scholarly journals Bone scintigraphy in the diagnosis of transthyretin amyloidosis: a different performance in Portuguese hereditary variant?

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A F Dias De Frias ◽  
P Rodrigues ◽  
R Costa ◽  
A Campinas ◽  
A Pereira ◽  
...  
Keyword(s):  
Bone Scintigraphy ◽  
Wall Thickness ◽  
Troponin T ◽  
Statistical Significance ◽  
Renal Involvement ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Visual Score ◽  
Positive Scan ◽  
Myocardial Involvement

Abstract Introduction Bone scintigraphy using radioactive technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) has been increasingly used to diagnose myocardial involvement of mutated or wild-type transthyretin amyloidosis (ATTR). However, most studies that proved a high sensitivity and specificity of the technique were not in patients with the “Portuguese variant” (Val30Met) mutation in transthyretin (TTR). Other authors had already suggested that in these patients the DPD scan could be less accurate. Methods Observational study of patients referred to Cardiology clinic with suspicion of ATTR cardiomyopathy. We only included patients with data from echocardiogram and DPD scan. For statistical analyses, SPSS was used, p<0.05 for statistical significance. Logistic regressions were used to test an association between DPD result and different covariates. Results Of 273 patients referred with suspicion of cardiac ATTR, we studied 97 patients that did an echocardiogram and a DPD scan. Among the 75 cases with mutated TTR (Val30Met), median age was 36 (IQR 34) and 60% were males. 60 had increased ventricular wall thickness (IVWT) >12 mm, but only 24 had a positive DPD (defined as a visual score >2). Even though a higher wall thickness was associated with a positive DPD (p=0.004), 18 patients with a negative scan had IVWT >14 mm. The DPD results was significantly associated with prior liver transplantation (LT) – p<0.001; 95% CI (7.1; 503.6) – and age at first symptoms – p<0.001; 95% CI (1.036; 1.113); 66.7±10.5 versus 34.8±10.2 years-old for those with and without a positive scan, respectively. Interestingly, fewer patients with a positive scan had neurologic symptoms (74% versus 96%, p=0.009), ophthalmologic, urologic or renal involvement, even though creatinine clearance was on average lower (p=0.01). We did not find a significant association between DPD result and sex, conduction disorders, NT-proBNP, troponin T or treatment with tafamidis. Patients on tafamidis had on average lower IVWT, independent of age (median of 13 versus 14 mm; p=0.020). 4 patients with negative DPD did an endomyocardial biopsy, that was positive for amyloid in 3 cases. In comparison, in the 22 cases with wild-type TTR, there were significantly more males (86%) and patients were older (median age was 81 (IQR 9)). All patients had IVWT (that was significantly higher than in mutated ATTR) and DPD scan was negative in only 2 patients (that had a visual score of 1). Systolic dysfunction was significantly more frequent (59% versus 8%). The occurrence of death or hospitalization for heart failure was significantly higher. Conclusions DPD-scintigraphy seems more sensitive in patients with late onset mutated ATTR or with wild-type ATTR. It is less accurate in early onset patients with Val30Met mutation and particularly if they underwent LT. In those patients, further investigation is needed before excluding myocardial involvement. FUNDunding Acknowledgement Type of funding sources: None.

Cardiac sympathetic denervation in wild-type transthyretin amyloidosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Aimo ◽  
A Gimelli ◽  
G Vergaro ◽  
D Genovesi ◽  
A Kusch ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Reference Value ◽  
Sympathetic Denervation ◽  
Related Phenomenon ◽  
Amyloid Burden ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Age Related ◽  
99Mtc Tetrofosmin ◽  
Cardiac Sympathetic Denervation

