Wild-type ATTR Research Articles

Prognostic value of cardiopulmonary exercise testing in patients with transthyretin cardiac amyloidosis.

The aim of this study is to evaluate the prognostic value of cardiopulmonary testing (CPET) in a cohort of patients with transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA is associated with a progressive reduction in functional capacity. The prognostic role of CPET parameters and in particular of normalized peak VO2 (%ppVO2) remains to be thoroughly evaluated. In this study, 75 patients with ATTR-CA underwent cardiological evaluation and CPET in a National Referral Center for cardiac amyloidosis (Careggi University Hospital, Florence). Fifty-seven patients (76%) had wild-type ATTR. Median age was 80 (75-83) years, 68 patients (91%) were men. Peak oxygen consumption (14.1 ± 4.1ml/kg/min) and %ppVO2 (68.4 ± 18.8%) were blunted. Twenty-seven (36%) patients had an abnormal pressure response to exercise. After a median follow-up of 25 (12-31) months, the composite outcome of death or heart failure hospitalization was registered in 19 (25.3%) patients. At univariate analysis %ppVO2 was a stronger predictor for the composite outcome than peak VO2. %ppVO2 and NT-proBNP remained associated with the composite outcome at multivariate analysis. The optimal predictive threshold for %ppVO2 was 62% (sensitivity: 71%; specificity: 68%; AUC: 0.77, CI 0.65-0.88). Patients with %ppVO2 ≤ 62%and NT-proBNP > 3000pg had a worse prognosis with 1- and 2-year survival of 69 ± 9% and 50 ± 10%, respectively. CPET is a safe and useful prognostic tool in patients with ATTR-CA. CPET may help to identify patients with advanced disease that may benefit from targeted therapy.

Abstract 10063: Changes in Clinical Phenotype of Patients With ATTR Cardiac Amyloidosis During the Past 20 Years

Introduction: Diagnostic and therapeutic advances have led to increased awareness of transthyretin cardiac amyloidosis (ATTR-CA). We sought to characterise the change in clinical phenotype of patients with ATTR-CA over the last 20-years. Methods: We studied 1967 patients diagnosed with ATTR-CA at the National Amyloidosis Centre (NAC) from 2002-2021. Results: Analysis by 5-year quartiles revealed a substantial incremental increase in patients diagnosed, with the most marked increases seen in wild-type ATTR. Increased diagnoses were accompanied by greater proportions of patients referred following bone scintigraphy and cardiac magnetic resonance imaging (3% vs 44% vs 67% vs 76%, P<0.001). Over time, median duration of symptoms prior to diagnosis diminished from 36-months between 2002-2006 to 12-months between 2017-2021 (P<0.001) and a greater proportion of patients had milder disease at the time of diagnosis across the 5-yearly quartiles (NAC stage 1: 34% vs 42% vs 44% vs 53%, P<0.001). The latter was associated with more favourable echocardiographic parameters of structure and function, including an incremental decrease in interventricular septal thickness(18.0±3.8mm vs 17.2±2.6mm vs 16.9±2.3mm vs 16.6±2.4mm, P=0.01), which was associated with improved survival. The improved survival associated with the year of diagnosis remained significant when censoring at trial or disease modifying medication start date (2012-2016 vs. 2017-2021: HR=1.05, 95%CI[1.03-1.07], P<0.001). Conclusions: Increased awareness and advances in cardiac imaging have been associated with a substantial increase in diagnosis of ATTR-CA and at a progressively earlier stage of the disease, which has contributed to improved survival in recent years. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.

Abstract 13273: Real-World Efficacy of Tafamidis in Patients With Transthyretin Amyloidosis and Heart Failure

Background: Tafamidis was associated with reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. Methods: We conducted a retrospective, observational cohort study using the TriNetX research network, a multicenter federated research network with data pooled from electronic health records. Patients with wild-type TTR amyloidosis and heart failure (HF) were identified based on ICD-10 codes on or before May 15, 2021. The study cohort was then divided into two groups based on treatment with tafamidis. Propensity score matching (PSM) was performed to balance the confounders. Rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared between the two cohorts. Results: We identified 1362 patients with wild-type ATTR amyloidosis with HF (tafamidis group =553, non-tafamidis group =809). After PSM, there were 421 patients in each group (mean age: 76 years, Female 14%, White race 64%). During the 12-month follow-up period, 38 (9.0%) patients experienced HFE in the tafamidis group compared to 58 (13.8%) patients in the non-tafamidis group (OR 0.62; CI0.40-0.95, p=0.030). Patients treated with tafamidis had lower all-cause mortality compared to the non-tafamidis group (10.7% vs. 16.4%; OR 0.61, CI 0.40-0.91, p=0.016). The treated cohort had a higher probability of event-free survival for HFE (HR 0.61; 95% CI 0.40-0.92, Log-Rank p= 0.018) and all-cause mortality (HR 0.619; 95% CI 0.425, 0.901, Log-Rank p= 0.011). Conclusion: This real-world analysis confirms that tafamidis use is associated with reduced HF exacerbations and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer term follow-up is needed to better understand the utility of tafamadis given the increasing recognition of ATTR-CM and its high cost.

Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases.

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.

Therapeutic value of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) with cardiomyopathy based on cardiovascular magnetic resonance (CMR) imaging

Abstract Background Tafamidis was approved in Europe for the treatment of cardiomyopathy (CM) in patients with transthyretin amyloidosis (ATTR) in April 2020. So far, real-world data addressing the therapeutic value of tafamidis for the treatment of ATTR-CM are scarce. The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type ATTR (ATTRwt) and CM (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging. Purpose The purpose of this study was to carefully analyse the therapeutic benefit of tafamidis in patients with wild-type transthyretin amyloidosis (ATTRwt) and cardiomyopathy (ATTRwt-CM) after one year of therapy based on serial multi-parametric cardiovascular magnetic resonance (CMR) imaging. Methods The present study comprised N=40 patients with ATTRwt-CM who underwent two serial multi-parametric CMR studies within a follow-up period of 12±3 months. Baseline (BL) clinical parameters, serum biomarkers and CMR findings were compared to follow-up (FU) values in patients with treated “with” tafamidis 61mg daily (n=20, group A) and those “without” tafamidis therapy (n=16, group B). CMR studies were performed on a 1.5-T system and comprised (amongst others) cine-imaging for assessment of cardiac anatomy and function including 3D longitudinal strain assessment. In addition, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was performed for measurement of pre- and post-contrast myocardial T1-values with additional calculation of extracellular volume fraction (ECV)-values. Results While left ventricular ejection fraction (LV-EF), left ventricular mass index (LVMi), left ventricular wall thickness (LVWT), native T1- and ECV-values remained unchanged in the tafamidis group A, a slight reduction in LV-EF (p=0.003) as well as a subtle increase in LVMi (p=0.034), in LVWT (p=0.001), in native T1- (p=0.038) and ECV-values (p=0.017) were observed in the untreated group B. Serum NT-proBNP levels showed an overall increase in both groups, however, with the untreated group B showing a relatively higher increase compared to the treated group A. Assessment of NYHA class did not result in significant intra-group differences when BL were compared with FU, but a trend to improvement in the treated group A compared to a worsening trend in the untreated group B (Δp=0.005). Conclusion Tafamidis does not improve cardiac phenotype in patients with ATTRwt-CM after one year of therapy. However, tafamidis seems to slow down cardiac disease progression in patients with ATTRwt-CM compared to those without tafamidis therapy based on multi-parametric CMR data already after one year of therapy. Funding Acknowledgement Type of funding sources: None.

Incidence and risk factors for pacemaker implantation in light chain and transthyretin cardiac amyloidosis

Abstract Background The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. Purpose We sought to characterise the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light chain (AL) and transthyretin (ATTR) CA. Methods Multicentre, retrospective, observational study. Consecutive patients with AL and ATTR-CA diagnosed or referred at participating Centres between 2017 and 2020 were included. Clinical data recorded within ± 1 month from baseline evaluation were collected from electronic medical records. The primary outcome of the study was the need for clinically-indicated PM implantation. Reversible causes of conduction system disease were systematically ruled out before PM implantation. Patients with PM (n=41) and/or permanent defibrillator in situ (n=13) at the time of CA diagnosis were excluded. Results The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were males, with median age 76 years. During a median follow-up of 33 months (interquartile range 21–46), 36 (8.9%) patients experienced the primary outcome: 10 patients with AL-CA, 2 with variant ATTR-CA and 24 with wild-type ATTR-CA (p=0.08). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p=0.002), PR interval (HR 1.013, p=0.002) and QRS >120 ms (HR 4.7, p=0.001) on baseline ECG were independently associated with PM implantation (Figure 1). In the individual patient, the contemporary presence of these 3 factors yielded the highest risk of PM implantation (HR 6.26, p=0.003). Conclusion In a large cohort of AL and ATTR-CA, the incidence of PM implantation was high accounting for ≈9% of patients in the 3 years following the diagnosis. History of atrial fibrillation, longer PR interval and QRS >120 ms identified CA patients at high-risk of future PM implantation (Figure 2). CA patients with these features might need close monitoring during follow-up for the development of conduction system disease requiring PM implantation. Funding Acknowledgement Type of funding sources: None.

