Atrial Amyloid Research Articles

Left atrial deformation discloses atrial amyloid infiltration among patients with increased myocardial thickness

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swedish research council Swedish heart and lung foundation Background Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative disease with thickening and stiffening of the heart walls as a result. Amyloid deposits are found not only in the ventricular walls, but in the atriums as well. Atrial function is known to play an integral part in the overall function of the heart. Purpose We aimed to evaluate left atrial deformation including left ventricular-atrial strain loop (LV-LA loop). The latter to test LA deformation and its dependence of LV deformation in ATTR CA and compare it to left ventricular hypertrophy (LVH). Methods Retrospective analysis was performed on available echocardiographic data, obtained between years 2004–2022. The study population was divided into three groups: healthy controls with no identified cardiac disease; ATTR-CA patients with verified ATTR-CA diagnosis and interventricular septal thickness end diastole (IVSd) of ≥14mm; LVH including IVSd ≥14mm and no CA diagnosis. Left heart strain measurements, including LV global longitudinal strain (LV GLS) and LA peak atrial longitudinal strain (LA PALS), were acquired from apical 4-chamber view during same single heart cycle. Strain coordinates throughout the heart cycle were plotted using MATHLAB, combining LV GLS and LA PALS to compute a strain-strain loop. A slope was determined using regression line to index relative function of the left ventricle to left atrium (GLS-PALS-slope). Results Data was gathered in total of 90 patients (67.8±1.2 years, 55,6% male) divided into three groups containing 30 patients each: ATTR-CA including 24 hereditary ATTR (including mutations; 19 Val30Met, one The60Ala, one Val122Ile, one Ala45Glys, one Ala97Ser and one His88Arg) and six wild type ATTR, LVH with increased myocardial thickness believed caused by aortic stenosis (n=13; one grade I, three grade II-III and eight grade III), essential hypertension (n=10) and hypertrophic cardiomyopathy (n=7, four of which had outflow obstruction). The lowest PALS and PALS-GLS slope was detected in ATTR-CA (p-value 0.005 respectively 0.003 between ATTR-CA compared to LVH). No significant statistical difference could be verified in GLS between ATTR-CA and LVH (p-value 0.114). A ROC curve of ATTR-CA demonstrated similar results between PALS and GLS-PALS slope (AUC 0.79 resp. 0.78) which was slightly higher than GLS (AUC 0.69). Slightly higher AUC was generated when slope was indexed with LAVI (AUC 0.80). Conclusions LA deformation demonstrates a strong ability to differentiate ATTR-CA from LV hypertrophy. Adding LV strain in relation to LA deformation showcases the mechanical dissociation of LA to LV in ATTR-CA, potentially unmasking atrial infiltration. Its use in prognostic evaluation needs further studies.

Time in therapeutic range of anticoagulation among patients with atrial fibrillation and cerebral amyloid angiopathy

Atrial fibrillation (AF) and cerebral amyloid angiopathy (CAA) present risks of ischemic stroke and intracerebral hemorrhage (ICH). Vitamin K antagonist use is associated with fluctuations in international normalized ratio (INR), which predispose to a higher bleeding risk. Patients with a diagnosis of AF and ICH while on a vitamin K antagonist were identified using the Rochester Epidemiology Project. Sixty patients were identified (mean age 81.3 years; 24 men). Thirty-three (55%) exhibited characteristics consistent with possible (n = 25) or probable (n = 8) CAA. Mean time in therapeutic range in the 30 days preceding ICH was 55.4%, with no difference between CAA and non-CAA patients. Mean time spent above therapeutic range (INR > 3.0) was 17.7%, with no difference between CAA and non-CAA patients. Following ICH, 21 (35%) died within 30 days, with total mortality at 76.7% after 176.4 person-years of follow-up (mean 2.9 years). Time in therapeutic range in the 30 days prior to ICH had no significant impact on 7-day mortality, nor risk of recurrent ICH or ischemic stroke. Patients with warfarin-related ICH were often outside of the therapeutic range within the month preceding hemorrhage but more frequently were subtherapeutic. Even with careful avoidance of supratherapeutic INR, vitamin K antagonist use in CAA patients is unlikely to have a major effect in preventing ICH and must be used with caution.

