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Pubblicazioni recenti - cardiac amyloidosis
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Natural history and impact of treatment with tafamidis on major cardiovascular outcome-free survival time in a cohort of patients with transthyretin amyloidosis.
Eur J Heart Fail2020 Oct;():. doi: 10.1002/ejhf.2028.
Bézard Mélanie, Kharoubi Mounira, Galat Arnault, Poullot Elsa, Guendouz Soulef, Fanen Pascale, Funalot Benoit, Moktefi Anissa, Lefaucheur Jean-Pascal, Abulizi Mukedaisi, Deux Jean-François, Gendre Thierry, Audard Vincent, El Karoui Khalil, Canoui-Poitrine Florence, Zaroui Amira, Itti Emmanuel, Teiger Emmanuel, Planté-Bordeneuve Violaine, Oghina Silvia, Damy Thibaud,
Abstract
AIMS:
Hereditary (ATTRv) and senile (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis is used in France to treat patients with ATTRv with neuropathy (alone or with cardiomyopathy). Recently, the Phase III ATTRACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTRACT trial and to assess the impact of tafamidis on major cardiovascular outcome-free (MCO-free) survival time without cardiac decompensation, heart transplant, or death.
METHODS AND RESULTS:
From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. 467 (72%) patients matched the inclusion criteria of the ATTRACT study. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (N=98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank p<0.001). This association was confirmed after considering confounding factors (age at inclusion, Nt-proBNP and amyloidosis type) with a propensity score (hazard ratio: 0.546, p=0.0132).
CONCLUSION:
In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTRACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcome in a real-life population.
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Prognostic significance of incidental suspected transthyretin amyloidosis on routine bone scintigraphy.
J Nucl Cardiol2020 Oct;():. doi: 10.1007/s12350-020-02396-7.
Suomalainen Olli, Pilv Jaagup, Loimaala Antti, Mätzke Sorjo, Heliö Tiina, Uusitalo Valtteri,
Abstract
BACKGROUND:
Transthyretin amyloidosis (ATTR) is an occasional incidental finding on bone scintigraphy. We studied its prognostic impact in elderly patients.
METHODS:
The study population consisted of 2000 patients aged over 70 years who underwent bone scintigraphies with clinical indications in three nuclear medicine departments (Kymenlaakso, Jorvi and Meilahti hospitals) in Finland. All studies were performed using Technetium labeled hydroxymethylene diphosphonate (HMDP). ATTR was suspected in patients with ?grade 2 Perugini grade uptake (grade 0-3). Heart-to-contralateral ratio (H/CL) of ? 1.30 was considered positive for ATTR. The overall and cardiovascular mortality were obtained from the Finnish National Statistical Service.
RESULTS:
There were a total of 1014 deaths (51%) and 177 cardiovascular deaths (9%) during median follow-up of 4 ± 2 years. ATTR was suspected in 69 patients (3.6%) of which 54 (2.7%) had grade 2 and 15 (.8%) had grade 3 uptake and in 47 patients (2.4%) by H/CL ratio. In multivariate analyses age, bone metastasis, H/CL ratio and grade 3 uptake were independent predictors of overall and cardiovascular mortality. Grade 2 uptake was a predictor of cardiovascular mortality.
CONCLUSIONS:
A suspected ATTR as an incidental finding on bone scintigraphy predicts elevated overall and cardiovascular mortality in elderly patients.
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Seeded fibrils of the germline variant of human ?-III immunoglobulin light chain FOR005 have a similar core as patient fibrils with reduced stability.
J Biol Chem2020 Oct;():. doi: jbc.RA120.016006.
