Restrictive cardiomyopathies

Transcription

1 European Journal of Echocardiography (2009) 10, iii23 iii33 doi: /ejechocard/jep156 Restrictive cardiomyopathies Petros Nihoyannopoulos 1 * and David Dawson 2 1 Cardiology Department, NHLI, Hammersmith Hospital, Imperial College London, London W12 0NN, UK; and 2 Echocardiography Department, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK KEYWORDS Restrictive cardiomyopathy; Diastolic function; Cardiomyopathy; Heart muscle disorders Introduction Restrictive cardiomyopathy is the least common type of cardiomyopathies without uniformly accepted diagnostic criteria. It is characterized by increased stiffness of the myocardium that causes pressure within the ventricle to rise precipitously with only small increase in volume. By definition, ventricular diastolic volumes are usually normal or reduced, wall thickness is normal or mildly increased, and systolic function is preserved. 1 Unlike the other cardiomyopathies that are classified according to morphological criteria, i.e. hypertrophic, dilated, right ventricular, restrictive cardiomyopathy is a functional classification. This automatically represents a challenge as many anatomical variants may have a common denominator the restrictive function. 2 The classic anatomical features of a restrictive cardiomyopathy are those of a small left ventricle (not dilated) with marked atrial dilatation and normal systolic function in the absence of pericardial disease. The resulting pathophysiological characteristics are those of a normal systolic contraction with a rapid but ill-sustained ventricular filling seen on pulsed-wave Doppler (E-wave) and with little or no late ventricular filling (A-wave). This filling pattern represents the cornerstone of restrictive physiology, which * Corresponding author. Tel: þ ; fax: þ address: petros@imperial.ac.uk Restrictive cardiomyopathies constitute a heterogenous group of heart muscle conditions that all have, in common, the symptoms of heart failure. Diastolic dysfunction with preserved systolic function is often the only echocardiographic abnormality that may be noted, although systolic dysfunction may also be an integral part of some specific pathologies, particularly in the most advanced cases such as amyloid infiltration of the heart. By far, the majority of restrictive cardiomyopathies are secondary to a systemic disorder such as amyloidosis, sarcoidosis, scleroderma, haemochromatosis, eosinophilic heart disease, or as a result of radiation treatment. The much more rare diagnosis of idiopathic restrictive cardiomyopathy is supported only by the absence of specific pathology on either endomyocardial biopsies or at post-mortem. Restrictive cardiomyopathy is diagnosed based on medical history, physical examination, and tests: such as blood tests, electrocardiogram, chest X-ray, echocardiography, and magnetic resonance imaging. With its wide availability, echocardiography is probably the most important investigation to identify the left ventricular dysfunction and should be performed early and by groups that are familiar with the wide variety of aetiologies. Finally, on rare occasions, the differential diagnosis from constrictive pericarditis may be necessary. corresponds to the dip-and-plateau contour of early diastolic pressure traces. It is also important to remember that while there are some typical echocardiographic characteristics of the various conditions that can affect the filling of the heart under the generic grouping of restrictive cardiomyopathies, each condition has a spectrum of cardiac involvement from a very early involvement with mild and perhaps subclinical disease to the very severe textbook-type appearance. Echocardiography today is a multimodality imaging technique on its own rights that when used appropriately and expertly in its full capacity, allows for the comprehensive description of cardiac involvement. Other imaging, particularly cardiac magnetic resonance may be complementary to echocardiography in that it is the only method that can depict the presence of myocardial fibrosis, which may well have important prognostic implications, although outcome data are scarce. Types of restrictive cardiomyopathies The purest form of this cardiomyopathy is the idiopathic restrictive cardiomyopathy in which the defined haemodynamic abnormalities occur without specific histological changes. Restrictive haemodynamics have been described in many additional conditions that affect the heart, giving rise to a variety of phenotypes that are grouped under the umbrella of restrictive cardiomyopathies. The archetype and the commonest of these diseases is cardiac amyloidosis. