Obliterative RCM is very rare. It may result from the end stage of the eosinophilic syndromes, in which an intracavitary thrombus fills the left ventricular apex and hampers the filling of the ventricles. The fibrosis of the endocardium may extend to involve the atrioventricular valves and cause regurgitation. Two forms of endomyocardial fibrosis (EMF) exist—an active inflammatory eosinophilia and chronic EMF.

In idiopathic (primary) RCM, progressive fibrosis of the myocardium occurs, but no thrombus forms. This entity also is said to lack specific histopathologic changes.

Etiology

RCM may be caused by various local and systemic disorders; many of them are rare and unlikely to be observed in the United States. These causes may be grouped into 4 broad categories as follows:

According to WHO guidelines, the term “cardiomyopathy” refers to diseases of the myocardium that are idiopathic (ie, primary cardiomyopathies). However, secondary infiltrative myocardial diseases, which are actually cardiac manifestations of systemic diseases, often are grouped together with cardiomyopathies.[5]

Idiopathic RCM may be caused by EMF or by Loeffler eosinophilic endomyocardial disease. Secondary restrictive cardiomyopathy may be caused by the following:

Idiopathic/primary RCM

A subset of patients have heart muscle disease of unknown cause that is manifested by heart failure and restrictive hemodynamics but is not characterized by significant ventricular hypertrophy, endocardial thickening or fibrosis, associated eosinophilia, or other diagnostically distinct histopathologic changes.

Males and females have been affected equally, but the prognosis appears to be worse in children than in adults. Children require relatively high filling pressures for maintenance of systolic output, and the therapeutic margin between volume depletion (leading to low output) and volume overload (leading to congestive heart failure) is narrow. A familial pattern has been noted in some cases.

In addition to the presenting symptoms of right- and left-side heart failure, as many as one third of patients with idiopathic RCM may present with thromboembolic complications. Pathologically, these patients have strikingly dilated atria, which may account for the increased cardiothoracic ratio on chest radiography. Echocardiography shows bilateral atrial enlargement with normal ventricular size but significant diffuse left ventricular hypertrophy, especially with amyloidosis. Histologic features include interstitial fibrosis, which is minimal in some and extensive in others.

Amyloidosis

Amyloidosis is characterized by intercellular accumulation of amyloid material in amounts sufficient to impair the function of the involved organs. On the basis of the amyloid protein composition, amyloidosis is classified into 4 different varieties as follows:

The cardiac involvement in primary amyloidosis most commonly is associated with restrictive physiology. Amyloid infiltration of the heart is common in the elderly population (systemic senile amyloidosis) and may exhibit impaired diastolic filling properties but has other features that are more typical of a dilated cardiomyopathy.

The myeloma protein fibrils composed of immunoglobulin light chains are deposited diffusely throughout the myocardium and create a firm and rubbery consistency. Typically, the heart does not collapse when removed from the chest during autopsy.

On histologic examination, interstitial deposition of insoluble amyloid fibrils in all 4 cardiac chambers is observed. This can result in increased wall thickness without cavity dilatation.

Involvement of the valves may create regurgitant lesions, but hemodynamically and clinically significant degree of regurgitation is unusual.

The granular sparkling (ie, scintillating) appearance on 2-dimensional echocardiography may be present and is typical, but not diagnostic, of cardiac amyloidosis. Echocardiography more typically shows biventricular thickening out of proportion to current or prior hypertension, biatrial enlargement, a restrictive filling pattern by Doppler echocardiography, and normal systolic function and ejection fraction until late in the disease.

In the early stages of the disease, typical restrictive hemodynamics may not be evident; however, in more advanced cases, typical restrictive hemodynamics are more likely. A corollary of these observations is that restrictive diastolic dynamics strongly predict cardiac death in patients with amyloidosis. Cardiac biopsy is needed to confirm the diagnosis if doubt remains after noninvasive tests.

Eosinophilic cardiomyopathy and EMF

Severe prolonged eosinophilia from any cause (eg, allergic, autoimmune, parasitic, leukemic, or idiopathic) can lead to eosinophilic infiltration of the myocardium. The intracytoplasmic granular content of activated eosinophils is believed to be responsible for the toxic damage to the heart. This eosinophilic cardiomyopathy, also known as Loeffler endocarditis, is associated with dense EMF, intraventricular thrombus formation, and obliteration of the ventricular cavity in its late stages; accordingly, it is included in the category of obliterative RCM.

