Atrial Amyloid Research Articles

Ultrastructural evidence for the formation of amyloid fibrils within cardiomyocytes in isolated atrial amyloid

Isolated atrial amyloid (IAA) frequently affects elderly human hearts in which only the atria are involved by the deposits. Biochemical analysis has indicated that the major subunit protein of IAA is α-human atrial natriuretic peptide (α-ANP), which is synthesized by the atrial muscle cells. To define the exact location of the formation of IAA fibrils, right atria from 25 patients undergoing cardiac surgery have been examined by an immunohistochemistry and immunoelectron microscopy with anti-α-ANP, apolipoprotein E, amyloid P component, transthyretin, and cathepsin B antisera. Of 25 patients, 19 were involved with IAA deposits which reacted with anti-α-ANP, apolipoprotein E, amyloid P component antisera but not with anti-transthyretin antiserum. In 8 of them, amyloid fibrils were seen not only in the interstitium of the atrial myocardium but also in the dilated transverse tubules of the cardiomyocytes. In some cardiomyocytes, amyloidfibrils were also demonstrated within the organelles such as coated and uncoated secretory vesicles or lysosomes.These findings lead to the inescapable conclusion that the polymerization of amyloid fibrils in IAA occurs within the cytoplasm of cardiomyocytes under some conditions.

Incidence and distribution of isolated atrial amyloid: histologic and immunohistochemical studies of 100 aging hearts.

The incidence and anatomic distribution of isolated atrial amyloid (IAA) in 100 aging hearts were studied histologically and immunohistochemically using antibodies against alpha-human-atrial natriuretic peptide (alpha-ANP), human transthyretin (TTR) and human amyloid P component (AP). Ninety-one of 100 hearts (91%) had amyloid deposits in the atria. Amyloid deposits in all 91 hearts reacted with alpha-ANP and AP antisera, and in four hearts other amyloid deposits that reacted with TTR antiserum were coincidentally seen in the atria. The prevalence of IAA deposition, using a semiquantitative evaluation, was significantly higher in the hearts from patients over 80 years of age, from women, those weighing over 450 g, with a thickened left ventricular wall (> 1.4 cm) and with multiple myocardial scars. IAA deposition showed a significant distribution in the auricle and left atrium; it was located mostly in the interstitium of the subendocardial layer and the subendocardial myocardium. These results indicate that IAA occurs more frequently than previously appreciated in the elderly and in patients with certain cardiac disorders.

Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant.

Cardiac amyloidosis is caused by amyloid deposits derived from different human plasma proteins. It can lead to cardiac conduction disturbances, restrictive cardiomyopathy, and low output heart failure. The heart is variably involved during the development of systemic amyloidosis and seems to be more frequently affected in immunoglobulin (primary) than in reactive (secondary) amyloidosis. Amyloid is common in the elderly. Isolated atrial amyloid, for which a major subunit is the atrial natriuretic peptide, seems to be three times more frequent than senile cardiac amyloid, which is derived from normal prealbumin (transthyretin). Like polyneuropathy, cardiac amyloidosis is a prominent clinical feature of hereditary amyloidosis, namely of the autosomal dominant transthyretin (TTR) type. All 28 cases of TTR amyloidoses reported so far were heterozygotes for a single nucleotide change in the gene for TTR that resulted in amino acid substitutions in the mature protein. A new TTR genetic variant is reported in a German family where the index patient presented at the age of 63 with anginal pain and arrhythmia. Electrocardiography was suggestive of a pseudoinfarction pattern, and echocardiography and cardiac catheterisation showed signs of hypertrophic nonobstructive cardiomyopathy with increased ventricular filling pressures and a prominent "a" wave. Amyloid of the TTR type was identified by immunohistochemistry in the endomyocardial biopsy specimen. Hybrid isoelectric focusing established heterozygosity by showing normal TTR protein and an electrically neutral TTR variant differing from all known TTR variants so far. The patient died in an accident before investigations were complete. Electrophoretic analysis of the plasma from his first degree relatives (son, daughter, brother, and mother) identified the asymptomatic 22 year old son as an apparently heterozygous carrier of the mutant TTR protein. Comparative tryptic peptide mapping and sequencing showed that isoleucine at position 68 of the amino acid sequence was replaced by leucine.