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 iii24 P. Nihoyannopoulos and D. Dawson This is however strictly speaking an infiltrative systemic disease that can on occasions also affect the heart leading to increased myocardial stiffness and a restrictive filling. Another condition that can lead to restrictive cardiomyopathy is the eosinophilic endomyocardial disease. Other infiltrative disorders such as haemosiderosis, sarcoidosis, and scleroderma as well as following radiotherapy may also lead to restrictive cardiomyopathy (Table 1). The fact that an aetiological factor and a specific pathological process have been documented in both, cardiac amyloidosis and endomyocardial disease, classify them as secondary restrictive cardiomyopathies. Cardiac amyloidosis This is by far the commonest cause of restrictive cardiomyopathy and the vast majority of the literature refer to cardiac amyloidosis when describing restrictive cardiomyopathy. However, and paradoxically, this type of cardiac involvement causes both diastolic but also systolic left ventricular dysfunction more often seen in mildly dilated cardiomyopathies. When the heart is involved, interstitial infiltration of the atria and ventricles leads to a firm and rubbery consistency of the myocardium in the most advanced cases. Systemic amyloidosis is a disorder of protein metabolism in which abnormal extracellular protein material is deposited in organs and tissues. 3 It causes considerable morbidity and is usually fatal. The heart is often involved in light chain amyloid leading to congestive heart failure (Figure 1). The advent of modern echocardiography has greatly contributed Table 1 Causes of restrictive cardiomyopathy Infiltrative disorders Amyloidosis Haemosiderosis Sarcoidosis Endomyocardial fibroelastosis Scleroderma Radiotherapy Idiopathic to the ante mortem recognition of amyloid infiltration of the heart. Not every form of amyloidosis involves the heart (Table 2). AL amyloidosis involves the heart in 90% of the cases and commonly presents as heart failure, whereas AA amyloidosis (secondary or reactive) only rarely affects the heart and when it does, it causes less structural and functional impairment than AL amyloidosis. An important type of amyloidosis associated with genetically variant proteins that also frequently affects the heart is the hereditary amyloidosis. The commonest form of hereditary amyloidosis is familial amyloid polyneuropathy, an autosomal dominant syndrome associated with some 60 different transthyretin mutations. 4 Familial amyloid polyneropathy may start at any time from the second decade of life and is characterized by peripheral and autonomic neuropathy in association with variable degree of visceral amyloidosis including the heart. Some mutations are more frequently associated with cardiac amyloidosis with ethnic variations. Amyloid deposition begins in the sub-endocardium with focal amyloid accumulations and extending within the myocardium between the muscle fibres. Importantly, the myocardial fibres remain normal with no hypertrophy but the amyloid inter-deposition between myocardial fibres lead to an overall increase of myocardial thickness seen on echocardiography. This is clearly different from the other forms of ventricular hypertrophy seen in hypertensives of hypertrophic cardiomyopathy patients where the myocardial fibres are hypertrophied. This mechanism of amyloid infiltration is responsible for the marked thickening of the left and right ventricular walls seen on echocardiography, normal or decreased LV cavity size, and reduced LV diastolic and systolic function. The walls of intramural coronary arteries as well as the conductive system are also infiltrated and this accounts for the electrocardiographic abnormalities seen in the form of first-degree A-V block. The endocardium may also be involved and may be associated with overlying thrombus. Amyloid infiltration of the heart also causes focal or diffuse valvular thickening but clinical valvular dysfunction is uncommon. Finally, in the most advanced cases, the small amyloid heart may be surrounded by a large pericardial effusion, which may be the cause of cardiomegaly seen in the X-rays. Cardiac amyloidosis can only be diagnosed definitively by biopsy and the echocardiographic features of among all types of amyloid are indistinguishable. The echocardiographic findings of amyloid infiltration of the heart, consist of: (i) thickened RV, (ii) thickened LV walls, (iii) granular or sparkling (ground glass) appearance of the myocardium, Table 2 Amyloid heart disease Figure 1 Amyloid deposition among normal myocytes. Note that the myocardial fibres (here cut cross-sectionally) are normally arranged. The amyloid protein is infiltrated in the interstitial tissue among myocytes. Primary amyloidosis (AL) Cardiac involvement common Secondary amyloidosis (amyloid A) Cardiac involvement rare Hereditary amyloidosis (TTR) Usually autosomal dominant Age-related amyloidosis Senile in 25% aged.80 years (TTR) Atrial in 90% aged.90 years (ANP)