EMF, which is observed exclusively in equatorial Africa and less frequently in Asia and South America, was believed to be the end stage of eosinophilic endomyocarditis. However, it now is considered a separate entity because it does not exhibit eosinophilia. EMF demonstrates pathology that is similar to that described above (Loeffler endocarditis) and therefore is grouped under obliterative RCM.

The prognosis is poor for patients with diffuse involvement of the heart in EMF, but localized lesions involving the valves are amenable to surgical repair or removal and replacement.

Postirradiation fibrosis

Radiation-induced myocardial and endocardial fibrosis also can cause RCM. However, this complication of radiotherapy, like pericardial constriction, is evident several years after treatment. Differentiating between constriction and restriction may be particularly difficult in these patients because the 2 conditions may coexist.

Epidemiology

Idiopathic restrictive cardiomyopathy is observed mainly in the United States. Loeffler endocarditis is common in the temperate zone, and chronic EMF is observed in the tropics. EMF occurs most commonly in children and young adults in tropical and subtropical Africa, primarily in Uganda and Nigeria.[7] EMF may account for up to one fourth of deaths due to cardiac disease in those areas

Prognosis

The course of RCM varies depending on the pathology, and treatment is often unsatisfactory. Prognosis generally is poor in the adult population, with progressive deterioration. The natural history of RCM is especially poor in children with heart failure. Adults experience a prolonged course of heart failure and may have complications of cardiac cirrhosis and thromboembolism. Patients who are refractory to supportive therapy usually die of low-output cardiac failure unless cardiac transplantation is an option.

History

Patients with restrictive cardiomyopathy (RCM) often present at an advanced stage of disease with pronounced cardiopulmonary symptoms. They usually complain of gradually worsening shortness of breath, progressive exercise intolerance, and fatigue. Fatigue and weakness are results of decreased stroke volume and cardiac output. Paroxysmal nocturnal dyspnea may be reported.

Patients may have distention of the abdomen secondary to ascites, but they frequently have profound bilateral peripheral edema. Abdominal discomfort or liver tenderness may be reported.

Chest pain secondary to angina or chest pain mimicking myocardial ischemia can be observed, primarily in patients with amyloidosis, possibly due to myocardial compression of small vessels. Patients may complain of palpitations, frequently due to atrial fibrillation, which is common in idiopathic RCM.

As many as one third of patients with idiopathic RCM may present with thromboembolic complications, especially pulmonary emboli secondary to blood clots in the legs. If atrial fibrillation is present, a high risk of left atrial clots and systemic emboli is present.

Patients may have a history of syncopal attacks from a variety of causes, but orthostatic hypotension secondary to a peripheral and/or autonomic neuropathy should be excluded. Syncope and sudden death are common in AL amyloidosis, but ventricular arrhythmias are uncommon. Electrical-mechanical dissociation is more common. Conduction disturbances are particularly common in some forms of infiltrative RCM, but not in amyloidosis.

Depending on the etiology, patients may have a prior history of radiation therapy, heart transplantation, chemotherapy, or a systemic disease.

Physical Examination

A careful general physical examination must be conducted to search for extracardiac manifestations of a systemic disorder that may cause secondary restrictive cardiomyopathy (eg, hemochromatosis, amyloidosis, sarcoidosis, or scleroderma).[5, 6] Particular attention should be paid to the cardiovascular and respiratory systems.

General examination

Patients may be more comfortable in the sitting position because of fluid in the abdomen or lungs. Weight loss and cardiac cachexia are not uncommon. Easy bruising, periorbital purpura, macroglossia, and other systemic findings, such as carpal tunnel syndrome, should advise the clinician to consider amyloidosis.

Increased jugular venous pressure is present, with rapid x and y descents; the most prominent finding is usually the rapid y descent. The degree of elevation of the jugular venous pressure indicates the severity of impaired filling of the right ventricle.

The jugular venous pulse fails to fall during inspiration and may actually rise (Kussmaul sign) in constrictive pericarditis. Although less common in RCM, Kussmaul sign cannot be used as an absolute means to distinguish RCM and constrictive pericarditis. The pulse volume is decreased, consistent with decreased stroke volume and cardiac output.

