Wild-type Transthyretin Amyloid Cardiomyopathy Research Articles

Importance of fourth heart sound and preserved left atrial function in wild-type transthyretin amyloidosis.

A fourth heart sound (S4) was reported to be almost never present in patients with amyloid light-chain cardiomyopathy. There have been no reports on S4 in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). This study aimed to clarify the clinical implications of S4 in patients with ATTRwt-CM. Seventy-six patients with ATTRwt-CM (mean age: 80.4±5.4years, 68 males) who had undergone phonocardiography (PCG) were retrospectively assessed. We measured S4 amplitude on digitally recorded PCG. S4 was considered to be present when its amplitude was 1.0mm or greater on the PCG. Distinct S4 was defined as S4 with an amplitude of 2.0mm or greater, which is usually recognizable by auscultation. According to the rhythm and presence or absence of S4, the patients were divided into three groups, namely, sinus rhythm (SR) with S4, SR without S4, and non-SR. Non-SR consisted of atrial fibrillation, atrial flutter, and atrial tachycardia. Thirty-six patients were in SR and the remaining 40 patients were in non-SR. In the 36 patients in SR, S4 was shown by PCG to be present in 17 patients (47%), and distinct S4 was recognized in 7 patients (19%) by auscultation. In patients who were in SR, those with S4 had higher systolic blood pressure (124±15 vs. 99±8mmHg, P<0.001), lower level of plasma B-type natriuretic peptide (308 [interquartile range (IQR): 165, 354] vs. 508 [389, 765] pg/mL, P=0.034) and lower level of high-sensitivity cardiac troponin T (0.068 [0.046, 0.089] vs. 0.109 [0.063, 0.148] ng/mL, P=0.042) than those without S4. There was no significant difference in left atrium (LA) volume index or LA reservoir strain between patients with S4 and without S4. Patients with S4 had more preserved LA systolic function than those without S4 (peak atrial filling velocity: 53±25 vs. 34±9cm/s, P=0.033; LA contractile strain: 4.1±2.1 vs. 1.6±2.0%, P=0.012). Patients in SR without S4 had worse short-term prognosis compared with the other two groups (generalized Wilcoxon test, P=0.033). S4 was present in 47% of the patients in SR with ATTRwt-CM. Patients in SR without S4 had more impaired LA systolic function than those in SR with S4. The absence of S4 portends a poor short-term prognosis in patients with ATTRwt-CM.

Impact of Tafamidis on Delaying Clinical, Functional, and Structural Cardiac Changes in Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy.

Background: This study aimed to evaluate the effect of treatment with tafamidis on clinical, laboratory, functional, and structural cardiovascular imaging parameters at the 12-month follow-up timepoint in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) and to assess the response to treatment in terms of disease progression. Methods: Patients with ATTRwt-CM undergoing treatment with tafamidis for >12 months were included. The patients underwent a comprehensive evaluation (including echocardiography, cardiac magnetic resonance imaging, six-minute walking test, assessment of quality of life, and laboratory tests) at baseline and the 12-month follow-up timepoint. Disease progression was assessed using a set of tools proposed by an international panel of experts, evaluating three main domains (clinical, biochemical, and structural). Results: The study cohort consisted of 25 patients (mean age of 75.9 ± 6.1 years, with 92% males). At the 12-month follow-up timepoint, an improvement in quality of life calculated with the KCCQ overall score (64 ± 20 vs. 75 ± 20, p = 0.002) and a reduction in pulmonary artery pressure (34 ± 10 mmHg vs. 30 ± 5 mmHg, p-value = 0.008) and in native T1 time were observed (1162 ± 66 ms vs. 1116 ± 52 ms, p-value = 0.001). Clinical, biochemical, and structural disease progression was observed in 6 (24%), 13 (52%), and 7 (28%) patients, respectively. Overall disease progression was observed in two patients (8%). Conclusions: This study described the impact of tafamidis treatment on clinical, laboratory, and functional parameters. Disease progression, assessed using a multiparametric tool recommended by a recent position paper of experts, was observed in a minority of patients.

Cardiac Biomarker Change at 1 Year After Tafamidis Treatment and Clinical Outcomes in Patients With Transthyretin Amyloid Cardiomyopathy.

Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes. In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P=0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P<0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes. Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Diagnostic Pitfall and Clinical Characteristics of Variant Versus Wild-Type Transthyretin Amyloid Cardiomyopathy in Asian Population: The Korean Nationwide Cohort Study.

Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia. Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%). Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation. A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.

Evolution and prognostic value of left ventricular deformation and myocardial work parameters in transthyretin amyloid cardiomyopathy.

Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized condition. It remains challenging to estimate the extent of disease and the prognosis for most patients. Myocardial work is a sensitive echocardiographic approach that improves the characterization of myocardial damage. We investigate the parameters of myocardial deformation and work in ATTR-CM patients and their changes over time. We analysed clinical, electrocardiographic, biological, and echocardiographic characteristics in 113 patients [median age 82 (77-85), 90.4% male] diagnosed with wild-type ATTR-CM based on international consensus at a single centre. We compared the data at baseline and 18-month follow-up. Thirty-four patients died and 12 were hospitalized for heart failure at a median follow-up of 935 days (interquartile range 691-1159 days). Left ventricular end-diastolic diameter, left atrial strain during reservoir phase (LASRES), left ventricular longitudinal strain, global work index (GWI), global constructive work significantly decreased from baseline to 18 months, while left ventricular wall thickness increased. Left ventricular ejection fraction, right ventricular free wall strain (FWS), global wasted work (GWW), and global work efficiency did not alter significantly. Strain parameters were identified as prognostic on baseline evaluation using a multivariate analysis: GWI, GWW, FWS, and LASRES. They were significantly associated with the risk of death and hospitalization for heart failure. Multi-chamber strain assessment may improve the surveillance of patients with ATTR-CM, and myocardial work parameters may improve clinical risk stratification in this population.

Abstract 11748: A Retrospective Observational Study Exploring Real-World Diagnostic Workup of Patients With Wild-Type Transthyretin Amyloid Cardiomyopathy and/or Light Chain Amyloidosis

Introduction: Light chain (AL) and transthyretin amyloidosis are the most common forms of cardiac amyloidosis. Despite having similar presentation, the prognosis and treatment pathways are distinct, placing importance on accurate diagnosis. Aim: Assess the real-world diagnostic workup for AL in patients with AL, wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), or both (AL+ATTRwt-CM). Methods: A retrospective study of Optum EHRs from Jan 2019-Dec 2021. Diagnostic workups in the 24 months prior to first diagnosis (index date) were assessed in mutually exclusive patient cohorts (aged ≥18 years) with AL (ICD10: E85.81 not E85.82), ATTRwt-CM (ICD10: E85.82 not E85.81), or AL+ATTRwt-CM (both ICD10 codes). Results: Of 49,466,996 patients in the database, 996, 526, and 31 met criteria for the AL, ATTRwt-CM, and AL+ATTRwt-CM cohorts, respectively ( Table ). Notable proportions of patients had no relevant workups (40%, 24%, and 23%) or no AL workups (40%, 29%, and 23%). Across cohorts, 54% (AL), 35% (ATTRwt-CM), and 61% (AL+ATTRwt-CM) received a workup for AL only, and &gt;60% had 1-3 types of AL workup. Among patients tested with the serum-free AL assay (n=681), serum (n=460), or urine (n=286) immunofixation (IF) methods, ≥60% were in the AL cohort; ≤36% were in the ATTRwt-CM cohort and ≤4% in the AL+ATTRwt-CM cohort ( Figure ). Conclusions: In Optum EHRs, &gt;20% of patients diagnosed with ATTRwt-CM or AL+ATTRwt-CM, and 40% with AL, had no relevant workups. Due to clinical urgency, it is critical to rule out AL in patients with cardiac amyloidosis using the AL assay or IF. These findings highlight the need for better diagnostic pathways for patients with suspected AL or ATTRwt-CM.

