Heart Fail Rev DOI 10.1007/s10741-014-9466-3

Echocardiography in cardiac amyloidosis Rodney H. Falk • C. Cristina Quarta

Ó Springer Science+Business Media New York 2015

Abstract Echocardiography is the most widely used noninvasive test in patients with heart failure or abnormal cardiac findings on examination. Patients with amyloidosis may have significant cardiac abnormalities, several of which are highly suggestive of the disease. This article reviews echocardiographic features found in cardiac amyloidosis. Keywords Amyloidosis  Heart failure  Echocardiography  Cardiomyopathy A distinct echocardiographic appearance in patients with cardiac amyloidosis has been recognized since the early days of echocardiography, when M-mode tracings were seen to show thickened left ventricular walls with normal to small left ventricular cavity size, left atrial enlargement and, occasionally, a pericardial effusion (Fig. 1). In the late stage disease, decreased fractional shortening of the left ventricle was also recognized, but even at this stage, left ventricular dilation is extremely uncommon. With the introduction of two-dimensional echocardiography, further features suggestive of infiltrative cardiomyopathy were noted, namely biatrial enlargement, thickened valves, right ventricular thickening and atrial septal

R. H. Falk (&)  C. C. Quarta Cardiac Amyloidosis Program, Section of Cardiology, Brigham and Women’s Hospital, 72, Francis Street, Boston, MA 02115, USA e-mail: [email protected]

thickening (Figs. 2, 3). The recognition that increased wall thickness in patients with cardiac amyloidosis, which is due to infiltration with amyloid, is associated with low voltage, led to attempts to distinguish the echocardiographic appearance in cardiac amyloid from true hypertrophy. Utilizing the voltage\mass ratio, Carroll et al. [1] demonstrated that an inverse correlation between voltage and muscle cross-sectional area (r = -0.79) in patients with amyloidosis, which they suggested would be useful in distinguishing patients with cardiac amyloidosis from those of true hypertrophy due to aortic stenosis or hypertensive disease. This finding underscores the fact that wall thickening in cardiac amyloidosis is due to infiltration and thus the term ‘‘left ventricular hypertrophy’’ when used in this disease is inappropriate. The introduction of pulsed wave Doppler, then continuous wave Doppler and finally color flow Doppler added not only to the diagnostic accuracy of echocardiography in cardiac amyloidosis, but also gave an insight into the pathophysiology of heart failure in this condition. Although all valves are often thickened, presumably due to amyloid infiltration, color flow Doppler generally reveals that the valvular dysfunction is usually volumetrically mild and as such rarely contributes significantly to congestive heart failure in this condition. In contrast, severe impairment of diastolic function was shown to be relatively common (Fig. 4), with progressive dysfunction occurring as the walls thicken [2].

C. C. Quarta Institute of Cardiology, DIMES, University of Bologna, Bologna, Italy

Prognostic implications of two-dimensional echocardiography and Doppler findings

C. C. Quarta S.Orsola-Malpighi Hospital, Bologna, Italy

The ability to characterized diastolic dysfunction in as well as ejection fraction by echocardiography led, in the 1990s,

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Heart Fail Rev Fig. 1 Typical M-mode at the level of the mitral chordae in a patient with advanced cardiac amyloidosis. Note the markedly decreased LV fractional shortening and normal LV cavity size. There is a small posterior pericardial effusion, not well seen on the M-mode image, but apparent on the 2D image posterior to the basal left ventricular segment. Note also the prolonged PR interval on the electrocardiogram

Fig. 2 Apical 4-chamber view in a 65-year-old AfricanAmerican man presenting with heart failure and found to have the Val122Ile transthyretin variant, with a positive endomyocardial biopsy for amyloid deposition. There is considerable LV thickening, absence of either right or left ventricular dilation and bi-atrial enlargement. The ejection fraction was low normal, but the patient had severe heart failure

to several publications evaluating prognosis based on the combination of 2D and Doppler echocardiographic findings. Low ejection fraction and restrictive Doppler filling patterns (especially the ‘‘irreversible’’ pattern) both demonstrated a worse prognosis [2, 3]. Although the left ventricle almost never dilates in cardiac amyloidosis, right ventricular dilation may occur late in the disease (probably as a combination of increased afterload from pulmonary hypertension and intrinsic right ventricular systolic dysfunction due to infiltration) and carries a poor prognosis [4, 5].