Atrial amyloid deposits in the failing human heart display both atrial and brain natriuretic peptide‐like immunoreactivity

Atrial amyloid deposits are common in the ageing human heart and contain alpha-atrial natriuretic peptide (proANP99-126) immunoreactivity. However, atrial myocytes secrete both amino and carboxy terminal fragments of the ANP prohormone (proANP1-126) and also express an homologous, but separate brain natriuretic peptide (BNP). Characteristic amyloid deposits were identified in the atria of 9/22 patients (26-63 years of age) with end-stage heart failure. Amyloid fibrils displayed immunoreactivity for both amino and carboxy terminal fragments of proANP1-126 and for the distinct BNP sequence. As in other endocrine organs, both mature and precursor peptide sequences appear to be constituents of amyloid fibrils. Whilst immunoreactivity for cardiac peptide hormones is co-localized in atrial amyloid deposits, it is uncertain whether the increase in natriuretic peptide expression which accompanies cardiac failure contributes to the incidence of isolated atrial amyloidosis.

The relation of atrial natrluretic factor to isolated atrial amyloid

Isolated atrial amyloid (IAA) is a very common age-related amyloid form which is seen only in the atria of the heart. Chemical characterization has indicated that the major subunit protein is atrial natriuretic factor (ANF). In this ultrastructural study we show that the fibrils in IAA most frequently are located extracellularly especially along the cell membranes of the myocytes, but that small deposits also seem to be present intracellularly. No obvious relation was noted between the fibrils and the endocrine granules. Antiserum to a low molecular fraction of IAA labeled amyloid fibrils and granules in the same way as a commercial antiserum to ANF, but no other structures in the myocyte. Finally we show that ANF can polymerize to fibrils with an amyloid appearance. The study thus supports the fact that ANF is an important and integrated part in the IAA fibrils.

The prevalence of isolated atrial amyloid.

The frequency of isolated atrial amyloid (IAA), a form of 'senile' cardiac amyloidosis, was determined in younger age groups. For the detection of amyloid the Sirius red staining technique was used. IAA first appears in the fourth decade; its prevalence increases roughly linearly by 15-20 per cent with each subsequent decade, reaching 95 per cent in the 81-90 years age group. The prevalence is higher in females than in males.

Atrial natriuretic peptide deposited as atrial amyloid fibrils

Deposition of amyloid in the atria is exceedingly common in the aging heart. We have extracted amyloid fibrils from atria and purified a major protein which had N-terminal amino acid sequence identical to that of atrial natriuretic peptide (ANP). Antisera to ANP and to the amyloid fibril protein both labelled atrial muscle cells and atrial amyloid in an identical way.

Isolated atrial amyloid contains atrial natriuretic peptide: a report of six cases.

Twenty five specimens of the human right atrial appendage were examined for immunoreactivity to alpha human atrial natriuretic peptide. In the electron microscope characteristic amyloid fibrils were identified around small blood vessels and adjacent to atrial muscle cells in eight of the surgical cases and in two necropsy cases. In six cases, four surgical and two necropsy, these fibrils contained immunoreactive alpha human atrial natriuretic peptide. Amyloid is known to occur in peptide secreting endocrine tumours and immunoreactive peptide may be incorporated in the amyloid matrix. The demonstration of atrial amyloid containing immunoreactive alpha human atrial natriuretic peptide suggests that some deposits of cardiac amyloid are of a type analogous to that found in other endocrine organs.

Frequency and distribution of senile cardiovascular amyloid: A clinicopathologic correlation

Atrium, ventricle, aorta, lung, kidney, and rectum were removed at autopsy from 85 consecutive elderly patients (aged 80 years or older) and examined for amyloid with Congo red. All tissues containing amyloid were counterstained with an antiserum specific for amyloid fibril protein ASc 1 and studied by immunofluorescence. Three distinct forms of amyloid were found: (1) all patients had senile aortic amyloid; (2) 78 percent of patients had isolated atrial amyloid; and (3) 25 percent of patients had senile cardiac amyloid of the ASc 1 type. The cardiac amyloid deposits were small and widely scattered in more than 80 percent of patients with isolated atrial amyloid and in more than 50 percent of patients with ASc 1-type amyloid. Of 21 patients with ASc 1 amyloid, 19 had extracardiac involvement (lung in 81 percent of cases and rectum in 57 percent of cases). The kidney was not involved in any patient. The mean heart weight, frequency of atrial fibrillation, percentage of patients with heart failure, and frequency of myocardial infarction were increased in patients with cardiac amyloid, but these differences failed to reach statistical significance. There was no difference in the mean left ventricular wall thickness or degree of coronary atherosclerosis.