I. Problem/Condition.

The nomenclature and classifications used in heart failure and associated cardiomyopathies often contain overlap and can lead to confusion. Restrictive cardiomyopathy is characterized by abnormal diastolic filling due to a stiff, non-compliant ventricle. Both the right and left ventricles can be affected, and systolic function is typically preserved. Ventricular stiffening may be caused by infiltrative processes (i.e. amyloidosis, sarcoidosis), non-infiltrative processes (i.e. scleroderma), storage disorders (i.e. hemochromatosis), or endomyocardial disease (i.e. endomyocardial fibrosis); 50 percent of cases are idiopathic. The most common specific cause of a restrictive cardiomyopathy is amyloidosis.

Patients typically present with the insidious onset of exercise intolerance caused by an inability to increase cardiac output because of impaired diastolic filling at increased heart rates. As the ventricles stiffen, the patient develops anasarca, ascites, peripheral edema, and hepatomegaly due to passive congestion of the peripheral venous system. Prognosis depends on the underlying cause of ventricular stiffening: median survival for patients with cardiac amyloid is well under one year; whereas, median survival for patients with idiopathic cardiomyopathy may be as long as 10-15 years.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The greatest diagnostic challenge in restrictive cardiomyopathy is differentiating it from constrictive pericarditis; physiology is similar in both, with impaired diastolic function and preserved systolic function. Once the diagnosis of restrictive cardiomyopathy is made, it is important to determine the specific cause.

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The types of restrictive cardiomyopathy can be classified according to their etiologies as infiltrative, non-infiltrative, due to a storage disease, or due to an endomyocardial process:

Non-infiltrative

  • Idiopathic cardiomyopathy (responsible for 50% of restrictive cardiomyopathy)

  • Familial cardiomyopathy

  • Hypertrophic cardiomyopathy

  • Scleroderma

  • Pseudoxanthoma elasticum

  • Diabetic cardiomyopathy

Infiltrative

  • Amyloidosis

  • Sarcoidosis

  • Gaucher disease

  • Hurler disease

  • Fatty infiltration

Storage disease

  • Hemochromatosis

  • Fabry disease

  • Glycogen storage disease

Endomyocardial causes

  • Endomyocardial fibrosis

  • Hypereosinophilic syndrome (Loeffler’s endocarditis)

  • Carcinoid heart disease

  • Metastatic cancers

  • Radiation

  • Anthracycline toxicity

  • Fibrous endocarditis cause by drugs

    serotonin

    methysergide

    ergotamine

    mercurial agents

    busulfan

B. Describe a diagnostic approach/method to the patient with this problem

In the patient presenting with the insidious onset of exercise intolerance, the first step is determining if the etiology is due to congestive heart failure. The next step is to determine whether the heart failure is due primarily to systolic or diastolic dysfunction. This can be accomplished with echocardiography.

In patients with primarily diastolic dysfunction, it is important to consider both a restrictive cardiomyopathy and constrictive pericarditis. Echocardiography is often the first step in this process. Findings consistent with a restrictive cardiomyopathy or constrictive pericarditis are discussed in detail below.

Sometimes, the diagnosis will be unclear following echocardiography, and other tests, like cardiac magnetic resonance imaging (MRI) and cardiac catheterization, will be required. In some cases, a patient may undergo echocardiography, catheterization and cardiac MRI without clinching the diagnosis.

Once a restrictive physiology is confirmed, the next step is determining the cause. Usually this requires biopsy, either of the myocardium or of other tissues affected by the same disease process (i.e. renal biopsy in a patient with scleroderma), but cardiac MRI is increasingly helpful in making the diagnosis.

1. Historical information important in the diagnosis of this problem.

Important items in the review of systems: angina, dyspnea, dyspnea on exertion, palpitations, lower extremity edema, diarrhea, flushing, dysphagia, urinary frequency, change in urine color, neurologic changes.

Other important information:

  • Has anyone in your family had heart trouble?

  • Any previous open chest surgeries?

  • Have you recently traveled to a tropical area?

  • Have you every been treated with serotonin, methysergide, ergotamine, mercurial agents, busulfan, or an anthracycline (daunorubicin, doxorubicin)?

  • Any personal history of cancer? Treatment with radiation?