Pradhan Tejaswini, Annamalai Karthikeyan, Sarkar Riddhiman, Huhn Stephanie, Hegenbart Ute, Schönland Stefan, Fändrich Marcus, Reif Bernd,
Abstract
Systemic antibody light chains (AL) amyloidosis is characterized by deposition of amyloid fibrils derived from a particular antibody light chain. Cardiac involvement is a major risk factor for mortality. Using MAS solid-state NMR, we studied the fibril structure of a recombinant light chain fragment corresponding to the fibril protein from patient FOR005, together with fibrils formed by protein sequence variants that are derived from the closest germline (GL) sequence. Both analyzed fibril structures were seeded with ex-vivo amyloid fibrils purified from the explanted heart of this patient. We find that residues 11-42 and 69-102 adopt ?-sheet conformation in patient protein fibrils. We identify arginine-49 as a key residue that forms a salt bridge to aspartate-25 in the patient protein fibril structure. In the germline sequence, this residue is replaced by a glycine. Fibrils from the GL protein and from the patient protein harboring the single point mutation R49G can be both heterologously seeded using patient ex-vivo fibrils. Seeded R49G fibrils show an increased heterogeneity in the C-terminal residues 80-102, which is reflected by the disappearance of all resonances of these residues. By contrast, residues 11-42 and 69-77, which are visible in the MAS solid-state NMR spectra, show 13C? chemical shifts that are highly similar to patient fibrils. The mutation R49G thus induces a conformational heterogeneity at the C-terminus in the fibril state, while the overall fibril topology is retained. These findings imply that patient mutations in FOR005 can stabilize the fibril structure.
Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
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Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.
Aging Cell2020 Oct;():e13246. doi: 10.1111/acel.13246.
Doustar Jonah, Rentsendorj Altan, Torbati Tania, Regis Giovanna C, Fuchs Dieu-Trang, Sheyn Julia, Mirzaei Nazanin, Graham Stuart L, Shah Prediman K, Mastali Mitra, Van Eyk Jennifer E, Black Keith L, Gupta Vivek K, Mirzaei Mehdi, Koronyo Yosef, Koronyo-Hamaoui Maya,
Abstract
Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina-brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APP/PS1; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre- and early-symptomatic disease stages. Here, we explored the link between retinal and cerebral AD-related biomarkers, including response to GA immunization, in cohorts of old, late-stage ADtg mice. This aged model is considered more clinically relevant to the age-dependent disease. Levels of synaptotoxic amyloid ?-protein (A?), angiopathic A?, non-amyloidogenic A?, and A?/A? ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right posterior brain hemispheres. We identified lateralization of A? burden, with one-side dominance within paired retinal and brain tissues. Importantly, OS and OD retinal A? levels correlated with their cerebral counterparts, with stronger contralateral correlations and following GA immunization. Moreover, immunomodulation in old ADtg mice brought about reductions in cerebral vascular and parenchymal A? deposits, especially of large, dense-core plaques, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Mass spectrometry analysis identified new parallels in retino-cerebral AD-related pathology and response to GA immunization, including restoration of homeostatic glutamine synthetase expression. Overall, our results illustrate the viability of immunomodulation-guided CNS repair in old AD model mice, while shedding light onto similar retino-cerebral responses to intervention, providing incentives to explore retinal AD biomarkers.
© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
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Daratumumab for relapsed AL amyloidosis - when cumulative real-world data precedes clinical trials: A multisite study and systematic literature review.
Eur J Haematol2020 Oct;():. doi: 10.1111/ejh.13535.
Shragai Tamir, Gatt Moshe, Lavie Noa, Vaxman Iuliana, Tadmor Tamar, Rouvio Ory, Zektser Miri, Horowitz Nethanel, Magen Hila, Ballan Mouna, Suru Celia, Luttwak Efrat, Levi Shai, Ziv-Baran Tomer, Avivi Irit, Cohen Yael C,
Abstract
OBJECTIVES:
Patients with relapsed/refractory AL amyloidosis (RRAL) have poor prognosis, but emerging data shows promising results with the use daratumumab. We evaluated daratumumab treatment in RRAL in real-world setting.
METHODS:
retrospective multi-site study of RRAL patients treated with daratumumab alone and in combinations.
RESULTS:
Forty-nine patients, diagnosed between 1.1.2008 and 1.2.2018 were included; 27% also had multiple myeloma. Revised Mayo score was ?3 in 67%. Hematologic overall response rate was 81%, 64% achieved very good partial response (VGPR) or better. Concurrent active multiple myeloma was associated with lower rates of VGPR (OR 0.19, 95% CI 0.04-0.81; p=0.03) in a multi-variate analysis. Cardiac and renal responses were 74% and 73%, respectively. Median progression-free survival (PFS) was 28.4 months and median overall survival (OS) was not reached; two-years PFS and OS were 68.6±7.5% and 90.4±4.6%, respectively. Hematologic response correlated with prolonged PFS and OS. Daratumumab was safe and well tolerated, no patients discontinued therapy due to toxicity. Our data was aligned with outcomes from a systematic literature review, which identified 10 case-series (n=517) and 2 clinical trials (n=62) meeting pre-specified criteria.
