Fig. 29.1
Isolated atrial amyloid. Autopsy examination showed slight rigidity of the left atrial wall. (a) The cardiac myocytes show hypertrophy but no distinct eosinophilic infiltrate in the interstitial space (H&E ×400). (b) Movat stain shows extracellular material stained orange red with very faint green strands in the interstitium (Movat stain ×400). (c) Examination of the thioflavin S stain under UV light microscopy shows irregular aggregates and strands of amyloid (light blue fluorescence) corresponding to the areas of orange-red and green staining on Movat (thioflavin S ×400)
The clinical significance of IAA, in particular, a causative relation to atrial tachyarrhythmias, remains controversial [3, 6, 7]. Conditions that lead to increased synthesis and secretion of ANP resulting in a high local concentration of the precursor protein have been postulated to accelerate amyloidogenesis. Accordingly, in some patients left atrial dilatation and chronic atrial fibrillation have been associated with increased serum ANP levels and severity of amyloid deposits found in the atrium. Serum ANP is also elevated in the elderly population, probably related to increased incidence of cardiac conditions that stimulate ANP secretion.
Senile Aortic Amyloid
Amyloid deposited in the aorta is believed to be the most common of the age-related amyloidoses, being detectable in 97 % of persons aged 50 or older [8]. Purification and amino acid sequence analysis of aortic amyloid revealed the major fibril protein to be an internal fragment of lactadherin called medin [9]. The precursor protein lactadherin is synthesized locally by vascular smooth muscle cells.
This type of amyloid is seen in the middle part of the media as small irregular aggregates or linear streaks parallel to the elastic lamellae that cause minimal distortion of the medial architecture. The amount of amyloid deposits is found to be greater in the thoracic aorta than in the abdominal aorta. Amyloid has also been detected in the media of basilar arteries and around the internal elastic lamina of temporal arteries [10].
There are no known consequences of aortic amyloid although one study has shown that oligomeric medin exerts toxic effect to smooth muscle cells in culture [11]. Medin also induces the production of matrix metalloproteinase 2 which degrades elastic laminae.
Senile aortic amyloid is distinct from that occasionally seen in the intima and adventitia. Amyloid derived from wild-type apolipoprotein A1 can be found within atheromatous plaques in the intima [12]. Amyloid occurring in the adventitia and vasa vasorum is part of senile and other types of systemic amyloidosis.
Valvular Amyloidosis
Cardiac valves are commonly infiltrated in systemic amyloidosis with deposits often grossly visible in mitral and tricuspid valves. Infiltration of the semilunar valves is less conspicuous. Valvular regurgitation associated with amyloid deposition is generally not clinically significant. On the other hand, localized small deposits of amyloid are incidental findings of no clinical importance in surgically excised cardiac valves with a reported prevalence ranging from 15.5 to 67 % in different case series [13–16]. The occurrence of this type of amyloid in valves does not correlate with age. Rather, it is strongly correlated with degenerative and postinflammatory fibrosis and calcification. The amyloid deposits are most common in stenotic aortic valves and are not seen in myxomatous degeneration. Amyloid deposits appear as small irregular plaques within areas of dense fibrosis and hyalinization and are also found at the periphery of calcific deposits (Fig. 29.2). The nature of this amyloid is yet to be established as it does not react with antibodies to the common amyloid proteins that affect the heart.
