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A 74-year-old woman with a history of diastolic heart failure and refractory atrial fibrillation (AF) presented with unstable angina for coronary artery bypass grafting. Routine pathological analysis of tissue specimens obtained from the left atrial appendage revealed subendocardial and interstitial fibrosis and patchy amyloid deposits with Congo red staining demonstrating filamentous deposits. Mass spectrometry was consistent with isolated atrial amyloidosis (IAA). IAA in this patient was found incidentally on routine postoperative pathology, but likely contributed to significant morbidity. The established relationship between IAA with AF and diastolic heart failure underscores the relevance. Further delineating the pathogenesis has potentially immense implications for the future management of associated conditions. To bridge the gaps in the understanding, a standardised approach to diagnosis is needed to open the door to a large-scale study and further work toward establishing evidence-based management pathways.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are very common conditions, particularly in the elderly. However, the mechanisms underlying the two disorders, including their intricate interaction have not been fully resolved. Here, our aim is to review the evidence on the role of the two types of senile amyloidosis in this connection. Two types of senile amyloidosis can be identified: wild-type transthyretin (TTR)-derived amyloidosis (ATTRwt) and isolated atrial amyloidosis (IAA). ATTRwt is an underlying condition that is being increasingly recognized in patients with HFpEF and often accompanied by AF. IAA is an established cause of AF, adding to the mechanism problem. New diagnostic and therapeutic possibilities have emerged that may facilitate clinical management of (senile) amyloidosis, which in turn may have implications for the management of HFpEF and AF.

OBJECTIVESDiffuse cardiac amyloidosis is a significant diagnosis with a poor prognosis. Isolated atrial amyloidosis (IAA) is the most common form of cardiac amyloidosis caused by accumulation of alpha-atrial natriuretic peptide. IAA has been associated with dysrhythmia, but otherwise remains a poorly characterized condition. The impact of incidental IAA on postoperative outcome following cardiac surgery has not previously been reported. The purpose of this study was to examine the impact of isolated atrial amyloid on patient outcomes following cardiac surgery.methodsA retrospective analysis was performed of all patients having excision of the left atrial appendage during cardiac surgery at our centre over a 5-year period. Patients with histological evidence of IAA were compared to patients without this diagnosis. IAA was diagnosed by immunohistochemistry for atrial natriuretic peptide.RESULTSA total of 167 patients underwent left atrial appendage excision and of these 26 (15.6%) were found to have IAA. Preoperative characteristics were similar between the 2 groups. A significantly greater proportion of patients with IAA experienced dysrhythmia requiring implantation of a permanent pacemaker (23.1% vs 7.8%, P = 0.03). There was also a significantly elevated incidence of perioperative death in the IAA group (11.5% vs 1.4%, P = 0.03) and inferior 1-year survival (84.6% vs 96.5%, P = 0.02).CONCLUSIONSThe presence of IAA may be associated with inferior outcomes following cardiac surgery, with increased morbidity in the early postoperative period and inferior long-term survival. Knowledge of the diagnosis preoperatively may facilitate management of patients.

Telocytes are interstitial cells with long, thin processes by which they contact each other and form a network in the interstitium. Myocardial remodeling of adult patients with different forms of atrial fibrillation (AF) occurs with an increase in fibrosis, age-related isolated atrial amyloidosis (IAA), cardiomyocyte hypertrophy and myolysis. This study aimed to determine the ultrastructural and immunohistochemical features of cardiac telocytes in patients with AF and AF + IAA. IAA associated with accumulation of atrial natriuretic factor was detected in 4.3–25% biopsies of left (LAA) and 21.7–41.7% of right (RAA) atrial appendage myocardium. Telocytes were identified at ultrastructural level more often in AF + IAA, than in AF group and correlated with AF duration and mitral valve regurgitation. Telocytes had ultrastructural signs of synthetic, proliferative, and phagocytic activity. Telocytes corresponded to CD117+, vimentin+, CD34+, CD44+, CD68+, CD16+, S100-, CD105- immunophenotype. No significant differences in telocytes morphology and immunophenotype were found in patients with various forms of AF. CD68-positive cells were detected more often in AF + IAA than AF group. We assume that in aged AF + IAA patients remodeling of atrial myocardium provoked transformation of telocytes into “transitional forms” combining the morphological and immunohistochemical features with signs of fibroblast-, histiocyte- and endotheliocyte-like cells.