3 Restrictive cardiomyopathies iii25 (iv) normal or small LV cavity size, (v) enlarged atria (Table 3), and (vi) depressed LV systolic and diastolic function (Figures 2 and 3). Figure 4 is from a patient with AL amyloidosis with marked wall thickening and an abnormal Table 3 Echocardiographic features of amyloid infiltration of the heart Increased LV wall thickness Increased RV wall thickness Small, well, or poorly contracting LV Enlarged LA Valve thickening (all valves) Mitral regurgitation (usually mild) Thickened atrial septum E/A ratio.1 Pericardial effusion (advanced disease) diastolic function. Note that the transmitral velocities exhibit a restrictive filling pattern with high early diastolic (E-wave) and low late diastolic (A-wave) filling wave and short deceleration time suggestive of elevated filling pressures. It also shows low mitral annular tissue velocities (Figure 4, top) both in the systolic wave and early diastolic (e 0 -wave). The E/e 0 ratio was consequently high, suggestive of elevated filling pressures. Involvement of the heart valves and atrial septum in the form of homogeneously thickening without affecting the valves motion is also characteristic in the most advanced stages. While the echocardiographic features of amyloid infiltration of the heart are fairly characteristic in the advanced stages of the disease, early cardiac infiltration may produce a mixed and confusing picture. The LV may be hypertrophied, small and well contracting with normal or mildly abnormal diastolic function. Because the ventricle is small, there is often an outflow-track gradient, which Figure 2 Systemic amyloidosis. Apical four-chamber view (A) and short-axis (B) demonstrating marked wall thickness (15 mm) concentrically. Note the homogeneous texture of both ventricles and the thickening of the mitral and tricuspid leaflets. The right ventricle is also thickened. Figure 3 Parasternal long-axis from a patient with cardiac amyloidosis with the corresponding M-mode echocardiogram to demonstrate the reduced left ventricular function. Note again the markedly thickened RV free wall.

4 iii26 P. Nihoyannopoulos and D. Dawson Figure 4 Amyloid heart disease. Top: mitral annular velocities demonstrating reduced systolic (s) as well as diastolic velocities (E 0 and a 0 ). Bottom: pulsed wave-doppler from the mitral valve demonstrating a restrictive pattern with very high early diastolic velocity (E-wave), short deceleration time (,130 ms), low late diastolic filling (A-wave) of the transmitral velocity suggesting of markedly impaired left ventricular diastolic function with elevated filling pressures. The E/e ratio was high (28) suggestive of high filling pressures. may mimic hypertrophic cardiomyopathy (Figure 5). The differential diagnosis here lies on the ECG, which in hypertrophic cardiomyopathy (HCM) patients will show high voltage with normal PR interval, whereas in amyloid hearts it will have low voltage in the precordial leads with prolonged PR interval (Figure 6). New echocardiographic modalities have greatly contributed to the diagnosis and follow-up of patients with cardiac amyloidosis. 5,6 Tissue-Doppler echocardiography can contribute to the earlier diagnosis of amyloid infiltration of the heart. In one study with biopsy-proven cardiac amyloidosis, 5 peak systolic and early diastolic mitral annular velocities (septal or lateral), as well as myocardial velocity gradients (strain rate) in systole and early diastole were equally reduced in both patients with or without a restrictive pattern on transmitral Doppler velocities. Importantly, those measurements were independent of both LV mass and patients age and were equally accurate in patients with either borderline or normal LV wall thickness. In another study 6 involving patients with AL amyloidosis, they showed that myocardial strain and strain rate measurements using tissue-doppler were more sensitive and accurate than tissue velocities alone for evaluating regional longitudinal myocardial function. Using myocardial strain and strain rate, they could detect early myocardial dysfunction in all myocardial regions during systole, early as well as late diastole before the onset of congestive heart failure. An increase in wall thickness was also associated with reduced systolic function in asymptomatic patients at the base and mid-ventricle. In heart failure patients, peak systolic strain and strain rate were even lower in all sites. 6 In contrast to standard echocardiography, strain and strain rate are able to demonstrate that significant differences in systolic function and all regions occur as cardiac amyloid infiltration progresses to congestive cardiac failure. This is important for amyloid patients during their period of treatment and perhaps assesses its effectiveness. Tissue velocities, although a little better than standard two-dimensional echocardiography for the detection of functional abnormalities, are not as good as strain and strain rate. Finally, it is important to bare in mind that strain measurements using Doppler techniques are angle dependent leading potentially to underestimation of values,