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AL and TTR amyloidosis are the two commonest forms to involve the heart. Although they share the echocardiographic 2D features of chronic amyloidosis, they have significantly different prognoses, with TTR amyloidosis having a far better prognosis than AL. Dubrey et al. blindly interpreted two-dimensional echoes for group of 36 patients, of whom 12 had ATTRm cardiomyopathy and 24 AL. No differences in LV structure were found between the two groups, despite a far worse survival in those with AL amyloidosis [6]. This study was, however, performed before the availability of

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Fig. 3 Subcostal view in a 56-year-old woman with AL amyloidosis, showing marked thickening of both right and left ventricles, biatrial enlargement and a moderate circumferential pericardial effusion. Significant elevation in pericardial pressure, sufficient to cause cardiac tamponade, may be present in cardiac amyloidosis without

the echocardiographic appearances of tamponade such as right atrial and right ventricular collapse. The absence of these signs reflects the high ventricular filling pressures due to diastolic dysfunction combined with the increased stiffness of the atrial walls and right ventricular free wall due to the effect of amyloid infiltration

tissue Doppler imaging, which has the potential to evaluate more subtle abnormalities of ventricular function. Both tissue Doppler and strain imaging have further refined both the diagnosis and prognosis of amyloidosis. Using Doppler-derived strain in AL amyloidosis, mean basal strain was a strong predictor of survival, with a cutoff of B12 % representing a significantly worse prognosis than in those [12 % [7]. However, Doppler-derived strain is a time-consuming technique with considerable interobserver variability and has largely been superseded by specklederived strain, a more robust technique. Utilizing this technique, Quarta et al. [8] studied 172 patients with cardiac amyloidosis, of whom 80 had AL amyloidosis, 56 had wild-type (ATTRwt) and 36 had mutant TTR (ATTRm). As a group, patients with ATTRwt had a greater mean wall thickness than either AL or ATTRm patient (17 ± 2, 15 ± 2 and 16 ± 2 mm, respectively), but although this was a statistically significant difference for the group (p \ 0.001) individual patients could not be distinguished based on wall thickness. Mean ejection fraction was lowest in the ATTRwt group. Worsening longitudinal strain was found to correlate with increasing wall thickness across all groups, although patients with AL amyloidosis had the worst prognosis despite thinner walls but virtually identical impairment of longitudinal strain compared to patients with ATTRwt. This suggests that additional mechanisms of LV impairment, independent of the degree of myocardial

infiltration, play a role in the LV impairment of AL amyloidosis. Tissue Doppler imaging in amyloidosis demonstrates that longitudinal ventricular contraction is impaired well before deterioration of the ejection fraction and that longitudinal dysfunction precedes the onset of heart failure. This is best detected by strain imaging, which shows an unusual and typical finding in cardiac amyloidosis, namely severe impairment of longitudinal strain at the base of the left ventricle, with relatively well-preserved apical strain. When strain is color coded, a rather typical ‘‘bulls eye’’ appearance is noted [9] (Fig. 5). This may be useful in helping to diagnose cardiac amyloidosis in a patient with unexplained left ventricular thickening, but does require dedicated software, which, while easily obtainable, is not routinely available on all echocardiographic machines.

Atrial function An oft-ignored feature of cardiac function in many diseases is the function of the atrium. Transmitral valve flow usually demonstrates an increased contribution to ventricular filling in patients with impaired left ventricular relaxation (grade one diastolic dysfunction), but it is an insensitive ‘‘stand-alone’’ marker of intrinsic atrial contractility as the

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Heart Fail Rev Fig. 4 a (top) Markedly decreased E0 measurement on the lateral wall tissue Doppler in a patient with cardiac amyloidosis. The E/e0 ratio was 20.8, consistent with elevated LV filling pressure and b (bottom) pulmonary venous flow measured by pulsed Doppler showed forward flow limited to diastole consistent, along with the tissue Doppler findings, of a restrictive flow pattern. The rhythm is atrial fibrillation

pattern of flow is dependent on multiple factors including left atrial pressure, left ventricular filling pressure and left ventricular compliance. Atrial function is very often significantly impaired in cardiac amyloidosis (Fig. 6), due to infiltration with amyloid protein [10] and has major clinical implications. Dubrey et al. [11] noted by two-dimensional echocardiography that left atrial thrombi may occur in cardiac amyloidosis even in sinus rhythm and subsequent reports from the Mayo Clinic demonstrated that the prevalence of atrial thrombi is remarkably high, both at autopsy [12] and during life [13], as seen on transesophageal echocardiography.