Abstract Background Tissue accumulation of misfolded transthyretin (TTR) may occur because of TTR gene mutations (variant amyloid TTR amyloidosis, ATTRv), or as an age-related phenomenon (wild-type ATTR, ATTRwt). Cardiac sympathetic denervation has been reported in ATTRv, but has never been investigated in ATTRwt. Methods Fifteen consecutive patients with ATTRwt cardiomyopathy (81% men, median age 82 years, no one with prior myocardial infarction) underwent Cadmium Zinc Telluride tomographic imaging for amyloid burden (99mTc-hydroxymethylene diphosphonate - 99mTc-HMDP), innervation (123I-metaiodobenzylguanidine – 123I-MIBG), and perfusion (99mTc-tetrofosmin). Results Median summed 99mTc-HMDP score was 60 (58–62), denoting a severe and diffuse amyloid burden. Planar 123I-MIBG examination showed decreased early and late H/M ratios (late H/M ratio: 1.5 [1.3–1.6], range 1.2–1.9, reference value ≥2.0). Summed 123I-MIBG score was 12 (6–22), with the most prominent denervation in the infero-septal, inferior, and infero-lateral regions; summed rest score was 7 (5–11), with lowest degrees of myocardial perfusion in the inferior and infero-septal regions. The correlation between amyloid burden (as relative 99mTc-HMDP uptake) and innervation (as relative 123I-MIBG uptake) did not achieve statistical significance at both segmental (p=0.252) and regional level (p=0.251). Nevertheless, denervation tended to worsen in parallel with the amyloid burden, and 123I-MIBG scores increased with 99mTc-HMDP scores. Segments and regions with more prominent hypoperfusion were those showing the more intense denervation (r=0.500 and 0.591, respectively; both p<0.001). Conclusions Patients with ATTRwt cardiomyopathy display cardiac sympathetic denervation, particularly in the inferior and septal myocardial wall. Myocardial hypoperfusion has a similar regional pattern, while the amyloid burden is more extensive. Funding Acknowledgement Type of funding source: None

scholarly journals P825 Multi-modality imaging for noninvasive diagnosis of transthyretin amyloid cardiomyopathy-single centre experience

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
M Gawor ◽  
J Wnuk ◽  
P Michalek ◽  
M Marczak ◽  
A Teresinska ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Thickness ◽  
Age Of Onset ◽  
Troponin T ◽  
Severe Aortic Stenosis ◽  
Wild Type ◽  
Maximal Wall Thickness ◽  
Amyloid Deposits ◽  
Right Ventricular Wall ◽  
Amyloid Cardiomyopathy

Abstract Background Thransthyretin amyloidosis (ATTR) is a rare progressive disease that may present as heart failure with preserved ejection fraction, severe aortic stenosis, hypertrophic cardiomyopathy (HCM) or resctrictive cardiomyopathy. There are two types of ATTR: hereditary ATTR (hATTR) caused by mutations in the TTR gene and wild-type ATTR (wtATTR) resulting from deposition of wild-type TTR protein. Purpose We describe the clinical heterogeneity of ATTR patients from our centre diagnosed noninvasively in 2018-2019. Methods All patients presented intensive cardiac uptake at 99mTc-DPD scintigraphy. Light chain amyloidosis was excluded. Results 8 patients were diagnosed with ATTR (Table 1). Three unrelated male patients were diagnosed with hATTR due to rare mutations: 2 of them had Phe33Leu, 1 patient had Glu89Lys mutation. Five patients (males) were diagnosed with wtATTR. Age of onset differed among the patients. Characteristic clinical features included cardiomyopathy with increased left and right ventricular wall thickness. Only 2 patients had restrictive filling pattern, 3 patients had atrial fibrillation. Laboratory examination showed increased level of troponin T and NT-proBNP. Three patients had bilateral carpal tunnel syndrome. Thanks to DPD-scintygraphy we excluded ATTR in two patients with false-positive results of histological exam for TTR-related amyloid deposits. Conclusions Although ATTR is known for its broad clinical spectrum, patients from our center presented mostly as HCM phenocopies but in different stages of heart failure. Appropriate diagnosis of ATTR is crucial and have direct therapeutic impact. Echocardiography raise the suspicion of amyloid cardiomyopathy, while other imaging technique (DPD-scintigraphy) confirm it or exclude it in noninvasive way. Patient 1 2 3 4 5 6 7 8 Mutation Glu89Lys Phe33Leu Phe33Leu wild type wild type wild type wild type wild type Sex male male male male male male male male Age of onset 57 56 55 77 78 80 77 76 Electrocardiogram AF low QRS voltage low QRS voltage AF, RBBB LVH LVH pseudoinfarct pattern, low QRS voltage AF, LVH Maximal wall thickness [mm] 23 20 18 28 22 23 18 20 LVEF% 45 40 40 60 65 60 45 55 Asymmetric hypertrophy pattern + - - - + + - + NYHA III II II II III II II II NT-proBNP pg/ml 2122 1200 1500 2755 222 2630 2426 hs-Troponin T ng/l 50 98 42 65 35 63 64 Abstract P825 Figure 1