Abstract 10676: Left Atrial Strain is Associated with Supraventricular Tachycardia in Cardiac Amyloidosis Patients

Introduction: In cardiac amyloidosis, supraventricular tachycardia is common. Probable mechanisms are left ventricular dysfunction resulting in left atrial disease, but also direct atrial amyloid infiltration. Although measurement of left ventricular global longitudinal strain is commonly used, the value of left atrial strain remains unclear. Hypothesis: Left atrial strain should be strongly associated with the occurrence of supraventricular tachycardia in cardiac amyloidosis patients. Methods: In 69 cardiac amyloidosis patients (75% male, mean age 65 years) in our Amyloidosis Expert Center, echocardiographic strain analysis was performed using EchoPAC (version 203, General Electric Healthcare) between March 2017 and May 2020. Results: Supraventricular tachycardia occurred in 34 (43%) cardiac amyloidosis patients, which were older (70±8 vs. 60±15 years, p=0.001) but had a similar left ventricular mass index and ejection fraction. Left atrial volume index was higher (56±21 vs. 45±18 ml/m 2 , p=0.02), left ventricular global longitudinal strain (11±4 vs. 14±4, p=0.004) and left atrial reservoir strain (12±9 vs. 23±16, p=0.001) were lower. Left atrial reservoir strain was associated with supraventricular tachycardia, independent of left ventricular global longitudinal strain or left atrial volume (B-value 0.88 (confidence interval 0.80 - 0.97), p=0.01). Conclusion: Low left atrial reservoir strain was associated with the occurrence of supraventricular tachycardia independent of left atrial volume and left ventricular global longitudinal strain and therefore a promising parameter in cardiac amyloidosis patients.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.

The Prevalence of Advanced Interatrial Block and Its Relationship to Left Atrial Function in Patients with Transthyretin Cardiac Amyloidosis.

Background: Advanced interatrial block (aIAB), which is associated with incident atrial fibrillation and stroke, occurs in the setting of blocked interatrial conduction. Atrial amyloid deposition could be a possible substrate for reduced interatrial conduction, but the prevalence of aIAB in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown. We aimed to describe the prevalence of aIAB and its relationship to left atrial function in patients with ATTR-CA in comparison to patients with HF and left ventricular hypertrophy but no CA. Methods: The presence of aIAB was investigated among 75 patients (49 patients with ATTR-CA and 26 with HF but no CA). A comprehensive echocardiographic investigation was performed in all patients, including left atrial strain and strain rate measurements. Results: Among patients with ATTR-CA, 27% had aIAB and in patients with HF but no CA, this figure was 21%, (p = 0.78). The presence of aIAB was associated with a low strain rate during atrial contraction (<0.91 s−1) (OR: 5.2 (1.4–19.9)), even after adjusting for age and LAVi (OR: 4.5 (1.0–19.19)). Conclusions: Advanced interatrial block is common among patients with ATTR-CA, as well as in patients with heart failure and left ventricular hypertrophy but no CA. aIAB is associated with reduced left atrial contractile function.

Histopathological changes in the right atrial appendages triggering atrial fibrillation: A tertiary care center study.

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 Hematoxylin &Eosin, 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) (P<0.05). 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.

P177 Left atrial strain in patients with cardiac amyloidosis. Relationship to left atrial amyloid deposition focusing on prognosis

