Utility of Genetic Testing in Patients with Transthyretin Amyloid Cardiomyopathy: A Brief Review.
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SUBMITTER: Merino-Merino AM
PROVIDER: S-EPMC10813439 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
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Utility of Genetic Testing in Patients with Transthyretin Amyloid Cardiomyopathy: A Brief Review.
Merino-Merino Ana-Maria AM Labrador-Gomez Jorge J Sanchez-Corral Ester E Delgado-Lopez Pedro-David PD Perez-Rivera Jose-Angel JA
Biomedicines 20231221 1
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly diagnosed condition. Although wild-type transthyretin amyloidosis (ATTRwt) is the most common ATTR-CM, hereditary transthyretin amyloidosis (ATTRv) may also occur. Currently, genetic testing for transthyretin pathogenic variants is recommended for patients with a confirmed clinical diagnosis of ATTR-CM. In fact, confirmation of this autosomal dominant pathogenic variant prompts genetic counselling and allows early identification o ...[more]
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Project description:The prevalence of transthyretin-associated amyloidosis cardiomyopathy (ATTR-CM) has grown because of newer non-invasive diagnosis tools. Detecting the presence of extra-cardiac ATTR manifestations such as musculoskeletal pathologies considered 'red flags', when there is minimal or non-cardiac clinical involvement is primordial to carry out an early diagnosis. The aim of this systematic review is to examine the prevalence of musculoskeletal, ATTR-deposition-related co-morbidities in patients already diagnosed with ATTR-CM, specifically carpal tunnel syndrome, ruptured biceps tendon, spinal stenosis, and trigger finger. We performed a systematic review using PRISMA guidelines. Inclusion criteria were all studies in English and Spanish language and participants had to be patients diagnosed with ATTR-CM, by any diagnostic method, with the musculoskeletal co-morbidities subject of this review. The quality of the studies was based on the Risk of Bias Tool. This systematic review included 22 studies for final analysis. Carpal tunnel syndrome is reported in 21 studies, brachial biceps tendon rupture is reported in three, and spinal stenosis in eight studies. No articles that accomplished all the inclusion criteria for trigger finger were found. Regarding to the quality of the studies, all of them were categorized as being of high and moderate quality. The frequent association between ATTR-CM and carpal tunnel syndrome, ruptured biceps tendon, and lumbar spinal is confirmed, and the onset of these co-morbidities usually precedes the diagnosis of by years. This association defines them as red flags that should be search proactively due to the current treatment possibilities and the severity of the presentation of cardiac amyloidosis.
| S-EPMC10966237 | biostudies-literature
Project description:The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.
| S-EPMC11371834 | biostudies-literature
Project description:Transthyretin amyloid cardiomyopathy (ATTR-CM) continues to be an easily overlooked, life-threatening, yet treatable cause of heart failure. Furthermore, its elusive diagnosis leads to late or misdiagnosis. As therapeutic advancements such as tafamidis usher in a promising new era in the management of ATTR-CM, the need for disease awareness and efficient diagnostic evaluation is crucial. With newer inexpensive imaging modalities and techniques, such as longitudinal strain imaging, T1 mapping on cardiac magnetic resonance imaging, and cardiac scintigraphy, the diagnosis of ATTR-CM no longer requires invasive evaluation with tissue biopsy. Here, the authors review current diagnostic tools to help clinicians diagnose ATTR-CM.