scholarly journals Súlyos szívelégtelenség hátterében álló transthyretin-amyloidosis elkésett diagnózisa

2021 ◽  
Vol 51 (2) ◽  
pp. 131-139
Author(s):  
Viktória Nagy ◽  
Gergely Rácz ◽  
Bence Radics ◽  
Lidia Hategan ◽  
Hedvig Takács ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Thickness ◽  
Heart Muscle ◽  
Low Voltage ◽  
Troponin T ◽  
Diagnostic Delay ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Transthyretin Amyloidosis ◽  
Familial Form

Several heart muscle diseases can cause heart failure, the etiological diagnosis of which may serve the basis of targeted, tailored, effective personalized therapy. Such a heart muscle disease is transthyretin amyloidosis (ATTR) which is an infiltrative disorder affecting most frequently the heart and peripheral nerves, due to the accumulation of transthyretin protein. Deposition of mutant transthyretin, due to mutations in the TTR gene encoding for transthyretin, occurs in the familial form of the disease (hATTR), while in senile amyloidosis, wild-type transthyretin accumulates (wtATTR). We report on a 79-years-old male patient who presented 9 years before because of novel onset atrial fibrillation. Echocardiography at that time showed severe concentric left ventricular hypertrophy which progressed through the years. Laboratory values displayed increased liver enzymes and troponin T levels. He was hospitalized several times because of left- and later right-sided heart failure, with increasing tendency towards hypotension. At last admission he was admitted to us after suffering syncope at home necessitating cardiopulmonary resuscitation. Transthoracic echocardiography showed severe, concentric biventricular hypertrophy (LV wall thickness 22 mm, RV wall thickness 12 mm), with depressed LV and RV function, apical sparing, and low cardiac output. Taking low voltage, seen on ECG, and other anamnestic data into consideration, the suspicion of ATTR amyloidosis was raised. The patient died after a short observational period due to intractable heart failure. Autopsy and histology revealed systemic amyloidosis, affecting predominantly the heart which was interpreted as wtATTR according to immunohistochemistry, negative TTR gene sequencing and the lack of monoclonal gammopathy. Our case illustrates the importance of the diagnostic delay which is very frequently encountered in TTR amyloidosis. Features of ATTR which includes the multidisciplinary nature of assessment, specialized diagnostic modalities and unique therapy call for the need of specialized diagnostic centers.

scholarly journals Correlation Between Quantitative Uptake of 99mTC-DPD and Echocardiographic Parameters in Cardiac ATTR: A Novel Follow-Up Strategy

2021 ◽  
Vol 8 ◽  
Author(s):  
Mehmet Harapoz ◽  
Scott Evans ◽  
Paul Geenty ◽  
Fiona Kwok ◽  
Graeme Stewart ◽  
...  
Keyword(s):  
Wall Thickness ◽  
Global Longitudinal Strain ◽  
Area Under The Curve ◽  
Tracer Uptake ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Receiver Operating Characteristic Curves ◽  
Echocardiographic Parameters ◽  
Invasive Techniques