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Atypical manifestations of cardiac amyloidosis Concentric left ventricular thickening is seen in [90 % of cases of cardiac amyloidosis, but occasional cases are seen with a non-dilated or minimally dilated left ventricle, normal wall thickness and reduced ejection fraction. These patients often have angina with non-obstructive epicardial coronary artery disease, and it is likely that the left ventricular systolic dysfunction and angina are manifestations of chronic myocardial ischemia due to small vessel involvement by amyloid, with relatively little myocardial infiltration [14, 15]. Another atypical manifestation, seen in

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Fig. 5 Apical 4-chamber view showing an example of preserved LV longitudinal strain at the LV apex, with severe impairment at the base. Each of the colored series of curves at the right of the figure represents the longitudinal strain in one of the six measured segments and corresponds to the colored dots superimposed on the LV image. The dotted line is the mean. The color map represents these six

segments with time corresponding to the x axis. The ventricle is ‘‘unfolded’’ so that the apex occurs in the center of the color coding map, and a typical ‘‘bulls eye’’ appearance is seen. This appearance is typical of cardiac amyloidosis and is very rarely seen in other causes of true hypertrophy

\5 % of cases, is an appearance mimicking classical hypertrophic cardiomyopathy, with asymmetric septal hypertrophy and even left ventricular outflow tract obstruction [16, 17]. Occasionally, if amyloidosis was unrecognized, such cases have been subject to septal myectomy [18]. Distinction between this appearance of amyloid heart disease and hypertrophic cardiomyopathy may be very difficult echocardiographically, but cardiac MR often shows a pattern of delayed gadolinium enhancement atypical for HCM, raising a suspicion of cardiac amyloidosis. Bortezomib is now widely used in the treatment of AL amyloidosis, and, although rare, bortezomib-induced systolic dysfunction has been described [19]. Thus in patients with AL amyloidosis undergoing chemotherapy, the finding of a severe decrease in left ventricular ejection fraction compared to pre-treatment should raise the possibility of chemotherapy-induced cardiotoxicity. In such cases, there may be an improvement in systolic dysfunction when bortezomib therapy is stopped. Endomyocardial biopsy remains the ‘‘gold standard’’ for diagnosing cardiac amyloidosis and, although usually without complications, can be associated with cardiac perforation leading to tamponade, or to damage to the tricuspid valve or its chordae causing tricuspid regurgitation. In the latter case, even volumetrically moderate tricuspid regurgitation may cause significant hemodynamic deterioration as RV systolic function is already impaired from amyloid infiltration, and neither the right ventricle nor the right atrium is able to dilate adequately to compensate for

the volume overload. Thus, a subacute deterioration in clinical status after cardiac biopsy, particularly with worsening right heart failure, should prompt a search for iatrogenic tricuspid regurgitation.

Conclusions The echocardiographic appearances seen in the advanced stages of cardiac amyloidosis are fairly pathognomonic as there are few, if any, similar-appearing adult cardiac diseases. Many patients present with classical echocardiographic features, and the diagnosis can be made with a high degree of certainty in the echocardiographic laboratory. However, in earlier-stage disease, even when the patient has symptomatic heart failure, the findings may be mistaken for true left ventricular hypertrophy unless the interpreting physician considers cardiac amyloidosis in the differential diagnosis. With the use of multimodality imaging (such as nuclear imaging and cardiac MR), the diagnosis of cardiac amyloidosis can now be made noninvasively with a high degree of accuracy, but the echocardiographer remains on the ‘‘front line’’ for raising the possibility of the diagnosis in early cases. Given the expanding therapeutic possibilities for the amyloidoses, early diagnosis is critical and once suspected; amyloidosis should be reported in the differential diagnosis on the echocardiographic report, thereby prompting the ordering clinician to pursue the diagnosis.

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Fig. 6 a (top) Transmitral Doppler tracing in a patient with senile systemic amyloidosis, whose initial presentation was a stroke. Note the normal deceleration time of the mitral valve tracing, suggesting that the LV filling pressure is not markedly elevated, and the nearabsent A wave due, in this case, to atrial failure. b (bottom) Strain

Conflict of interest

The authors have no conflict of interest.

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imaging in the same patient. The atrial strain is severely impaired, with a mean peak strain of 8 %, normal being [25 %. The source of the stroke was thromboembolism from the left atrium despite sinus rhythm

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Echocardiography in cardiac amyloidosis.

Echocardiography is the most widely used noninvasive test in patients with heart failure or abnormal cardiac findings on examination. Patients with am...
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