CONCLUSIONS:
Our data supports favorable safety tolerability and efficacy of daratumumab among nonselective RRAL patients in a real-world setting.
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Ventricular Arrhythmias in Cardiac Amyloidosis: A Review of Current Literature.
Clin Med Insights Cardiol2020 ;14():1179546820963055. doi: 10.1177/1179546820963055.
Khanna Shaun, Lo Phillip, Cho Kenneth, Subbiah Rajesh,
Abstract
Cardiac Amyloidosis is an infiltrative cardiomyopathy which occurs secondary to deposition of mis-folded protein in the myocardium, with the two most common subtypes being AL amyloidosis and TTR amyloidosis. The pathogenesis of the disease is multifaceted and involves a variety of mechanisms including an inflammatory response cascade, oxidative stress and subsequent separation of myocyte fibrils. Cardiac Amyloidosis frequently results in congestive cardiac failure and arrhythmias, from a disruption in cardiac substrate with subsequent electro-mechanical remodelling. Disease progression is usually demonstrated by development of progressive pump failure, which may be seen with a high arrhythmic burden, usually portending a poor prognosis. There is a paucity of literature on the clinical implications of ventricular arrhythmias in the context of cardiac amyloidosis. The important diagnostic investigations for these patients include transthoracic echocardiography, cardiac magnetic resonance imaging and an electrophysiology study. Whilst there are no robust management guidelines, studies have indicated benefits from contemporary pharmacological therapy and case-by-case catheter ablation. There are novel directed therapies available for TTR amyloidosis that have shown to improve overall survival. The role of ICD therapy in cardiac amyloidosis is controversial, with benefits seen predominantly in early phases of the disease process. The only definitive surgical therapy includes heart transplantation, but is largely indicated for progressive decompensated heart failure (Figure 1). Further large-scale studies are required to better outline management paradigms for treating ventricular arrhythmias in cardiac amyloidosis.
© The Author(s) 2020.
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Amyloid A amyloidosis in a patient with Caplan's syndrome, with special reference to genetic predisposition.
Mod Rheumatol Case Rep2020 Jul;4(2):212-217. doi: 10.1080/24725625.2020.1749361.
Nakamura Tadashi, Shiraishi Naoki, Morikami Yasuhiro, Fujii Hiromi, Yoshinaga Takeshi,
Abstract
Secondary amyloid A (AA) amyloidosis, which is a disorder of protein conformation and metabolism, is an important serious complication of inflammatory diseases, especially rheumatoid arthritis (RA). AA amyloidosis develops when AA fibrils, which are derived from the acute-phase reactant, serum amyloid AA (SAA) protein, in the circulation, are deposited in organs and cause systemic organ dysfunction. Caplan's syndrome, or rheumatoid pneumoconiosis, is a rare type of lung disease in which individuals suffering from RA develop lung nodules that are associated with occupational exposure to silica and coal dust. Confirmation of diagnosing as Caplan's syndrome requires the patient's occupational history, imaging studies, and serology. A 72-year-old male, working as a tunnel construction worker for 38?years, with RA who had both chronic cardiac and renal dysfunction was referred to our hospital. He received a diagnosis of pneumoconiosis about 20?years ago, after which he was also diagnosed with RA. So far we performed medical English literature searches on the combination of Caplan's syndrome with AA amyloidosis; there were no articles in relation to such association. Although RA is one of the most common underlying diseases that occur with AA amyloidosis, our report here is the first description of a case of Caplan's syndrome associated with AA amyloidosis. In this report, we provide details about this rare disease occurring with AA amyloidosis and discuss on the possible pathogenesis of AA amyloidosis from a genetic point of aetiological view.
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Temporal artery involvement in AL amyloidosis: an important differential diagnosis for giant cell arteritis. A case report and literature review.
Mod Rheumatol Case Rep2020 Jan;4(1):90-94. doi: 10.1080/24725625.2019.1650993.
