Diffuse Diseases of the Myocardium: MRI-Pathologic Review of Nondilated Cardiomyopathies

Transcription

1 Cardiopulmonary Imaging Review Giesbrandt et al. Diffuse Diseases of the Myocardium Cardiopulmonary Imaging Review FOCUS ON: Kirk J. Giesbrandt 1 Candice W. olan 1 rian P. Shapiro 2 William D. Edwards 3 Patricia J. Mergo 1 Giesbrandt KJ, olan CW, Shapiro P, Edwards WD, Mergo PJ Keywords: cardiac MRI, cardiomyopathy, radiologicpathologic correlation DOI: /JR Received July 16, 2012; accepted after revision November 4, Department of Radiology, Mayo Clinic, Mayo 2S-131, 4500 San Pablo Rd, Jacksonville, FL ddress correspondence to K. J. Giesbrandt (giesbrandt.kirk@mayo.edu). 2 Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, FL. 3 Department of natomic Pathology, Mayo Clinic, Rochester, MN. CME/SM This article is available for CME/SM credit. WE This is a Web exclusive article. JR 2013; 200:W266 W X/13/2003 W266 merican Roentgen Ray Society Diffuse Diseases of the Myocardium: MRI-Pathologic Review of Nondilated Cardiomyopathies OJECTIVE. This article will present correlation of the key radiologic findings with gross and microscopic pathology for the characterization of diffuse myocardial diseases using advanced imaging techniques. Our goal is to provide a focused and in-depth review of the pathophysiology underlying each entity and to emphasize the structural basis for the corresponding imaging characteristics. This article is limited to those disorders characterized by ventricular wall thickening without chamber dilatation, including hypertrophic cardiomyopathy, hypertensive cardiomyopathy, and cardiac amyloidosis. CONCLUSION. For the characterization of diffuse myocardial diseases using advanced imaging techniques, it is essential to understand the underlying pathologic changes in the heart. With these techniques, such as cardiac MRI, the various cardiomyopathies can be differentiated accurately, which may potentially obviate invasive testing and endomyocardial biopsy. C ardiovascular disease remains the leading cause of mortality in the United States; most deaths are attributable to coronary artery disease. Coronary atherosclerosis is an extremely common clinical entity that will be encountered daily by anyone involved with cardiovascular imaging. lthough coronary artery disease can result in cardiomyopathy, causing left ventricular failure and arrhythmias, many other disease states also result in myocardial injury that can mimic ischemic symptoms. wide variety of cardiomyopathies exist, classified as primary if only the heart muscle is involved or classified as secondary if the heart muscle is involved as part of a more widespread systemic disorder. With the growing use of cardiac MRI to exploit distinguishing tissue characteristics, the underlying cause of cardiomyopathy can be easily identified if one understands the pathologic basis of each disease. In this article, we review the structural basis of selected cardiomyopathies and show their typical gross and microscopic features. The corresponding characteristic imaging findings of each disease are then presented. Differentiating the cause of the cardiomyopathies on the basis of imaging is an important service that the radiologist can provide the patient, potentially averting the need for further expensive and invasive testing as well as guiding the clinical treatment options. Cardiac MRI Cardiac MRI has emerged as a powerful tool for evaluating cardiac and vascular diseases. It provides robust high-quality images that may be tailored to any of a number of disease states. lthough it is frequently considered the modality of choice in the characterization of myocardial structure and function, it has also proven useful in the evaluation of myocardial ischemia, infarcts, viability, infiltrative processes, and cardiac masses. Cardiac MRI is also an excellent method for studying the right ventricle, atria, valves, and pericardium, and it may be used to quantify flow in and out of any heart chamber as well. Specifically, the ability of cardiac MRI to integrate findings of late enhancement after gadolinium administration with changes in myocardial tissue properties renders it particularly well suited for the characterization and evaluation of cardiomyopathies. Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is often associated with a widely variable clinical course and heterogeneous morphologic expression. The clinical presentation has a wide range, from asymptomatic to sudden death. W266 JR:200, March 2013