| S-EPMC7237598 | biostudies-literature
Project description:Clinical algorithms stipulate that transthyretin amyloid cardiomyopathy (ATTR-CM) can be diagnosed noninvasively by technetium-99m pyrophosphate (PYP) imaging when light chain (AL) amyloidosis has been excluded. We sought to define the distribution of light chain abnormalities and final diagnosis of ATTR-CM among patients referred for PYP imaging. We conducted a retrospective cohort study of 378 sequential patients with suspected ATTR-CM, referred for PYP imaging from October 2014 to January 2019. PYP scans were adjudicated as per guidelines. We found that 97 patients (26%) had abnormal plasma cell dyscrasia (PCD) markers, including serum free light chain (FLC) and/or urine/serum immunofixation electrophoresis (IFE). After exclusions for incomplete data or known AL amyloidosis, the final study population with abnormal PCD testing was n = 82. Final adjudication of amyloidosis was determined by multidisciplinary clinical assessment and/or tissue biopsy. The median age of cohort was 75 (68 to 81) years, 88% were men, and 33% were Black. Of the 82 patients, 62 had positive PYP scans (76%) and 20 had negative PYP scans (24%). A total of 64 patients had adjudicated ATTR-CM, confirmed by tissue biopsy in 41 (64%). Of those with confirmed ATTR-CM, 44 (69%) had abnormal FLC ratio between 1.65 and 3.1 and normal IFE. In conclusion, among patients referred for technetium-99m-PYP imaging for suspected ATTR-CM, 26% exhibited abnormalities of PCD markers. An FLC ratio 1.65 to 3.1, with normal IFE was noted in 69% of those with ATTR-CM, suggesting that ATTR-CM can be diagnosed noninvasively without cardiac biopsy in patients with positive PYP scan and similar plasma cell testing results.
| S-EPMC9675982 | biostudies-literature
Project description:BackgroundPrevious studies have reported that tafamidis treatment was associated with better outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with those without tafamidis treatment. Therefore, we aimed to systematically assess the association of tafamidis treatment with outcomes in patients with ATTR-CM.MethodsThe protocol for this systematic review and meta-analysis was registered in the PROSPERO (CRD42022381985). Pubmed, Ovid Embase, Scopus, Cochrane Library, and Web of Science were interrogated to identify studies that evaluated the impact of tafamidis on prognosis in ATTR-CM, from January 1, 2000 to June 1, 2023. A random-effects model was used to determine the pooled risk ratio (RR) for the adverse endpoints. In addition, the main outcomes included all-cause death or heart transplantation, the composite endpoints included all-cause death, heart transplantation, cardiac-assist device implantation, heart failure exacerbations, and hospitalization.FindingsFifteen studies comprising 2765 patients (mean age 75.9 ± 9.3 years; 83.7% male) with a mean follow-up duration of 18.7 ± 17.1 months were included in the meta-analysis. There was a decrease in left ventricular ejection fraction (LVEF) (standard mean differences (SMD: -0.17; 95% confidence interval (CI), -0.31 to -0.03; P = 0.02) but were no significant differences in intraventricular septum (IVS) thickness or global longitudinal strain (GLS) after tafamidis treatment. However, subgroup analysis showed no significant deterioration in LVEF in the patients with wild-type ATTR after tafamidis treatment (SMD: -0.11; 95% CI, -0.34 to 0.12, P = 0.34). In addition, the group with tafamidis treatment had a decreased risk for all-cause death or heart transplantation compared to patients without treatment (the pooled RR, 0.44; 95% CI, 0.31-0.65; P < 0.01). Subgroup analysis showed that there was no significant difference of tafamidis on the outcomes in patients with wild-type or hereditary ATTR (RR, 0.44; 95% CI, 0.27-0.73 versus 0.21, 95% CI, 0.11-0.40, P = 0.08). Furthermore, tafamidis treatment was associated with a lower risk of the composite endpoint (RR, 0.57; 95% CI, 0.42-0.77; P < 0.01).InterpretationOur findings suggested that there was no significant deterioration in LVEF in the patients with wild-type ATTR after tafamidis treatment. In addition, tafamidis treatment was associated with a low risk of all-cause death and adverse cardiovascular events.FundingThis work was supported by grants from the Natural Science Foundation of Sichuan Province [Grant Number: 23NSFSC4589] and the National Natural Science Foundation of China [Grant Number: 82202248].