Cardiac amyloidosis in Latin America: Gaps and opportunities to increase awareness of the disease. Findings from the AMILO-LATAM research group

BackgroundCardiac amyloidosis (CA) is an under-diagnosed disease presenting as a restrictive cardiomyopathy with high morbidity and mortality. Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is mostly seen in elderly patients, with increasing prevalence as life expectancy is growing. New diagnostic imaging techniques and treatments allow for a better prognosis, but lack of clinical awareness delays timely diagnosis and appropriate management. Our purpose was to investigate the knowledge of clinicians regarding ATTR-CM and to assess the availability of imaging resources in the Latin-American region. Methods and ResultsTwo online surveys were distributed among clinicians and nuclear medicine professionals, respectively: one asking about awareness of CA in different clinical scenarios, and the other about the availability of diagnostic resources and studies performed. 406 responses were received for the first survey and 82 for the second, representing 17 and 14 countries, respectively. A significant lack of awareness was identified among clinicians, although appropriate diagnostic resources are generally available. Survey data showed that very few patients are evaluated for ATTR-CM in most Latin-American countries. ConclusionsThe surveys demonstrated the need for educational programs and other measures to increase clinical awareness and early detection of CA, so patients receive timely treatment and management of the disease.

Incidence and Predictors of Ventricular Arrhythmias in Transthyretin Amyloid Cardiomyopathy.

Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is characterized by heart failure, conduction abnormalities and arrhythmias. The incidence of ventricular arrhythmias, particularly ventricular tachycardias (VTs), in wtATTR-CM is unclear. With the development of targeted therapies and improved overall prognosis, there is an unmet need to identify patients at high risk for VTs who might benefit from ICD therapy. Between 2017 and 2022, 72 patients diagnosed with wtATTR-CM were prospectively evaluated for the presence of ventricular arrhythmias using a Holter ECG. VTs were defined as >3 consecutive beats with a heart rate > 100 beats per minute originating from a ventricle. The incidence of VTs was 44% (n = 32/72) in unselected wtATTR-CM patients. Patients with VT showed significantly more severe left ventricular (LV) hypertrophy (septum diameter 21 ± 2.6 vs. 19 ± 3.0 mm, p = 0.006), reduced LV ejection fraction (47 ± 8 vs. 52 ± 8%, p = 0.014) and larger left atria (32 ± 7 vs. 28 ± 6 mm2, p = 0.020), but no differences in cardiac markers such as NTproBNP and troponin. In a multivariable model, LV hypertrophy (LV mass indexed, OR = 1.02 [1.00-1.03], p = 0.031), LV end-diastolic diameter (OR = 0.85 [0.74-0.98], p = 0.021) and LV end-systolic diameter (OR = 1.19 [1.03-1.349], p = 0.092) were predictive for VT occurrence with an area under the receiver operating characteristic of 0.76 [0.65-0.87]. The incidence of ventricular arrhythmia in wtATTR-CM is high and is associated with an advanced stage of left ventricular disease. Further studies are needed evaluating the role of VTs in predicting sudden cardiac death and the benefit of ICD therapy in wtATTR-CM.

Usefulness of automatic assessment for longitudinal strain to diagnose wild-type transthyretin amyloid cardiomyopathy

BackgroundLeft ventricular (LV) apical sparing by transthoracic echocardiography (TTE) has not been widely accepted to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM), because it is time consuming and requires a level of expertise. We hypothesized that automatic assessment may be the solution for these problems. Methods-and-ResultsWe enrolled 63 patients aged ≥70 years who underwent 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy on suspicion of ATTR-CM and performed TTE by EPIQ7G, and had enough information for two-dimensional speckle tracking echocardiography at Kumamoto University Hospital from January 2016 to December 2019. LV apical sparing was described as a high relative apical longitudinal strain (LS) index (RapLSI). Measurement of LS was repeated using the same apical images with three different measurement packages as follows: (1) full-automatic assessment, (2) semi-automatic assessment, and (3) manual assessment. The calculation time for full-automatic assessment (14.7 ± 1.4 sec/patient) and semi-automatic assessment (66.7 ± 14.4 sec/patient) were significantly shorter than that for manual assessment (171.2 ± 59.7 sec/patient) (p < 0.01 for both). Receiver operating characteristic curve analysis showed that the area under curve of the RapLSI evaluated by full-automatic assessment for predicting ATTR-CM was 0.70 (best cut-off point; 1.14 [sensitivity 63%, specificity 81%]), by semi-automatic assessment was 0.85 (best cut-off point; 1.00 [sensitivity, 66%; specificity, 100%]) and by manual assessment was 0.83 (best cut-off point; 0.97 [sensitivity, 72%; specificity, 97%]). ConclusionThere was no significant difference between the diagnostic accuracy of RapLSI estimated by semi-automatic assessment and that estimated by manual assessment. Semi-automatically assessed RapLSI is useful to diagnose ATTR-CM in terms of rapidity and diagnostic accuracy.