2 Diffuse Diseases of the Myocardium When present, symptoms often include syncope, chest pain, or dyspnea on exertion. Treatment decisions may be adjusted on the basis of three clinical paths: presence of left ventricular (LV) outflow obstruction, high risk of sudden death, and progressive symptoms [1]. ccepted risk factors for sudden cardiac death include family history of sudden death, unexplained syncope, sustained or unsustained ventricular tachycardia, abnormal blood pressure response to exercise, and extreme LV hypertrophy (> 30 mm) [2]. Many genetic mutations have been linked to hypertrophic cardiomyopathy, with most involving sarcomeric proteins [3]. Pathology On gross examination of the heart, typical findings include thickened ventricular walls and increased cardiac mass (with heart weights % above the expected mean value, based on sex and body size) (Fig. 1). Small patchy areas of fibrosis may also be visible grossly. Mitral papillary muscles tend to be particularly hypertrophied and prominent. lthough severe LV hypertrophy is considered a risk factor for sudden cardiac death, a relatively normal LV wall thickness does not protect against sudden cardiac death. In at least 90% of patients with HCM, the ventricular septum is disproportionately hypertrophied, such that the ratio of septal to LV free wall thicknesses is > 1.3 (Fig. 1). The asymmetrically hypertrophied region may extend onto the anterior or inferior free walls or, rarely, may be limited to the free wall without septal involvement. Excessive hypertrophy of the ventricular septum may be limited to the subaortic, midventricular, or apical regions or may involve the entire septum from base to apex. In < 10% of patients with HCM, the LV hypertrophy is symmetric, without disproportionate thickening. Fig. 1 Hypertrophic cardiomyopathy., Short-axis steady-state free precession MR images show characteristic morphologic features, with marked septal wall thickening shown by asterisks., Photograph of gross specimen shows marked biventricular hypertrophy and asymmetric left ventricular hypertrophy, with disproportionate septal thickening (ratio of septal to left ventricular free wall thickness, > 1.3). In cases with septal wall predominance, the LV luminal space may be decreased, with or without LV outflow tract obstruction. Displacement of the mitral papillary muscles and the anterior mitral leaflet or inherently abnormal papillary muscles and valve leaflets can lead to mechanical damage, with thickening and fibrosis of the leaflets and tendinous cords [3]. Studies have shown that patients with HCM have a greater frequency of intrinsic papillary muscle and mitral valve leaflet abnormalities than those without HCM [3, 4]. long the subaortic septum, a patchy area of fibrosis in the mirror-image shape of the anterior mitral leaflet is commonly observed in patients with LV outflow tract obstruction. This is thought to be the result of repeated contact by the anterior mitral valve leaflet against the ventricular septum with each cardiac cycle [5]. Key findings on microscopic examination include appreciable myocyte hypertrophy (with Fig. 2 Hypertrophic cardiomyopathy. and, High-power photomicrographs show focal myocyte disarray (), characteristic of hypertrophic cardiomyopathy, compared with areas of normally oriented cardiac myocytes () in same patient. JR:200, March 2013 W267

3 Giesbrandt et al. Fig. 3 Hypertrophic cardiomyopathy. Multiple three-chamber steady-state free precession cine images show systolic anterior motion of anterior mitral valve leaflet (arrows), with associated turbulent dephasing of signal in left ventricular outflow tract. Fig. 4 Hypertrophic cardiomyopathy (HCM). and, Three-chamber steady-state free precession MR images () and photograph of gross pathology specimen () show reverse septal curvature, subtype of HCM, with convexity of septum bowing into ventricle leading to crescentic shape of left ventricle when viewed in short axis. increased cell diameters and large hyperchromatic nuclei), myocyte