Oiwa Hiroshi, Katoh Nagaaki, Kojo Shoichiro, Yoshinaga Tsuneaki, Taniguchi Kohei, Shiote Yasuhiro,
Abstract
AL amyloidosis (AL) is a systemic disorder due to extracellular tissue deposition of amyloid fibrils, composed of immunoglobulin light chains. Since the description of AL involving temporal arteries in 1986, this disorder has been known as one of the differential diagnoses of giant cell arteritis (GCA). We encountered a case of an elderly female presenting with headache and tender and enlarged temporal arteries, that was pathologically diagnosed with temporal artery involvement of AL due to Bence-Jones-type MM. To our knowledge, this was the first case of AL with temporal artery involvement in Japan, that presented with GCA-like features. Literature review of AL cases with temporal artery involvement showed close similarity between these disorders, but suggested that vasculature involvement (extremity claudication, kidney or heart), macroglossia, carpal tunnel syndrome and normal or low (<0.5?mg/dL) CRP levels may predict AL rather than GCA. Physicians should keep in mind that AL involving temporal arteries can be a pitfall in the diagnosis of GCA, as seen in our and previous cases.
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The role of induction therapy before autologous stem cell transplantation in low disease burden AL amyloidosis patients.
Amyloid2020 Oct;():1-9. doi: 10.1080/13506129.2020.1835635.
Huang Xianghua, Ren Guisheng, Chen Wencui, Guo Jinzhou, Zhao Liang, Zeng Caihong, Ge Yongchun, Liu Zhihong,
Abstract
BACKGROUND:
Induction therapy is recommended before autologous stem cell transplantation (ASCT) for AL amyloidosis patients with high disease burden [bone marrow plasma cells (BMPCs) > 10%], but the role of induction therapy before ASCT in patients with low disease burden (BMPCs ? 10%) is still unknown.
METHODS:
A total of 227 patients with AL amyloidosis were included in this study. Among 227 patients, 124 patients received bortezomib-based induction prior to ASCT and were defined as group A, 35 patients received other chemotherapeutic induction and were defined as group B, and the other 68 patients without induction were defined as group C. We compared the differences of efficacy and prognosis between the three groups.
RESULTS:
The haematological overall response rates (ORR) of groups A, B and C were 91%, 67% and 75%, respectively. The complete response rates (CR) of groups A, B and C were 50%, 25% and 20%, respectively. Both the ORR and CR rates of group A were significantly higher than those of groups B and C. The renal response rates of groups A, B and C were 64%, 46% and 47%, respectively. The cardiac response rates of groups A, B and C were 74%, 45% and 40%, respectively. The renal and cardiac responses rates of group A were also significantly higher than those of the other two groups. After a median follow-up of 44?months, the median OS was not reached. The 5-year estimated overall survival (OS) rates of groups A, B and C were 81%, 57% and 67%, respectively. The median progression-free survival (PFS) was 83?months for all patients. The 5-year estimated PFS rates of groups A, B and C were 61%, 38% and 49%, respectively. Both the OS and PFS of group A were higher than those of both group B and group C. On multivariate analysis, baseline dFLC > 50?mg/L was associated with worse survival, but induction with bortezomib was associated with better survival.
CONCLUSION:
Our study demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy.
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Role of Nuclear Imaging in Cardiac Amyloidosis Management: Clinical Evidence and Review of Literature.
Curr Med Imaging2020 ;16(8):957-966. doi: 10.2174/1573405615666191210103452.
Frantellizzi Viviana, Cosma Laura, Pani Arianna, Pontico Mariano, Conte Miriam, De Angelis Cristina, De Vincentis Giuseppe,
Abstract
Cardiac amyloidosis (CA) is an infiltrative disease characterized by the extracellular deposition of fibrils, amyloid, in the heart. The vast majority of patients with CA has one of two types between transthyretin amyloid (ATTR) and immunoglobulin light chain associated amyloid (AL), that have different prognosis and therapeutic options. CA is often underdiagnosed. The histological analysis of endomyocardial tissue is the gold standard for the diagnosis, although it has its limitations due to its invasive nature. Nuclear medicine now plays a key role in the early and accurate diagnosis of this disease, and in the ability to distinguish between the two forms. Recent several studies support the potential advantage of bone-seeking radionuclides as a screening technique for the most common types of amyloidosis, in particular ATTR form. This review presents noninvasive modalities to diagnose CA and focuses on the radionuclide imaging techniques (bone-seeking agents scintigraphy, cardiac sympathetic innervation and positron emission tomography studies) available to visualize myocardial amyloid involvement. Furthermore, we report the case of an 83-year old male with a history of prostate cancer, carcinoma of the cecum and kidney cancer, submitted to bone scan to detect bone metastasis, that revealed a myocardial uptake of 99mTC-HMPD suggestive of ATTR CA. An accurate and early diagnosis of CA able to distinguish beyween AL and ATTR CA combined to the improving therapies could improve the survival of patients with this disease.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study.