Patients frequently have ascites and pitting edema of the lower extremities. The liver is usually enlarged and full of fluid, which may be painful. However, the liver may be enlarged and firm due to amyloid infiltration. Splenomegaly is rare.

Cardiovascular system examination

Heart sounds S1 and S2 are normal, with a normal S2 split. A loud early diastolic filling sound (S3) may be present but is uncommon in amyloidosis. A fourth heart sound (S4) is almost never present, possibly secondary to amyloid infiltration of the atria. Murmurs due to mitral and tricuspid valve regurgitation may be heard, but they are secondary to the myocardial disease and usually not hemodynamically significant.

Respiratory system examination

Breath sounds are decreased due to pleural effusion, frequently bilateral, and large in amyloidosis. Crepitations or rales are rarely heard, even in advanced heart failure of amyloidosis.

Complications

Complications of RCM may include the following:

Approach Considerations

Laboratory studies are performed to establish the diagnosis of restrictive cardiomyopathy (RCM), to quantitate the severity of the disease, and to monitor the patient.

Other investigative modalities are also employed in the workup, in particular to facilitate differentiation between RCM and constrictive cardiomyopathy (see Table 2 below).

Table 2. Investigation of Constrictive Cardiomyopathy and Restrictive Cardiomyopathy


View Table

See Table

Laboratory Studies

A complete blood count (CBC) with peripheral smear helps establish eosinophilia. Blood gas analysis is performed to monitor hypoxia. Serum electrolyte, blood urea nitrogen (BUN) and creatinine levels should be obtained, as well as a liver function profile.

Serum iron concentrations, percent saturation of total iron-binding capacity, and serum ferritin levels are all increased in hemochromatosis.

Serum brain natriuretic peptide (BNP) levels should be assessed. Data suggest that serum BNP levels are nearly normal in patients with constrictive physiology of heart failure and grossly elevated in patients with restrictive physiology, despite nearly identical clinical and hemodynamic presentation.[8]

Radiography and Angiography

Chest radiograph typically shows cardiomegaly with bilateral pleural effusions, absence of cardiomegaly, normal cardiac silhouette, no pericardial calcification (seen in constrictive pericarditis), and manifestations of pulmonary venous hypertension and pulmonary congestion

Angiography may show a small, thick-walled cavity in eosinophilic endomyocardial disease, which may be distorted significantly by a mural thrombus.

Echocardiography

Two-dimensional imaging

Two-dimensional echocardiography shows a nondilated, normally contracting, nonhypertrophied left ventricle and marked dilatation of both atria. However, amyloidosis and glycogen storage diseases typically show diffuse increased left ventricular thickening.

The ventricular cavity size may be normal or reduced. The wall thickness may be increased in patients with infiltrative diseases. Mural thrombus and cavity obliteration are features of obliterative cardiomyopathy. In contrast, dilated cardiomyopathy shows dilatation of all the chambers of the heart, and increased wall thickness, especially of the ventricular septum, is observed in hypertrophic cardiomyopathy.

Abnormal myocardial textures can also be appreciated using echocardiography. For example, granular speckling of the ventricular walls suggests the presence of infiltrative disease, such as amyloidosis.

Pericardial thickening is not reliably observed on echocardiography; magnetic resonance imaging (MRI) is suggested for exclusion of a thick pericardium.

Doppler imaging

Doppler echocardiography shows features of restriction to diastolic filling. Accentuated early diastolic filling of the ventricles (E), shortened deceleration time, and diminished atrial filling (A), which results in a high E-to-A ratio on the mitral inflow velocities, are present. Variations of this diastolic (transmitral) blood flow with respiration help differentiate between constrictive pericarditis and RCM.

Because both of the ventricles are encased in a common constricting pericardial sac, an inspiratory increase in inflow to the right ventricle causes a reciprocal reduction in the transmitral inflow to the left ventricle. Thus, a pattern of respiratory variation, with a diminished peak transmitral diastolic flow during inspiration, is characteristic of pericardial constriction but not of RCM. In contrast, in RCM, the left-sided filling pressures are elevated further in inspiration.

