Wild-type Transthyretin Amyloidosis Research Articles

The Clinical Impact of Proteomics in Amyloid Typing

The Clinical Impact of Proteomics in Amyloid Typing

Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis.

BackgroundWild‐type transthyretin (ATTRwt) amyloidosis is the most common systemic amyloidosis in Western countries and manifests mainly as progressive restrictive cardiomyopathy.ObjectiveTo study the prevalence of ATTR deposits in ligament tissue in patients undergoing surgery for lumbar spinal stenosis and to assess whether these deposits are associated with cardiac amyloidosis.Materials and methodsA total of 250 patients, aged 50–89 (57% women), none with known cardiovascular disease, were included. Ligaments were investigated microscopically for amyloid. ATTR type was determined by immunohistochemistry and fibril type by Western blot. The amount of amyloid was graded 0‐4. All patients with grade 3‐4 ATTR deposits were offered cardiac investigation including ECG, cardiac ultrasound, plasma NT‐proBNP and cardiac magnetic resonance (CMR), including modern tissue characterization.ResultsAmyloid was identified in 221 of the samples (88.4%). ATTR appeared in 93 samples (37%) of whom 42 (17 women and 25 men) were graded 3‐4; all had fibril type A (mixture of full‐length TTR and fragmented TTR). Twenty‐nine of 42 patients with grade 3‐4 ATTR deposits accepted cardiovascular investigations; none of them had definite signs of cardiac amyloidosis, but five men had a history of carpal tunnel syndrome.ConclusionsThe prevalence of ATTR deposits in ligamentum flavum in patients with lumbar spinal stenosis was high but not associated with manifest ATTR cardiac amyloidosis. However, the findings of fibril type A, the prevalence of previous carpal tunnel syndrome and ATTR amyloid in surrounding adipose and vascular tissue indicate that amyloid deposits in ligamentum flavum may be an early manifestation of systemic ATTR disease.

Impact of tricuspid regurgitation on survival in patients with cardiac amyloidosis

Tricuspid regurgitation (TR) is a common finding and has been associated with poorer outcome in patients with heart failure. This study sought to investigate the prognostic value of TR in patients with cardiac amyloidosis (CA). Two-hundred and eighty-three patients with CA – 172 (61%) wild-type transthyretin–amyloidosis (ATTRwt) and 111 (39%) light-chain amyloidosis (AL) – were consecutively enrolled between December 2010 and September 2019. Transthoracic echocardiographies at time of diagnosis were reviewed to establish the presence and severity of TR and its relationship with all-cause mortality during patients’ follow-up. Seventy-four (26%) patients had a moderate-to-severe TR. Moderate-to-severe TR was associated with NYHA status (P < 0.001), atrial fibrillation (P = 0.003), greater levels of natriuretic peptides (P = 0.002), worst renal function (P = 0.03), lower left ventricular ejection fraction (P = 0.02), reduced right ventricular systolic function (P = 0.001), thicker tricuspid leaflets (P = 0.019), greater tricuspid annulus diameter (P = 0.001), greater pulmonary artery pressure (P = 0.001), greater doses of furosemide (P = 0.001) and anti-aldosterone (P = 0.01) and more anticoagulant treatment (P = 0.001). One hundred and thirty-four (47%) patients met the primary endpoint of all-cause mortality. After multivariate Cox analysis, moderate-to-severe TR was significantly associated with mortality (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: [1.01–3.51], P = 0.044) in patients with ATTRwt. There was no correlation between TR and death (HR: 0.84, 95% CI: [0.46–1.51], P = 0.562) in patients with AL. Moderate-to-severe TR is frequent in CA and it is an independent prognosis factor in patients with ATTRwt but not in patients with AL.

Wild type transthyretin amyloidosis, a reason not to be forgotten for heart failure of preserved ejection fraction in the elderly.

Wild type transthyretin amyloidosis, a reason not to be forgotten for heart failure of preserved ejection fraction in the elderly.

Utility of Neuropathy Screening for Wild-Type Transthyretin Amyloidosis Patients.

Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain. This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls. Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III-IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III-IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I-II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9-29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient. Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.

Estimating the Gender Distribution of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis.