Atrial fibrillation(AF) is as an abnormal irregular rhythm with chaotic generation of electrical signals in the atria of the heart. Various studies in the West have proved that atrial substrates, like isolated atrial amyloidosis can trigger the development of atrial fibrillation. In India, these structural changes have been analyzed on autopsied hearts.To determine the role of Atrial Amyloid as a substrate for Atrial fibrillation in ante mortem hearts.Atrial appendages were obtained from seventy five patients undergoing open heart surgery at a tertiary care hospital in south India. They were stained with HematoxylinEosin, Masson's Trichrome and Congo red stains and were examined for myocarditis, fibrosis and amyloidosis, respectively. 30 (40%) patients were in AF. Amyloid deposits were seen in 3 cases. All the three were in AF and had undergone mitral valve replacement (MVR) (P0.05). 2 out of the 3 amyloid-positive cases showed active myocarditis and severe scarring but there was no statistically significant correlation between these factors.Amyloid and myocarditis, independently act as an arrythmogenic substrates in the development of atrial fibrillation and are also increasingly associated with female gender and MVR. We hypothesize that the amyloid deposits are due to isolated atrial amyloidosis as they were seen only in young individuals. Some patients in sinus rhythm (SR) had large left atria and myocarditis and probably are at a higher risk for developing AF. Hence, follow-up of these patients is required for prevention of severe organ damage and timely therapeutic intervention.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are very common conditions, particularly in the elderly. However, the mechanisms underlying the two disorders, including their intricate interaction have not been fully resolved. Here, our aim is to review the evidence on the role of the two types of senile amyloidosis in this connection. Two types of senile amyloidosis can be identified: wild-type transthyretin (TTR)-derived amyloidosis (ATTRwt) and isolated atrial amyloidosis (IAA). ATTRwt is an underlying condition that is being increasingly recognized in patients with HFpEF and often accompanied by AF. IAA is an established cause of AF, adding to the mechanism problem. New diagnostic and therapeutic possibilities have emerged that may facilitate clinical management of (senile) amyloidosis, which in turn may have implications for the management of HFpEF and AF.

to analyze the morphological features of the myocardium of the atrial appendages in patients with different forms of atrial fibrillation (AF) and to compare the findings with the clinical parameters of patients.Light and electron microscopies were used to examine the myocardium of the atrial appendages in adult patients with paroxysmal (PAF), persistent (PrAF), or long-standing persistent atrial fibrillation (LPAF) and in comparison group patients with sinus rhythm without history of AF. A morphometric method was employed to evaluate myocardial fibrosis and to measure the diameter of cardiomyocytes (CMCs); the degree of lipomatosis and amyloidosis was semiquantitatively determined; and the content of CMC myofibrils was estimated. Atrial natriuretic peptide content in the myocytes was measured by immunoconfocal microscopy.In all groups, the patients with AF were found to have signs of atrial structural remodeling: fibrosis, lipomatosis, isolated atrial amyloidosis, CMC hypertrophy with the phenomena of a partial loss of myofibrils without significant differences between these parameters in different groups. In PAF patients, atrial remodeling was accompanied by hypertrophy of a number of CMCs with their higher myofibrilar mass; the increased CMC size in the left atrial appendage prevented left atrial enlargement; the degree of amyloidosis negatively correlated with the CMC myofibrillar loss that was recorded in the minor CMCs; the degree of CMC myolysis positively correlated with mitral valve insufficiency and left atrial enlargement. In contrast to the clinical and morphological changes that are typical of PAF, in LPAF the increase in CMC sizes was positively correlated with left atrial enlargement and mitral annular dilatation; while the myofibrillar loss phenomenon was noted in the most hypertrophied CMCs; the degree of amyloidosis was positively correlated with CMC myofibrillar loss. In the patients with PrAF, the size of CMCs did not correlate with their myofibril content.The patients with PAF were ascertained to have opposite changes in the ratio of CMC hypertrophy to left atrial enlargement, amyloidosis, and CMC myofibrillar loss, hypertrophy of CMCs and their myofibril content in comparison with these indicators in LPAF.Цель исследования - анализ морфологических особенностей миокарда ушек предсердий у пациентов с разными формами фибрилляции предсердий (ФП) и сопоставление полученных данных с клиническими параметрами пациентов. Материал и методы. Методами световой и электронной микроскопии исследован миокард ушек предсердий взрослых пациентов с пароксизмальной (ПФП), персистирующей (ПРФП) и длительно персистирующей фибрилляцией предсердий (ДПФП) и пациентов группы сравнения с синусовым ритмом без ФП в анамнезе. Методом морфометрии оценивали фиброз миокарда, измеряли диаметр кардиомиоцитов (КМЦ), полуколичественно определяли выраженность липоматоза, амилоидоза и оценивали содержание миофибрилл в КМЦ. Методом иммуноконфокальной микроскопии в миоцитах определяли содержание предсердного натрийуретического пептида. Результаты. У пациентов всех групп с ФП обнаружены признаки структурного ремоделирования миокарда предсердий: фиброз, липоматоз, изолированный амилоидоз предсердий, гипертрофия КМЦ с явлениями частичной утраты миофибрилл без достоверных различий между этими параметрами в разных группах. У пациентов с ПФП перестройка миокарда предсердий сопровождалась гипертрофией части КМЦ с увеличением в них массы миофибрилл; увеличение размера КМЦ ушка левого предсердия предотвращало дилатацию левого предсердия; выраженность амилоидоза отрицательно коррелировала с утратой миофибрилл, которую регистрировали в мелких КМЦ, степень миолиза КМЦ положительно коррелировала с недостаточностью митрального клапана и дилатацией левого предсердия. В противоположность клинико-морфологическим изменениям, характерным для ПФП, при ДПФП увеличение размера КМЦ положительно коррелировало с дилатацией левого предсердия и фиброзного кольца митрального клапана, феномен утраты миофибрилл при этом отмечен в наиболее гипертрофированных КМЦ, выраженность амилоидоза положительно коррелировала с утратой миофибрилл в КМЦ. У пациентов с ПРФП не обнаружено взаимосвязи размера КМЦ и содержания в них миофибрилл. Заключение. У пациентов с ПФП выявлены противоположные изменения в соотношении гипертрофии КМЦ и дилатации левого предсердия, амилоидоза и утраты миофибрилл в КМЦ, гипертрофии КМЦ и утраты в них миофибрилл по сравнению с этими показателями при ДПФП.