Vutrisiran: First Approval

Vutrisiran (AMVUTTRA™) is a subcutaneously administered transthyretin-directed small interfering ribonucleic acid (siRNA) therapeutic (also called RNA interference, or RNAi therapeutic) being developed by Alnylam Pharmaceuticals, Inc. for the treatment of amyloid transthyretin-mediated (ATTR) amyloidosis, including hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. Vutrisiran was approved in June 2022 in the USA for the treatment of the polyneuropathy of hATTR amyloidosis in adults and received a positive opinion in the EU in July 2022 for the treatment of hATTR amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy. Vutrisiran is also under regulatory review for the treatment of the polyneuropathy of hATTR amyloidosis in adults in Japan and Brazil. This article summarizes the milestones in the development of vutrisiran leading to this first approval in hATTR amyloidosis.

Hereditary Transthyretin Amyloidosis Cardiomyopathy: The South Florida Experience

Numerous studies have examined distinct populations with hereditary transthyretin amyloidosis (hATTR); however, to the best of our knowledge, no studies have focused on the hATTR population of South Florida, a region characterized by its diverse population, with a prominent Black, Afro-Caribbean, and Hispanic presence. We performed a retrospective observational study of patients diagnosed with hATTR cardiomyopathy from 2010 to 2020 at the University of Miami Hospital located in Miami, Florida. Patients with either a positive endomyocardial biopsy or Technetium-99m Pyrophosphate scan were selected and classified into hATTR or wild-type ATTR (ATTRwt), based on genetic testing results. A subsequent electronic medical record review was performed, and baseline characteristics were obtained for both groups. A total of 144 patients were identified to have ATTR and were included in this study. Of these patients, 36% had hATTR (n=52), and 64% had ATTRwt (n=92). Baseline age, gender, and race characteristics in the hATTR and ATTRwt groups were consistent with previous observational studies. When comparing our findings with preliminary data from the Transthyretin Amyloidosis Outcome Survey reported in 2016, we observed a higher proportion of Val122Ile (75% vs 44% of all hATTR cases), a lower proportion of hATTR cases (36% vs 52%), and a higher proportion of ATTRwt (64% vs 48%). Preliminary data from the Transthyretin Amyloidosis Outcome Survey did not report specific data about Hispanic patients with hATTR, with only 7% of all cases reported being from non-Caucasian and non-Black patients. Hispanic patients represented 25% of all hATTR cases within our population, with 69% of them being positive for the Val122Ile allele. In conclusion, the large presence of Black and Afro-Caribbean subjects within the South Florida region, in combination with its prominent Hispanic population and the high proportion of adults aged more than 65years, results in a unique population composition that could help explain the higher-than-expected frequency of Val122Ile and ATTRwt cases observed within our study.

Transthyretin cardiac amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.

Prevalence and clinical outcomes of transthyretin amyloidosis: a systematic review and meta-analysis.