Clinical characteristics and health care resource use of patients at risk for wild-type transthyretin amyloid cardiomyopathy identified by machine learning model

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening systemic disorder that is an underrecognized cause of heart failure (HF). When the diagnosis of wild-type ATTR-CM (ATTRwt-CM) is delayed, patients often undergo additional assessments, deferring appropriate management as symptoms potentially worsen. Prompt recognition of patients at risk for ATTRwt-CM is essential to facilitate earlier diagnosis and disease-modifying treatment. A previously developed machine learning model performed well in identifying ATTRwt-CM in patients with HF vs controls with nonamyloid HF using medical claims/electronic health records, providing a systematic framework to raise disease suspicion. OBJECTIVE: To further evaluate this model's performance in identifying ATTRwt-CM using a large claims database of older adults with HF and confirmed ATTRwt-CM or nonamyloid HF; and to explore the characteristics and health care resource utilization (HCRU) of patients with confirmed and suspected ATTRwt-CM. METHODS: In this retrospective study, the prior model was applied using Humana administrative claims for patients diagnosed with ATTRwt-CM (cases) and nonamyloid HF (controls [1:1]). Patients were aged 65-89 years, had at least 2 claims for HF diagnosis (2015-2020), and were continuously enrolled in a Medicare Advantage prescription drug plan for at least 12 months before and at least 6 months after HF diagnosis. For the assessment of characteristics and HCRU, the suspected risk level was categorized based on the predicted probability (PP) from model output (high, moderate, and low risk: PP≥0.70; ≥0.50 and < 0.70; and < 0.50, respectively). RESULTS: Of 267,025 eligible patients, 119 (0.04%) had confirmed ATTRwt-CM; of 266,906 patients with nonamyloid HF, 10,997 (4.1%), 68,174 (25.5%), and 187,735 (70.3%) were categorized as high, moderate, and low risk for ATTRwt-CM, respectively. The model demonstrated sensitivity/specificity/accuracy/receiver operating characteristic area under the concentration-time curve of 88%/65%/77%/0.89, respectively, in differentiating ATTRwt-CM from nonamyloid HF. In patients with confirmed ATTRwt-CM, the mean (SD) time between HF and ATTRwt-CM diagnoses was 751 (528) days; 65% and 48% were hospitalized before and after ATTRwt-CM diagnosis, respectively. Atrial fibrillation was more common in patients with confirmed ATTRwt-CM and high risk (39% and 55%) vs low risk (27%). Hospitalization and emergency department visits after HF diagnosis were reported in 57% and 46% of patients with high ATTRwt-CM risk, respectively. CONCLUSIONS: The ATTRwt-CM predictive model performed well in identifying disease risk in the Humana Research Database. Patients at high risk for ATTRwt-CM had high HCRU and may benefit from the earlier suspicion of ATTRwt-CM. The model may be used as a tool to identify patients with a suspected high risk for the disease to facilitate earlier detection and treatment. DISCLOSURES: This study was sponsored by Pfizer. Medical writing support was provided by Donna McGuire of Engage Scientific Solutions and funded by Pfizer. Drs Bruno and Schepart and Mr Casey are currently employees of Pfizer and equity holders in this publicly traded company. Dr Reed was an employee of Pfizer at the time that this analysis was planned and conducted. Mr Sheer and Dr Simmons are currently employees of Humana, which received research funding from Pfizer. Dr Nair was an employee of Humana at the time that this analysis was planned and conducted.

Clinical characteristics, outcome, and therapeutic effect of tafamidis in wild-type transthyretin amyloid cardiomyopathy.