Pulsed-wave tissue Doppler imaging

The use of pulsed-wave Doppler imaging is used in some centers as a noninvasive approach to distinguishing RCM from constrictive pericarditis. In addition to the information obtained by standard Doppler imaging, pulsed-wave Doppler imaging can define myocardial contraction and relaxation. This results in a measure referred to as the myocardial velocity gradient. Small studies have suggested that the myocardial velocity gradient is a specific measure that distinguishes these 2 entities well.

Cardiac Catheterization

Ventricular pressure tracings of increased right heart pressures, typical venous wave pattern, and the dip-and-plateau or square-root contour of the ventricular diastolic pressures (deep and rapid early decline in ventricular pressure at the onset of diastole, with a rapid rise to a plateau in early diastole) obtained by cardiac catheterization are the same in pericardial constriction and in RCM. This dip-and-plateau or square-root sign of ventricular pressure is manifested in the atrial pressure tracing as a prominent descent followed by a rapid rise to a plateau.

A few criteria favor the pericardial disorder, as follows:

In RCM, the variance between right and left ventricular diastolic pressures is more likely to be greater than 5 mm Hg, RVEDP is more likely to be less than one third the RVSP, and RVSP is more likely to be higher than 50 mm Hg.

Electrocardiography

The findings on electrocardiography (ECG) depend on the stage of the disease and the specific diagnosis. The ECG may be normal or just show some nonspecific ST-T wave changes, but rhythm disorders (notably atrial fibrillation) are common.

Conduction abnormalities are uncommon in amyloidosis. Low QRS voltage is common in amyloidosis, out of proportion to the thick left ventricle on echocardiography. A pseudoinfarct pattern is possible, secondary to myocardial infiltration and/or small vessel–induced ischemia or infarction.

Other Studies

Radionuclide imaging

Radionuclide imaging shows increased diffuse uptake of technetium-99m (99m Tc) pyrophosphate and indium-111 (111 In) antimyosin in cardiac amyloidosis.

Cardiovascular magnetic resonance (CMR)

Cardiovascular magnetic resonance (CMR) has been used to assess abnormal myocardial interstitium. Preliminary reports suggest a characteristic pattern of global subendocardial late gadolinium enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics in RCM.

Biopsy

Ventricular biopsy obtained from either the right or the left ventricle has proved useful in certain cases in establishing whether endocardial or myocardial disease is present. Growing experience in this technique indicates a high diagnostic yield in diseases that may present with restriction hemodynamics, when noninvasive studies have failed to establish a clear-cut diagnosis.

Amyloidosis demonstrates apple-green birefringence, stained with Congo red, viewed under a polarizing microscope. Fine-needle aspiration of abdominal fat is easier and safer than myocardial biopsy for determination of amyloidosis. Confirmation of the diagnosis of AL amyloidosis demands a search for a plasma cell dyscrasia.

Liver biopsy is performed for diagnosis of hemochromatosis.

Approach Considerations

Restrictive cardiomyopathy (RCM) has no specific treatment. However, therapies directed at individual causes of RCM have been proven to be effective. Examples of this include corticosteroids for sarcoidosis and Loeffler endocarditis, endocardiectomy for endomyocardial fibrosis and Loeffler endocarditis, phlebotomy and chelation for hemochromotosis, and chemotherapy for amyloidosis. The mainstays of medical treatment include diuretics, vasodilators, and angiotensin-converting enzyme inhibitors (ACEs) as indicated, as well as anticoagulation (if not contraindicated).[9]

In selected patients, permanent pacing, LVAD therapy, and transplantation (heart or heart-liver) may be considered.

Pharmacologic Therapy

The goal of treatment in RCM is to reduce symptoms by lowering elevated filling pressures without significantly reducing cardiac output. Beta blockers and cardioselective calcium channel blockers (eg, verapamil, diltiazem) may be of benefit, by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation. In addition, low-medium dose diuretics lower preload and may provide symptomatic relief. Small initial doses should be administered to prevent hypotension because patients are frequently extremely sensitive to alterations in left ventricular volume. Higher doses may be needed if the serum albumin level is low secondary to concomitant nephrotic syndrome.