IntroductionThis study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt).MethodsA systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution.ResultsTwenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5–91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% (p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% (p value 0.002) lower male proportion compared to other studies.ConclusionsStudies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research.Electronic supplementary materialThe online version of this article (10.1007/s40119-020-00205-3) contains supplementary material, which is available to authorized users.

Impact of tricuspid regurgitation on survival in patients with cardiac amyloidosis.

AimsTricuspid regurgitation (TR) is a common finding and has been associated with poorer outcome in patients with heart failure. This study sought to investigate the prognostic value of TR in patients with cardiac amyloidosis (CA).Methods and resultsTwo‐hundred and eighty‐three patients with CA—172 (61%) wild‐type transthyretin amyloidosis (ATTRwt) and 111 (39%) light‐chain amyloidosis (AL)—were consecutively enrolled between December 2010 and September 2019. Transthoracic echocardiographies at time of diagnosis were reviewed to establish the presence and severity of TR and its relationship with all‐cause mortality during patients' follow‐up. Seventy‐four (26%) patients had a moderate‐to‐severe TR. Moderate‐to‐severe TR was associated with New York Heart Association status (P < 0.001), atrial fibrillation (P = 0.003), greater levels of natriuretic peptides (P = 0.002), worst renal function (P = 0.03), lower left ventricular ejection fraction (P = 0.02), reduced right ventricular systolic function (P = 0.001), thicker tricuspid leaflets (P = 0.019), greater tricuspid annulus diameter (P = 0.001), greater pulmonary artery pressure (P = 0.001), greater doses of furosemide (P = 0.001), and anti‐aldosterone (P = 0.01) and more anticoagulant treatment (P = 0.001). One hundred and thirty‐four (47%) patients met the primary endpoint of all‐cause mortality. After multivariate Cox analysis, moderate‐to‐severe TR was significantly associated with mortality [hazard ratio 1.89, 95% confidence interval (1.01–3.51), P = 0.044] in patients with ATTRwt. There was no correlation between TR and death [hazard ratio 0.84, 95% confidence interval (0.46–1.51), P = 0.562] in patients with AL.ConclusionsModerate‐to‐severe TR is frequent in CA, and it is an independent prognosis factor in patients with ATTRwt but not in patients with AL.

Prevalence of wild type transtyrethin cardiac amyloidosis in a heart failure clinic.

AimsWild type transthyretin amyloidosis (ATTRwt) has gained interest during recent years due to better diagnostic tools and the emergence of treatment options. Little is known about the prevalence of the disease. We aimed to investigate the prevalence in a heart failure population with myocardial hypertrophy.Methods and resultsAll patients with an ICD code of heart failure living within the catchment area of Umeå University hospital and intraventricular septum >14 mm were offered screening with 3,3‐diphosphono‐1,2‐propanodicarboxylic acid (DPD) scan and a clinical work up. Out of 2238 patients with heart failure, 174 patients were found to have a septum >14 mm. Ten patients were already diagnosed with hereditary ATTR cardiomyopathy, 12 patients had ATTRwt cardiomyopathy, 12 patients had known HCM, one patient had AL amyloidosis, and four patients had already undergone a negative DPD scan (DPD uptake grade 0 and 1) within the last 3 years. This left 134 patients who we tried to contact for screening, but 48 patients had either died or declined to participate. Out of 86 screened patients, 13 had a DPD uptake of grade 2 or 3 without other amyloid disease making the total number of patients with ATTRwt in this population 25.ConclusionsApproximately 20% of investigated patients in a cohort with heart failure and increased myocardial wall thickness has ATTRwt. Calculated for the whole population of heart failure patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6000.

Abstract 16603: Appropriate Timing of Pacemaker Implantation in Patients With Wild-Type and Variant Amyloidogenic Transthyretin Cardiac Amyloidosis