Isolated atrial amyloidosis (IAA) is a common localized form of amyloid deposition within the atria of the aging heart. The main constituents of amyloid fibrils are atrial natriuretic peptide (ANP) and the N-terminal part of its precursor form (NT-proANP). An ‘aggregation-prone’ heptapeptide (114KLRALLT120) was located within the NT-proANP sequence. This peptide self-assembles into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies reveal. Consequently, remedies/drugs designed to inhibit the aggregation tendency of this ‘aggregation-prone’ segment of NT-proANP may assist in prevention/treatment of IAA, congestive heart failure (CHF) or atrial fibrillation (AF).

Amyloidosis is a rare disease in which insoluble extracellular protein fibrils in β-pleated sheets infiltrate multiple organs, causing organ dysfunction and failure. Amyloidoses are generally classified into light chain or primary systemic amyloidosis, hereditary amyloidosis (most commonly, transthyretin amyloidosis), senile systemic amyloidosis, secondary amyloidosis, and isolated atrial amyloidosis. At least 100 different amyloidogenic proteins have been identified in humans and can be differentiated by mass spectroscopy after laser capture microdissection and genetic testing. Organ involvement can include kidneys, skin, blood vessels, central and peripheral nervous systems, lungs, liver, intestines, and heart. Developments in noninvasive techniques are facilitating earlier and more accurate diagnosis. Management depends on the specific disease type, thus early and accurate diagnosis is imperative. Prognosis generally correlates with degree of cardiac involvement but varies widely with specific amyloid protein type. New treatment strategies involving chemotherapy and organ transplantation are improving survival, but prognosis is guarded.

Telocytes, a recently discovered type of interstitial cells, have a very distinctive morphology - the small cell body with long extensions, named telopodes. In our review, apart from introducing general aspects of telocytes, we focus on properties, functions and future potential of those cells in cardiovascular system. However, physiological functions of telocytes in cardiovascular system are still regarded as quite enigmatic. Previous studies claim that they play a role in organogenesis and regeneration, bioelectrical signalling, mechanoelectrical coupling, anti-oxidative protection, angiogenesis and regulation of blood flow. As well, they are presumably connected with the presence of blood-myocardium barrier and proper organisation of extracellular matrix. Moreover, there exists a significant link between the quantity of telocytes in tissue and numerous cardiovascular diseases such as: myocardial infarction, cardiomyopathies, systemic sclerosis, heart failure, atrial fibrillation, isolated atrial amyloidosis, myxomatous valve degeneration and hyperplastic consequences of vascular injury. Thanks to their unique properties, telocytes might be a breakthrough in treatment of cardiovascular diseases, as they may be effective in reversing effects of myocardial infarction. Telocytes also may play a major role in tissue engineering - they might be the key factor in creating stable and efficient vascular network in larger synthetic tissues or organs (Tab. 1, Fig. 3, Ref. 53).