Aims: There has been a paradigm shift in diagnosis of cardiac transthyretin amyloidosis (ATTR) with non-invasive techniques including technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy. We evaluated structural and functional biventricular alterations by transthoracic echocardiography (TTE) and determined the correlation with 99mTc-DPD tracer uptake in ATTR.Materials and Methods: ATTR patients (wild-type, hereditary or asymptomatic transthyretin [TTR] variant carriers) with 99mTc-DPD and TTE were selected; 99mTc-DPD uptake was analyzed quantitatively. TTE assessment of left ventricle (LV) and right ventricle (RV) parameters was performed.Results: Forty ATTR patients (wild-type n = 17; hereditary ATTR and TTR variant carriers n = 23; median age 68.8 ± 22 years) were included. TTE parameters displaying good correlation with 99mTc-DPD tracer uptake included LV average wall thickness (r = 0.837), LV indexed mass (LVMI; r = 0.802), RV wall thickness (r = 0.610), average e' (r = −0.830), E/e' ratio (r = 0.786), LV global longitudinal strain (GLS; r = 0.714) and RV GLS (r = 0.632; p < 0.001 for all). Hereditary ATTR and TTR variant carriers without cardiac tracer uptake had normal echocardiographic parameters. Receiver operating characteristic curves demonstrated strong diagnostic accuracies for structural (LV wall thickness, LVMI and RV wall thickness; area under the curve (AUC) of 0.96 for all) and functional (LV and RV GLS; AUC of 0.86 and 0.88, respectively) parameters.Conclusion: Good correlations between TTE biventricular structural and functional parameters were demonstrated with quantitative 99mTc-DPD uptake. Echocardiography may potentially assume a significant role in longitudinal follow-up for monitoring disease progression and for evaluating treatment response.

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

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Katelyn Young ◽  
Kinjal Banerjee ◽  
Maulin Patel ◽  
Sangeeta Prabhakar Bhat ◽  
Colin Reynolds ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cardiac Amyloidosis ◽  
Chart Review ◽  
Diagnostic Testing ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Highly Sensitive ◽  
Amyloid Light Chain ◽  
Positive Results ◽  
Echocardiographic Findings

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

scholarly journals Value of Longitudinal Strain to Identify Wild-Type Transthyretin Amyloidosis in Patients With Aortic Stenosis

2021 ◽  
Author(s):  
Guillaume Robin ◽  
Thomas Cognet ◽  
Frédéric Bouisset ◽  
Eve Cariou ◽  
Simon Méjean ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Longitudinal Strain ◽  
Wild Type ◽  
Transthyretin Amyloidosis

scholarly journals Hereditary transthyretin amyloidosis: predictors of conduction disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.F Dias De Frias ◽  
P Rodrigues ◽  
M Trepa ◽  
M Fontes-Oliveira ◽  
R Costa ◽  
...  
Keyword(s):  
Troponin T ◽  
Pacemaker Implantation ◽  
Outcome Data ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
P Value ◽  
Neurologic Manifestations ◽  
Ventricular Pacing ◽  
Transthyretin Amyloidosis ◽  
Formal Indication