Tafamidis improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, real-world data on the therapeutic effect of tafamidis are lacking. This study aimed to evaluate the clinical course, outcomes, and effectivity monitoring of the therapeutic effect of tafamidis in patients with ATTR-CM. This is a single-centre, retrospective observational study. We evaluated the clinical characteristics and outcomes in 125 consecutive patients with wild-type ATTR-CM (ATTRwt-CM) treated with tafamidis (treatment group) and 55 untreated patients (treatment-naïve group). We monitored the therapeutic effect of tafamidis for 12months by evaluating serial cardiac biomarker and imaging findings. The treatment group had significantly more favourable outcome in all-cause mortality and hospitalization due to heart failure than the treatment-naïve group in both the entire cohort (P<0.01) and the propensity score-matched cohort (P<0.05). Kaplan-Meier survival curves showed that tafamidis treatment significantly reduced all-cause mortality (P=0.03, log-rank test), with the curves diverging after approximately 18months of treatment in the propensity score-matched cohort. On inverse probability of treatment weighting analysis, tafamidis treatment showed a reduced all-cause mortality [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.11-0.93; P=0.04]. High-sensitivity cardiac troponin T (hs-cTnT)>0.05ng/mL, B-type natriuretic peptide (BNP)>250pg/mL, and estimated glomerular filtration rate (eGFR)<45mL/min/1.73m2 scored 1 point each. Multivariate logistic regression analysis revealed that a high score (2-3 points) was a significantly poor prognostic factor of composite clinical outcomes, including all-cause death and hospitalization for heart failure (HR, 1.55; 95% CI, 1.22-1.98; P<0.01) for patients in the treatment group. After 12months of tafamidis treatment, hs-cTnT levels decreased significantly [0.054 (0.036-0.082) vs. 0.044 (0.033-0.076); P=0.002], with no significant changes in BNP levels, echocardiographic parameters, native T1 value, and extracellular volume fraction on cardiac magnetic resonance imaging. The prognosis of patients with ATTRwt-CM treated with tafamidis was more favourable than that of untreated patients. Patient stratification combined with biomarkers (hs-cTnT, BNP, and eGFR) predicted clinical outcomes. hs-cTnT may be a useful biomarker for evaluating the therapeutic effect of tafamidis.

Endothelial Function Is Preserved in Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy

Heart failure (HF) is associated with endothelial dysfunction. Vascular function per se plays an important role in cardiac function, whether it is a cause or consequence. However, there is no information on vascular function in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). The purpose of this study was to evaluate vascular function in patients with ATTRwt-CM. We measured flow-mediated vasodilation (FMD) as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function and brachial artery intima-media thickness (bIMT) and brachial-ankle pulse wave velocity (baPWV) as indices of arterial stiffness in 22 patients with ATTRwt-CM and in 22 one-by-one matched control patients using vascular function confounding factors. FMD was significantly greater in patients with ATTRwt-CM than in the controls (5.4 ± 3.4% versus 3.5 ± 2.4%, p = 0.038) and the N-terminal pro-brain natriuretic peptide (NT-proBNP) level was significantly greater in patients with ATTRwt-CM than in the controls (2202 ± 1478 versus 470 ± 677 pg/mL, p < 0.001). There were no significant differences in NID, bIMT or baPWV between the two groups. There was a significant relationship between NT-proBNP and FMD in patients with ATTRwt-CM (r = 0.485, p = 0.022). NT-proBNP showed no significant relationships with NID, bIMT or baPWV. Conclusions: Endothelial function was preserved in patients with ATTRwt-CM. Patients with ATTRwt-CM may have compensatory effects with respect to endothelial function through elevation of BNP.

Right ventricular-dominant transthyretin deposition: an early stage or a rare phenotype of wild-type transthyretin amyloid cardiomyopathy?