5 Restrictive cardiomyopathies iii27 Figure 5 Parasternal long-axis view and corresponding continuous wave-doppler recording from the LV outflow track from a patient later confirmed to have amyloid heart disease. Note on the left, there is systolic anterior motion of the mitral leaflets (arrow) together with left ventricular hypertrophy. Doppler records a high LV outflow track velocity of 4.2 m/s. The overall picture is indistinguishable from hypertrophic cardiomyopathy (see text). Figure 6 Twelve-lead ECG recording from a patient with amyloid infiltration of the heart. Note the low voltage in the precordial leads and a prolonged PR interval at 20 ms. particularly near the apex. Another problem particularly with strain rate is the rather poor signal-to-noise ratio that makes reproducible measurements difficult. Newer techniques based on two-dimensional imaging speckle tracking should be more robust. Key points: non-dilated ventricles, granular myocardial appearance, homogeneously thickened valves, and atrial septum and diastolic dysfunction (restrictive filling). 2D imaging with low dynamic range and or grey scale compression may mimic the appearance of sparkling/granular myocardium by increasing image contrast. The echocardiographic findings of cardiac amyloidosis during early infiltration may be limited to mildly increased ventricular wall thickness and reduced tissue- Doppler peak systolic and early diastolic mitral annular velocities. With advanced infiltration, findings typically consist of increased LV and RV wall thickness, biatrial enlargement, Iron overload haemosiderosis Iron overload results from predominantly two clinical scenarios. The first is conditions in which the plasma iron content exceeds the iron-binding capacity of transferrin (e.g. hereditary haemochromatosis), while erythropoiesis remains normal. Iron is deposited in parenchymal cells of the liver, the heart, as well as in other endocrine tissues.

6 iii28 P. Nihoyannopoulos and D. Dawson The second involves conditions in which iron overload results from an increased catabolism of erythrocytes (e.g. transfusional iron overload). Here, iron accumulates in reticuloendothelial macrophages first and then spills over into parenchymal cells. Iron loading of tissues is particularly dangerous, because it leads to tissue damage and fibrosis. In the heart, it will lead to myocardial fibrosis and impaired ventricular function with either a restrictive type or dilated cardiomyopathy. Haemochromatosis is a rare disorder characterized by cirrhosis, diabetes, changes in skin pigmentation, endocrine failure, heart failure, and arthropathy. Hereditary haemochromatosis is a polygenetic disease associated with mutations in at least four different iron-metabolism genes. It results to dysregulated iron absorption that can lead to total-body iron overload with secondary tissue damage in a wide range of organs, including the heart. Clinical features are caused by inappropriate iron release by enterocytes and macrophages, progressive parenchymal iron deposits with the potential for severe organ damage, while erythropoiesis remains normal. 7 Long-term transfusion therapy is a routine, often lifesaving treatment for patients with intractable anaemia resulting from thalassaemia, bone marrow failure, or aggressive treatment of cancer. It is also used for patients with serious complications of sickle cell disease. Repeated transfusion leads to rapid iron loading and can cause what is known as transfusional siderosis. In transfusional siderosis iron is ultimately deposited in the same sites as in other iron-overload disorders (hepatocytes, the myocardium, and endocrine tissues). Cardiomyopathy is more prominent in patients with transfusional iron overload than in those with haemochromatosis, probably because of rapid iron loading. Echocardiographic criteria for cardiac infiltration are nonspecific and need to be taken into the clinical context. Left ventricular size is usually normal at the beginning with possible regional or global hypokinesia and an increased in wall thickness. While systolic function is often maintained, there may be abnormal diastolic function on Doppler depending on the severity of iron overload with a restrictive filling pattern in most advanced cases. The right ventricle may also be involved with normal size but increased thickness. When patients become symptomatic with breathlessness and oedema, the left atrium may be enlarged. The key diagnosis here is to assess the pulmonary pressures, which will be almost invariably elevated due to high filling pressures. It is therefore crucial to measure the tricuspid regurgitant velocity, which will be usually above 3 m/s. Sarcoidosis Sarcoidosis can affect patients of all ages but most commonly develops before the age of 50 years. The precise aetiology is unknown. Sarcoidosis commonly involves the lungs, eyes, and skin so that a possible airborne antigens has been raised. 