ACEIs and angiotensin II inhibitors are poorly tolerated in patients with amyloidosis. Even small doses may result in profound hypotension, probably secondary to an autonomic neuropathy. Beta-blockers and calcium channel blockers have not been shown to improve day-to-day symptoms or to favorably alter the natural history in patients with diastolic heart failure. No published data are available on the use of intravenous (IV) inotropic or vasodilator drugs.

Patients with a history of atrial fibrillation should be anticoagulated. In patients with atrial fibrillation, the rate should be controlled adequately. Removal of the atrial contribution to ventricular filling may worsen the existing diastolic dysfunction, and a rapid ventricular response may further compromise diastolic filling, creating a crisis. Therefore, maintaining sinus rhythm is important, and medications such as amiodarone and beta-blockers are often used.

Digoxin should be used with caution because it is potentially arrhythmogenic, particularly in patients with amyloidosis.

Antiplasma cell therapy with melphalan may slow the progress of systemic amyloidosis by stopping production of the paraprotein responsible for the formation of amyloid. The prognosis of patients with primary systemic amyloidosis remains poor, with a median survival of approximately 2 years despite intervention with alkylating-based chemotherapy in selected cases. In specific cases, chemotherapy has dramatic benefits, with improvement in systemic and cardiac manifestations.

The treatment of Loeffler endocarditis consists of correctly identifying the condition before the end-stage fibrosis occurs. Medical therapy with corticosteroids, cytotoxic agents (eg, hydroxyurea), and interferon to suppress the intense eosinophilic infiltration of the myocardium is appropriate during the early phase of Loeffler endocarditis and improves symptoms and survival. Conventional heart failure medication is also given.

Chelation therapy or therapeutic phlebotomy is effective in patients with hemochromatosis to decrease the iron overload.

Pacemaker Implantation

Patients with idiopathic restrictive cardiomyopathy (RCM) may have fibrosis of the sinoatrial and atrioventricular nodes that result in complete heart block, and, therefore, require permanent pacing. If cardioversion to treat atrial fibrillation is attempted, particularly in patients with amyloidosis, the abnormal sinus node may fail as an effective pacemaker. Patients with sinus node dysfunction and/or advanced conduction system disease also require treatment with implantation of a pacemaker.

Endomyocardectomy

As noted, treatment of Loeffler endocarditis depends on correctly identifying the condition before the end-stage fibrosis occurs and typically involves early pharmacotherapy (see Pharmacologic Therapy).

In the fibrotic stage of Loeffler endocarditis, surgical therapy, with excision of the fibrotic endocardium and replacement of the mitral and tricuspid calves, is palliative but may provide symptomatic improvement. The operative mortality is in the range of 15-25%.

Cardiac Transplantation

Cardiac transplantation or ventricular mechanical support therapy can be considered in highly selected patients with refractory symptoms who have idiopathic or familial RCM and amyloidosis. Patients treated with an LVAD with HCM have similar mortalities compared with those with dilated cardiomyopathy.[10] When noncardiac organ involvement is absent, a few patients with amyloidosis have undergone successful cardiac transplantation, combined with postoperative high-dose chemotherapy, to abolish recurrent amyloid production.

Combined heart and liver transplantation in patients with heart and liver failure due to hemochromatosis has been successful in small numbers of patients. However, early morbidity and mortality are higher in dual-organ transplantation than in single-organ transplantation.

Transplantation is a treatment option for cardiac sarcoidosis, but recurrence of sarcoid granulomas can occur in the transplanted heart.

A surgical approach offers a cure for pericardial constriction but carries a potential for significant morbidity for RCM. Thus, establishing a clear diagnosis is crucial, and the advent of current sophisticated imaging technology helps in that regard (see Workup). Fewer patients now need exploratory open-heart surgery to establish the correct diagnosis.

Stem cell transplantation used in conjunction with high-dose chemotherapy is still considered experimental by most cardiologists. Its routine use has not yet been established.

Finally, whether patients who have radiation-induced cardiac diseases are candidates for heart transplant is uncertain. This stems from data that has shown that these patients have poor early and late outcomes after cardiac trasplantation related to fibrosis related procedural complications and new or recurrent malignancies.[11]

Medication Summary

Treatment of restrictive cardiomyopathy (RCM) is symptomatic. Treatment goals include decreasing systemic and pulmonary congestion, lowering ventricular filling pressure, augmenting systolic pump function, and reducing the risk for embolism.[9]

Hydrochlorothiazide (Microzide)

Clinical Context:  Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Furosemide (Lasix)

Clinical Context:  Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dose must be individualized to the patient. Depending on response, administer furosemide at increments of 20-40 mg no sooner than 6-8 hours after the previous dose until the desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose increments until a satisfactory effect is achieved.