Background and Objectives: It has been shown that cardiac conduction disorders can be seen in patients with wild-type amyloidogenic transthyretin (ATTRwt) and variant ATTR (ATTRv) cardiac amyloidosis. However, its appropriate timing of pacemaker implantation has not been clarified yet. Methods and Results: The consecutive 100 patients with ATTRwt cardiac amyloidosis who diagnosed by myocardium biopsy and/or technetium-99m-pyrophosphate scintigraphy and 62 patients with ATTRv cardiac amyloidosis who diagnosed by means of genetic screening were included in this study. In patients with ATTRwt cardiac amyloidosis, 21 patients have normal conduction at the time of diagnosis. However, conduction disorder had seen in only 5 patient (first degree atrioventricular block (AVB); 4 patients, complete AVB; 1 patients) and only one patient underwent cardiac implantable electric device (CIED) implantation during follow-up period. On the other hand, in patients with ATTRv cardiac amyloidosis, 36 patients have normal conduction at the time of diagnosis. However, conduction disorder had seen in 13 patient (first degree AVB; 8 patients, second degree AVB; 3 patients, trifascicular block; 1 patients, complete AVB; 1 patients) (5/21 vs 13/36, p=0.335) and 6 patients underwent CIED implantation during follow-up period (1/21 vs 6/36, p=0.186). Furthermore, in ATTRwt cardiac amyloidosis, 10 patients (first degree AVB; 2 patients, second degree AVB; 1 patient, trifascicular block; 7 patients) had underwent CIED implantation because of cardiac conduction disorders and/or prevention of sudden cardiac death. However, only 4 patients with trifascicular block progressed to complete AVB.On the other hand, In ATTRv cardiac amyloidosis, 14 patients (first degree AVB; 2 patients, second degree AVB; 4 patient, trifascicular block; 8 patients) had underwent CIED implantation for same reason. However, only 3 patients with trifascicular block progressed to complete AVB. Conclusions: Patients with ATTRv cardiac amyloidosis were more likely to progress conduction disorders than those with ATTRwt cardiac amyloidosis. However, prophylactic pacemaker implantation might had not need in both ATTRwt and ATTRv patients with first or second degree AVB.

Abstract 16136: Underutilization of Appropriate Testing for Transthyretin Amyloidosis Despite Suspicious Clinical &amp; Echocardiographic Findings

Introduction: Both hereditary (hATTR) and wild-type (wtATTR) transthyretin amyloidosis are under-recognized causes of cardiomyopathy (CM) and heart failure. Certain findings on Transthoracic Echocardiography (TTE) and cardiac Magnetic Resonance Imaging (cMRI) are suggestive but not diagnostic of ATTR. Although biopsy historically has been the gold standard for diagnosis, patients can be diagnosed with the highly sensitive and specific technetium-99m pyrophosphate scan (Tc-99m PYP). Genetic testing is recommended to confirm hATTR in patients diagnosed with ATTR cardiac amyloidosis. Despite growing awareness of this condition, many cases remain undiagnosed. This study evaluated if patients with TTEs concerning for infiltrative CM received appropriate diagnostic testing for ATTR-CM. Methods: Our echocardiography registry was queried from January 2011 to March 2020 for patients with our echo lab’s embedded infiltrative CM code. Data on demographics, comorbidities, TTE variables, cMRI results, PYP scans, genetic testing and biopsy results were retrieved from electronic medical records. Thorough manual chart review excluded other causes of CM. Data was expressed as mean ± SD and n (%). Results: We retrieved 510 patients (mean age 64 ± 16 years; 43% female) with TTEs suspicious for infiltrative CM revealing a mean interventricular septal diameter (IVSd) of 1.6 ± 0.3 cm. Only 67 (13%) patients underwent cMRI with 11 (16%) suggestive of cardiac amyloidosis. Of the patients with suspicious TTEs, 16 (3.1%) had PYP scans and 24 (4.7%) had tissue biopsy, with positive results in 7 (44%) and 11 (46%), respectively. Genetic testing in 31 (6%) patients revealed known hATTR mutations in 2 (6.5%) patients. Cardiac amyloidosis was diagnosed in 23 (4.5%) with 11 ATTR (2 hATTR), 5 amyloid light chain, and 7 unknown subtype. Conclusion: Despite clinical and TTE findings suspicious for ATTR-CM, many patients did not undergo appropriate confirmatory testing (see Figure 1).

Natural history and impact of treatment with tafamidis on major cardiovascular outcome-free survival time in a cohort of patients with transthyretin amyloidosis.

Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death. From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n=98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P=0.0132). In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population.