Objective: Isolated atrial amyloidosis (IAA) is associated with atrial tachyarrhythmias. However, only a few studies have appraised atrial tachyarrhythmias and atrial depolarization abnormalities in connection with high-grade IAA. We conducted a collaborative retrospective study to assess this association. Methods: One hundred consecutive autopsied hearts were studied histologically for IAA. To increase the specificity for atrial depolarization abnormalities in this preliminary study, we excluded those specimens with intermediate amyloid involvement, i.e. IAA grades 1 and 2 (grade 0 = absent or trivial deposits; grade 1 = small deposits; grade 2 = moderate deposits; grade 3 = dense, large deposits). We then screened for baseline, premortem electrocardiograms (ECGs) to assess rhythm. In those with sinus rhythm, the P wave axis, duration, dispersion and terminal force in V1 were determined under magnification. Results: Of the 27 premortem ECGs corresponding to the autopsy specimens with grades 3 (sample) or 0 (controls) IAA, 9 showed sinus rhythm, 13 showed atrial fibrillation, 1 showed atrial flutter and 4 were uninterpretable. Fourteen autopsied hearts (52%) were positive for grade 3 IAA. Ten of those had atrial tachyarrhythmias (9 atrial fibrillation and 1 atrial flutter) compared to 4 of the 13 hearts with grade 0 IAA (72 vs. 31%, respectively; p = 0.03). Although there was excellent interobserver agreement using intraclass correlation coefficients, there were no significant differences in P wave measurements among the small number of patients with sinus rhythm for grade 3 versus grade 0 IAA. Conclusion: In a collaborative, preliminary, pilot assessment of autopsied hearts for which premortem ECGs were necessarily screened retrospectively, significantly more hearts with high-grade IAA were associated with atrial tachyarrhythmias compared to those with low-grade IAA. A larger study with an appropriately matched autopsy control group is needed to confirm these and previous observations.

Amyloid is identified microscopically as an amorphous extracellular hyaline material that exhibits “apple-green” birefringence with Congo red stains. Amyloid is not a chemically distinct entity, and currently available molecular methods are capable of identifying over 20 amyloidogenic precursor proteins. Some of the more common diseases associated with amyloidosis include plasma cell dyscrasias, chronic inflammatory disorders, hereditary-familial mutations involving transthyretin, Alzheimer's disease, and so-called “senile” or age-related amyloidosis. The amyloid deposits in these various diseases may be isolated to a single organ such as the heart or brain, or the amyloidosis may be systemic. The senile types of cardiac amyloidosis can result from overproduction of atrial natriuretic factor or from accumulation of otherwise normal or wild-type transthyretin. We present the case of an 83-year-old hospitalized woman with known atrial fibrillation and previous pacemaker implantation who had cardiac arrest unresponsive to attempted resuscitation. Autopsy disclosed prominent amyloidosis involving the left atrium, and subsequent molecular studies identified the amyloidogenic material as alpha atrial natriuretic factor. Since the clinical management and genetic implications of the various diseases associated with amyloidosis are markedly different, we stress the importance of molecular classification whenever possible.

Background Increasing evidence indicates that proteotoxicity plays a pathophysiologic role in experimental and human cardiomyopathy. In organ‐specific amyloidoses, soluble protein oligomers are the primary cytotoxic species in the process of protein aggregation. While isolated atrial amyloidosis can develop with aging, the presence of preamyloid oligomers ( PAO s) in atrial tissue has not been previously investigated. Methods and Results Atrial samples were collected during elective cardiac surgery in patients without a history of atrial arrhythmias, congestive heart failure, cardiomyopathy, or amyloidosis. Immunohistochemistry was performed for PAO s using a conformation‐specific antibody, as well as for candidate proteins identified previously in isolated atrial amyloidosis. Using a myocardium‐specific marker, the fraction of myocardium colocalizing with PAO s ( PAO burden) was quantified (green/red ratio). Atrial samples were obtained from 92 patients, with a mean age of 61.7±13.8 years. Most patients (62%) were male, 23% had diabetes, 72% had hypertension, and 42% had coronary artery disease. A majority (n=62) underwent aortic valve replacement, with fewer undergoing coronary artery bypass grafting (n=34) or mitral valve replacement/repair (n=24). Immunostaining detected intracellular PAO s in a majority of atrial samples, with a heterogeneous distribution throughout the myocardium. Mean green/red ratio value for the samples was 0.11±0.1 (range 0.03 to 0.77), with a value ≥0.05 in 74 patients. Atrial natriuretic peptide colocalized with PAO s in myocardium, whereas transthyretin was located in the interstitium. Adjusting for multiple covariates, PAO burden was independently associated with the presence of hypertension. Conclusion PAOs are frequently detected in human atrium, where their presence is associated with clinical hypertension.

Primary amyloidosis, systemic senile amyloidosis, isolated atrial amyloidosis, and transthyretin isoleucine 122 amyloidosis frequently involve the heart. Amyloid fibrils infiltrate the myocardium, impairing ventricular contraction and relaxation. The clinical manifestations of cardiac infiltration in these disorders are protean, though congestive heart failure and arrhythmias are most common. Treatment of cardiac amyloidosis is directed at the underlying cause and at relief of symptoms. Heart transplantation is not a viable treatment option for patients with primary amyloidosis; its role in the other amyloidoses has not been established. The prognosis of patients with cardiac amyloidosis varies and is largely determined by the underlying disorder responsible for amyloid infiltration.

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.