Abstract Introduction Pacemakers are frequently needed due to a high prevalence of conduction disease in mutated ATTR amyloidosis (mATTR). We aimed to identify the variables associated with the need of pacemaker implantation in this population. Methods We retrospectively studied 255 patients with suspicion of heart involvement of mATTR observed at our cardiology clinic during the last year. Clinical and outcome data were retrieved by chart review. We have defined the need for pacemaker implantation as: 1) the formal guidelines indications or 2) Ventricular pacing >10% in patients who had prophylactic pacemaker implantation prior to liver transplantation (LT). This way, we have defined 3 different groups: group 1: patients with no evidence of conduction disease; group 2: patients with conduction disease, but no formal indication for pacemaker implantation; and group 3: patients with formal indication for pacemaker implantation or ventricular pacing >10% in patients who had prophylactic pacemaker implantation prior to hepatic transplantation. Results We included 255 patients (50±14 years, 53% male, 52.5% treated with tafamidis and 27% had prior LT, and 10% with atrial fibrillation), 43.3% with no evidence of conduction disease, 32.3% with conduction disease, but no formal indication for pacemaker implantation and 24.4% with formal indication for pacemaker implantation. Patients with formal indication for pacemaker implantation were older, with longer duration of neurologic manifestations, with higher concentration of both Troponin T and NT-proBNP and with higher number of organs affected. In multivariate analysis, longer duration of neurologic manifestations (OR 1.090 – 95% IC: 1.036–1.145, p-value 0.001), Left ventricular (LV) maximal wall thickness (OR 1.230 – 95% CI: 1.070–1.414, p-value 0.004), neurologic staging (OR 3.420 – 95% CI: 1.443–8.104, p-value 0.005) and higher number of organs affected (OR 1.719 – 95% CI: 1.218–2.424, p-value 0.002) all showed to be independent predictors of the need for pacemaker implantation, in contrast to LV ejection fraction and serum concentration of Troponin T and NT-proBNP. We've also found a statistical significant association between conduction disease and ophthalmic manifestations. Conclusions Our findings suggest that the need for pacemaker implantation in patients with mATTR is closer linked to the duration, severity and affected number of organs than to cardiac biomarkers or echocardiographic findings. Funding Acknowledgement Type of funding source: None

Abstract 34: Acetylation of GATA 4 Enhanced Direct Cardiac Reprogramming of Induced Cardiomyocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Vivek P Singh ◽  
Megumi Mathison ◽  
Jaya P Pinnamaneni ◽  
Deepthi Sanagasetti ◽  
Narasimhaswamy S Belaguli ◽  
...  
Keyword(s):  
Ventricular Function ◽  
Troponin T ◽  
Novel Mutation ◽  
Cardiac Regeneration ◽  
Negative Control ◽  
Direct Reprogramming ◽  
Wild Type ◽  
Reprogramming Efficiency

Objective: Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) by forced expression of cardiomyogenic factors, GMT (GATA4, Mef2c and Tbx5), has recently been demonstrated, suggesting a promising statregy for cardiac regeneration. However, the efficiency of direct reprogramming is usually relatively low and requires extensive epigenetic redesigning, although the underlying mechanism are largely unknown. Methods: In a recent study, we created a novel mutation in rat GATA 4 by replacing lysine residue with glutamine at position 299 i.e. (K299Q), to mimic constitutive acetylation and examined whether constitutive acetylation of GATA4, when compared with wild type GATA4, further enhance GMT-mediated direct reprogramming efficiency of induced cardiomyocytes in vitro and accordingly ventricular function after myocardial infarction in rat, in vivo . Results: We found that acetylated GATA 4 (K299Q), in the presence of Mef2c and Tbx5 upregulated cardiac-specific markers, suppressed fibroblast genes, in rat cardiac fibroblasts (RCFs) more efficiently when compared with Mef2c, Tbx5 plus wild type GATA4. FACS analyses revealed that G(K299Q) MT induced significantly more cardiomyocyte marker cardiac troponin T (cTnT) expression compared with GMT alone. Mechanistic studies demonstrated that the K299Q substitution, resulting in enriched p300 occupancy at the GATA 4 promoter, induced acetylation of Histine 3, decreased HDAC expression. In addition, substitution augmented the increase in an acetylated form of GATA-4 and its DNA binding and transcriptional activity, compared with wildtype GATA 4. In agreement with upregulated cTNT gene expression in vitro , echocardiographic analysis demonstrate that the acetylated G(K299Q) MT vectors have improved effect in enhancing ventricular function than GMT vectors from postinfarct baselines as compared to negative control [G(K299Q) MT, 15.6% ± 2.7%; G(WT)MT, 12.8% ± 1.7%; GFP, -2.3% ± 1.1%]. Conclusions: Collectivily, these data indicate that acetylated GATA4 (K299Q) significantly increases reprogramming efficiency of induced cardiomyocytes (iCMs), in vitro and in vivo, and provide new insight into the molecular mechanism underlying cardiac regeneration.

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