An 86-year-old Japanese man was referred to our hospital because of leg oedema. Electrocardiography revealed a right bundle branch block, and transthoracic echocardiography showed a left ventricular septal wall thickness of 15 mm. On cardiovascular magnetic resonance imaging (CMR), late gadolinium enhancement areas and high native T1 value areas extended in the basal region of the left ventricular lateral wall (Panels A and C), the right ventricular (RV) side of the septum, and the RV free wall (Panels B and D). Abnormal accumulation of 99mTc-labelled pyrophosphate (99mTc-PYP) in the myocardium was visualized in concordance with the abnormal areas on CMR (Panels E and F). The patient was diagnosed with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) due to the histological evidence of transthyretin deposition in the myocardium and no transthyretin gene mutation. In this case, both CMR and 99mTc-PYP scintigraphy, which are reliable imaging tools for transthyretin deposition in the myocardium, revealed RV-dominant transthyretin deposition. Based on the UK ATTR-CM staging system, this case was classified as Stage 1. Since no cases of RV-dominant transthyretin deposition have been reported in the literature, it is unclear whether RV-dominant transthyretin deposition is an early stage or a very rare clinical phenotype of wild-type ATTR-CM. Nonetheless, clinicians should be aware of an RV-dominant transthyretin deposition pattern in wild-type ATTR-CM.

Real-World Characteristics of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: An Analysis of Electronic Healthcare Records in the United States.

Tafamidis was approved for the treatment of hereditary and wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) in May 2019, based on findings from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). This retrospective cohort study evaluated the factors associated with tafamidis prescription after diagnosis of ATTRwt-CM in the real world. Between May 2019 and December 2020, 430 patients with 6 months' database activity were indexed from the de-identified US Optum electronic healthcare records at first diagnosis of ATTRwt-CM or prescription of tafamidis, then followed until last activity or death. Of these, 209 patients were prescribed tafamidis during follow-up, 167 (80%) within 1 month, 98% by 6 months, and 100% by 9 months. Median time from index to tafamidis prescription, calculated using the Kaplan-Meier method, was 5.8 months (95% confidence interval [CI] 2.4-not evaluable). Factors associated with tafamidis prescription in a multivariable Cox proportional hazards regression (hazard ratio [95% CI]) included age ≥65 years (2.1 [1.07-4.05]), male sex (1.6 [1.07-2.28]), having heart failure/cardiomyopathy (2.4 [1.54-3.82]), and having had technetium-99m pyrophosphate myocardial scintigraphy (1.7 [1.28-2.28]). The clinical characteristics of patients with ATTRwt-CM who were prescribed tafamidis in the real world were broadly comparable with those who took part in ATTR-ACT. Further studies are needed to evaluate hereditary and ATTRwt-CM patient populations in the real world and assess the long-term outcomes associated with disease management pathways. ClinicalTrials.gov identifier: NCT01994889.

Evolution and prognostic value of deformations parameters and myocardial work in transthyretin amyloid cardiomyopathy

Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized condition. Prognosis is related to the early diagnosis and treatment. It remains clinically challenging to estimate the risk for many patients at the time of the diagnosis. Myocardial work is a novel echocardiographic tool, that improve characterization and prognostic value of the myocardial damages. We sought to analyze echocardiographic deformation parameters, their evolution, and to evaluate their incremental prognostic value, in ATTR-CM patients. We retrospectively analyzed clinical, electrocardiographic, biological, and echocardiographic characteristics in 113 consecutive patients (median age 82 [77–85], 90,4% men) diagnosed for a wild-type ATTR-CM based on international consensus. Baseline and 18 months follow-up evaluation were taken into account. All the data came from a single center and all the images were recorded on the same platform (Ve95, GE-healthcare). Eighty-six patients were treated with Tafamidis. Thirty-four patients died and twelve were hospitalized for heart failure at a median follow-up of 935 days (IQR 691–1159) days. Right ventricle strain (RVS), left atrial strain during contraction phase (LASct), global and basal longitudinal strain, Global Work Index (GWI) and TAPSE significantly decreased from baseline to 18 months follow-up. Left ventricular ejection fraction (LVEF), global wasted work (GWW) and global work efficiency (GWE) did not differ significantly. Using a multivariate analysis, two parameters could be highlighted for their prognostic value on baseline evaluation: GWI < 1347 mmHg and a RV end-diastole area of > 19 cm2 were significantly associated with the risk of death and/or hospitalization for heart failure. Treated patients with Tafamidis had a significantly better survival. Myocardial work, and particularly GWI might be consider at baseline as well as RV size to best assess the risk of major events in ATTR-CM patients.