Systematic evidence on the prevalence and clinical outcome of transthyretin amyloidosis (ATTR) is missing. We explored: (i) the prevalence of cardiac amyloidosis in various patient subgroups, (ii) survival estimates for ATTR subtypes, and (iii) the effects of novel therapeutics on the natural course of disease. A systematic review of literature published in MEDLINE before 31 December 2021 was performed for the prevalence of cardiac amyloidosis and all-cause mortality of ATTR patients. Extracted data included sample size, age, sex, and all-cause mortality at 1, 2, and 5 years. Subgroup analyses were performed for ATTR subtype, that is, wild-type ATTR (wtATTR) versus hereditary ATTR (hATTR), hATTR genotypes, and treatment subgroups. We identified a total of 62 studies (n=277 882 individuals) reporting the prevalence of cardiac amyloidosis, which was high among patients with a hypertrophic cardiomyopathy phenotype, heart failure with preserved ejection fraction, and the elderly with aortic stenosis. Data on ATTR mortality were extracted from 95 studies (n=18 238 ATTR patients). Patients with wtATTR were older (p=7 × 10-10 ) and more frequently male (p=5 × 10-20 ) versus hATTR. The 2-year survival of ATTR was 73.3% (95% confidence interval [CI] 70.9-75.7); for non-subtyped ATTR 70.4% (95% CI 66.9-73.9), for wtATTR 76.0% (95% CI 73.0-78.9]) and for hATTR 77.2% (95% CI 74.0-80.4); in meta-regression analysis, wtATTR was associated with higher survival after adjusting for confounders. There was an interaction between survival and hATTR genotypes (p=10-15 , Val30Met having the lowest and Val122Ile/Thr60Ala the highest mortality). ATTR 2-year survival was higher on tafamidis/patisiran compared to natural disease course (79.9%, 95% CI 74.4-85.3 vs. 72.4%, 95% CI 69.8-74.9, p < 0.05). We report the prevalence of ATTR in various population subgroups and provide survival estimates for the natural course of disease and the effects of novel therapeutics. Important gaps in worldwide epidemiology research in ATTR were identified.

SUCCESSFUL MANAGEMENT OF REFRACTORY CONSTIPATION USING KAMPO MEDICINE MASHININGAN IN A PATIENT WITH WILD-TYPE ATTR CARDIAC AMYLOIDOSIS

TYPE: Case Report TOPIC: Cardiovascular Disease INTRODUCTION: A wild-type ATTR amyloidosis is a systemic disease with multi-organ dysfunction, involving heart, kidney, skin, and gastrointestinal tract, due to deposition of wild-type transthyretin in each organ. CASE PRESENTATION: We had a 76-year-old man diagnosed with wild-type ATTR cardiac amyloidosis, whose heart failure symptom improved by anti-heart failure medications but constipation refractory to multiple conventional medications persisted. Following the conversion from lubiprostone to Kampo medicine mashiningan, his average days per one evacuation decreased from around 7.0 days down to 1.6 days. DISCUSSION: Amyloid-related gastrointestinal comorbidities are often refractory to the conventional medications. Mashiningan might increase the proportion of soft feces via increasing intestinal fluid secretion through cystic fibrosis transmembrane conductance regulator chloride channel activation. CONCLUSIONS: Mashininigan might be alternative option to improve refractory constipation in patients with cardiac amyloidosis. DISCLOSURE: Nothing to declare. KEYWORD: heart failure

Cerebral Ischemic Events: An Overlooked Complication of Transthyretin Cardiac Amyloidosis in Afro-Caribbean Patients

AimThe link between transthyretin cardiac amyloidosis (CATTR), and cerebral ischemic events (CIE) has only been hinted at till now, impeding progress in patient management. We seek to evaluate the frequency and characteristics of CIE in Afro-Caribbean patients followed for CATTR at our institution.MethodsIn this single-center retrospective observational study, Afro-Caribbean patients followed for CATTR between July 2005 and October 2019 were included. Occurrence of CIE was investigated, and their cardioembolic origin determined. Analysis of patient characteristics was conducted according to CIE and CATTR profiles.ResultsOverall, 120 CATTR patients were included: 17 wild-type ATTR (14.2%), 73 ATTR-V122I (60.8%), and 22 ATTR-I107V (18.3%). Thirty-six patients (30.0%) presented with CIE, including three transient ischemic attacks and 33 permanent ischemic strokes (75.8% with a cardioembolic pattern). CIE was concomitant with CATTR diagnosis in 16 (16/36: 44.4%) patients, while 14 patients (14/36: 38.9 %) experienced CIE over a median CATTR follow-up of 2.0 years (min-max range: 0.8–4.4 years). CATTR-CIE patients presented with atrial fibrillation (66.7%), left atrial enlargement (77.8%), a CHA2DS2-VASc ≥ 3 (97.2%) and a high anticoagulant intake (75.0%). Multivariate analysis retained only a high CHA2DS2-VASc score as an independent predictor of CIE risk (Hazard Ratio [95% CI]: 12.03 [1.62–89.24]).ConclusionConcomitant CIE, and CATTR diagnosis, potentially carries a worse prognosis. A CHA2DS2-VASc score ≥3 seems to be a strong and independent predictive factor of CIE in CATTR patients. Further studies are needed to assess the efficacy and timeliness of anticoagulation in CATTR patients, independently of atrial fibrillation.