Life (Basel)2020 Oct;10(10):. doi: E247.
Cicco Sebastiano, Solimando Antonio Giovanni, Buono Roberta, Susca Nicola, Inglese Gianfranco, Melaccio Assunta, Prete Marcella, Ria Roberto, Racanelli Vito, Vacca Angelo,
Abstract
Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a ? free light chain form. The 32 AL with complete Ig were 31 ?-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria ( = 0.02). TnI and NT-proBNP were significantly increased compared to nCA ( = 0.031 and = 0.047, respectively). In CA patients we found an increased LDH compared to nCA ( = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA ( = 0.002), a decreased Ejection Fraction % ( = 0.0018) and Doppler velocity E/e' ratio ( = 0.0095). Moreover, CA patients had an enhanced right atrium area ( = 0.0179), right ventricle basal diameter ( = 0.0112) and wall thickness ( = 0.0471) compared to nCA, and an increased inferior cava vein diameter ( = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients ( = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; = 0.031) as well as Gamma globulins (r = 0.43, = 0.033), Monoclonal components (r = 0.72; = 0.047) and IgG values (r = 0.62, = 0.018). Conversely, a significant negative correlation with LDH (r = -0.57, = 0.005), IVS (r = -0.51, = 0.008) and diastolic function evaluated as E/e' (r = -0.60, = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis.
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Serum high-density lipoprotein cholesterol serves as a prognostic marker for light-chain cardiac amyloidosis.
Int J Cardiol2020 Oct;():. doi: S0167-5273(20)33987-5.
Yang Tingjie, Wan Ke, Song Rizhen, Guo Xinli, Xu Yuanwei, Wang Jie, Zhang Qing, Alexander Kevin Michael, Liao Ronglih, Chen Yucheng,
Abstract
BACKGROUND:
Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM.
METHOD:
In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C < 40 mg/dL and HDL-C ? 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C.
RESULTS:
Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy.
CONCLUSIONS:
HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis.
Copyright © 2020 Elsevier B.V. All rights reserved.
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Uncommon Disease in a Rare Location: The Mystery of the Rapidly Progressive Cardiomyopathy.
Circulation2020 Oct;142(16):1591-1595. doi: 10.1161/CIRCULATIONAHA.120.048323.
Ajufo Ezimamaka, Kansagra Ankit, Torrealba Jose, Grodin Justin L,
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Diuretic Dose and NYHA Functional Class Are Independent Predictors of Mortality in Patients With Transthyretin Cardiac Amyloidosis.
JACC CardioOncol2020 Sep;2(3):414-424. doi: 10.1016/j.jaccao.2020.06.007.
Cheng Richard K, Levy Wayne C, Vasbinder Alexi, Teruya Sergio, De Los Santos Jeffeny, Leedy Douglas, Maurer Mathew S,
Abstract
BACKGROUND:
With increasing diagnoses and available treatment options for transthyretin amyloidosis cardiomyopathy (ATTR-CM), risk stratification of ATTR-CM patients is imperative.
OBJECTIVES:
We hypothesized that diuretic dose and New York Heart Association (NYHA) functional class are independent predictors of mortality in ATTR-CM and would be incrementally additive to existent risk scores.
METHODS:
Consecutive ATTR-CM patients referred to a single center were identified. Adjusted Cox proportional hazards models determined the association between diuretic dose (furosemide equivalent in mg/kg) at time of diagnosis and the primary outcome of all-cause mortality. The incremental value of adding diuretic dose and NYHA functional class to existing ATTR-CM risk scores was assessed for discrimination and calibration.