Initial experience with transcatheter tricuspid valve repair in patients with cardiac amyloidosis.

Wildtype transthyretin amyloid cardiomyopathy is an under-recognized cause of heart failure in elderly patients. Transcatheter tricuspid valve repair is a newly emerging therapeutic option for severe tricuspid regurgitation (TR). We present first insights into safety and possible benefits of this procedure in patients with cardiac amyloidosis. Eight patients with cardiac non-hereditary (wildtype) transthyretin (ATTRwt) amyloidosis and severe to torrential TR, undergoing successful transcatheter tricuspid valve repair, were included in the analysis and compared to a control group of 21 patients without cardiac amyloidosis. All patients presented with an advanced stage of amyloid cardiomyopathy. Primary endpoint was reduction in TR at 3months follow-up. Secondary endpoints were feasibility, safety, hospitalization or death, clinical improvement, cardiac biomarkers, and structural and functional right heart parameter obtained by echocardiography. Transcatheter tricuspid valve repair resulted in a significant reduction of TR (IV to II, P=0.008) in all eight patients with cardiac amyloidosis (100%). Device success (amyloidosis 75% vs. control group 86%, P=0.597) and overall probability of hospitalization or death (amyloidosis 13% vs. control group 25%, P=0.646) were similar compared with those in the control group at 3months follow-up. Transcatheter tricuspid valve repair led to an improvement of New York Heart Association functional class (P=0.031) and 6min walking distance (from 313±118 to 337±106, P=0.012). TR reduction in amyloidosis patients was less extensive compared with that in control group (TR-reduction 1.6±0.3, P=0.008 vs. control group 2.3±0.3, P<0.0001). Furthermore, these patients showed no significant improvement of structural right heart parameters. Transcatheter tricuspid valve repair is a safe and feasible new treatment option in patients with amyloid cardiomyopathy and has the potential to improve TR-grade and clinical status. However, the benefit appears to be less pronounced compared with patients without cardiac amyloidosis.

Time-dependent change of relative apical longitudinal strain index in patients with wild-type transthyretin amyloid cardiomyopathy.

This study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). 165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52%) had LV apical sparing (relative apical longitudinal strain index (RapLSI)>1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95% confidence interval (CI), 1.01-1.41; p<0.05); E/e' ratio (OR, 1.06; 95% CI, 1.00-1.11; p<0.05); and heart-to-contralateral ratio by 99mTc-labeled pyrophosphate scintigraphy (OR, 3.40; 95% CI, 1.07-10.83; p<0.05).Next, we compared RapLSI at the time of diagnosis with that during the follow-up period (396days (346-458) after diagnosis) in 92 patients. RapLSI increased significantly during the follow-up period compared with RapLSI at diagnosis in the non-LV apical sparing group (0.89±0.32 vs 0.74±0.18, p<0.01) but not in the LV apical sparing group (1.33±0.53 vs 1.39±0.45, p=0.46). A total of 12 patients (29%) in the non-LV apical sparing group developed LV apical sparing and 11 patients (22%) in LV apical sparing group diminished LV apical sparing during the follow-up period. Approximately half of ATTRwt-CM patients did not have LV apical sparing at diagnosis. Because RapLSI in ATTRwt-CM significantly changed over time, repeated two-dimensional speckle tracking analysis is important for suspected ATTR-CM patients.

Suspicion, screening, and diagnosis of wild-type transthyretin amyloid cardiomyopathy: a systematic literature review.

Wild‐type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non‐invasive diagnosis by bone scintigraphy, and the development of disease‐modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at‐risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light‐chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at‐risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high‐quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at‐risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.