8 Multiple environmental and genetic risk factors have been held responsible for the development of sarcoidosis, which may be the end result of immune responses to those triggers. The main feature of sarcoidosis is the presence of CD4þ T cells that interact with antigenpresenting cells to initiate the formation and maintenance of granulomas in the various organs. Sarcoidal granulomas are organized, structured masses composed of macrophages and their derivatives, epithelioid cells, giant cells, and T cells. Sarcoidal granulomas may persist, resolve, or lead to fibrosis. 9 Sarcoidal granulomas produce angiotensinconverting enzyme (ACE), which is elevated in 60% of patients with sarcoidosis. However, the value of serum ACE levels in diagnosing or managing sarcoidosis remains controversial. The definitive diagnosis is made by biopsy obtained from the involved organ, including transbronchial biopsy when necessary. Granulomas may resolve with little consequences in the majority of instances. Sarcoidosis often first comes to clinical attention when abnormalities are detected on a chest X-ray during routine screening. Sarcoidal granulomas can involve any organ but in more than 90% of patients, clinical sarcoidosis is manifested as intrathoracic lymph-node enlargement, pulmonary involvement, skin or ocular signs and symptoms, or some combination of these findings. General symptoms include fatigue, night sweats, and weight loss. The organ system that is most affected varies with the given patient. Pulmonary fibrosis occurs in 20 25% of patients with sarcoidosis. An acute variant of this condition is the Löfgren s syndrome, which occurs in 9 34% of patients and consists of arthritis, erythema nodosum, and bilateral hilar adenopathy. Cardiac granulomas are found in 25% of autopsy patients but cardiac sarcoidosis is clinically apparent in only 5% of all patients. Cardiac involvement is patchy with the most common locations of granulomas found in the left ventricular free wall and basal ventricular septum, often involving the conducting system. Cardiac magnetic resonance with late Gadolinium enhancement can clearly demonstrate those localized area of myocardial fibrosis (Figure 7). Clinically, cardiac sarcoidosis is manifested as a cardiomyopathy with loss of muscle function or tachyarrhythmias, including heart block, syncope, and sudden death. Echocardiographic findings are non-specific and can be in the form or regional LV dysfunction and/or impaired diastolic function to a variable extend from impaired relaxation o restrictive filling in the most advanced cases. Eosinophilic endomyocardial disease The diastolic filling abnormality in endomyocardial disease appears to be related to the presence of a thick endocardial fibrotic shell with finger-like penetrations into the myocardium. This develops through a well-defined pathological process after initial damage induced by toxic eosinophils. As in the case of cardiac amyloidosis, the fact that both have an aetiological factor and that a specific pathological process has been documented makes their description as primary cardiomyopathies, controversial. Definitions The definition of hypereosinophilic syndrome is when the eosinophilic count is greater than /L in the peripheral blood. There are two types of hypereosinophilic syndromes: The commonest is the secondary hypereosinophilia which occurs as the result of certain tumours, lymphoma,