| S-EPMC10474377 | biostudies-literature
Project description:AimsAlthough systemic embolism is a potential complication in transthyretin amyloid cardiomyopathy (ATTR-CM), data about its incidence and prevalence are scarce. We studied the incidence, prevalence and factors associated with embolic events in ATTR-CM. Additionally, we evaluated embolic events according to the type of oral anticoagulation (OAC) and the performance of the CHA2 DS2 -VASc score in this setting.Methods and resultsClinical characteristics, history of atrial fibrillation (AF) and embolic events were retrospectively collected from ATTR-CM patients evaluated at four international amyloid centres. Overall, 1191 ATTR-CM patients (87% men, median age 77.1 years [interquartile range-IQR 71.4-82], 83% ATTRwt) were studied. A total of 162 (13.6%) have had an embolic event before initial evaluation. Over a median follow-up of 19.9 months (IQR 9.9-35.5), 41 additional patients (3.44%) had an embolic event. Incidence rate (per 100 patient-years) was 0 among patients in sinus rhythm with OAC, 1.3 in sinus rhythm without OAC, 1.7 in AF with OAC, and 4.8 in AF without OAC. CHA2 DS2 -VASc did not predict embolic events in patients in sinus rhythm whereas in patients with AF without OAC, only those with a score ≥4 had embolic events. There was no difference in the incidence rate of embolism between patients with AF treated with vitamin K antagonists (VKAs) (n = 322) and those treated with direct oral anticoagulants (DOACs) (n = 239) (p = 0.66).ConclusionsEmbolic events were a frequent complication in ATTR-CM. OAC reduced the risk of systemic embolism. Embolic rates did not differ with VKAs and DOACs. The CHA2 DS2 -VASc score did not correlate well with clinical outcome in ATTR-CM and should not be used to assess thromboembolic risk in this population.
| S-EPMC9542906 | biostudies-literature
Project description:ImportanceTransthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive cardiomyopathy that commonly presents with concomitant chronic kidney disease. Chronic kidney dysfunction is associated with worse outcomes, but the prognostic value of changes in kidney function over time has yet to be defined.ObjectiveTo assess the prognostic importance of a decline in estimated glomerular filtration rate (eGFR) in a large cohort of patients with ATTR-CM.Design, setting, and participantsThis retrospective, observational, single-center cohort study evaluated patients diagnosed with ATTR-CM at the National Amyloidosis Centre (NAC) in the UK who underwent an eGFR baseline assessment and a follow-up assessment at 1 year between January 2000 and April 2024. Data analysis was performed in June 2024.Main outcomes and measuresThe primary outcome was the risk of all-cause mortality associated with decline in kidney function (defined as a decrease in eGFR >20%).ResultsAmong 2001 patients, mean (SD) age was 75.5 (8.4) years, and 263 patients (13.1%) were female. The median (IQR) change in eGFR was -5 mlL/min/1.73 m2 (-12 to 1), and 481 patients (24.0%) experienced decline in kidney function. Patients who experienced decline in kidney function more often had the p.(V142I) genotype than patients with stable kidney function (99 [20.6%] vs 202 [13.3%]; P < .001) and had a more severe cardiac phenotype at baseline, as evidenced by higher median (IQR) concentrations of serum cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 2949 pg/mL [1759-5182] vs 2309 pg/mL [1146-4290]; P < .001; troponin T: 0.060 ng/mL [0.042-0.086] vs 0.052 ng/mL [0.033-0.074]; P < .001), while baseline median (IQR) kidney function was similar between the 2 groups (eGFR: 63 mL/min/1.73 m2 [51-77] vs 61 mL/min/1.73 m2 [49-77]; P = .41). Decline in kidney function was associated with a 1.7-fold higher risk of mortality (hazard ratio [HR], 1.71; 95% CI, 1.43-2.04; P < .001), with a similar risk across the 3 genotypes (wild type: HR, 1.64; 95% CI, 1.31-2.04; p.(V142I): HR, 1.70; 95% CI, 1.21-2.39; non-p.(V142I): HR, 1.51; 95% CI, 0.87-2.61) (P for interaction = .93) and the 3 NAC disease stages (stage 1: HR, 1.69; 95% CI, 1.22-2.32; stage 2: HR, 1.69; 95% CI, 1.30-2.18; stage 3: HR, 1.61; 95% CI, 1.11-2.35) (P for interaction = .97). Decline in kidney function remained independently associated with mortality after adjusting for increases in NT-proBNP and outpatient diuretic intensification (HR, 1.48; 95% CI, 1.23-2.76; P < .001).Conclusions and relevanceIn this retrospective cohort study, decline in kidney function was frequent in patients with ATTR-CM and was consistently associated with an increased risk of mortality, even after adjusting for established markers of worsening ATTR-CM. eGFR decline represents an independent marker of ATTR-CM disease progression that could guide treatment optimization in clinical practice.