Prognostic value of right ventricular global longitudinal strain in transthyretin amyloid cardiomyopathy

BackgroundThis study was performed to investigate whether right ventricular global longitudinal strain (RV-GLS) provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Methods and resultsAmong 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 111 patients who had enough information for two-dimensional speckle tracking imaging were retrospectively analyzed. During a median follow-up of 615 days, 26 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group were significantly older (81.1 ± 7.4 years vs. 78.2 ± 6.2 years, p = 0.009) and had significantly higher interventricular septal thickness in diastole (16.6 ± 3.1 mm vs. 15.3 ± 2.4 mm, p = 0.048), lower RV-GLS (10.9 ± 2.7% vs. 12.8 ± 3.5%, p = 0.010), and lower right ventricular free wall longitudinal strain (RVFWLS) (13.1 ± 3.3% vs. 15.5 ± 3.8%, p = 0.004). In the univariate Cox proportional hazard analysis, age, left atrial volume index (LAVI), RV-GLS, and RVFWLS were significantly associated with cardiovascular death [age, hazard ratio (HR), 1.10; 95% confidence interval (CI), 1.02–1.19, p = 0.010; LAVI, HR, 1.02; 95% CI, 1.00–1.03, p = 0.009; RV-GLS, HR, 0.86; 95% CI, 0.75–0.97, p = 0.017; RVFWLS, HR 0.89; 95% CI, 0.79–1.00; p = 0.041]. Multivariable Cox proportional hazard analysis showed RV-GLS was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (HR, 0.86; 95% CI, 0.74–0.99; p = 0.038). Receiver operating characteristic analysis showed that the area under the curve of RV-GLS for cardiovascular death was 0.668 and that the best cut-off value of RV-GLS was 11.59% (sensitivity, 69.2%; specificity, 63.5%). In the Kaplan–Meier analysis, patients with ATTRwt-CM who had low RV-GLS (<11.59%) had a significantly higher probability of total cardiovascular death (p = 0.004) and heart failure-related hospitalization (p = 0.013). ConclusionRV-GLS has significant prognostic value in patients with ATTRwt-CM and provides greater prognostic power than conventional echocardiographic findings.

A simple staging system using biomarkers for wild-type transthyretin amyloid cardiomyopathy in Japan.

AimsIt has been reported that a staging system combining N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity troponin T (hs‐cTnT) or estimated glomerular filtration rate (eGFR) is useful in patients with wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM). However, these studies were mainly conducted in Western countries, and their usefulness for the Japanese population is unclear. We examined and validated the staging system using hs‐cTnT, eGFR, and B‐type natriuretic peptide (BNP) in Japanese patients with ATTRwt‐CM.Methods and resultsWe retrospectively evaluated 176 patients with ATTRwt‐CM. The cut‐off values of hs‐cTnT and eGFR were selected as 0.05 ng/mL and 45 mL/min/1.73 m2, respectively, based on a previous report. The optimal cut‐off value of BNP was 255.6 pg/mL to predict all‐cause mortality (sensitivity, 75%; specificity, 58%; area under the curve, 0.69; 95% confidence interval [CI], 0.61–0.78; P < 0.001) based on a receiver operating characteristic curve. We defined the cut‐off value of BNP as 250 pg/mL. Increased hs‐cTnT (>0.05 ng/mL) and BNP (>250 pg/mL) and decreased eGFR (<45 mL/min/1.73 m2) were significant predictors of poor prognosis (P < 0.05). We calculated the score by adding 1 point if hs‐cTnT and BNP levels increased or eGFR decreased by more than the cut‐off value. The hazard ratio of all‐cause death adjusted by age and sex, using score 0 as a reference, was 0.44 (95% CI 0.08–2.49, P = 0.44) for score 1, 3.69 (95% CI 1.21–11.21, P = 0.02) for score 2, and 5.40 (95% CI 1.57–18.54, P = 0.007) for score 3. We divided patients into a low score group (0–1 point) and high score group (2–3 points). Kaplan–Meier analyses revealed significant differences in all‐cause death and rehospitalization for heart failure (log rank test; P < 0.001), and after adjusting for sex and age, the hazard ratio of all‐cause death was 6.96 (95% Cl 2.88–16.83, P < 0.001) and that for rehospitalization for heart failure was 4.27 (95% Cl 2.26–8.07, P < 0.001) in the high‐risk group, compared with those in the low‐risk group. The median survival period was 32.0 months in the high‐risk group.ConclusionsThis simple staging system, which combines hs‐cTnT, BNP, and eGFR, was useful for predicting prognosis in Japanese patients with ATTRwt‐CM. This system can objectively evaluate the disease progression of ATTRwt‐CM and may be useful for patient selection for disease‐modifying therapy.