Diagnosis Of ATTR Amyloidosis Research Articles

A case report of ATTR-amyloidosis following cardiac transplantation: thick ventricles that look alike

Abstract Background Transthyretin (ATTR-) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with HFpEF may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation. Case Summary We present a case of a 82-year old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before he required pacemaker implantation due to 3rd degree AV block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR-amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after one month because of gastro-intestinal intolerance. Ultimately, our patient died two years later due to heart failure. Discussion Our case shows the long delay between the onset of transthyretin deposition, the presence of clinical signs and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.

Diagnostics of cardiac amyloidosis

The early diagnosis of cardiac amyloidosis is decisive for the success of treatment of affected persons. The thorough clinical investigation of the patient should be followed by appropriate diagnostics using modern procedures. The main symptoms are dyspnea, loss of performance and edema and in later stages cardiac arrhythmias in the form of atrioventricular conduction disturbances and atrial fibrillation but ventricular arrhythmias occur more rarely. During heart failure due to cardiac amyloidosis an increase of cardiac enzymes frequently occurs (e.g., creatine kinase, troponin, N‑terminal pro-brain natriuretic peptide), which can be included in the risk stratification and treatment monitoring, taking certain limitations into consideration. The investigation of light chains in serum and/or urine should be carried out immediately, as soon as there is a clinical and echocardiographic suspicion of cardiac amyloidosis. Subsequently, either cardiac magnetic resonance imaging (MRI) or bone scintigraphy should be carried out, depending on the locally available options. Depending on the results of these two imaging procedures, a decision must be made as to whether further diagnostic steps (e.g., endomyocardial biopsy) are necessary. In the last decade bone scintigraphy has proven to be a blessing for the diagnostics of cardiac amyloidosis but many partial aspects and limitations necessitate special and careful consideration. A Perugini score of 2 or 3 is initially "indicative" of cardiac amyloidosis but not yet "confirmative" for a specific subtype. Only after an additional negative result of the light chain determination, can the diagnosis of ATTR amyloidosis be noninvasively made. Cardiac amyloidosis shows a particularly characteristic contrast enhancement in cardiac MRI, which mostly begins in the inner (subendocardial) layers of the basal left ventricular (LV) wall and frequently appears to be circular in the cross-sectional view of the left ventricle. Supplementary T1 and extracellular volume fraction mapping results, which are shown as color-coded maps, enable the rapid and elegant assessment of the myocardial structure and the extent of amyloid deposition. An additional investigation of the TTR gene is recommended in the case of ATTR amyloidosis for a differentiation between hereditary and acquired ATTR, as from this, further therapeutic consequences can be derived.