Atrial fibrillation (AF) is known to cause significant changes in atrial architecture and atrial electrophysiology. Pre-existing morphological alterations can provide an electrophysiologic substrate, which increases the likelihood of AF. Such structural remodelling processes encompass degenerative tissue changes like interstitial fibrosis and amyloidosis, which occur in the myocardium, whereas inflammatory changes are also present at the level of the atrial endocardium. True inflammation (eg, invasion of inflammatory cells) is rarely seen in fibrillating atria. In patients with AF, atria are usually enlarged. Pathophysiologically, the left atrial appendage (LAA) appears to contribute to the regulation of cardiovascular pressure-volume relations because it is the main source of synthesis of atrial natriuretic peptides (ANPs). Due to substantially reduced blood flow velocities in the LAA and due to prothrombotic endocardial changes during AF, the LAA is considered as the main site of atrial thrombogenesis. In this respect, expression of inflammatory markers like vascular cell adhesion molecule 1 (VCAM-1) and C-reactive protein (CRP) have been identified as local and systemic markers to determine this prothrombogenic state. Serum amyloid A (SAA) is considered as an acute phase protein, which is expressed in the liver during systemic infections or inflammatory reaction. Interestingly, extrahepatic expression has been described. So far it is unknown, however, if SAA is expressed in the atria. Furthermore, it is unclear if SAA could serve as a surrogate marker to predict inflammatory changes in the heart. In addition to fibrotic and inflammatory changes, isolated atrial amyloidosis (IAA) has recently been found to be of importance for the development of atrial conduction disturbances and AF. Amyloidosis represents a diverse group of diseases (conformational diseases) characterized by

Atrial natriuretic peptide (ANP), whose amyloid is responsible of isolated atrial amyloidosis (IAA), is known to play an important role in the pathophysiology of congestive heart failure (CHF). We provide here the microscopic examination of atrial biopsies from 36 young (mean 40 years) CHF patients distinguished in idiopathic dilated cardiomyopathy (DC) affected and hypertrophic Cardiomyopathy (HC) affected, endorsing the presumptive association of early CHF with IAA. We utilized a multiple method, using Congo red (CR) staining, CR fluorescence (CRF), and immunohistochemistry to assess the presence of IAA in CHF. Immunostaining showed a moderate deposition of IAA in the atrium surrounding working myocardium with small intracellular deposits. Our findings suggest a monitoring of young CHF cases for the development of IAA. Our study also demonstrated how the concurrent use of immunohistochemistry, CR, and CRF may greatly enhance the detection of low-grade amyloid deposits.

Deposition of amyloid in the atria (isolated atrial/cardiac amyloid) is fairly common in the aging heart. It consists of amyloid fibrils, formed both by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the precursor molecule of ANP, proANP. This study examines whether amyloidogenic determinants (short peptides/amyloid forming favoring regions) exist in the sequence of NT-proBNP, the N-terminal part of proBNP, and if these determinants form amyloid-like fibrils in vitro. We have predicted a possible amyloidogenic determinant in the sequence of the NT-proBNP, and we conclusively show, after its synthesis, that it forms amyloid-like fibrils in vitro, utilizing transmission electron microscopy, X-ray diffraction, attenuated total reflectance Fourier-transform infrared spectroscopy, and polarizing microscopy. Thus, for the first time, in this study, a possible biological role is attributed to a certain, specific part of this important cardiac prohormone/natriuretic peptide, which acts as an important biomarker indicative of heart failure. Its possible direct involvement in isolated cardiac amyloidosis, atrial fibrillation, and other types of cardiac amyloidoses is indicated and discussed. Since these cardiac hormones and their prohormones play key roles in cardiovascular homeostasis through natriuresis, diuresis, vasorelaxation, and inhibition of renin and aldosterone secretion (pathophysiology of hypertension and cardiovascular regulation), we also try to suggest these specific, short peptides as possible future structural targets of efforts toward inhibiting formation of natriuretic peptide(s) amyloid. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 67–75, 2012.

Aims Atrial Natriuretic Peptide (ANP)-containing amyloid is frequently found in the elderly heart. No data exist regarding ANP aggregation process and its link to pathologies. Our aims were: i) to experimentally prove the presumptive association of Congestive Heart Failure (CHF) and Isolated Atrial Amyloidosis (IAA); ii) to characterize ANP aggregation, thereby elucidating IAA implication in the CHF pathogenesis. Methods and Results A significant prevalence (85%) of IAA was immunohistochemically proven ex vivo in biopsies from CHF patients. We investigated in vitro (using Congo Red, Thioflavin T, SDS-PAGE, transmission electron microscopy, infrared spectroscopy) ANP fibrillogenesis, starting from α-ANP as well as the ability of dimeric β-ANP to promote amyloid formation. Different conditions were adopted, including those reproducing β-ANP prevalence in CHF. Our results defined the uncommon rapidity of α-ANP self-assembly at acidic pH supporting the hypothesis that such aggregates constitute the onset of a fibrillization process subsequently proceeding at physiological pH. Interestingly, CHF-like conditions induced the production of the most stable and time-resistant ANP fibrils suggesting that CHF affected people may be prone to develop IAA. Conclusions We established a link between IAA and CHF by ex vivo examination and assessed that β-ANP is, in vitro, the seed of ANP fibrils. Our results indicate that β-ANP plays a crucial role in ANP amyloid deposition under physiopathological CHF conditions. Overall, our findings indicate that early IAA-related ANP deposition may occur in CHF and suggest that these latter patients should be monitored for the development of cardiac amyloidosis.