Fig. 29.2
Incidental amyloid in a calcified aortic valve. (a) Light micrograph of an aortic valve with marked calcification. There is abundant fibrosis and several cores of basophilic deposits corresponding to areas of calcified extracellular matrix. At this low magnification, there is no overt “amorphous” amyloid deposition identified (H&E ×100). (b) The rectangular highlighted portion of the valve in (a) shows a close-up of the extracellular matrix and calcium deposits but no overt amyloid deposits (H&E ×300). (c) The same area of the valve is shown as a bright field micrograph stained with Congo red. A small focus of the matrix is stained red (“congophilic”). The calcium deposits are basophilic (Congo red ×300). (d) Examination of the same field under polarized light microscopy shows the extracellular collagen as a birefringent white matrix. In contrast, the small area of congophilic material shows apple green birefringence under the polarized visible light (Congo red ×300). (e) At higher magnification, the congophilic area of the extracellular matrix of the valve stands out in bright field microscopy (Congo red ×900). (f) Polarized light microscopy shows distinct apple green birefringence of the congophilic deposits (Congo red ×900). (g) Ultraviolet light microscopy of the Congo red-positive deposit in the valve is autofluorescent when analyzed with a tetramethylrhodamine isothiocyanate (TRITC) filter (Congo red ×900). (h) Thioflavin S stain of the same valve shows the amyloid deposition as bright blue fluorescence with the 4′,6-diamidino-2-phenylindole (DAPI) filter (thioflavin S ×900). (i) The amyloid deposit in the same thioflavin S-stained slide appears bright green with the fluorescein isothiocyanate (FITC) filter (thioflavin S ×900)
Systemic Amyloidoses
Immunoglobulin Light Chain Amyloidosis
The most common type of amyloid protein deposited in the heart is derived from monoclonal immunoglobulin light chains (AL) secondary to a plasma cell dyscrasia. This type of amyloidosis, termed AL amyloidosis, involves the heart in about half of the patients with plasma cell dyscrasia. Cardiac amyloidosis almost always occurs in the presence of other organ involvement such as the renal and gastrointestinal system. There is a slight male predominance in most studies, although the gender discrepancy is small compared to that seen in transthyretin amyloidosis. The mean age at diagnosis is 60 years. AL amyloidosis is more commonly due to λ (lambda) immunoglobulin light chains in IgG monoclonal gammopathies. A slight predominance of κ (kappa) immunoglobulin light chains is observed among patients with the rare IgM-related AL amyloidosis [17]. Cardiac involvement confers a poor prognosis with median survival of a year from the time of diagnosis if left untreated [18, 19]. Compared to patients with transthyretin amyloidosis, those who have AL amyloidosis have a higher frequency of hemodynamic impairment despite a lesser degree of cardiac infiltration measured by left ventricular wall thickness on echocardiography [20]. A direct cardiotoxic effect of amyloidogenic light chains has been proposed to explain this discordant clinical observation [21].
In approximately 10 % of primary AL amyloidosis, a monoclonal protein is not demonstrated in serum or urine despite a positive identification of AL amyloidosis on tissue. In such cases, a diagnosis of nonsecretory immunoglobulin-derived amyloidosis is made.
Transthyretin Amyloidosis
The precursor fibril protein of senile systemic amyloidosis (SSA) is normal or wild-type transthyretin (TTR), previously known as prealbumin. TTR is synthesized mainly by the liver and acts as transporter protein for thyroxine and retinol. The protein consists of 127 amino acids encoded by 4 exons located in chromosome 18. Analysis of the protein in SSA revealed normal TTR with predominantly C-terminal fragments admixed with intact full-length monomers [22].
Senile Systemic (Transthyretin) Amyloidosis
The heart is the predominant site of amyloid deposition in SSA; thus, this condition was previously referred to as senile cardiac amyloidosis before it was demonstrated that the amyloid deposit found in other organs is the same as that in the heart. The amyloid deposits are microscopic and patchy in distribution. In the heart, senile amyloid deposits occur in intramural coronary arteries with smaller amounts focally present in the interstitium of the atrial and ventricular myocardium. In organs other than the heart, amyloid is confined mainly in the wall of arteries and sometimes veins [23].
The true incidence of SSA is difficult to determine as a number of autopsy studies predate accurate typing of amyloid. SSA appears to have minimal associated clinical disease manifestations and thus it is usually not suspected during life. For unknown reasons, some patients suffer from massive deposition of wild-type TTR that clinically manifest as congestive heart failure or arrhythmias starting in the seventh decade [24]. Interestingly, symptomatic SSA occurs almost exclusively in men.