RESULTS:
309 patients were identified, with mean age 73.2 ± 9.8 years, 84.1% male, and 66% wild type. Daily mean diuretic dose was 0.6 ± 1.0 mg/kg and significantly associated with all-cause mortality (unadjusted hazard ratio: 2.12 per 1-mg/kg increase, [95% confidence interval: 1.71 to 2.61] and fully adjusted hazard ratio: 1.43 [95% confidence interval: 1.06 to 1.93]). Testing previously published ATTR risk scores, adding diuretic dose as categories (0 mg/kg, >0 to 0.5 mg/kg, >0.5 to 1 mg/kg, and >1 to 2 mg/kg) improved the area under the curve of the Mayo risk score from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787 while preserving calibration. Adding NYHA functional class further improved the area under the curve to 0.798 and 0.816, respectively.
CONCLUSIONS:
Diuretic dose and NYHA functional class are independent predictors of mortality in ATTR-CM patients and provide incremental value to existing ATTR-CM risk scores.
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Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.
Eur J Heart Fail2020 Oct;():. doi: 10.1002/ejhf.2027.
Damy Thibaud, Garcia-Pavia Pablo, Hanna Mazen, Judge Daniel P, Merlini Giampaolo, Gundapaneni Balarama, Patterson Terrell A, Riley Steven, Schwartz Jeffrey H, Sultan Marla B, Witteles Ronald,
Abstract
AIMS:
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.
METHODS AND RESULTS:
In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80mg, 20mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80mg or 20mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80mg (P =0.0030) and 20mg (P=0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80mg (Cox hazards model [95% CI]: 0.690 [0.487-0.979], P=0.0378) and 20mg (0.715 [0.450-1.137], P=0.1564). The mean (SE) change in NT-proBNP from baseline to Month 30 was -1170.51 (587.31), P=0.0468 with tafamidis 80mg vs. 20mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80mg vs 20mg (0.700 [0.501-0.979], P=0.0374). Incidence of adverse events in both tafamidis doses were comparable to placebo.
CONCLUSION:
Tafamidis, both 80mg and 20mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data, and the lack of dose-related safety concerns, support tafamidis 80mg as the optimal dose. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Indexed left ventricular mass to QRS voltage ratio is associated with heart failure hospitalizations in patients with cardiac amyloidosis.
Int J Cardiovasc Imaging2020 Oct;():. doi: 10.1007/s10554-020-02059-1.
Slivnick Jeremy A, Wallner Alexander L, Vallakati Ajay, Truong Vien T, Mazur Wojciech, Elamin Mohamed B, Tong Matthew S, Raman Subha V, Zareba Karolina M,
Abstract
In cardiac amyloidosis (CA), amyloid infiltration results in increased left ventricular (LV) mass disproportionate to electrocardiographic (EKG) voltage. We assessed the relationship between LV mass-voltage ratio with subsequent heart failure hospitalization (HHF) and mortality in CA. Patients with confirmed CA and comprehensive cardiovascular magnetic resonance (CMR) and EKG exams were included. CMR-derived LV mass was indexed to body surface area. EKG voltage was assessed using Sokolow, Cornell, and Limb-voltage criteria. The optimal LV mass-voltage ratio for predicting outcomes was determined using receiver operating characteristic curve analysis. The relationship between LV mass-voltage ratio and HHF was assessed using Cox proportional hazards analysis adjusting for significant covariates. A total of 85 patients (mean 69?±?11 years, 22% female) were included, 42 with transthyretin and 43 with light chain CA. At a median of 3.4-year follow-up, 49% of patients experienced HHF and 60% had died. In unadjusted analysis, Cornell LV mass-voltage ratio was significantly associated with HHF (HR, 1.05; 95% CI 1.02-1.09, p?=?0.001) and mortality (HR, 1.05; 95% CI 1.02-1.07, p?=?0.001). Using ROC curve analysis, the optimal cutoff value for Cornell LV mass-voltage ratio to predict HHF was 6.7 gm/m2/mV. After adjusting for age, NYHA class, BNP, ECV, and LVEF, a Cornell LV mass-voltage ratio?>?6.7 gm/m2/mV was significantly associated with HHF (HR 2.25, 95% CI 1.09-4.61; p?=?0.03) but not mortality. Indexed LV mass-voltage ratio is associated with subsequent HHF and may be a useful prognostic marker in cardiac amyloidosis.
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Quantitative clinical nuclear cardiology, part 2: Evolving/emerging applications.
J Nucl Cardiol2020 Oct;():. doi: 10.1007/s12350-020-02337-4.