Congo red screening of 211 consecutive cardiac biopsy specimens obtained during cardiac surgery from 167 patients revealed 26 (16%) instances of isolated atrial amyloidosis (IAA). The ages of IAA-positive patients ranged from 25 to 52 years (mean age, 39 years). Twenty-three (88%) IAA-positive biopsy specimens were from patients with chronic rheumatic heart disease (CRHD) while three (12%) were from patients with an atrial septal defect (ASD). The prevalence of IAA in the CRHD patients was 23%, appreciably higher than that in the ASD patients (15%) and in other patients with atrial biopsies. The prevalence of IAA in both CRHD and ASD patients was significantly higher (P < .001) than in controls. Controls consisted of 247 healthy adults who were autopsied after traumatic deaths, with an age range of 18 to 89 years (mean age, 38 years). Only seven (3%) control subjects were IAA positive; all were over 40 years of age. Isolated atrial amyloidosis deposits were permanganate resistant and immunohistochemically positive for human amyloid P (AP) protein and negative for human amyloid-associated (AA) protein and immunoglobulin light chains. They were observed as fine congophilic and birefringent deposits in intramyocardial vessel walls, along the myocardial sarcolemma, and in the subendocardium. There was associated myocyte hypertrophy but no atrophy. Electron microscopy demonstrated typical nonbranching amyloid fibrils. It is postulated that stretching of the atria in chronic heart disease results in a raised prevalence of IAA. Recent reports that IAA contains atrial natriuretic peptide, a polypeptide hormone product of atrial myocytes, supports this view.

The human heart can be frequently affected by an organ-limited amyloidosis called isolated atrial amyloidosis (IAA). IAA is a frequent histopathological finding in patients with long-standing atrial fibrillation (AF). The aim of this paper was to investigate the ultrastructure of cardiomyocytes and telocytes in patients with AF and IAA. Human atrial biopsies were obtained from 37 patients undergoing cardiac surgery, 23 having AF (62%). Small fragments were harvested from the left and right atrial appendages and from the atrial sleeves of pulmonary veins and processed for electron microscopy (EM). Additional fragments were paraffin embedded for Congo-red staining. The EM examination certified that 17 patients had IAA and 82% of them had AF. EM showed that amyloid deposits, composed of characteristic 10-nm-thick filaments were strictly extra-cellular. Although, under light microscope some amyloid deposits seemed to be located within the cardiomyocyte cytoplasm, EM showed that these deposits are actually located in interstitial recesses. Moreover, EM revealed that telopodes, the long and slender processes of telocytes, usually surround the amyloid deposits limiting their spreading into the interstitium. Our results come to endorse the presumptive association of AF and IAA, and show the exclusive, extracellular localization of amyloid fibrils. The particular connection of telopodes with amyloid deposits suggests their involvement in isolated atrial amyloidosis and AF pathogenesis.

This case presentation describes the very rare condition of isolated atrial amyloidosis and it's associated complications. A 53-year-old male presented to hospital in severe pulmonary edema secondary to spontaneous intramural left atrial hemorrhage and subsequent wall dissection causing acute "pre-mitral valve" obstruction. The patient was subsequently found to have AL subtype amyloid, which has never before been reported in isolated atrial amyloidosis. The prognosis is poor in AL type amyloidosis with cardiac involvement.

We have recently demonstrated that human α-atrial natriuretic peptide (α-hANP), an amyloidogenic peptide responsible for isolated atrial amyloidosis, binds to a dimeric form of apo A-I belonging to small high-density lipoproteins (HDL). This binding phenomenon is considered a protective mechanism since it inhibits or strongly reduces the ANP aggregation process. The observation that plasma exhibits at least four times greater amyloid inhibitory activity than HDL prompted us to determine whether small HDL are the only ANP plasma-binding factors. After incubation of whole plasma with labelled ANP, the macromolecular complexes were subjected to two-dimensional gel electrophoresis followed by autoradiography. The results presented here provide novel evidence of additional binding proteins, in addition to apo A-I dimer, able to bind ANP in vitro and to prevent its aggregation. The mass spectrometry analysis of the radioactive spots identified them as albumin, α-1 antitrypsin, orosomucoid and apo A-IV-TTR complex. The putative impact of these findings in the amyloidogenic/antiamyloidogenic peptides network is discussed.