7 Restrictive cardiomyopathies iii29 Figure 7 Cardiac magnetic resonance imaging with delayed gadolinium enhancement in a short-axis (left) and apical four-chamber (right) views. Notice the localized intramyocardial brightness (arrows) indicative of intramyocardial fibrosis. Table 4 Echocardiographic features of endomyocardial fibrosis LV thrombus at the apex Good LV function (including the apex) RV thrombus Endocardial thickening of the LV Restriction to mitral and tricuspid valve mobility Mitral and tricuspid regurgitation (often severe) E/A ratio.1 vasculitis or parasitic or infectious disease as well as the hypereosinophilia that follows hypersensitivity reaction. The more rare form is the primary hypereosinophilic syndrome. 10 This occurs with no apparent cause and has been described by Loffler in In certain African countries or the tropics, hypereosinophilia is common leading to endomyocardial fibrosis, but this may be the result of parasitic infestation and not a primary hypereosinophilic syndrome as such. In most European patients, there is no serological evidence for parasites, allergies, or inflammatory disease and the disease is clearly idiopathic. Pathophysiology Eosinophils when degranulated become toxic and can damage the heart. 11 The pathogenesis follows the progressive degranulation of eosinophils with granule dissolution and secretion of toxic products causing endomyocardial cell injury followed by fibrosis. Subsequently, there is thrombus formation and restrictive LV and RV filling. It affects usually young men and can affect all organs, including the heart, lungs, nervous system leading to neurological deficits. Echocardiography The echocardiographic characteristics of hypereosinophilic syndrome are typical and pathognomonic in the advanced stages of the disease (Table 4). There is extensive LV and RV thrombus usually packing the ventricular apices (Figure 8). This was called the box-glove sign during ventriculography because of the left ventricular apex resemblance of a box glove. Echocardiography can clearly demonstrate Figure 8 Apical four-chamber view from a patient with endomyocardial fibrosis. Note the packing of the left and right ventricular apex and the marked dilatation of the atria. the thrombus obliterating the apex of the left ventricle but also of the right ventricle. Unlike patients with coronary artery disease or dilated cardiomyopathy where the apical thrombus is adjacent to a severely hypokinetic or akinetic myocardium, in endomyocardial fibroelastosis (EMF), the left ventricle is contracting well, which is characteristic of

8 iii30 P. Nihoyannopoulos and D. Dawson the condition. The only differential diagnosis here is apical hypertrophic cardiomyopathy but here again the ECG should differentiate the two conditions. The ventricular systolic function in EMF is usually preserved, but there is restriction to ventricular filling manifested by an early diastolic halt on the M-mode echocardiogram (Figure 9). With high-resolution twodimensional echocardiography, a distinct highly echogenic line is seen covering the endocardial surface of the left and right ventricles. This echo-dense area lining the Figure 9 M-mode and two-dimensional echocardiography from the same patient with endomyocardial fibrosis. During diastole, the left ventricle fills rapidly in early diastole and then remains flat during the rest of diastole. Note that the systolic function is preserved. endocardium corresponds to areas of fibrosis extending from the apex to the basis of the ventricles and the papillary muscles (Figure 10). Cardiac magnetic resonance imaging can also demonstrate the presence of intraventricular thrombus as well as the amount and extent of endocardial fibrosis (Figure 11). This fibrotic material will eventually extend to the ventricular inflow track and involve the mitral and/or tricuspid chords and leaflets leading to leaflet restriction and valvular regurgitation (Figure 12). Bi-atrial enlargement is usually marked and results from the restrictive ventricular filling imposed by the noncompliant ventricle. The extent of valvular involvement, however, should be described with echocardiography. Scleroderma Scleroderma or systemic sclerosis is a complex disease in which the principal features are extensive fibrosis, vascular alterations, and autoantibodies against various cellular antigens. Scleroderma can lead to severe dysfunction and failure of almost any internal organ including the heart. Severely debilitating oesophageal dysfunction is the most common visceral complication, while lung involvement is the leading cause of death. Vascular injury is an early event in scleroderma. It precedes fibrosis and involves small vessels, particularly the arterioles. Myocardial fibrosis is the hallmark of cardiac involvement in systemic sclerosis and it accounts for the majority of cardiac manifestations in those patients. It may lead to sudden cardiac death due to ventricular arrhythmias. Its Figure 10 Parasternal short-axis (left) and four-chamber (right) views from a patient with hypereosinophilic syndrome. Notice the bright endocardial halo surrounding the LV cavity. In the apical four-chamber view, both the RV and the LV apices are packed with thrombus. Figure 11 Cardiac magnetic resonance imaging with corresponding images from the same patient as in Figure 9 showing again the extent of endocardial fibrosis (short-axis and four chamber).