| S-EPMC11571068 | biostudies-literature
Project description:AimsTo clarify the usefulness of left atrial (LA) function and left ventricular (LV) function obtained by two-dimensional (2D) speckle tracking echocardiography to diagnose concomitant transthyretin amyloid cardiomyopathy (ATTR-CM) in patients with aortic stenosis (AS).Methods and resultsWe analysed 72 consecutive patients with moderate to severe AS who underwent 99m Tc-pyrophosphate (PYP) scintigraphy at Kumamoto University Hospital from January 2012 to September 2020. We divided these 72 patients into 2 groups based on their 99m Tc-PYP scintigraphy positivity or negativity. Among 72 patients, 16 patients (22%) were positive, and 56 patients (78%) were negative for 99m Tc-PYP scintigraphy. In clinical baseline characteristics, natural logarithm troponin T was significantly higher in the 99m Tc-PYP scintigraphy-positive than scintigraphy-negative group (-2.9 ± 0.5 vs. -3.5 ± 0.8 ng/mL, P < 0.05). In conventional echocardiography, the severity of AS was not significantly different between these two groups. In 2D speckle tracking echocardiography, the relative apical longitudinal strain (LS) index (RapLSI) [apical LS/ (basal LS + mid LS)] was significantly higher (1.09 ± 0.49 vs. 0.78 ± 0.23, P < 0.05) and the peak longitudinal strain rate (LSR) in LA was significantly lower in the 99m Tc-PYP scintigraphy-positive than scintigraphy-negative group (0.36 ± 0.14 vs. 0.55 ± 0.20 s-1 , P < 0.05). Multivariable logistic analysis revealed the peak LSR in LA and RapLSI were significantly associated with 99m Tc-PYP scintigraphy positivity. Receiver operating characteristic analysis showed that the area under the curve (AUC) of the peak LSR in LA for 99m Tc-PYP scintigraphy positivity was 0.79 and that the best cut-off value of the peak LSR in LA was 0.47 s-1 (sensitivity: 78.6% and specificity: 72.3%). The AUC of RapLSI for 99m Tc-PYP scintigraphy positivity was 0.69, and the cut-off value of RapLSI was decided as 1.00 (sensitivity: 43.8% and specificity: 87.5%) according to the previous report. The 99m Tc-PYP scintigraphy positivity in patients with RapLSI ≥ 1.0 and the peak LSR in LA ≤ 0.47 s-1 was 83.3% (5/6), and the 99m Tc-PYP scintigraphy negativity in patients with RapLSI < 1.0 and the peak LSR in LA > 0.47 s-1 was 96.6% (28/29).ConclusionsLeft atrial and LV strain analysis were significantly associated with 99m Tc-PYP scintigraphy positivity in ATTR-CM patients with moderate to severe AS. The combination of the peak LSR in LA and RapLSI might be a useful predictor of the presence of ATTR-CM in patients with moderate to severe AS.
| S-EPMC9065867 | biostudies-literature
Project description:BackgroundTafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).MethodsPatients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE.ResultsMedian follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06).ConclusionsIn the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.
| S-EPMC8763250 | biostudies-literature
Project description:Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive and increasingly recognized cause of heart failure which is associated with high mortality and morbidity. ATTR-CM is characterized by the misfolding of TTR monomers and their deposition within the myocardium as amyloid fibrils. The standard of care for ATTR-CM consists of TTR-stabilizing ligands, such as tafamidis, which aim at maintaining the native structure of TTR tetramers, thus preventing amyloid aggregation. However, their efficacy in advanced-staged disease and after long-term treatment is still a source of concern, suggesting the existence of other pathogenetic factors. Indeed, pre-formed fibrils present in the tissue can further accelerate amyloid aggregation in a self-propagating process known as "amyloid seeding". The inhibition of amyloidogenesis through TTR stabilizers combined with anti-seeding peptides may represent a novel strategy with additional benefits over current therapies. Finally, the role of stabilizing ligands needs to be reassessed in view of the promising results derived from trials which have evaluated alternative strategies, such as TTR silencers and immunological amyloid disruptors.
| S-EPMC10143494 | biostudies-literature