P288 PREVALENCE OF AMYLOID TRANSTHYRETIN CARDIOMYOPATHY IN ELDERLY SUBJECTS FROM THE GENERAL POPULATION: FIRST RESULTS FROM THE CATCH STUDY

Abstract Background Amyloid transthyretin cardiomyopathy (ATTR–CM) has become treatable. Wild–type ATTR–CM is an age–related disorder. Establishing the exact prevalence of ATTR–CM in elderly subjects from the general population may be useful for healthcare providers and policy makers. Methods The Characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners in a part of Tuscany (Italy) where there is no cluster of variant ATTR. The study started on March 12, 2021 and is ongoing. Patients with 1) any clinical red flag of amyloidosis, 2) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and/or 3) hs–troponin T &amp;gt; 14 ng/L are referred to diphosphonate scintigraphy and search for a monoclonal protein. Results As of October 13, 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR–CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR–CM in the elderly population can be calculated as 2/266=0.8%. Conclusions The CATCH study is expected to enroll at least 1,000 subjects and will provide the first data on the epidemiology of ATTR–CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR–CM.

Incidence and risk factors for pacemaker implantation in light‐chain and transthyretin cardiac amyloidosis

The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light-chain (AL) and transthyretin (ATTR) CA. Consecutive patients with AL and ATTR-CA diagnosed at participating centres (2017-2020) were included. Clinical data recorded within ±1month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically-indicated PM implantation. Patients with PM (n=41) and/or permanent defibrillator in situ (n=13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were male, median age 76 years. During a median follow-up of 33 months (interquartile range 21-46), 36 (8.9%) patients experienced the primary outcome: 10 AL-CA, 2 variant ATTR-CA and 24 wild-type ATTR-CA (p=0.08 at time-to-event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p=0.002), PR interval (HR 1.013, p=0.002) and QRS >120 ms (HR 4.7, p=0.001) on baseline electrocardiogram were independently associated with PM implantation. The absence of these three factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6months. In a large cohort of AL and ATTR-CA patients, 8.9% received a PM within 3 years after diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation.

Abstract 21: Characteristics Of Patients With Transthyretin Amyloid Cardiomyopathy Receiving Tafamidis Therapy: Experience At An Advanced Heart Failure Program

Background: While the safety and efficacy of tafamidis are described in clinical trials, data on its real-world application are lacking. This study summarized the characteristics of patients initiating first-time treatment with tafamidis at the Cardiac Amyloidosis Clinic at Georgia Heart Institute. Methods: A retrospective analysis of the clinical characteristics and treatment progress of patients diagnosed with transthyretin amyloid (ATTR) cardiomyopathy receiving tafamidis therapy from May 6, 2019, to Oct 1, 2021. Results: In total, 18 patients were identified who had received tafamidis. Two patients were excluded from the analysis as they did not receive care from our clinic. Of the remaining 16 patients, 2 African American and 1 Caucasian patients with a mean age of 59.5 years old, carried V122I mutation. The other 13 patients, Caucasian with a mean age of 81.4 years old, possessed wild-type ATTR amyloidosis. No patients with V30M mutation were identified. Of the patients included, 14 male and 2 female, the 2 female patients had wild-type ATTR amyloidosis. At the time of tafamidis initiation, 10 patients were at the UK National Amyloidosis Centre (NAC) stage 1 amyloid cardiomyopathy, 5 patients at NAC stage 2, and 1 patient at NAC stage 3. The median (IQR) levels of NT-proBNP were 2240 (1098 - 4148) pg/mL at baseline, and 1446 (800 - 2795) pg/mL at 12 months after initiation of therapy. The mean eGFR of patients with wild-type ATTR and V122I mutation were 58 and 72 mL/min/1.73 m2, respectively. Four patients received additional therapy with 1) doxycycline, 2) doxycycline and tauroursodeoxycholic acid, 3) diflunisal, 4) patisiran. There were 13.33% patients on beta-blockers, 53.33% received ACEI/ARBs, and 86.67% took aldosterone antagonists. No adverse events were reported nor therapy discontinuation. Conclusion: Our findings are consistent with published data with wild-type ATTR more frequently seen in males and V122I mutation predominantly seen in individuals of African descent. Overall, in a real-world setting, tafamidis was associated with a decline in NT-proBNP and well-tolerated in our patients.