Slomka Piotr J, Moody Jonathan B, Miller Robert J H, Renaud Jennifer M, Ficaro Edward P, Garcia Ernest V,
Abstract
Quantitative analysis has been applied extensively to image processing and interpretation in nuclear cardiology to improve disease diagnosis and risk stratification. This is Part 2 of a two-part continuing medical education article, which will review the potential clinical role for emerging quantitative analysis tools. The article will describe advanced methods for quantifying dyssynchrony, ventricular function and perfusion, and hybrid imaging analysis. This article discusses evolving methods to measure myocardial blood flow with positron emission tomography and single-photon emission computed tomography. Novel quantitative assessments of myocardial viability, microcalcification and in patients with cardiac sarcoidosis and cardiac amyloidosis will also be described. Lastly, we will review the potential role for artificial intelligence to improve image analysis, disease diagnosis, and risk prediction. The potential clinical role for all these novel techniques will be highlighted as well as methods to optimize their implementation.
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International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM).
Blood Cancer J2020 Oct;10(10):102. doi: 10.1038/s41408-020-00366-3.
Mateos María-Victoria, Kumar Shaji, Dimopoulos Meletios A, González-Calle Verónica, Kastritis Efstathios, Hajek Roman, De Larrea Carlos Fernández, Morgan Gareth J, Merlini Giampaolo, Goldschmidt Hartmut, Geraldes Catarina, Gozzetti Alessandro, Kyriakou Charalampia, Garderet Laurent, Hansson Markus, Zamagni Elena, Fantl Dorotea, Leleu Xavier, Kim Byung-Su, Esteves Graça, Ludwig Heinz, Usmani Saad, Min Chang-Ki, Qi Ming, Ukropec Jon, Weiss Brendan M, Rajkumar S Vincent, Durie Brian G M, San-Miguel Jesús,
Abstract
Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2?g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2-3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ?3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable.
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Quantitative Clinical Nuclear Cardiology, Part 2: Evolving/Emerging Applications.
J Nucl Med2020 Oct;():. doi: jnumed.120.242537.
Slomka Piotr J, Moody Jonathan B, Miller Robert J H, Renaud Jennifer, Ficaro Edward P, Garcia Ernest V,
Abstract
Quantitative analysis has been applied extensively to image processing and interpretation in nuclear cardiology in order to improve disease diagnosis and risk stratification. This is Part 2 of a two-part continuing medical education article, which will review the potential clinical role for emerging quantitative analysis tools. The article will describe advanced methods for quantifying dyssynchrony, ventricular function and perfusion, and hybrid imaging analysis. This article discusses evolving methods to measure myocardial blood flow with positron emission tomography and single photon emission computed tomography. Novel quantitative assessments of myocardial viability, microcalcification and in patients with cardiac sarcoidosis and cardiac amyloidosis will also be described. Lastly, we will review the potential role for artificial intelligence to improve image analysis, disease diagnosis, and risk prediction. The potential clinical role for all these novel techniques will be highlighted as well as methods to optimize their implementation.
Copyright © 2020 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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[Diagnosing cardiac amyloidosis in magnetic resonance imaging: The discriminating factors].
Ann Cardiol Angeiol (Paris)2020 Oct;():. doi: S0003-3928(20)30132-3.
Goïorani F, Dagrenat C, Brocchi J, Couppie P, Leddet P,
Abstract
Infiltrative cardiomyopathies refers to deposits of substances in the myocardial tissue resulting in a structural abnormality and/or alteration of cardiac function. Cardiac amyloidosis is an extracellular infiltration of amyloid fibril. Cardiac magnetic resonance imaging (MRI) is essential (in the) for its diagnosis. MRI sequences (morphological, viability and parametric mapping) allow a structural and dynamic analysis of the cardiac function as well as a characterization of the myocardial tissue: edema, fatty infiltration, fibrosis. In cardiac amyloidosis, the morphological sequences classically highlight ventricular hypertrophy and thickening of the heart valves. Ventricular functions are assessed by the cine sequences (The cine sequences make it possible to evaluate the ventricular functions.) The viability sequences show (a more diffuse distribution of hypersignals) an abnormal pattern of late gadolinium enhancement in both circumferential and sub-endocardial distribution. The relaxometry sequences or parametric T1 and/or T2 mapping allow the spatial visualization of quantitative changes of the myocardium. The presence of macroscopic myocardial edema or fibrosis causes a prolongation of the native T1 and an increase of the extracellular volume.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
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