Transthyretin-Associated Familial Amyloidosis
Single point mutations are thought to destabilize the TTR native structure and cause dissociation, misfolding, and aggregation to form amyloid deposits in tissues. When variant forms of TTR are deposited, it is predominantly found in peripheral nerves and heart causing familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy, respectively. To date, there are more than 100 TTR variants reported. The majority of patients are male heterozygous carriers.
Hereditary TTR amyloidosis is autosomal dominant with variable penetrance regarding age of onset and organ involvement. One of the most common variant, Val122Ile, is present in approximately 4 % of the African Americans and is a known cause of late-onset cardiac amyloidosis in this population. In Sweden, Portugal, and Japan, there are endemic foci of Val30Met mutation associated with familial amyloidotic polyneuropathy. In this latter group of patients, cardiomyopathy is a late event and occurs in less than a quarter of patients [25]. The prevalence of other rare mutations varies according to geographical origin and appears to be associated with more pronounced cardiomyopathy rather than polyneuropathy. Patients typically present about a decade earlier than those affected by SSA.
Analysis of extracted amyloid in familial TTR amyloidosis shows both mutant and wild-type TTR. Moreover, fibril composition may be associated with the timing of disease onset and degree of cardiac involvement. In a study of Val30Met mutation carriers, the fibril composition was a mixture of full-length and fragmented forms in patients who manifest late while early disease onset was associated with deposition of only full-length TTR and lesser amount of cardiac deposits [26].
Other Systemic Amyloidoses Affecting the Heart
Amyloid A Protein
Cardiac amyloidosis secondary to deposition of acute-phase reactant serum amyloid A protein (AA) is a rare complication of chronic inflammatory and infectious diseases and malignancy. When it involves the heart, it is usually an incidental finding discovered on autopsy without clinical cardiac dysfunction. Amyloid is distributed mainly in small arteries and arterioles and to a much lesser extent in the myocardial interstitium [27]. In a large series of patients with AA amyloidosis, heart failure was noted in only 1 of 374 patients and cardiac infiltration was detected on echocardiography in 2 of 224 patients [28].
β2-Microglobulin
Patients on long-term dialysis treatment are at risk of developing systemic amyloidosis of β2-microglobulin type with predilection for osteoarticular interstitial deposition. Amyloid deposition within blood vessel wall of visceral organs is mainly seen in patients who had been on dialysis for more than 10 years [29]. Small amounts of amyloid are almost always present in the small vessels of the heart and gastrointestinal tract in autopsy series [30]. Amyloid is also seen in the endocardium and cardiac valves. Symptomatic disease is limited to destructive osteoarthropathy and carpal tunnel syndrome. Systemic manifestations are rare with only anecdotal reports of cardiac compromise and death.
Apolipoprotein AI
Aside from transthyretin-associated amyloidosis, the other forms of hereditary autosomal dominant systemic amyloidosis are rare but have been reported to involve the heart in some cases. Apolipoprotein AI is a major component of high-density lipoprotein and is synthesized by the liver and small intestine. The wild-type full-length protein forms amyloid deposits in atherosclerotic plaques. A hereditary systemic amyloidosis associated with mutations in the N-terminal segment of the apolipoprotein AI gene shows preferential involvement of the kidney and liver. However, those mutations occurring in the carboxyl terminal portion of the protein tend to be associated with cutaneous, laryngeal, and slowly progressive cardiac amyloidosis [31].
Fibrinogen
Mutations in the fibrinogen α-chain gene are a common cause of hereditary renal amyloidosis. Cardiovascular amyloid deposition in patients with fibrinogen amyloidosis is noted in the myocardium, in atheromatous plaques, and in arteries and veins of explanted livers [32].
Clinical Features of Cardiac Amyloidosis
Amyloid deposition in the extracellular matrix of the heart alters myocyte contractility and electrical conduction. Only the systemic forms of amyloidosis produce clinically significant heart disease, and there are no distinguishing clinical features for the different molecular types of systemic amyloidosis involving the heart. Symptomatic patients show signs and symptoms of congestive heart failure with or without arrhythmias. The disease can also manifest with acute coronary syndrome or sudden cardiac death [33]. The clinical presentation of cardiac amyloidosis can mimic hypertrophic cardiomyopathy and constrictive pericardial disease.