Retrospective Evaluation Of Suspected Vs. Confirmed Transthyretin Amyloid Cardiomyopathy (ATTR-CM) Cases

<h3>Intoduction</h3> Transthyretin amyloidosis (ATTR) is a progressive and potentially fatal disease which results from the accumulation of misfolded amyloid fibrils in various organs and tissues. The deposition of these fibrils in the heart can lead to transthyretin amyloid cardiomyopathy (ATTR-CM). Literature reports that this disease is often misdiagnosed as heart failure or a variety of other conditions due to otherwise non-specific symptoms. For these reasons, the true prevalence of ATTR-CM is not well known. It has been estimated there are approximately 100,000 people in the United States living with ATTR-CM, and only one to two percent of these patients have been diagnosed. The primary objective of this study was to determine both the suspected and confirmed numbers of hereditary ATTR (hATTR) and wild-type ATTR (wtATTR) cases within a large managed care organization in western Pennsylvania. The secondary objective was to determine (in the suspected ATTR-CM population) the percentage of patients who had a cardiologist visit during the study period. <h3>Hypothesis</h3> The hypothesis of this evaluation is that there may be many undiagnosed members with ATTR-CM due to the presence of certain medical conditions commonly associated with the disease. <h3>Methods</h3> : This retrospective review of pharmacy and medical claims included UPMC Health Plan members ages 65 and older who were continuously enrolled from March 1, 2019 through February 29, 2020 with both pharmacy and medical benefits through UPMC Health Plan. Members were included in the suspected ATTR-CM population who had a select diagnosis of heart failure and at least one of the 10 medical condition combinations that are commonly associated with ATTR-CM during the study period; this population excluded patients with a diagnosis of ATTR-CM. The confirmed ATTR-CM population included patients with at least one ICD-10 code for either wtATTR or hATTR during the study period. <h3>Results</h3> 183,580 continuously enrolled members who were 65 and older during the study period were reviewed. Of these members, 11,928 had a diagnosis of heart failure. 986 members were identified for the suspected ATTR-CM population with a mean age of 80 (SD 7.68). Each combination group had more female than male matches. In the suspected ATTR-CM population, 94% of patients had a cardiologist visit during the study period. Separately, as a comparison, there were 214 members who had a confirmed diagnosis of ATTR-CM. <h3>Conclusion</h3> Both cardiovascular and non-cardiovascular medical conditions typically associated with ATTR-CM were common among members ≥ 65 years of age with heart failure; therefore, ATTR-CM may be underdiagnosed in this patient population.

Cardiogenic Shock with an Unsuspecting Etiology

<h3>Introduction</h3> Deciphering the underlying etiology of cardiogenic shock when the patient is in extremis is often challenging. In these situations, performing an autopsy may give useful insight. <h3>Case Report</h3> A 68 year old male with prior medical history of hypertension, diabetes and non-ischemic cardiomyopathy presented to an outside hospital with hypotension and junctional bradycardia. EKG was consistent with low voltage and echo showed EF of 30-35% with small LV cavity (4.5 cm). Coronary angiogram from a year ago was negative for CAD. Patient was planned to have CRT-D, however, went into VT storm and developed cardiogenic shock. IABP was inserted initially but since patient developed progressive shock, device was upgraded to an Impella. However, despite best efforts, the patient developed progressive cardiogenic shock with multiorgan failure and eventually died. Prior to patient's demise, consent was obtained from the family to perform an autopsy. Blood sample was also obtained for genetic testing. The autopsy revealed diffuse wild type ATTR amyloid involving multiple organs including heart, lung, kidneys, GI tract and prostate. Genetic testing for TTR was negative. <h3>Summary</h3> This case clearly demonstrates that autopsy should be recommended in cases where the underlying etiology of cardiomyopathy is unknown. This case also gives useful insight into the aggressive and multi-organ presentation of wild type ATTR amyloid.

Exercise And The Development Of Transthyretin Amyloid Cardiomyopathy - Is There An Association?