This editorial refers to “Amyloid deposition as a cause of atrial remodelling in persistent valvular atrial fibrillation”1 by O. Leone et al. on page 1237 Atrial fibrillation (AF) is known to cause significant changes in atrial tissue architecture and electrophysiology.1,2 It has become clear over recent years that pre-existing alterations, such as autonomic dysbalance, degenerative tissue changes and fibrosis, can provide an electrophysiological and morphological substrate, which increases the likelihood of AF. In particular, alterations of the interstitial matrix in atrial tissue seem to be significant contributory factors.1 Increased amounts of fibrous tissue in fibrillating human atria were reported as early as 30 years ago3 and it is known to impair cell-to-cell coupling, thus causing heterogeneity in intra- and inter-atrial conduction. Initially, subsequent changes in atrial conduction may be subtle. However, isolated atrial amyloidosis (IAA) has recently been found to be of importance for the development of atrial conduction disturbances and AF.4 Amyloidosis represents a diverse group of diseases characterised by the presence of extracellular proteinaceous deposits showing characteristic structural and tinctorial properties. Amyloidoses are classified on the basis of the amyloid protein deposited and the clinical presentation5 and may affect the heart as part of a systemic disease, as in immunoglobulin-derived AL amyloidosis. In senile cardiovascular amyloidosis, the fibril protein consists of transthyretin (non-hereditary ATTR amyloidosis), and amyloid is observed in … *Correspondence to: A. Goette, Division of Cardiology, Otto-von-Guericke-University Hospital, Leipziger Str. 44, 39120 Magdeburg, Germany. E-mail address: andreas.goette{at}medizin.uni-magdeburg.de

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.

Congo red screening of 211 consecutive cardiac biopsies obtained during cardiac surgery from 167 patients revealed 26 (16%) instances of isolated atrial amyloidosis (IAA). IAA-positive patients ranged from 25 to 52 years in age with a mean of 39 years. Controls consisted of 247 healthy adults autopsied for traumatic deaths, with an age range of 18 to 89 years and a mean of 38 years. Only 7 (3%) control subjects were IAA-positive, all above 40 years of age. 23 (88%) IAA-positive biopsies were from patients with chronic rheumatic heart disease (CRHD) and 3 (11%) atrial septal defect (ASD). The prevalence of IAA in CRHD was 23%, appreciably higher than that in ASD (15%) and other patients with atrial biopsies. The prevalence in both CRHD and ASD was significantly higher (P

Congo red screening of 211 consecutive cardiac biopsies obtained during cardiac surgery from 167 patients revealed 26 (16%) instances of isolated atrial amyloidosis (IAA). IAA-positive patients ranged from 25 to 52 years in age with a mean of 39 years. Controls consisted of 247 healthy adults autopsied for traumatic deaths, with an age range of 18 to 89 years and a mean of 38 years. Only 7 (3%) control subjects were IAA-positive, all above 40 years of age. 23 (88%) IAA-positive biopsies were from patients with chronic rheumatic heart disease (CRHD) and 3 (11%) atrial septal defect (ASD). The prevalence of IAA in CRHD was 23%, appreciably higher than that in ASD (15%) and other patients with atrial biopsies. The prevalence in both CRHD and ASD was significantly higher (P>0.001) than in the controls. IAA deposits were permanganate-resistant and immunohistochemically negative for AA protein. They were observed in intramyocardial vessel walls, along the myocardial sarcolemma and the subendocardium. There was associated myocyte hypertrophy but no atrophy. Electron microscopy demonstrated typical non-branching amyloid fibrils. It is postulated that mechanical and physiological stress to the atria results in a raised prevalence of IAA. The association of atrial natriuretic peptides with IAA would support this view.

The major subunit protein in isolated atrial amyloid (IAA) is ANF. Patients with congestive cardiac failure have high levels of ANF. The main objective was to study if there was a correlation between cardiac failure and IAA. Eighty autopsied patients were investigated; 48 with congestive cardiac failure were compared with 32 without cardiac failure. Congo red stained sections from both atria and left ventricle were studied under polarized light. Statistical analysis revealed an age-adjusted 4.3-fold increase in the risk of having amyloidosis of IAA type if cardiac failure was present. IAA could be a consequence of cardiac failure. However, since a few patients without cardiac failure had rather heavy amyloid infiltration, there must be other factors of importance in the pathogenesis of IAA.

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 ASc1 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 ASc1 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 ASc1-type amyloid. Of 21 patients with ASc1 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.