disarray, focal interstitial fibrosis, and patchy endocardial fibrosis [3, 5, 6]. Myocyte disarray is characterized by myocytes oriented obliquely and perpendicularly to each other in whorls or in a herringbone pattern (Fig. 2). Of note, myocyte disorganization is not specific for HCM but is usually more prominent in HCM than in other types of heart disease [5 7]. Other less-specific findings include intramural arteriolar dysplasia and dilated venous channels. Radiology Radiology Cardiac MRI represents a noninvasive means to evaluate chamber morphology and function in HCM while also showing papillary muscle or mitral valve abnormalities, perfusion abnormalities, and fibrosis with late gado- W268 JR:200, March 2013

4 Diffuse Diseases of the Myocardium Fig. 5 Hypertrophic cardiomyopathy., Short-axis delayed contrast-enhanced cardiac MR image shows patchy foci of midmyocardial enhancement of septum at right ventricular insertion sites (arrows)., Photograph of gross specimen shows biventricular hypertrophy with disproportionate septal thickening (four-chamber view). C, Light microscopy image illustrates interstitial scarring (light pink), which leads to gadolinium retention and foci of hyperenhancement. Fig. 6 Hypertensive cardiomyopathy., Photograph of gross cardiac specimen in patient with chronic hypertension (left) shows marked symmetric left ventricular hypertrophy compared with normal cardiac specimen (right). few foci of scarring (arrow) are present but not as extensive as in hypertrophic cardiomyopathy., Multiple short-axis steady-state free hypertrophic precession MR images show symmetric left ventricular wall thickening. linium enhancement. Studies have shown cardiac MRI to be at least a useful supplement to echocardiography, with certain features better visualized with MRI [4, 8]. Diseased areas that can be underestimated with echocardiography usually included the anterolateral free wall, posterior septum, or apex. Right ventricle involvement, when present, is also better visualized with cardiac MRI. s previously mentioned, the morphologic appearance is widely variable, with many infiltrative diseases mimicking HCM, such as nderson-fabry disease or sarcoidosis. LV outflow tract obstruction may or may not be present. When it is present, systolic anterior motion of the anterior mitral valve leaflet will generally also be seen (Fig. 3). nterior motion of the mitral valve during systole, which is often seen best on cine steady state free precession (SSFP) images in the three-chamber long-axis view, can further exacerbate LV outflow obstruction and lead to mitral regurgitation. Repetitive impaction of the leaflet on the septal surface commonly leads to patchy endocardial fibrosis in the mirror-image shape of the anterior mitral leaflet. Subtypes of HCM include the septal-predominant type (most common), asymmetric HCM with reversed septal contour (Fig. 4), HCM with C JR:200, March 2013 W269

5 Giesbrandt et al. midventricular obstruction, apical HCM, and symmetric (or concentric) HCM. s indicated by the variation in appearance, the cardiac segments involved by wall thickening can range from few to many, and the segmental involvement is not necessarily contiguous [4]. ecause of the segmental thickening of the wall, measurements at multiple levels of the LV (apical, mid, and basal) are often performed. The hearts of many patients show < 50% of the total segments involved [8]. Overall increased LV mass index has been shown to correlate with worse clinical outcomes, but this is not a requirement for diagnosis, with one group of investigators reporting 21% of HCM patients with a normal range LV mass index [9]. ccepted standards for hypertrophy include an end-diastolic LV wall thickness of 17 mm and a septal-tofree-wall thickness ratio of > 1.3 [3]. Foci of late gadolinium enhancement usually occur in areas of hypertrophy, and late C Fig. 7 Cardiac amyloidosis., Short-axis steady-state free precession images show characteristic features, with small pericardial effusion (arrow) and ventricular wall thickening., Photograph of surgical specimen from myxomatous mitral valve shows grossly visible amyloid deposits (yellow-tan lesions along surface). C, Photograph of cardiac specimen in four-chamber view shows with grossly visible amyloid deposits (pale tan), wall thickening, and biatrial dilatation. gadolinium enhancement has also been correlated with increased interstitial collagen. Fibrosis, with corresponding late gadolinium enhancement, may be seen in HCM. lthough late gadolinium enhancement is not specific for HCM, a patchy nonvascular distribution in the midventricular wall and along the right ventricular insertion points on the septum, which can also be seen in pulmonary hypertension, are suggestive of HCM (Fig. 5). W270 JR:200, March 2013