Class Summary

Diuretics are used to reduce pulmonary and systemic congestion. Symptomatic treatment may improve symptoms of venous congestion through elimination of retained fluid and preload reduction. Initiate therapy with a low dosage because relatively high levels of ventricular filling pressure must be maintained for adequate diastolic filling.

Nitroglycerin PO

Clinical Context:  Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure. This agent is available as lingual pump spray, sublingual tablets, oral tablets, patches, and ointments.

Class Summary

Nitrates are used to reduce preload in diastolic dysfunction.

Carvedilol (Coreg, Coreg CR)

Clinical Context:  Nonselective beta- and alpha-adrenergic blocker. Also has antioxidant properties. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.

Class Summary

May improve symptoms by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation.

Verapamil (Calan, Isoptin)

Clinical Context:  Nondihydropyridine calcium-channel blocker that inhibits extracellular calcium ion influx across membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction and thereby dilating main coronary and systemic arteries.

Diltiazem (Cardizem, Cardizem CD, Dilacor Tiazac)

Clinical Context:  Nondihydropyridine calcium-channel blocker that inhibits extracellular calcium ion influx across membranes of myocardial cells and vascular smooth muscle cells, resulting in inhibition of cardiac and vascular smooth muscle contraction and thereby dilating main coronary and systemic arteries.

Class Summary

May improve symptoms by increasing left ventricular filling time, improving ventricular relaxation, and decreasing compensatory sympathetic stimulation.

Hydralazine

Clinical Context:  Hydralazine decreases systemic resistance through direct vasodilation of arterioles.

Isosorbide dinitrate/hydralazine (BiDil)

Clinical Context:  A fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), a predominantly arterial vasodilator, is indicated for heart failure in blacks, in part on the basis of results from the African American Heart Failure Trial.

Two previous trials in the general population of patients with severe heart failure found no benefit but suggested benefit in patients who are black. In comparison with placebo, this combination showed a 43% reduction in mortality, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure among blacks.

Class Summary

Vasodilators are used to reduce ventricular filling pressure. Avoid excessive decrease in preload and diastolic filling.

Warfarin (Coumadin)

Clinical Context:  Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Heparin

Clinical Context:  Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents reaccumulation of clot after spontaneous fibrinolysis.

Class Summary

Anticoagulants are used to prevent embolism from ventricular thrombus.

Digoxin (Lanoxin)

Clinical Context:  Digoxin is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Class Summary

Cardiac glycosides are used to treat atrial fibrillation and systolic dysfunction in RCM. Digitalis and other positive inotropic agents generally are not indicated unless systolic pump function and contractility are impaired. Digitalis must be used with caution in patients with amyloid cardiomyopathy; such patients may be digoxin sensitive (arrhythmogenic) because of amyloid fibril binding of digoxin.

Author

Alan Vainrib, MD, Fellow, Department of Cardiology, Stony Brook University Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Asa William (Peter) Viccellio, MD, Professor, Vice-Chair, Department of Emergency Medicine, State University of New York at Stony Brook

Disclosure: Nothing to disclose.

Vivek J Goswami, MD, Director of Nuclear Cardiology, Austin Heart; Clinical Assistant Professor, Texas A&M Health Science Center College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Gary Edward Sander, MD, PhD, FACC, FAHA, FACP, FASH, Professor of Medicine, Director of CME Programs, Team Leader, Root Cause Analysis, Tulane University Heart and Vascular Institute; Director of In-Patient Cardiology, Tulane Service, University Hospital; Visiting Physician, Medical Center of Louisiana at New Orleans; Faculty, Pennington Biomedical Research Institute, Louisiana State University; Professor, Tulane University School of Medicine

Disclosure: Forest Labs Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

A Antoine Kazzi, MD, Deputy Chief of Staff, American University of Beirut Medical Center; Associate Professor, Department of Emergency Medicine, American University of Beirut, Lebanon

Disclosure: Nothing to disclose.