Abstract Background In cardiac amyloidosis (CA), the left atrium (LA) is frequently infiltrated by the amyloid fibrils. It is currently known that LA strain is a marker of LA function and prognosis in many cardiac diseases, however its significance in CA remains unknown. Purpose Our aim was to investigate correlation between LA strain measured by Cardiovascular Magnetic Resonance (CMR) and amyloid deposit in LA, and also evaluate the LA strain on the prognostic significance. Methods and results Of 74 consecutive patients with biopsy-proven CA, we analyzed 42 patients (age 72 ± 10 years; 76 % males) with contrast-enhanced CMR, and examined LA late gadolinium enhancement (LGE) and CMR derived LA strain using feature tracking method. Of the 42 patients, 29 patients (69 %) was transthyretin cardiac amyloidosis (ATTR-CA) in the majority. We divided these 42 patients into two groups according to the CMR measured peak atrial longitudinal strain (PALS) (&amp;gt; = or &amp;lt; median); high-strain (&amp;gt; = 6.67 %, n = 21) and low-strain (＜ 6.67 %, n = 21) and compared the patient’s characteristics, blood test data, echocardiography and CMR parameters. There were no significant differences between two groups in these parameters but in the extent of LA-LGE (54 % vs 80 %, p = 0.008). The PALS correlated with the extent of LA-LGE (ρ= 0.50, p = 0.001). In multivariate analysis including LVEF, E/e’ and BNP, LA-LGE was an independent determinant of PALS. During three-year follow up, the LA strain significantly related to heart failure hospitalization in the ATTR-CA patients (p = 0.036)(Figure). Conclusions In CA patients, CMR measured LA longitudinal strain correlates with the LA-LGE. It also provides useful information for poor prognosis of patients with ATTR-CA. Abstract P177 Figure. Heart failure hospitalization in ATTR-CA

Amyloidosis in surgically resected atrial appendages: a study of 345 consecutive cases with clinical implications.

Histomorphologic parameters of atrial appendages removed during the Cox-Maze procedure have been shown to correlate with recurrence of atrial fibrillation. While amyloid deposition has been noted within atrial appendages, the incidence and significance remains incompletely understood. More accurate amyloid typing methodologies and targeted pharmacotherapeutics have recently been developed, prompting pathologists to provide more detailed information about the type of amyloid identified in such samples. This study sought to fully characterize the morphologic characteristics of atrial amyloid as well as its incidence and clinical significance. Tissue archives were queried for atrial appendages removed during the cardiac surgeries (2010-2014). Patient demographics, imaging features, and salient clinical findings were recorded. Pattern and extent of amyloid deposition were recorded. Typing of the amyloid protein, when present, was performed on a subset of cases by laser capture microdissection with mass spectrometry-based proteomic analysis. A total of 383 atrial appendages from 345 consecutive patients were included in the study (mean age, 69 years; range, 26-92 years). Amyloid was present in 46% of patients. A linear relationship was observed between age and presence of atrial amyloidosis. Women were more likely to have atrial amyloidosis. Two distinct morphologies of amyloid were observed: filamentous and nonfilamentous, and correlated perfectly with amyloid type (filamentous = AANF-type amyloid; nonfilamentous = ATTR-type amyloid). Filamentous deposits were observed in 91% of those with amyloid. Amyloid was more likely to be found in the left atrial appendage than the right. Patients with atrial amyloid, irrespective of type, were more likely to have experienced stroke or TIA and more likely to have atrial arrhythmia preoperatively. Postoperatively, those with atrial amyloid are more likely to experience recurrence of arrhythmia than those who did not have atrial amyloid. Understanding the morphologic characteristics of AANF-type amyloid will allow for identification by the light microscopy and obviates the need for expensive ancillary typing techniques. The finding of nonfilamentous amyloid, should still prompt confirmation of amyloid type so that targeted therapy may be employed.

P2458Restricted left atrial motion as a result of atrial stiffening in patients with cardiac amyloidosis