  • How long have the symptoms been present?

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Physical examination is notable for elevated jugular venous pressure, often with Kussmaul’s sign (paradoxical increase in jugular venous pressure with inspiration). Kussmaul’s sign is also associated with constrictive pericarditis, and occurs secondary to impaired diastolic filling of the right ventricle. On auscultation, S3and S4 are commonly heard, and the irregularly irregular rhythm of atrial fibrillation is also common (though patients in atrial fibrillation will not have an S4).

In patients with an infiltrative process, the conduction system may become involved, leading to complete heart block or other arrythmias. If the autonomic nerves, blood vessels, or adrenal glands become involved (as is relatively common in amyloidosis), the patient may have orthostatic hypotension.

Other findings on physical examination will be specific to the disease process causing restrictive cardiomyopathy rather than to the cardiomyopathy itself. Patients with restrictive cardiomyopathy due to systemic sclerosis may present with symmetric skin thickening, Raynaud’s phenomenon, and/or flat white patches in the mouth; those with restrictive cardiomyopathy secondary to hemochromatosis may present with tanned skin.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

There are several tests that may be helpful in diagnosing restrictive cardiomyopathy, including brain natriuretic peptide (BNP), chest x-ray, electrocardiogram (EKG), echocardiogram, cardiac computed tomography (CT), cardiac MRI, and cardiac catheterization. Unfortunately, none of the tests are perfectly sensitive or specific, and many patients undergo all tests without reaching a definitive conclusion.

Plasma BNP levels are typically elevated in a restrictive cardiomyopathy and there is a very limited amount of evidence that levels can play a role in differentiating restrictive cardiomyopathy and constrictive pericarditis. In general, higher values are thought to be associated with a restrictive cardiomyopathy, though this finding is unlikely to be enough to differentiate between the two conditions.

Chest x-ray is unlikely to demonstrate any findings specific to restrictive cardiomyopathy. However, it may reveal findings consistent with the causative process, such as sarcoidosis, or it may reveal pericardial calcifications, a finding consistent with the alternative diagnosis of pericardial constriction.

Patients with restrictive cardiomyopathy will often have atrial enlargement, and this can be reflected on EKG with increased P wave amplitude. Other conduction abnormalities (atrioventricular block, bundle branch block) are more commonly seen in restrictive cardiomyopathy than in constrictive pericarditis.

Neverthless, echocardiography is a key test in diagnosing restrictive cardiomyopathy. Findings consistent with a restrictive cardiomyopathy include preserved left ventricular function and atrial enlargement on two-dimensional imaging. Doppler assessments will also reveal the diastolic dysfunction that characterizes this disorder. One specific finding that suggests diastolic dysfunction due to abnormal myocardium (as opposed to abnormal pericardium in constrictive pericarditis) is tissue Doppler imaging that reveals reduced myocardial relaxation velocities.

Echocardiography can also reveal findings consistent with the process causing the restrictive cardiomyopathy. For example, in amyloidosis, one can see thickening of the myocardium and valve leaflets and/or speckling of the myocardium. In restrictive cardiomyopathy, the pericardium also appears normal (it can appear abnormal in constrictive pericarditis) and there is an absence of interventricular dependence.

Interventricular dependence is the hallmark of a diagnosis of constrictive pericarditis, and is typically seen on echocardiogram as abnormal septal motion or leftward movement of the septum and decreased size of the left ventricle with increasing preload (such as with inspiration) due to a pericardium that constricts/limits the normal expansion of the right and left ventricular free walls. This is sometimes referred to as septal bounce.

Cardiac catheterization can provide further information, and also allows for endomyocardial biopsy. Hemodynamic measurement of intracardiac pressures on cardiac catheterization can also reproducibly demonstrate the presence of interventricular dependence (with inspiration representing a high preload state, and expiration representing a low preload state); significant interventricular dependence on cardiac catheterization is both sensitive and specific for constrictive pericarditis.

However, there is considerable overlap between individual patients, so the value of this test on the individual-patient level is limited. Endomyocardial biopsy performed in conjunction with cardiac catheterization may help determine the nature of the process causing the restrictive physiology.