The frequency of cardiac amyloidosis in 182 patients receiving carpal tunnel release surgery

Abstract Introduction Retrospective studies have suggested that a significant proportion of patients with cardiac amyloidosis received surgical treatment for carpal tunnel syndrome (CTS) 5–10 years before diagnosis of their cardiac condition. So far, one cross-sectional study has investigated the presence of localized and systemic amyloidosis in 98 patients undergoing carpal tunnel release surgery (CTRS). Ten percent were shown to have amyloid deposits in the carpal tunnel while two had cardiac involvement caused by either AL amyloidosis or wild-type transthyretin amyloidosis (ATTR). Purpose To investigate the prevalence of cardiac amyloidosis among unselected and consecutive patients undergoing CTRS. Methods Tissue samples from the carpal tunnel of 182 CTRS patients were stained with Congo Red. Amyloid positive samples were subtyped by immunoelectron microscopy and mass spectrometry. Amyloid positive patients underwent investigations for cardiac amyloidosis including ECG-recording, echocardiography and strain imaging, cardiac magnetic resonance imaging and whole-body scintigraphy (99m-tc-DPD). Genetic investigation of the gene for TTR was performed in patients with ATTR amyloidosis or an undetermined subtype. Patients were also investigated by measurements of NT-proBNP, troponins, immunoglobulins, M-protein in serum and urine, and free light kappa and lambda chains in serum. Results In total, 16% (29/182) of the patients had amyloid positive biopsies. They were significantly older than amyloid negative patients (73 years vs 53 years, p&amp;lt;0.001). The prevalence of males was significantly higher in the amyloid positive group (66% vs 25%, p&amp;lt;0.001). The presence of bilateral CTS was not associated with amyloid deposits. The subtype of amyloid was shown to be (a) ATTR in 86% (n=25) of patients, (b) localized light-chain amyloidosis in 3% (n=1), and (c) fibrinogen alpha amyloidosis in 3% (n=1), while the amount of tissue did not allow subtyping in 7% (n=2). All ATTR patients had a normal genetic investigation. So far, 24 of the 29 amyloid positive patients have completed all clinical investigations and no one fulfilled diagnostic criteria of cardiac amyloidosis. Conclusion A significant number of CTRS patients, (14%), had wild-type ATTR amyloidosis confined to the carpal tunnel. None of these had cardiac involvement. These findings were different from the results in the previous prospective study and were likely to be explained by differences in the patient cohorts investigated. We investigated unselected patients in contrast to the highly selected cohort in the previous study. Based on the findings in the current study the proportion of CTRS patients with localized amyloidosis who may develop systemic disease is unknown. Therefore, it is necessary to perform long term follow-up of these patients before routine investigations for amyloidosis may be recommended. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Financial support was obtained by an unrestricted research grant from Alnylam Pharmaceuticals

Temporal Trends of Wild-type Attr Amyloidosis in the Transthyretin Amyloidosis Outcomes Survey

Introduction Wild-type transthyretin amyloidosis (ATTRwt) is an infiltrative cardiomyopathy (CM) underdiagnosed in older adults. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, observational survey of patients with inherited (ATTRv) and ATTRwt amyloidosis, and asymptomatic gene carriers. Temporal trends in ATTRwt diagnosis were explored in this analysis. Hypothesis ATTRwt CM diagnosis has trended up since introducing scintigraphy. Methods Demographic and diagnostic data of CM patients enrolled in THAOS up to the 06January2020 data cut-off were analyzed. Diagnosis frequency between ATTRwt and ATTRv with cardiac phenotype (p.Val142Ile, p.Leu131Met, p.Thr60Ala, p.Ile88Leu), and ATTRwt diagnostic modality, were compared by year. Results A total of 1,069 ATTRwt patients (94.6% male) from 15 countries were identified. Symptoms were reported at a mean (SD) age of 68.8 (11.1) years and diagnosis made at 76.1 (7.1) years. Median (Q1, Q3) time to diagnosis from symptom onset was 4.7 (1.0, 10.9) years. ATTRwt diagnoses increased from single digits to >100 per year, whereas ATTRv with cardiac phenotype increased after 2007 then plateaued after 2011 (Panel A). ATTRwt diagnosis with biopsies increased and peaked in 2014 with a subsequent decline, compared to an increase in diagnosis with scintigraphy since 2012 (Panel B). Conclusions In the last decade, ATTRwt CM amyloidosis diagnoses increased with a concomitant shift from using biopsy to scintigraphy. Despite rising use of scintigraphy, half of the patients experienced diagnosis delays of >4.7 years.