Abstract Background Left atrial (LA) involvement of abnormal amyloid fibrils could induce LA dysfunction and stiffening in patients with cardiac amyloidosis (CA). Thus, the assessments of LA function and stiffness might be a potential approach to diagnose CA phenotype among patients with hypertrophied hearts. Purpose We sought to determine whether LA reservoir strain with speckle tracking echocardiography could be used a marker of LA stiffness in a derivation cohort. Furthermore, we tested to our hypothesis that LA reservoir strain could differentiate CA patients from hypertrophic cardiomyopathy (HCM) in an independent validation cohort. Methods In the derivation cohort, echocardiography was performed simultaneously with measurements of pulmonary capillary wedge pressure (PCWP) in 50 patients with suspected or established heart failure and relatively preserved left ventricular (LV) ejection fraction (56±10%). LA maximum and minimum volume index, and reservoir strain were measured from apical four-chamber view. LA stiffness index was computed as a pressure rise from x-trough to v-wave divided by an increase from minimum to maximum indexed LA volume (Figure A). In an independent validation group, we studied a total of 33 biopsy-proved CA patients and 127 HCM patients (LV ejection fraction: 57±11% vs. 66±10%, P&lt;0.01) in sinus rhythm on the date of comprehensive echocardiographic study. Among them, cardiac magnetic resonance imaging (CMR) could be evaluated in 17 CA patients and 98 HCM patients. Furthermore, right heart catheterization was performed with 12 CA patients and 12 HCM patients in the CMR group. Results The derivation cohort study found that there was a significant curvilinear correlation of LA reservoir strain to LA stiffness index (Figure B). In the validation cohort, LA reservoir strain was reduced in patients with CA compared with HCM in all participants (11.6±5.6% vs. 18.5±6.9%, P&lt;0.01), although there was no significant difference of LA maximal volume index between 2 groups (37±16 ml/m2 vs. 37±12 ml/m2, p=0.89). In the CMR group, the late gadolinium enhancement was observed in the LA wall in 16 patients with CA (94.1%) as shown in Figure C. In contrast, the LA enhancement revealed only in 1 patient with HCM (1.0%). Among patients with invasive measures, LA stiffness index [median (interquartile range)] was higher in patients with CA than that in patients with HCM [1.1 (0.4–2.8) vs. 0.2 (0.1–0.6), P=0.01]. Conclusions LA reservoir function was fairly limited in patients with CA compared with HCM. Restricted LA motion might be related to atrial amyloid deposits or fibrosis, which potentially provokes atrial chamber stiffening.

Isolated atrial amyloid: a potential contributor to morbidity and mortality following cardiac surgery.

Diffuse 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. A 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. A 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). The 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.

High recurrence of atrial fibrillation in patients with high tissue atrial natriuretic peptide and amyloid levels after concomitant maze and mitral valve surgery

BackgroundHemodynamic burden is thought to play a role in valvular atrial fibrillation (AF), but the detailed pathophysiology is unclear. We hypothesized that atrial natriuretic peptide (ANP) tissue levels and amyloid deposits in the left atrial appendage (LAA) were associated with the pre-operative hemodynamic status and post-operative rhythm outcome in patients undergoing a concomitant mitral valve and maze surgery. MethodsWe quantified the fibrosis, atrial amyloid deposits, ANP tissue levels, and multiple biomarker proteins (Western blot) in LAA tissues taken from 26 patients (53.8% male, 58.4±9.7 years) who underwent concomitant maze and mitral valve surgery. The histologic and biochemical results were compared with the pre-operative pulmonary artery pressure (PAP) and post-operative rhythm outcome. ResultsThe ANP tissue level was positively correlated with the atrial amyloid deposit areas (R=0.880, p<0.001), but not with the degree of fibrosis. The pre-operative systolic PAP negatively correlated with both the ANP tissue expression level (R=−0.467, p=0.019) and atrial amyloid deposit area (R=−0.589, p=0.008). The angiotensin II tissue expression level was significantly higher in tissues without ANP expression than in those with expression (p=0.003). AF recurrence after the maze operation was significantly lower in patients without than in those with ANP expression (log rank p=0.031, HR 3.779, 95% CI 1.163–12.277, p=0.027). ConclusionsA lower ANP atrial tissue expression and amyloid deposits were correlated with a high pre-operative hemodynamic loading, and those patients had a paradoxically lower AF recurrence after relief of the hemodynamic burden by concomitant maze and mitral valve surgery.