Using light and electron microscopy, 65 cases of amyloid deposits in the heart were examined. Five different groups were distinguished: I. isolated atrial amyloidosis, II. senile cardiac amyloidosis, III. cardiac amyloid accompanying chronic infections and tumors, IV. cardiac amyloid accompanying plasma cell dyscrasia, V. idiopathic cardiac amyloidosis. Seen structurally, no principal differences in the precise localization of the amyloid deposits were found in any of the groups investigated. Amyloid is always deposited in the vicinity of cells with myocytic cell differentiation (i.e. the heart muscle cells, non-striated muscle cells of the vessels), whereby the relevant basement membranes serve as conductors. A systematic relationship between amyloid and the collagenous fibers of the interstitium or the tunica adventitia of the vessels could not be demonstrated, which shows the concept "pericollagen" to be inadequate for the morphological characterization of amyloid deposits in the heart. Whereas for group I a localized mechanism for the production of amyloid must be considered, in the case of groups II-V a vascular principle expression of a generalized amyloidosis seems to be the major factor. The question of the differing concentration of amyloid deposits in the heart suggests that localized factors (e.g. changes in the myocytic basement membranes) and quantitative changes of the amyloid-building proteins may also be important.

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.

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.

Objectives. We investigated the expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and their genes in the hearts of patients with cardiac amyloidosis and those with isolated atrial amyloidosis. Background. The expression of ANP and BNP is augmented in the ventricles of failing or hypertrophied hearts, or both. The expression of ANP and BNP in the ventricles of hearts with cardiac amyloidosis, which is hemodynamically similar to restrictive cardiomyopathy, is not yet known. ANP is the precursor protein of isolated atrial amyloid. Methods. We analyzed the immunohistocytochemical localizations of ANP and BNP as well as the expression of their mRNAs by in situ hybridization in the myocardium and measured the plasma levels of ANP and BNP in patients with cardiac amyloidosis. Results. Four of the five right and all six left ventricular endomyocardial biopsy specimens obtained from six patients with cardiac amyloidosis were immunohistochemically positive for both ANP and BNP; none of the biopsy specimens from eight normal subjects were positive for ANP or BNP. All four of the right atria obtained at operation showed positive immunoreactions for both peptides. Electron microscopy identified specific secretory granules in ventricular myoctyes of the patients with cardiac amyloidosis, but not in ventricular myocytes from the normal control subjects. Double immunocytochemical analysis revealed the co-localization of ANP and BNP in the same granules and that isolated atrial amyloid fibrils were immunoreactive for ANP and BNP, whereas ventricular amyloid fibrils were negative for both peptides. Both ANP mRNA and BNP mRNA were expressed in the ventricles of the patients with cardiac amyloidosis but not in the normal ventricles. The autopsy study of four patients with cardiac amyloidosis revealed an almost transmural distribution of ANP and BNP, with predominance in the endocardial side. Plasma BNP levels in the patients were markedly elevated ([mean ± SD] 1,165.1 ± 561.2 pg/ml) compared with those in the control subjects (8.9 ± 6.0 pg/ml, p Conclusions. Expression of ANP and BNP and their genes was augmented in the ventricular myocytes of the patients with cardiac amyloidosis. Both regional mechanical stress by amyloid deposits and hemodynamic stress by diastolic dysfunction may be responsible for the expression of the peptides in patients with cardiac amyloidosis.

In a material of seventy-two persons over 70 years of age. forty-seven cases of amyloidosis of the heart were found. In thirty-nine cases, deposits occurred only in the atria (isolated atrial amyl-oidosis. IAA), while in eight cases amyloid also was seen in the ventricles (senile cardiac amyloidosis, SCA). In some of the latter cases, small amyloid deposits occurred in other organs, especially the lungs. Some definite differences existed between the amyloid substance in SCA and IAA. Thus, tryptophan was demonstrated histochemically in SCA but not in IAA, and, furthermore, amyloid fibrils isolated from patients with IAA lacked protein ASCA, the fibril subunit protein of senile cardiac amyloid. It is concluded that the ageing heart may be the target of two different forms of amyloid, one only affecting the atria, while the other is more widespread within the heart and sometimes also is found in other organs.

Congo red screening of 27,052 routine biopsy specimens from 22,827 patients over a 5 1/2-year period in the Department of Pathology, University of Malaya detected 186 cases of amyloidosis. The categories of amyloidosis encountered and their prevalences in relation to each other were: systemic AL (5.9%); systemic AA (3.2%); isolated atrial (14%); primary localized cutaneous (7.5%); other primary localized deposits (3.2%); localized intratumour (58%); and dystrophic (8.6%). A third of patients with systemic AL amyloidosis had coexistent immunocyte abnormality. The commonest underlying pathology for systemic AA amyloidosis was leprosy. Notable among the types of localized amyloidosis revealed by this study were isolated atrial amyloidosis, which appeared to complicate chronic rheumatic heart disease, and intratumour amyloidosis complicating nasopharyngeal carcinoma. Other tumours in which amyloid deposits were observed included basal cell carcinoma, islet cell tumour and medullary carcinoma of the thyroid. Dystrophic amyloidosis was observed in fibrotic tissues, such as damaged cardiac valves and osteoarthritic joints. Heredofamilial amyloidosis, senile systemic amyloidosis and degenerative cerebral amyloidosis were notably absent from this study.