6 Diffuse Diseases of the Myocardium Postulated causes for fibrotic changes and late gadolinium enhancement include, but are not limited to, increased collagen deposition, inherent microvascular dysplasia with subsequent ischemia, and ischemic changes secondary to a supply-and-demand mismatch related to the prominent myocyte hypertrophy [1, 3, 4, 10]. Late gadolinium enhancement has correlated clinical prognostic significance, with worse clinical outcomes when present [2 4]. Hypertensive Cardiomyopathy Chronic systemic arterial hypertension is widely prevalent among the adult population in the United States. Hypertensive cardiomyopathy represents left ventricular hypertrophy (LVH) that has resulted from a heart pumping against chronically increased back pressure, usually from systemic hypertension or, less commonly, aortic valvular stenosis. In the case of the latter, associated findings, such as a bicuspid aortic valve or poststenotic dilatation of the ascending aorta, may be present. Hypertensive heart disease is linked to an increase in adverse cardiac events, such as arrhythmia, atrial fibrillation, heart failure, and myocardial infarct [11]. dditionally, LVH itself is associated with increased cardiac mortality regardless of cause [12]. The heart failure associated with hypertensive cardiomyopathy often involves diastolic dysfunction. However, as subendocardial interstitial fibrosis increases, myocardial contractility can be compromised and eventually lead to systolic dysfunction as well [13]. Pathology Hypertension is the most common cause of LVH. The hypertrophy is characteristically symmetric, without disproportionate septal Fig. 8 Cardiac amyloidosis., Short-axis delayed contrast-enhanced cardiac MR image shows late gadolinium enhancement in noncoronary vascular distribution., Photomicrograph of endomyocardial biopsy specimen shows marked amyloid deposition (light pink), with secondary atrophy of myocytes. thickening. Patchy subendocardial fibrosis may be evident grossly (Fig. 6). Microscopically, cardiac myocytes show the typical features of pressure hypertrophy, including increased cell diameters, prominent hyperchromatic nuclei, and focal nuclear replication. Small areas of subendocardial fibrosis are commonly observed and are associated with proliferation of fibroblasts. The fibrosis may be interstitial or perivascular. This is thought to be due to increased collagen deposition and decreased degradation [13]. Fibrosis may involve not only the left ventricle but also the right ventricle and one or both atria. In general, the severity of hypertrophy and fibrosis correspond with the severity and duration of hypertension. Hypertrophy and hyperplasia of smooth muscle cells in the media of myocardial arterioles may also be detected [11, 13]. Other vascular lesions include a decrease in the Fig. 9 Cardiac amyloidosis. and, Short-axis delayed contrast-enhanced MR images in healthy patient () and patient with amyloidosis (). Deposition of amyloid leads to poor nulling of myocardium relative to blood pool. Normal cardiac muscle can be nulled to black whereas blood pool appears white. In contrast, in patients with amyloidosis, myocardium remains diffusely bright and of similar signal intensity to blood pool. JR:200, March 2013 W271