David FM Brown, MD, Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

Disclosure: Nothing to disclose.

Chief Editor

Henry H Ooi, MB, MRCPI, Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Assistant Professor of Medicine, Vanderbilt University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Sarath Reddy, MD, Alan Forker, MD, Gunateet Goswami, MD, Nafisa Kuwajerwala, MD, Paul J Kaloudis, MD, and Andrew Wackett, MD, to the development and writing of the source articles.

References

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  3. Schlant RC, Alexander RW, eds. The Heart. McGraw-Hill; 1994:1637-45.
  4. Higano ST, Azrak E, Tahirkheli NK, Kern MJ. Hemodynamic rounds series II: hemodynamics of constrictive physiology: influence of respiratory dynamics on ventricular pressures. Catheter Cardiovasc Interv. Apr 1999;46(4):473-86. [View Abstract]
  5. Davies MJ, Mann JM. Systemic pathology. In: The Cardiovascular System. Vol 10. 1995:1409-16.
  6. Wald DS, Gray HH. Restrictive cardiomyopathy in systemic amyloidosis. QJM. May 2003;96(5):380-2. [View Abstract]
  7. Braunwald E, Abelmann WH. Atlas of Heart Diseases. Vol 2. 1994:53-61.
  8. Leya FS, Arab D, Joyal D, Shioura KM, Lewis BE, Steen LH, et al. The efficacy of brain natriuretic peptide levels in differentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol. Jun 7 2005;45(11):1900-2. [View Abstract]
  9. Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergency Medicine: A Comprehensive Study Guide. McGraw-Hill; 2004:381.
  10. Topilsky Y, Pereira NL, Shah DK, et al. Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy. Circ Heart Fail. May 2011;4(3):266-75. [View Abstract]
  11. Uriel N, Vainrib A, Jorde UP, Cotarlan V, Farr M, Cheema FH. Mediastinal radiation and adverse outcomes after heart transplantation. J Heart Lung Transplant. Mar 2010;29(3):378-81. [View Abstract]
  12. Hare JM. The Dilated, Restrictive, and Infiltrative Cardiomyopathy. In: Bonow RO, MD, Mann DL, Zipes DP, Libby P. Braunwald's Heart Disease, 9th Edition. 2. 9th. Elsevier; 2012:68; 1561-1581.
Clinical Features Constrictive Pericarditis Restrictive Cardiomyopathy
HistoryPrior history of pericarditis or condition that causes pericardial diseaseHistory of systemic disease (eg, amyloidosis, hemochromatosis)
General examinationPeripheral stigmata of systemic disease
Systemic examination - Heart soundsPericardial knock, high-frequency soundPresence of loud diastolic filling sound S3, Low-frequency sound
MurmursNo murmursMurmurs of mitral and tricuspid insufficiency
Prior chest radiographPericardial calcificationNormal results of prior chest radiograph
Investigation Constrictive Cardiomyopathy Restrictive Cardiomyopathy
Chest radiographPericardial calcificationAtrial dilatation causing increased cardiothoracic ratio, normal ventricular size
CT scan/MRIPericardial thickeningNo pericardial thickening
EchocardiographyNormal-sized ventricles and atria; pericardial thickening, pericardial effusion may be observedNondilated, normally contracting, nonhypertrophied ventricles and marked dilatation of both atria; speckled texture of myocardium in cases of amyloid infiltration of the heart
Doppler flow velocities on echocardiographyRespiratory changes (ie, decreased peak transmitral diastolic flow) during inspiration Equalization of the right- and left-sided filling pressures No respiratory changes Greater elevation in the left-sided filling pressures
Catheterization hemodynamics:

1) RVSP

2) RVEDP:RVSP ratio

3) RVEDP/LVEDP equalization

1) = 50 mm Hg

2) = 0.33

3) = 5 mm Hg difference

1) = 50 mm Hg

2) = 0.33

3) = 5 mm Hg difference

Cardiac biopsyNormal myocardiumOften diagnostic, showing abnormal myocardium
CT = computed tomography; LVEDP = left ventricular end-diastolic pressure; MRI = magnetic resonance imaging; RVEDP = right ventricular end-diastolic pressure; RVSP = right ventricular systolic pressure.