Cerebral embolism due to atrial myopathy in a cardiac amyloidosis patient diagnosed by cardiac magnetic resonance imaging

A 55-year-old woman was admitted with heart failure. On the third hospital day, she suddenly developed cerebral infarction. The resting 12-lead electrocardiography showed normal sinus rhythm, and atrial fibrillation or flutter were never detected on electrocardiographic monitoring throughout the whole hospital days. She had no other conventional risk factor for cerebral infarction. Transthoracic echocardiography showed left ventricular hypertrophy. Transesophageal echocardiogram revealed strong spontaneous echo contrast in the left atrium (LA), and the blood flow in the left atrial appendage was extremely decreased (22.3cm/s). Late gadolinium enhancement in cardiac magnetic resonance (CMR) imaging showed global subendocardial hyperenhancement of the left ventricle and both atria. Endomyocardial biopsy specimen was positive for amyloid by Congo red staining. Marked amyloid infiltration to both atria might cause atrial dysfunction leading to thrombus formation in the LA. CMR is thought to be a useful noninvasive tool to detect atrial myopathy in cardiac amyloidosis patients.<Learning objective: In cardiac amyloidosis patients, late gadolinium enhancement on CMR in the atria might be an important sign, which would suggest atrial amyloid deposition with impaired atrial function. CMR is thought to be a useful noninvasive tool to detect even atrial myopathy in cardiac amyloidosis patients. Furthermore, we recommend to evaluate the atrial function using transesophageal echocardiography in these patients. If impaired atrial function was detected, despite with or without atrial fibrillation, they should receive anticoagulation therapy for preventing the thromboembolic event.>

Updates in Cardiac Amyloidosis: A Review

Systemic amyloidosis is a relatively rare multisystem disease caused by the deposition of misfolded protein in various tissues and organs. It may present to almost any specialty, and diagnosis is frequently delayed.[1][1] Cardiac involvement is a leading cause of morbidity and mortality, especially

Amyloid diseases of the heart: current and future therapies

Amyloid diseases in man are caused by as many as 23 different pre-cursor proteins already described. Cardiologists predominantly encounter three main types of amyloidosis that affect the heart: light chain (AL) amyloidosis, senile systemic amyloidosis (SSA) and hereditary amyloidosis, most commonly caused by a mutant form of transthyretin. In the third world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Much less common, are the non-transthyretin variants, including mutations of fibrinogen, the apolipoproteins apoA1 and apoA2 and gelsolin. These rarer types do not usually cause significant cardiac compromise. Occurring worldwide, later in life and of less clinical significance, isolated atrial amyloid (IAA) also involves the heart. Heart involvement by amyloid often has devastating consequences. Clinical outcome depends on amyloid type, the extent of systemic involvement and the treatment options available. An exact determination of amyloid type is critical to appropriate therapy. In this review we describe the different approaches required to treat this spectrum of amyloid cardiomyopathies.

The Association of Atrial Tachyarrhythmias with Isolated Atrial Amyloid Disease: Preliminary Observations in Autopsied Heart Specimens

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.

Patterns of isolated atrial amyloid: A study of 100 hearts on autopsy

Isolated atrial amyloid (IAA), one of the most common members of the family of age-related ("senile") amyloids, seems to play a role in the pathogenesis of atrial fibrillation. Patterns of IAA deposition were histologically studied in the hearts of 100 elderly patients. The incidence (%) and severity (grade 0-3) of atrial IAA deposits increase with age, from 75% incidence and 0.50 average grade in patients aged 51-60 years, to 86% incidence and 1.49 average grade in those aged 81-90 years. Deposits are more pronounced in females (88% incidence, 1.45 average grade) than in males (68% incidence, 0.79 average grade). Left atrial deposits are more pronounced (78% incidence, 1.25 average grade) than right atrial deposits (67% incidence, 1.09 average grade). The distribution of IAA in the walls of the left atrium is uneven, with deposits being more pronounced in the anterior wall than in both the posterior wall and the left appendage. IAA deposits are heavier (1.34 average grade) in patients with chronic atrial fibrillation than in those with sinus rhythm (1.01 average grade); the difference, however, lacks statistical significance. Hypertension, diabetes mellitus, hypertrophy of the heart, coronary atherosclerosis, and dilatation of the atria show no significant relationship to the incidence or severity of atrial amyloidosis.