99mTc-DPD myocardial uptake and regional longitudinal strain in aTTR amyloidosis cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND amyloid cardiomyopathy is characterized by a typical "apical sparing" pattern of systolic longitudinal strain (LS) as visualized by echocardiography. Strain is well preserved at the apex of the left ventricle (LV) with a gradient from apex to base and the greatest impairment in the basal segments. The reason of this distribution is not clear. It could be a function of different amount of amyloid deposition. SPECT images using Technetium 99m bone tracers have shown a distribution mimicking regional LS. PURPOSE to compare regional myocardial LS and myocardial distribution of 99m Technetium-DPD (99m Tc-DPD) uptake in patients affected by aTTR amyloidosis cardiomyopathy. METHODS between 2016-2021 70 patients referred to our Cardiology Unit with heart failure/shortness of breath on exertion and showing significant left ventricular hypertrophy at 2-D echocardiography underwent 99m Tc-DPD scintigraphy to test the presence of cardiac amyloid. Grade 2-3 myocardial uptake at 180 minutes in the absence of abnormalities in the analysis of serum free light chains and serum and urine protein electrophoresis with immunofixation was considered sufficient for the diagnosis of aTTR amyloidosis. When scintigraphy was positive a SPECT study was performed to obtain semi quantitative measurements of segmental myocardial uptake (expressed as % of total myocardial uptake). Regional mean count was calculated by using a 6 basal, 12 mid and 2 apical segmental model. All patients underwent standard and 2D speckle tracking echocardiography. Mean systolic LS was calculated for each of 18 segments and mean basal (6 segments), mean mid (6 segments) and mean apical (6 segments) LS was calculated. RESULTS 46/70 patients had a positive scan and fulfilled criteria for aTTR amyloidosis. 33/46 had SPECT analysis. Male/female ratio was 29/4, age = 80 ± 6 years; 9/33 aortic stenosis; 19/33 carpal tunnel; 25/33 wild-type aTTR (4/33 ongoing genetic test); LV mass-=228 ± 48 g/m2; RWT = 0,73 ± 0,14; EF= 53 ± 9; EF to GLS ratio= 5,6 ±1,8. ANOVA showed a significant difference between basal, mid and apical strain as well as between basal, mid and apical uptake (-5,5 ± 4,4; -9,6 ± 3,2; -15,9 ± 5,6; p < 0,001; 55 ± 14; 62 ± 10; 51 ± 11; p = 0,0019). Comparison between groups showed that mean LS at the apex was significantly lower compared to basal and mid mean LS (Bonferroni test, p < 0,001) (Fig 1). Apical myocardial uptake was significantly lower compared to mid segment but not to basal (Bonferroni test, p = 0,02, p = 0,6 respectively) (Fig 1). Spearman’s test showed a correlation between LS and myocardial 99m Tc-DPD uptake (p = 0,01, Rho = 0,24). CONCLUSIONS Our data show that in this group of patients with cardiac aTTR amyloidosis apical LS is significantly lower compared to basal and mid segments and apical myocardial 99m Tc-DPD uptake is significantly lower compared to mid segments; a correlation between myocardial 99m Tc-DPD uptake distribution and the degree of LS impairment is present. Abstract Figure.

Phenotypic heterogeneity and diagnostic features of transthyretin amyloidosis with polyneuropathy

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vindakel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vindakel significantly slows down the progression of the disease, improves the prognosis and quali ty of life in patients with ATTR polyneuropathy.

The Changing Face of Amyloidosis Referrals at a Tertiary Center over the Past 3 Decades

▪Amyloidosis is an increasingly recognized group of disorders, characterized by the deposition of misfolded protein aggregates in various tissues and organs. For over 50 years, the Amyloidosis Center at Boston University Medical Center (BUMC) has taken lead in the comprehensive evaluation and treatment of patients with this disease. The center serves as a tertiary referral site both nationally and globally, with patients visiting from 18 countries in recent years. Historically, immunoglobulin light chain (AL) amyloidosis associated with a plasma cell dyscrasia has had the greatest prevalence at our center. Other forms of amyloidosis, such as the hereditary mutant transthyretin (ATTRm) and age-related wild type transthyretin (ATTRwt) amyloidoses, have been seen less commonly due in part to underdiagnosis and a perceived paucity of effective treatments.We report here the spectrum of referrals at the Amyloidosis Center at BUMC from 1990 to 2017. We used data from a prospectively maintained database of consented patients. Of the 3084 patients seen for an initial evaluation at our center during this period, patients with AL amyloidosis decreased from 86% to 79% to 65% in the first, second and third decade, respectively. In the same time intervals, ATTRm amyloidosis cases increased from 12% to 14% to 19% of the total patients; an even steeper increase, from 2% to 7% to 16%, was seen in patients with ATTRwt amyloidosis.There is a marked trend towards more referrals of ATTR amyloidosis at BUMC. We believe this reflects increasing awareness and advancements in the diagnostic and therapeutic landscape of ATTR amyloidosis. In the early 2000s, the potential for misdiagnosis of hereditary ATTR as AL amyloidosis was recognized (Lachmann, et al. N Engl J Med. 2002). Accordingly, biochemical analysis by immunogold electron microscopy or laser capture tandem mass spectrometry has become a standard for more accurate typing of amyloid protein. Availability and utilization of these specific pathological modalities may in part explain the growing proportion of ATTR amyloidosis seen at our center.Perhaps an even more significant factor is the development of nuclear cardiac imaging techniques, which accurately diagnose ATTR cardiac amyloidosis without the need for endomyocardial biopsy. In the last decade, technetium associated bone-avid tracers, such as pyrophosphate (PYP), have been found to be highly sensitive and specific in identifying ATTR cardiac amyloidosis among patients with heart failure (Gillmore, et al. Circulation. 2016). Ease of performance and interpretation, availability and standardization have spurred widespread adaptation of this imaging modality, thereby allowing for recognition of ATTR cases that were undiagnosed in prior decades.A recent surge in diagnosis of ATTR amyloidosis is coincident with an evolving therapeutic landscape. There have been a number of clinical trials for ATTR amyloidosis, investigating transthyretin protein suppression and stabilization, as well as fibril clearance. Three therapies have completed phase III trials and are pending US regulatory review and registration. Publicity surrounding these trials has led physicians and patients to seek referral to tertiary centers for evaluation for novel treatments. The rise in new ATTR referrals at BUMC is countered by a decline in AL amyloidosis referrals, from a former average of 102 new cases per year to 91 per year in the last decade. We believe this to be largely owed to increasing experience with and adoption by community hematologists of the therapeutic options for AL amyloidosis, which are derived from treatments for multiple myeloma.In conclusion, once thought to be exceedingly rare, ATTR is becoming an increasingly prevalent form of amyloidosis at tertiary centers, comprising nearly 1 of every 3 new referrals at BUMC in the past decade. We anticipate that this proportion will rise further as PYP nuclear imaging becomes incorporated into screening algorithms for heart failure and awareness spreads about the anticipated approval of new pharmaceuticals for ATTR amyloidosis. DisclosuresBerk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator.