The serum cardiac biomarkers troponin T or I, B-type natriuretic peptide (BNP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are sensitive markers of myocardial dysfunction. Higher levels of these biomarkers are predictive of early mortality in patients with AL amyloidosis [34]. Electrocardiogram shows low voltage in the limb leads and a pseudoinfarction pattern (i.e., the presence of a QS wave pattern in the absence of myocardial infarction).
Imaging will show cardiomegaly with biatrial dilatation and normal or mildly dilated left ventricle. Characteristic echocardiographic findings are suggestive of an infiltrative process with increased ventricular wall thickness in the absence of hypertension, restrictive filling pattern, and sparkling appearance of the interventricular septum. The atrial septum and atrioventricular valves may also be thickened. Pericardial effusion may be present. There is early manifestation of diastolic dysfunction. Ejection fraction is preserved until late in the disease. The presence of accompanying right ventricular hypertrophy and right-sided heart failure is a useful diagnostic clue.
Magnetic resonance imaging of the heart may show late enhancement with gadolinium in a diffuse subendocardial distribution. Technetium-99m pyrophosphate and technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid are used as scintigraphic tracers for the visualization of TTR amyloid myocardial infiltration [35]. The use of positron emission tomography (PET) tracer Pittsburgh compound B, 11C-PIB, and 18F-florbetapir has shown promising preliminary results for early detection of cardiac involvement in both AL and ATTR amyloidosis [36, 37].
Clinical Diagnosis
There is no single clinical test that is sufficiently reliable for the diagnosis of cardiac amyloidosis. A tissue biopsy remains the gold standard for diagnosis of amyloidosis. Biopsy of various sites such as abdominal fat and gastrointestinal tract is commonly performed to establish a diagnosis of systemic amyloidosis. A negative biopsy of an extracardiac site, however, does not necessarily rule out cardiac amyloidosis. Moreover, biopsy of a clinically affected organ, such as performing an endomyocardial biopsy in a patient with unexplained heart failure, will have the greatest diagnostic yield. In other instances, the predominant clinical manifestation is that of congestive heart failure or hypertrophic cardiomyopathy; thus, these patients are initially evaluated by cardiologists. Not uncommonly, the diagnosis of a systemic amyloidosis is first made on an endomyocardial biopsy.
Once a tissue diagnosis is made, it is imperative to identify the precursor protein. The typing method used varies by centers and by pathologist experience and preference. In the heart, the clinically relevant forms of amyloidosis are those caused by immunoglobulin light chains and transthyretin. Together, they account for more than 95 % of cardiac amyloidosis that the pathologist is expected to encounter in practice.
A diagnosis of AL amyloidosis is supported by the presence of monoclonal gammopathy as demonstrated in serum or urine immunofixation, serum free light chain assay, and bone marrow biopsy. The criteria for evaluation of organ involvement and treatment response in AL amyloidosis have been standardized by a consensus panel [38]. If TTR staining of diagnostic tissue is positive, DNA testing from blood or tissue must be performed to rule out mutations in the TTR gene. SSA is a diagnosis of exclusion that requires the absence of plasma cell dyscrasia and mutation in the TTR gene. The absence of extracardiac manifestations such as heavy proteinuria and macroglossia is also consistent with a diagnosis of SSA [19]. The heart is occasionally affected in hereditary amyloidosis with predominant renal involvement and sequencing of apolipoprotein AI, AII, gelsolin, and fibrinogen α-chain may be warranted on rare occasions [39, 40].