Recently, cardiac MRI has been used to aid in the diagnosis of restrictive cardiomyopathy. Similar to echocardiogram, it may be able to identify structural abnormalities that help with the diagnosis of a specific cause of restrictive cardiomyopathy (such as amyloidosis or sarcoidosis) or identify an abnormal pericardium. Cardiac CT can also be helpful to identify abnormal pericardium. Cardiac MRI also has the ability to demonstrate the physiology of interventricular dependence described above in the paragraph on echocardiographic imaging.

III. Management while the Diagnostic Process is Proceeding

A. Management of restrictive cardiomyopathy.

The most important step in treating restrictive cardiomyopathy involves identifying and correcting reversible underlying causes. First, constrictive pericarditis must be ruled out, since it is possible to surgically correct constrictive pericarditis, but not restrictive cardiomyopathy. Second, any underlying process causing the restrictive cardiomyopathy should be determined, and any treatment directed at that process should be initiated.

While pursuing an underlying cause (and in those cases where no underlying cause can be determined, or those where the underlying cause cannot be treated), the key to management of restrictive cardiomyopathy is to ensure proper fluid balance; these patients are preload dependent but are exquisitely sensitive to volume and may become volume overloaded. Diuretics are the mainstay of therapy for patients with volume overload, but excessive use can lead to decreased filling pressures with decreased cardiac output and signs/symptoms of hypoperfusion. Overdiuresis is best treated with cautious fluid boluses.

Unfortunately, no other cardiac medications typically used in heart failure are known to be of benefit in patients with a restrictive cardiomyopathy.

These patients are also extraordinarily sensitive to the loss of sinus rhythm, as they require the atrial contribution to ventricular filling to maintain adequate stroke volume. It is therefore important to maintain or restore sinus rhythm in any patient with restrictive cardiomyopathy, atrial fibrillation, and signs of hypoperfusion.

Over the long-term, many patients will develop arrythmias that require management with pacemakers or intra-cardiac defibrillators. In patients with atrial fibrillation, anti-coagulation is also indicated.

The definitive treatment of restrictive cardiomyopathy is determined by the underlying disease process. Cardiac amyloid is often treated with chemotherapy; endomyocardial fibrosis and eosinophilic cardiomyopathy are commonly treated with cytotoxic drugs and glucocorticoids, but surgery is sometimes a palliative option; iron-chelation or phlebotomy is often helpful in patients with hemochromatosis. In certain patients, cardiac transplantation can have good results, but the primary disease process often recurs in the transplanted heart.

What's the evidence?

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Hassan, WM, Fawzy, ME, Al Helaly, SA, Hegazy, H, Malik, S.. “Pitfalls in diagnosisclinicalechocardiographichemodynamic findings in endomyocardial fibrosis a 25-year experience”. Chest. vol. 128. 2005. pp. 3985-92.

Hershberger, RE, Lindenfeld, J, Mestroni, L, Seidman, CE, Taylor, MRG, Towbin, JA. “Genetic evaluation of cardiomyopathy: A Heart Failure Society of America practice guideline”. J Cardiac Fail. vol. 15. 2009. pp. 83-97.

Kushwaha, SS, Fallon, JT, Fuster, V. “Restrictive cardiomyopathy”. N Engl J Med. vol. 336. 1997. pp. 267-76.

Leya, FS, Arab, D, Joyal, D, Shloura, KM, Lewis, BE, Steen, LH, Cho, L. “The efficacy of brain natriuretic peptide levels in differentiating constrictive pericarditis from restrictive cardiomyopathy”. J Am Coll Cardiol. vol. 45. 2005. pp. 2007-13.

Nishimura, RA. “Constrictive pericarditis in the modern era: a diagnostic dilemma”. Heart. vol. 86. 2001. pp. 619-23.

Shah, KB, Inoue, Y, Mehra, MR. “Amyloidosis and the heart”. Arch Intern Med. vol. 166. 2006. pp. 1805-13.

Talreja, DR, Nishimura, RA, Oh, JK, Holmes, DR. “Constrictive pericarditis in the modern era: novel criteria for diagnosis in the cardiac catheterization laboratory”. J Am Coll Cardiol. vol. 51. 2008. pp. 315-9.

Williams, L, Frenneaux, M.. “Is it primarily tricuspid regurgitation, constriction, or restriction”. Heart. vol. 95. 2009. pp. 1380-1.

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