In vivo quantification of amyloid burden in TTR-related cardiac amyloidosis.

Cardiac transthyretin-related (ATTR) amyloidosis is a severe cardiomyopathy for which therapeutic approaches are currently under development. Because non-invasive imaging techniques such as cardiac magnetic resonance imaging and echocardiography are non-specific, the diagnosis of ATTR amyloidosis is still based on myocardial biopsy. Thus, diagnosis of ATTR amyloidosis is difficult in patients refusing myocardial biopsy. Furthermore, myocardial biopsy does not allow 3D-mapping and quantification of myocardial ATTR amyloid. In this report we describe a 99mTc-DPD-based molecular imaging technique for non-invasive single-step diagnosis, three-dimensional mapping and semiquantification of cardiac ATTR amyloidosis in a patient with suspected amyloid heart disease who initially rejected myocardial biopsy. This report underlines the clinical value of SPECT-based nuclear medicine imaging to enable non-invasive diagnosis of cardiac ATTR amyloidosis, particularly in patients rejecting biopsy.

Characterization of conformation-specific, human-derived monoclonal antibodies against TTR aggregates with potential for diagnostic and therapeutic use

Misfolding and aggregation of transthyretin (TTR) is the basic pathophysiological mechanism of hereditary and wild type TTR amyloid (ATTR) amyloidosis. Polyneuropathy and/or cardiomyopathy with heart failure dominates the clinical presentation of the disease. Conformational changes of the TTR protein structure produce toxic intermediates that introduce cell death and ultimately loss of organ function. Reliable and early diagnosis of ATTR amyloidosis are, however, difficult to obtain based on the patients’ clinical presentation, since different types of neuropathies or cardiomyopathies often exhibit similar clinical findings, especially early after onset of disease. Since misfolded TTR aggregates constitutes an early phase of amyloid formation, availability of a diagnostic tests able to detect misfolded TTR aggregates either biochemically or by imaging techniques would facilitate a correct and early diagnosis of ATTR amyloidosis. By comprehensive genetic sequence analyses of the human immune repertoire for TTR-specific memory B-cells, we cloned and recombinantly expressed human-derived monoclonal antibodies, which specifically bind with high affinity and selectivity to misfolded TTR but not physiological TTR tetramers. These antibodies specifically detect ATTR deposits in ATTR amyloidosis patients’ biopsies and TTR aggregates in corresponding tissues from TTR transgenic mouse-models. The selectivity of the human antibodies for misfolded TTR is driven by their targeting of cryptic or conformational epitopes which are exposed in misfolded and/or aggregated wild type as well as mutant TTR. These conformation-specific, human-derived monoclonal antibodies are promising candidates for diagnostic use, and for the development of disease-modifying therapies for TTR amyloidosis by targeting and facilitating the removal of disease-causing TTR aggregates.