Gross Morphology of Cardiac Amyloidosis
The localized forms of amyloidosis (isolated atrial or aortic) are practically imperceptible on gross examination. In contrast, examination of hearts from patients with severe amyloid deposition causing cardiac dysfunction often reveals typical gross findings that are diagnostic of amyloidosis. The heart often shows cardiomegaly that can range from mild to severe (Fig. 29.3). The heaviest hearts of up to 1,000 g are observed in TTR amyloidosis. The walls of the atria and ventricles appear rigid and do not easily collapse even in the fresh state upon opening the heart. Both atria are commonly dilated to a moderate degree (Fig. 29.4). Grossly, amyloid can be seen in the mural and valvular endocardium as fine translucent to yellow-tan granularity (Fig. 29.5a). This is most conspicuous in the left atrium and mitral valve. The atrioventricular valves are more commonly affected than the semilunar valves (Fig. 29.5b, c). In about half of patients, all four valves show amyloid deposits. Ventricular dilatation of a moderate degree is uncommon. The myocardium is firm and rubbery in consistency. The right and left ventricles are uniformly increased in wall thickness. The left ventricular hypertrophy is concentric with more or less equal thickness of the free wall and interventricular septum. Some patients will have asymmetric septal hypertrophy that may mimic hypertrophic cardiomyopathy (Fig. 29.5d). Intracardiac thrombi, mostly in the atria, are sometimes present (Fig. 29.5b).
Fig. 29.3
Four-chamber view of a heart infiltrated by amyloid deposits. This image shows a formalin-fixed heart in which the atria are stiff and do not collapse as the atria of a normal heart after fixation. The endocardium of the left atrium is as usual distinctly white because of the normal multiple elastic lamellae present in this chamber but with conspicuous yellow-ochre discolored plaques. These yellow-ochre plaques represent subendocardial and endocardial amyloid deposits. In addition, the left ventricle shows faint plaques of paler brown material towards the subendocardium also representing amyloid deposits
Fig. 29.4
Atrial involvement in transthyretin amyloidosis. Four-chamber view with close-up of the atria in a case of transthyretin-type amyloidosis. There is a fine granularity (resembling wet sandpaper) of the endocardium over the pectinate muscles and crista terminalis of the right atrium as well as the endocardium of the tricuspid valve. The left atrium shows the more conspicuous lesions of yellow-ochre plaques throughout the white atrial endocardium. These plaques are also present on the posterior leaflet of the mitral valve
Fig. 29.5
Gross pathology of valvular and septal involvement in amyloidosis. (a) Left atrium and mitral valve show distinct plaques of yellow-ochre material that bulge on the endocardial surface of these two structures. These deposits have also been described as “glassy” or “waxy.” Some thebesian veins opening into the atrium are distinctly visible in left side of the image. (b) Anterior leaflet of the tricuspid valve is thickened by coarse plaques protruding above its atrial surface. They may resemble organizing vegetations, but on microscopic examination they are composed of amyloid deposits and not of organizing fibrin deposits or fibrous tissue. Note the tan-white, nodular fibrin thrombi lodged in the trabecular portion of the atrial pectinate muscles on the right side of the image. (c) Long axis view of the left atrium, mitral valve, and aortic valve. The amyloid plaques and small nodules are easily identified over the endocardium of the atrium and the left ventricular outflow tract. Coarser deposits are present on the anterior and posterior leaflets of the mitral valve as well as the posterior and right cusps of the aortic valve. (d) This four-chamber view of a heart weighing more than 1,000 g shows distinct asymmetric septal hypertrophy. Note the faint discoloration of the subendocardial myocardium in both the interventricular septum and the left ventricular free wall. In addition, there is fine granularity of the atrial endocardium
Amyloid can be observed in the endocardium, in the interstitium of the atrial and ventricular myocardium, and in subendocardial adipose tissue (Fig. 29.6). The major epicardial coronary arteries do not show amyloid deposits [41], but amyloid is often demonstrable in the subepicardial adipose tissue and nerves on microscopy. Intramural coronary arteries and arterioles as well as coronary veins are variably involved, but sometimes can be diffuse and severe enough to cause myocardial ischemia (Fig. 29.7). Amyloid deposition is also found in the conduction system in a minority of cases.