9 Restrictive cardiomyopathies iii31 Figure 12 Colour-Doppler imaging from the same patient as in Figure 10 showing the extent of mitral regurgitation. Calculated regurgitant volume 35 ml (moderate). detection and histological confirmation are difficult because of an often-asymptomatic course, non-specific findings by non-invasive techniques and patchy distribution in the myocardium. Physical examination is again non-specific with peripheral oedema and neck-vein distention, consistent with right heart failure. Electrocardiography may show atrial and ventricular premature beats, right bundle-branch block, or other conduction abnormalities. Echocardiography is usually abnormal at this stage with either regional or global left and right ventricular systolic dysfunction. Most often however there will be evidence of some diastolic dysfunction on Doppler. Radiation Irradiation of the heart incidental to the treatment of malignancies can cause a spectrum of cardiovascular complications. These include pericarditis, myocardial fibrosis, muscular dysfunction, valvular abnormalities, and conduction disturbances. Cardiac damage associated with radiotherapy may be progressive. Usually, it involves the pericardium with pericardial thickening, which may lead to constriction. Echocardiography therefore may play an important role here to make the diagnosis. In more advanced instances, radiotherapy may induce myocardial fibrosis, which will lead to restrictive cardiomyopathy. This will, however, be difficult to separate from constrictive pericarditis as the two may coexist. Using echocardiography, early diastolic velocity of septal mitral annulus (e 0 ) and deceleration time of mitral inflow reduced with the early diastolic mitral inflow velocity E/e 0 ratio higher in patients who receive radiotherapy. This will be suggestive of elevated filling pressures and a myopathic process due to radiotherapy (fibrosis). Idiopathic (primary) restrictive cardiomyopathy In its purest for, the diagnosis of restrictive cardiomyopathy using strict haemodynamic criteria is supported by the absence of specific pathology on either endomyocardial biopsies or evaluation of whole heart specimens. Patients are typically in advanced heart failure (class III or IV of the NYHA classification), the atria are usually disproportionate dilated compared with the normal ventricular size, the left ventricle has normal or near normal systolic function in the absence of hypertrophy. Histology is normally nondistinctive and can show normal findings or non-specific degenerative changes, including myocyte hypertrophy, disarray, and a degree of interstitial fibrosis. When myocardial disarray is present, some form of hypertrophic cardiomyopathy needs to be considered. Again, the role of genetic testing here may be of paramount importance. In a recent study, 12 the authors demonstrated that restrictive cardiomyopathy is not a single entity but is instead a heterogeneous group of disorders that can present with a spectrum of cardiac phenotypes, including HCM, dilated cardiomyopathy, or left ventricular non-compaction. Mutations in sarcomere protein genes (cardiac troponin I and Troponin T) are an important cause of apparently idiopathic restrictive cardiomyopathy and should prompt routine family screening. Echocardiography is non-specific but the suspicion should rise when left atria size is increased with small, wellcontracting ventricles, in the absence of any significant hypertrophy. These findings supported by a restrictive pattern or prolonged relaxation on. Doppler should prompt the diagnosis of cardiomyopathy. This diagnosis of restrictive cardiomyopathy may also be supported by demonstrating elevated LV filling pressures either by recording high tricuspid regurgitant velocities (.2.7 m/s) or an elevated pulmonary vascular resistance. Restrictive physiology Increased ventricular filling pressures with the typical dip-and-plateau pattern are the haemodynamic hallmarks of restrictive cardiomyopathies, whatever the aetiology. Atrial pressures usually exceed 15 mmhg, right atrial pressure is required to be more than 7 mmhg and pulmonary capillary wedge pressure more than 12 mmhg. 13 In contrast with the equalization of left- and right-sided diastolic pressures in constrictive pericarditis, diastolic pressures are separable by more than 5 mmhg in restrictive cardiomyopathy due to unequal involvement and compliance of the two ventricles. However, in restrictive cardiomyopathy, this separation is not seen at baseline and it is often not demonstrable despite provocative tests such as volume loading, leg rising, exercise, or pharmacological interventions. Even the dip-and-plateau may be absent is restrictive cardiomyopathies. Patients with restrictive cardiomyopathy either due to cardiac amyloidosis or endomyocardial fibrosis show a spectrum of ventricular filling abnormalities from a more