Wild-type Transthyretin Amyloid Myopathy With an Inclusion Body Myositis Phenotype

Senile systemic amyloidosis (SSA), or wild-type transthyretin (wtATTR) amyloidosis, is associated most commonly with cardiomyopathy and carpal tunnel syndrome. SSA-associated skeletal myopathy is rare. We describe the case of a patient with SSA who exhibited asymmetric quadriceps and finger flexor weakness, a phenotype usually seen in inclusion body myositis.

Abstract 410: Transthyretin Amyloid Fibrils Deposited in the Microenvironment Alter Cardiac Myocyte and Fibroblast Function and Cytoskeletal Structure

Age-related wild type transthyretin amyloidosis (ATTRwt) is a systemic condition that is characterized by deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in various organ systems. This disease manifests as an infiltrative cardiomyopathy hallmarked by extracellular deposition of misfolded TTR fibrils in the cardiac tissue, leading to cardiac dysfunction and heart failure with preserved ejection fraction (HFpEF); this disease is underdiagnosed and may affect 25% of elderly men and women. We hypothesize that deposition of amyloidogenic TTR fibrils alters cardiomyocyte contractility and sarcomere structure via modulation of cell growth due to altered microenvironmental features such as substrate stiffness. Recombinant TTR fibrils were deposited on glass substrates or substrates mimicking the stiffness of the healthy myocardium (10kPa). Neonatal rat ventricular myocytes exhibited decreased rate of linear contractility via line scan kymography and altered cytoskeletal structure when exposed to deposited TTR fibrils, with greater maladaptive effects seen on 10kPa substrates. Isolated adult mouse atrial cardiomyocytes plated on TTR fibril-containing substrates had attenuated calcium transient amplitude and a prolonged decay constant, consistent with lower amplitude. We also hypothesize that deposited TTR fibrils induce cardiac fibroblast activation and promote progression of fibrosis. Isolated cardiac fibroblasts grown on TTR-coated glass showed a reorganization of the F-actin cytoskeleton, with preferential distribution to the cell periphery. Barrier removal tests after confluence resulted in significantly faster migration velocity of fibroblasts cultured on TTR fibrils. Increased reduction of MTS tetrazolium by a colorimetric assay suggests a significant TTR-related increase in the proliferation rate of cells. Together, results suggest that amyloidogenic TTR fibrils may affect cardiac myocyte and fibroblast structure and function through both chemical and mechanical pathways. As recently approved therapies for ATTRwt are cost-prohibitive and are intended to slow disease progression only, better understanding of disease mechanisms may elucidate novel therapeutic targets.

Non-invasive detection and differentiation of cardiac amyloidosis using 99mTc-pyrophosphate scintigraphy and 11C-Pittsburgh compound B PET imaging

Purpose To investigate the utility of the combined use of 11C-Pittsburgh compound B (11C-PiB) positron emission tomography (PET) imaging and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy for detection and differentiation of three major types of cardiac amyloidosis, i.e. immunoglobulin light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt) amyloidosis. Methods Whole-body 11C-PiB PET and 99mTc-PYP scintigraphy were performed in 17 patients with AL amyloidosis, 22 patients with ATTRv, and eight patients with ATTRwt amyloidosis. The correlations between organ involvement and the uptake of 11C-PiB and 99mTc-PYP were analyzed in each patient. Results Cardiac amyloidosis was detectable by 99mTc-PYP scintigraphy or 11C-PiB PET in all systemic amyloidosis patients with cardiac involvement. 99mTc-PYP scintigraphy and 11C-PiB PET showed an interesting complementary relation. Strict combination of positive 11C-PiB and negative 99mTc-PYP uptake (PiB pattern) was observed in all AL amyloidosis patients with cardiac involvement. In contrast, strict combination of positive 99mTc-PYP and negative 11C-PiB uptake (PYP pattern) was observed in all ATTRwt amyloidosis patients with cardiac involvement. ATTRv amyloidosis patients with cardiac involvement were divided into two groups: PiB pattern or PYP pattern. All of the early-onset V30M (p.V50M) ATTRv patients showed the PiB pattern, whereas all of the late-onset V30M and non-V30M ATTRv patients showed the PYP pattern. Conclusions All three major types of cardiac amyloidosis can be detected and differentiated non-invasively by combined use of the two amyloid imaging methods and TTR gene testing.