Fig. 29.6
Right ventricular endomyocardial biopsy showing involvement of venules, adipose tissue, and myocardial interstitium. (a) Tortuous eosinophilic “amorphous” aggregates are visible towards the left side of the micrograph, as well as interspersed within the adipose tissue (H&E ×50). (b) Immunohistochemical staining for transthyretin shows that the tortuous material is amyloid present in small collapsed veins, arterioles, and adipose tissue. The stain further highlights the focal amyloid deposits in the myocardial interstitial space which are not very conspicuous on H&E (TTR immunohistochemistry ×50)
Fig. 29.7
Intramural coronary artery amyloidosis. A predominant involvement of intramural coronary arteries with only mild interstitial amyloid deposition was found in an elderly patient who died suddenly. The patient had a history of angina pectoris with no significant stenosis of the epicardial coronary arteries. The amyloid deposits replace the media and intima, encroaching upon the lumen of this artery (H&E ×400)
Endomyocardial Biopsy Evaluation
Endomyocardial biopsy is performed first to establish the diagnosis and second to determine the type of amyloid. An adequate specimen should consist of at least 4–6 pieces for routine histologic processing and light microscopy evaluation. A separate piece can be fixed in glutaraldehyde for possible electron microscopy. Histochemical stains used to identify amyloid deposits include Congo red, thioflavin S or T, methyl violet, and modified sulfated Alcian blue. The choice of stain depends on the preference and interpretation experience of the pathologist. It is also recommended to routinely stain all biopsies with trichrome which will be very useful to differentiate amyloid from collagen in the interstitium.
Amyloid is conspicuous on routine hematoxylin and eosin-stained slide as pale eosinophilic material. It is usually described as “amorphous,” but it is rather homogeneous and lacks the fibrillary structure of collagen strands in fibrous tissue. It widens the interstitial space causing distortion and separation of myocytes. It can also be seen in any other structure within the biopsy including endocardium, vasculature, and adipose tissue. The pattern of amyloid deposition can be interstitial, endocardial, or vascular. The interstitial pattern can be further described as predominantly pericellular or nodular. In the interstitial pericellular pattern, the amyloid diffusely and completely encircles individual myocytes. The entrapped myocytes commonly undergo atrophy. In the interstitial nodular pattern, the amyloid appears as eosinophilic nodules that expand the interstitium and displace the myocytes. In cases of marked amyloid deposition, a mixed pattern is usually observed. The arterioles are more commonly involved than the small veins. The vessel wall appears thickened with or without significant compromise of the lumen. It should be noted that in some biopsies, vascular infiltration is more prominent than interstitial deposition. The ventricular endocardial deposits are usually minimal.
In endomyocardial biopsies, as also observed in autopsy hearts, the pattern of amyloid deposition often provides a clue as to the type of amyloid present (Table 29.1). Interstitial pericellular pattern is often the predominant morphologic feature and is more extensive in distribution in AL amyloidosis, while it is focal with a “chicken wire” appearance in TTR amyloidosis (Fig. 29.8a–e). Vascular amyloid can be seen in both types, but is more readily observed in AL amyloidosis (Fig. 29.8f, g) and rarely seen in TTR amyloidosis on a biopsy. The interstitial nodular pattern is more commonly seen in TTR amyloidosis (Fig. 29.9). Endocardial deposits (Fig. 29.10) are seen in cases with severe amyloid infiltration and are not particularly predominant in one type over the other. Although these differences in the usual pattern of amyloid deposition in the heart exist, these observations do not allow for a reliable means to distinguish between the different types of cardiac amyloidosis based on morphologic features alone.
Table 29.1
Histologic patterns of amyloid deposition in the heart
Pattern of amyloid deposition | ||||
|---|---|---|---|---|
Interstitial perimyocytic | Interstitial nodular | Vascular | Endocardial | |
AL amyloidosis | +++ | + | ++ | +/− |
TTR amyloidosis | ++
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