10 iii32 P. Nihoyannopoulos and D. Dawson Figure 13 Diagrammatic representation of the transmitral early (E-wave) and late (A-wave) velocities during diastole throughout the respiratory cycle. Note the dynamic differences between restrictive cardiomyopathy and constrictive pericarditis during inspiration and expiration. In constrictive pericarditis, the transmitral velocities are reduced while the tricuspid velocities are increased in deep inspiration, while the opposite happens during expiration. In restrictive cardiomyopathy, there is little respiratory variation. advanced typical restrictive pattern to a milder form of abnormal relaxation with long isovolumic relaxation time, reduced rate of acceleration to the low early peak velocity (E-wave). Distinction between restrictive cardiomyopathy and constrictive pericarditis In the vast majority of instances, the distinction between restrictive cardiomyopathy and constrictive pericarditis is easy, based on the comprehensive appearances of the left ventricle as indicated above. Occasionally, however restrictive cardiomyopathy presents a clinical and haemodynamic picture that is often indistinguishable from constrictive pericarditis. The differential diagnosis is crucial as constrictive pericarditis may be curable by surgical pericardial resection, whereas restrictive cardiomyopathy is not. Endomyocardial biopsy may be sometimes useful in revealing the presence of myocardial disease. In addition to echocardiographic findings, computed tomography and cardiac magnetic resonance imaging can be used to define pericardial thickness with or without the presence of calcification. To date, the commonest cause of constrictive pericarditis is after open-heart surgery followed by radiation therapy and uraemia. These conditions rarely lead to calcification so that imaging techniques such as CMR or CT may not be sufficient to cover the entire spectrum of pericardial constriction. Consequently, when pericardial thickening is present, the diagnosis is relatively straightforward but when this is not the case, dynamic-doppler echocardiography during the respiratory cycle will play a crucial role in the differential diagnosis. Normally, there is interdependence between the RV and LV during respiration as the pericardium transmits the intrathoracic pressures to the intrapericardial and intracardiac chambers. During inspiration, there is a drop in intrathoracic pressures which will be transmitted to the intracardiac chambers with a parallel reduction of pulmonary capillary and left ventricular diastolic pressures, keeping the transmitral and trans-tricuspid diastolic gradients virtually unchanged (,20%), an increase of venous return and a slight increase in RV size. In constrictive pericarditis, the pericardium is thickened forming a shell around the heart, so that the drop in intrathoracic pressures will not be transmitted to the intracardiac pressures so that the systemic venous and RA pressures will not fall during inspiration and the transmitral gradient will be reduced as oppose to the trans-tricuspid gradient which will be increased. Consequently, during inspiration the transmitral velocities will be reduced (E-wave) and tricuspid velocities increased (E-wave) in constrictive pericarditis, whereas restrictive cardiomyopathy will remain unchanged 14 (Figure 13). Conclusions While it is convenient to classify cardiomyopathies in four major groups, there is an overlap between the anatomic and functional characteristics in many instances. As the genetic demystification of the cardiomyopathies continues, the boundaries of the various types of cardiomyopathies may better be determined. Until that time, we should continue to categorizing our patients in the four groups and echocardiography is currently the best imaging modality to do so. Cardiomyopathies have a familial nature and it is important to screen family members, as often the diagnosis may be more revealing once the family screening has been completed and again, the role of echocardiography here is pivotal. As the causes and pathophysiology of cardiomyopathies are better understood, it may be argued that, in future, the term idiopathic may no longer be sustainable. Conflict of interest: none declared. Funding We are grateful to the British Society of Echocardiography for providing the funding for the illustrations. References 1. Ammash NM, Seward JB, Bailey KR, Edwards WD, Tajik AJ. Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation 2000; 101: Nihoyannopoulos P. Cardiomyopathies. In: Nihoyannopoulos P, Kisslo J eds, Echocardiography. Springer; Pepys MB. Amyloidosis. In: Weatherall DJ, Ledingham JGG, Warrell DA eds, Oxford Textbook of Medicine. Oxford: University Press; Vol 2, p Benson MD, Uemichi T. Transthyretin amyloidosis. Amyloid Int J Exp Clin Invest 1996;3:44 56.

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