Endomyocardial Biopsy Characterization of Heart Failure With Preserved Ejection Fraction and Prevalence of Cardiac Amyloidosis

ObjectivesThis study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics. BackgroundMyocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking. MethodsPatients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF). ResultsOf the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m2 (25th to 75th percentile: 32 to 45 kg/m2), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm2) was greater in patients with HFpEF versus controls (60.4 cells/mm2 [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm2 [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro−B-type natriuretic peptide and troponin I levels. ConclusionsIn this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.

Gateway and journey of patients with cardiac amyloidosis.

AimsAdvances have been made over the last decade in the management of cardiac amyloidosis (CA), but a delayed diagnosis is still common. The aim of this study was to describe the journey to CA diagnosis from initial clinical and to analyse time to diagnosis.Methods and resultsBetween January 2001 and May 2019, 270 consecutive patients with CA diagnosed at Toulouse University Hospital were retrospectively included in this cross‐sectional study: 111 (41%) light chain amyloidosis, 122 (45%) wild‐type transthyretin amyloidosis, and 37 (14%) hereditary transthyretin amyloidosis.CA onset occurred mostly with dyspnoea (50%) or systematic follow‐up (10%). The cardiologist was the first line specialist in 68% of patients, followed by the nephrologist (9%) and neurologist (8%). Patients encountered a median (minimum–maximum) number of two (1–7) physician specialists and performed a median (minimum–maximum) number of three (1–8) tests before diagnosis. Median delay between symptom onset and CA diagnosis was 8 [IQR 5–14], 10 [IQR 3–34], and 18 [IQR 4–49] months, respectively, in light chain amyloidosis, wild‐type transthyretin amyloidosis, and hereditary transthyretin amyloidosis subgroups (P = .060). Having performed electromyography or spirometry was associated with a longer delay in diagnosis in the overall population: odds ratio = 1.13; 95% confidence interval 1.02 to 1.24; and odds ratio = 1.13; 1.03 to 1.24, respectively, probably due to non‐specific initial symptoms.ConclusionsCA is a protean disease with various first line specialists causing a diagnostic wandering despite increasing medical community awareness. It requires a multidisciplinary specialist care networks to educate and manage symptoms and therapies.

Acquired and inherited amyloidosis: Knowledge driving patients' care.

Until recently, systemic amyloidoses were regarded as ineluctably disabling and life-threatening diseases. However, this field has witnessed major advances in the last decade, with significant improvements in therapeutic options and in the availability of accurate and non-invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk-adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild-type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.

Prediction of Medium-Term Mortality in Japanese Patients With Wild-Type Transthyretin Amyloidosis

Background: The prognostic factors in Japanese patients with wild-type transthyretin amyloidosis (ATTRwt) have not been elucidated.Methods and Results: In this study we retrospectively analyzed the clinical characteristics and outcomes of 47 patients with ATTRwt (mean (±SD) age at diagnosis 80.3±4.6 years; 41 males). Fifteen patients died within 2 years of their diagnosis. Receiver operating characteristic and Kaplan-Meier analyses revealed that the best predictors of 2-year mortality were low serum albumin (≤3.75 g/dL), elevated high-sensitivity cardiac troponin T (hs-cTnT; >0.086 ng/mL), and reduced left ventricular ejection fraction (LVEF; <50%). According to the total number of these 3 risk factors, patients were stratified into 4 subgroups: low risk (no risk factors; n=15), intermediate-low risk (1 risk factor; n=15), intermediate-high risk (2 risk factors; n=7), and high risk (3 risk factors; n=10). The estimated 2-year survival rate of patients classified as low risk, intermediate-low risk, intermediate-high risk, and high risk was 93%, 80%, 83%, and 11%, respectively (P<0.001).Conclusions: Low serum albumin, elevated hs-cTnT, and reduced LVEF are associated with a worse prognosis in Japanese patients with ATTRwt. The combination of these factors may be useful for predicting medium-term mortality in patients with ATTRwt.