7 Giesbrandt et al. number (or density) of capillaries, which also predisposes to ischemia [13]. Radiology Cardiac MRI provides a method to reproducibly measure LV mass and LVH in addition to evaluating for fibrosis. Given the prognostic implications of LVH and fibrosis, this ability is of utmost importance. Moreover, because treatment with angiotensin-converting enzyme inhibitors has been shown to decrease the myocardial collagen content and possibly cause regression of hypertrophy, reproducible serial measurements may be needed [11, 13]. LVH and increased LV wall thickness are morphologically evident on cardiac MRI (Fig. 6). These findings can be difficult to distinguish from hypertrophic cardiomyopathy, particularly in older patients with an age-related subaortic septal bulge. In this regard, Sipola et al. [14] showed that LVH in hypertensive cardiomyopathy is more symmetric, with maximum wall thickness usually involving the septum. In contrast, HCM is more asymmetric, with greater involvement of the anterior free wall and septum. HCM patients also occasionally show regional septal bulge and right ventricular hypertrabeculation, whereas this is not seen with hypertensive cardiomyopathy. Sipola and colleagues [14] also found that a maximum wall thickness of 17 mm was the most accurate feature in diagnosing HCM versus mild or moderate hypertensive LVH. It is important to note, however, that patients with severe hypertension can have wall thicknesses measuring > 20 mm. Fibrosis, as shown by late gadolinium enhancement, is not as commonly encountered in hypertensive cardiomyopathy as with HCM [14]. When present, there is usually no specific pattern of late gadolinium enhancement except that it is usually not subendocardial [11, 12]. If seen, this is a useful finding because late gadolinium enhancement is associated with worse diastolic dysfunction [11, 15]. Cardiac myloidosis myloidosis is an infiltrative process characterized by the extracellular deposition of glycoproteins into various tissues and organs. Several subtypes of amyloidosis exist. However, cardiac involvement is most commonly either of the primary L type, associated with abnormal λ or κ light chains produced by plasma cells, or of the TTR type, in which abnormal transthyretin is produced by the liver and may represent either familial amyloidosis or senile systemic amyloidosis [16]. pproximately half of the patients with primary amyloidosis exhibit features of cardiac involvement [17]. The myocardial interstitial deposition of amyloid glycoproteins leads to restrictive hemodynamics, which can clinically present as congestive heart failure, arrhythmias, or sudden cardiac death. Congestive heart failure is associated with an especially poor prognosis, with a median survival of < 6 months after the onset of symptoms [18]. Pathology The deposition of amyloid fibrils occurs as a result of protein misfolding, which leads to the formation of β-pleated sheets [19]. When amyloid fibers are stained with Congo red and examined microscopically under crosspolarization, they characteristically exhibit apple-green birefringence. These bloodborne misfolded proteins may accumulate in various organs and tissues. ggregation of amyloid protein and enlargement of the organs can lead to organ dysfunction. In the heart, the amorphous interstitial amyloid fibrils are generally deposited along the sarcolemmal membrane of myocytes. ecause amyloid has a firm consistency, its deposition in the heart eventually leads primarily to diastolic dysfunction. Over time, entrapped myocytes, in which uptake of oxygen and nutrients and release of carbon dioxide and other waste products has been hampered by coating of amyloid, can become atrophic. Moreover, amyloid can deposit within small intramural coronary arteries and may cause sufficient luminal narrowing to cause microfocal areas of ischemic injury. The classic findings of amyloidosis with cardiac dysfunction are substantial thickening of the ventricular walls without chamber dilatation and thickening of the atrial endocardium and atrial septum. oth atria tend to dilate in response to elevated ventricular enddiastolic pressures. In later stages of the disease, amyloid infiltration of the valve leaflets may occur and lead to valve dysfunction [20]. mild degree of ventricular dilatation can develop in the setting of end-stage disease. Radiology The gross findings of biatrial enlargement with ventricular, atrial, septal, and valvular thickening are easily identified on cardiac MRI (Fig. 7). Pleural and pericardial effusions are commonly seen as well [21]. myloid deposition in the myocardium changes the intrinsic characteristics of the tissue, which, in turn, results in changes in signal intensity on T1-weighted