Introduction Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Hypothesis Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. Methods In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Results Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Conclusions Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease. Cardiac amyloidosis is an infiltrative heart disease that is associated with multi-organ dysfunction as a result of systemic misfolded protein deposition. Transthyretin (ATTR) amyloidosis is a type of amyloidosis that is increasingly being recognized as a cause of heart failure. Novel pharmacologic treatments for ATTR amyloid cardiomyopathy (ATTR-CM) have recently become available sparking a renewed interest in the pathophysiology of this disease. Other than certain genetic mutations, risk factors for the development of ATTR-CM are largely unknown. In the experience of our heart failure clinic, we have empirically observed that ATTR-CM patients frequently have a substantial history of vigorous athletic activity. We sought to identify a novel association between exercise and ATTR-CM. Cumulative lifetime strenuous physical activity is a novel risk factor for the development of ATTR-CM. In this single-center observational study, we recruited adults diagnosed with ATTR-CM and control subjects diagnosed with heart failure from non-amyloid cause. 50 ATTR-CM subjects and 22 controls were administered an in-depth lifetime physical activity survey. The survey identified type and quantity of physical activity from age 20 years until present day. Cumulative lifetime strenuous physical activity was quantified in metabolic equivalents of task (MET-minutes) of strenuous physical activity per active decade. Clinical and biochemical data were obtained retrospectively from the time of initial heart failure diagnosis. Wild-type ATTR amyloidosis was present in 82% (N=41) of ATTR-CM subjects, and 18% (N=9) of ATTR-CM subjects had genotype-confirmed hereditary ATTR amyloidosis. Both the ATTR-CM group and control group were male predominant (94% [N=47] vs 90.9% [N=20], p=0.63). ATTR-CM subjects were older at the time of diagnosis than controls (75.7 ±8.8 years vs. 63.6 ±9.4 years, p<0.0001). Left ventricular ejection fraction at the time of diagnosis was higher in ATTR-CM subjects than controls (49 ±14% vs. 32 ±15%, p<0.0001). Cumulative lifetime strenuous physical activity was higher in the ATTR-CM subjects than controls (1.44 × 106 MET-minutes per active decade vs. 0.751 × 106 MET-minutes per active decade, p=0.04). Findings from this study suggest that increased cumulative lifetime strenuous physical activity per active decade is associated with ATTR-CM compared to other types of CM. Though larger prospective studies are needed to confirm this association, identifying strenuous exercise as a novel risk factor for ATTR-CM may offer new insight into the pathophysiology of this disease.

ATTR Epidemiology, Genetics, and Prognostic Factors

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease and an underestimated cause of both heart failure and conduction abnormalities. It is characterized by pathologic accumulation of extracellular protein arising from unstable transthyretin (TTR) tetramers, which dissociate into monomers that misfold, aggregate, and form insoluble fibrils that are resistant to proteolysis. Cardiac amyloidosis appears in two distinct forms: hereditary and wild-type. There is considerable heterogeneity in the clinical presentation of ATTR, ranging from primarily cardiac, primarily neuropathic, or mixed cardiac and neuropathic disease. Pathogenic variants in the TTR gene that predominantly involve the heart include Val122Ile, Leu111Met, and Ile68Leu. The wild-type form of ATTR is also predominantly cardiac. Phenotypic heterogeneity is linked to differences among specific pathogenic TTR variants, geography, and the subtype of endemic versus nonendemic disease. Factors contributing to wild-type ATTR are largely unknown, but similar factors likely influence the penetrance of hereditary ATTR. Recognition of ATTR-CM is improving due to the increased use of cardiac scintigraphy as a noninvasive diagnostic tool, and early recognition of cardiac infiltration is crucial to optimize long-term prognosis.

Coexistence of Positive 99mTc-DPD Scintigraphy and Monoclonal Gammopathy: A Frequent Challenge.

Cardiac involvement is common in amyloidosis, and the vast majority of cases of amyloid cardiomyopathy are attributed to primary amyloidosis or transthyretin amyloidosis (ATTR). Although the coexistence of scintigraphy suggestive of ATTR with monoclonal gammopathy of undetermined significance is well documented, the correct diagnosis is still challenging in non-referral centers. We performed a retrospective study reviewing all amyloid cardiomyopathy cases diagnosed at our center over the last 5 years, and described our experience and diagnostic approach. During the last 5 years, 74 patients with positive scintigraphy were identified. Of these patients, 41 were included in this study as they had all necessary tests for a complete diagnosis. Two of these 41 patients had variant ATTR and 29 had wild-type ATTR. Ten patients had monoclonal gammopathy (24.4%), and it was consequently impossible to obtain a specific diagnosis. During follow-up, 14 patients (34.1%), five of them from the monoclonal gammopathy group, died, reflecting the severity of disease. In patients with ATTR-suggestive scintigraphy, monoclonal gammopathy frequently occurs concomitantly, thus not allowing to establish a specific diagnosis. A biopsy could only be replaced by genetic testing in selected cases.