Myocardial sleeves of pulmonary veins and atrial fibrillation: a postmortem histopathological study of 100 subjects

Atrial fibrillation (AF) is triggered by ectopic beats originating from extensions of the left atrial myocardium over the pulmonary veins (PVs), so-called myocardial sleeves. A total of 100 hearts (393 PVs) obtained at autopsy were studied. Of these, 50 were from patients with chronic AF and 50 from controls in sinus rhythm. Out of a total of 393 PVs studied, a sleeve was present in 349 PVs (88.8%). The myocardial sleeves frequently harboured senile atrial amyloid and scarring. These two changes were evaluated semi-quantitatively (grade 0-3). Amyloidosis was found in 68% of all hearts and in 55% of all sleeves. It was more frequent in patients with AF (58.5%) than in those without (51.7%), however, without statistical significance (p values 0.948, 0.306, 0.166 and 1). Scarring was present in all 349 sleeves studied. It was significantly more severe in patients with AF (average grade 2.44) than in those without (average grade 2.00) (p values <0.001, <0.1, <0.05 and <0.01). In conclusion, amyloidosis and particularly scarring of the myocardial sleeves of the pulmonary veins, appear to be common in the elderly population as an arrhythmogenic substrate for AF.

Natriuretic peptide Val7Met substitution and risk of coronary artery disease in Greek patients with familial hypercholesterolemia

Atrial natriuretic peptide (ANP or NPPA) is the precursor protein of the form of amyloidosis called isolated atrial amyloid (IAA), which is related to the increased incidence of cardiac pathological conditions with age. Familial hypercholesterolemia (FH) patients are characterized by high concentrations of low-density lipoprotein cholesterol (LDL-C), which frequently gives rise to premature coronary artery disease (CAD). However, not all FH patients have the same clinical phenotype. The aim of the present study was to assess the relationship between ANP polymorphisms and apolipoprotein (Apo) A1 levels and CAD risk in FH patients. Transition T2238C, which leads to ANP with two additional arginines, and G664A (Val7Met) were investigated with lipid values and clinical phenotype in 83 FH patients. ApoA1 and HDL cholesterol levels were lower in GA patients compared to GG homozygotes for the G664A polymorphism. No association was found between the G664A polymorphism and CAD in our population. Moreover, ApoA1 and high-density lipoprotein cholesterol (HDL-C) levels did not differ among the different genotypes of the T2238C polymorphism, even after adjusting for age and sex. The 664A allele of the ANP polymorphism is associated with lower levels of ApoA1 and HDL-C in FH patients, but not with CAD risk. Concerning the T2238C polymorphism, no effect was found on lipid parameters or CAD incidence.

Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation.

Structural changes, like atrial fibrosis, may increase the likelihood of atrial fibrillation (AF) occurring in response to triggering events. The influence of isolated atrial amyloidosis (IAA) is largely unknown. Right atrial appendages (1 or 2 entire cross sections) were obtained from 245 patients undergoing open-heart surgery. Atrial amyloid was identified by Congo red staining and classified by immunohistochemistry. Amyloid was found in 40 (16.3%) of 245 patients, and all deposits were immunoreactive for atrial natriuretic peptide (ANP). Thirty-eight (15.5%) patients suffered from persistent AF. The presence of amyloid correlated with age and P-wave duration and was related to sex, valve diseases, and the presence of AF (P<0.01). The association between atrial amyloid, AF, and P-wave duration was independent of age and sex. According to multiple logistic regression analysis, amyloid was the only age- and sex-independent predictor for the presence of AF. Atrial fibrosis was not a predictor for AF, and the amount of amyloid correlated inversely with the degree of interstitial fibrosis (P=0.001; r=-0.55). Our study provides evidence that IAA affects atrial conduction and increases the risk of AF. The occurrence of IAA depends on age leading to the formation of an amyloid nidus. The progression and consequences of IAA are then influenced by pathological conditions, such as valve diseases, that increase synthesis and secretion of ANP. The inverse correlation between IAA and atrial fibrosis suggests that these patients may not benefit from treatment with ACE inhibitors to reduce the amount of atrial fibrosis.

Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients With Cardiac Amyloidosis

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 < 0.05).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.