imaging [22]. myloid deposition also results in diffuse enhancement of the myocardium with late gadolinium enhancement, as seen in Figure 8. This late gadolinium enhancement may be more prominent in the subendocardial region but nonvascular in distribution, which differentiates this finding from those seen in coronary ischemic disease. Nulling of the myocardium infiltrated with amyloid protein may occur at a shorter inversion time than the blood pool, which is the opposite of normal myocardium [23] (Fig. 9). This may cause difficulty in determining the optimal inversion time, which in and of itself should raise concern for amyloidosis. Summary thorough understanding of the pathophysiology underlying the nondilated cardiomyopathies allows easier identification of the corresponding imaging characteristics. References 1. Gersh J, Maron J, onow RO, et al CCF/ H guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the merican College of Cardiology Foundation/merican Heart ssociation Task Force on Practice Guidelines. J m Coll Cardiol 2011; 58:e212 e Green JJ, erger JS, Kramer CM, Salerno M. Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. JCC Cardiovasc Imaging 2012; 5: Noureldin R, Liu S, Nacif MS, et al. The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2012; 20: To C, Dhillon, Desai MY. Cardiac magnetic resonance in hypertrophic cardiomyopathy. JCC Cardiovasc Imaging 2011; 4: Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopathology 2004; 44: Lamke GT, llen RD, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy: a study of 204 cases ( ). Cardiovasc Pathol 2003; 12: llen RD, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of subaortic septal myectomy not associated with hypertrophic cardiomyopathy: a study of 98 cases ( ). Cardiovasc Pathol 2003; 12: Maron MS, Maron J, Harrigan C, et al. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J m Coll Cardiol 2009; 54: Olivotto I, Maron MS, utore C, et al. ssessment and significance of left ventricular mass by cardio- W272 JR:200, March 2013

8 Diffuse Diseases of the Myocardium vascular magnetic resonance in hypertrophic cardiomyopathy J m Coll Cardiol 2008; 52: Ho CY. Hypertrophic cardiomyopathy in Circulation 2012; 125: Raman SV. The hypertensive heart: an integrated understanding informed by imaging. J m Coll Cardiol 2010; 55: Rudolph, bdel-ty H, ohl S, et al. Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular hypertrophy relation to remodeling. J m Coll Cardiol 2009; 53: Díez J, González, López, Querejeta R. Mechanisms of disease: pathologic structural remodeling is more than adaptive hypertrophy in hypertensive heart disease. Nat Clin Pract Cardiovasc Med 2005; 2: Sipola P, Magga J, Husso M, et al. Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation. Eur Radiol 2011; 21: Moreo, mbrosio G, De Chiara, et al. Influence of myocardial fibrosis on left ventricular diastolic function: noninvasive assessment by cardiac magnetic resonance and echo. Circ Cardiovasc Imaging 2009; 2: Kholová I, Niessen HW. myloid in the cardiovascular system: a review. J Clin Pathol 2005; 58: Dubrey SW, Cha K, nderson J, et al. The clinical features of immunoglobulin light-chain (L) amyloidosis with heart involvement. QJM 1998; 91: Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997; 337: Merlini G, Westermark P. The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies. J Intern Med 2004; 255: Krombach G, Hahn C, Tomars M, et al. Cardiac amyloidosis: MR imaging findings and T1 quantification, comparison with control subjects. J Magn Reson Imaging 2007; 25: Chou TR, Tietjen P. Pleural amyloidosis as a cause of pleural effusions. Chest 2002; 122(suppl 4):239S 240S 22. Celletti F, Fattori R, Napoli G, et al. ssessment of restrictive cardiomyopathy of amyloid or idiopathic etiology by magnetic resonance imaging. m J Cardiol 1999; 83: Mahrholdt H, Wagner, Judd RM, et al. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies. Eur Heart J 2005; 26: FOR YOUR INFORMTION This article is available for CME/SM credit. Log onto click on JR (in the blue Publications box), click on the article name, add the article to the cart, and proceed through the checkout process. The reader s attention is directed to a related article which begins on w274. JR:200, March 2013 W273