Amyloid cardiomyopathy: the different facets of a not so rare disease (RCD code III 3A.1, III 3A.2)

Systemic amyloidosis is a relatively rare multisystem disease caused by the deposition of misfolded protein in various tissues and organs. It may present to almost any specialty, and diagnosis is frequently delayed.[1][1] Cardiac involvement is a leading cause of morbidity and mortality, especially

A 74-year-old man presented with decreasing exercise tolerance and mild ankle edema. He was previously fit but was now breathless on climbing 2 flights of stairs. He had no history of angina, orthopnea, or paroxysmal nocturnal dyspnea. His medical history included non–insulin-dependent diabetes mellitus treated for 10 years and mild hypertension. Six years earlier he had been diagnosed with a monoclonal gammopathy of unknown significance. At that time, a bone marrow biopsy showed 30% overall cellularity with 5% to 10% plasmacytosis (normal <4%) and immunoglobulin light-chain restriction. Approximately 3 years ago, he developed deep vein thrombosis and was treated with low-molecular-weight heparin. A year later, leg swelling occurred and was attributed to venous insufficiency. The following year, he developed progressive fatigue on exertion, and an abnormal ECG (Figure 1) led to a treadmill test that was considered normal. An echocardiogram showed concentric wall thickening (Movie 1 in the Data Supplement), and the possibility of cardiac amyloidosis was raised. A fat pad biopsy was negative for amyloid deposits. The bone marrow biopsy performed in 2005 (when his monoclonal gammopathy of unknown significance was diagnosed) was restained and was negative for amyloid. At that time, serum-free λ light chains were 108.9 mg/L (normal range, 5.7–26.3) with κ light chains of 13 mg/L (normal, 3.3–19) and an abnormal ratio of 0.12 (normal, 0.26–1.65). His brain natriuretic peptide measured 275 pcg/mL. He was treated with oral diuretics, which improved leg swelling, but because of persistent symptoms, he sought medical care at our institution. On review of symptoms, he denied jaw claudication, symptoms of postural hypotension, easy bruising, or tongue swelling. He did give a history suggestive of neuropathy with a leathery feeling in his feet but no numbness in his hands. Medications included metformin 500 mg twice a day, aspirin 80 mg daily, lisinopril …

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

Hereditary transthyretin amyloid cardiomyopathy

Since &quot;the implementation of good clinical practice&quot;(GCP), especially after 2015, the overall quality of new drug cli-nical trials in China has made significant progress, but compared with developed countries, there are still some obvious quality problems in clinical trials in China. Clinical trials of new drugs of traditional Chinese medicine are an important part of clinical trials of new drugs in China. In addition to some common problems in all clinical trials, there are also some special quality problems. In terms of security data, such as the collection of human safety data is not standardized, the management and judgment of unexpected serious adverse reactions(SUSAR) were not professional and timely, the relationship between adverse events and trial drug was not fully judged by investigator, In terms of effective data, such as primary efficacy outcome of the scale cannot be traced, TCM syndrome data cannot meet the requirements of &quot;source data&quot; in the revised GCP and the quality of traditional Chinese medicine placebo is not high, in terms of overall quality system construction, the sponsors and research institutions have not established a quality assurance system that conforms to the characteristics of new drug research of traditional Chinese medicine, etc. The quality of clinical trials of new drugs of traditional Chinese medicine is based on the current GCP and ICH-GCP in China, we should also consider the characteristics of clinical trials of new traditional Chinese medicine drugs, and formulate targeted quality control measures according to the characteristics of these new drugs of traditional Chinese medicine, to improve the overall quality of clinical trials of new drugs of traditional Chinese medicine in China, which has important strategic significance for promoting the research and development of new drugs of traditional Chinese medicine in China.

BackgroundThe prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis are substantially influenced by cardiac involvement. ATTR amyloidosis has better...

Cardiac amyloidosis is an important cause of restrictive cardiomyopathy and congestive heart failure. There are two major types of cardiac amyloidosis: cardiac amyloid light-chain (AL) and transthyretin-related cardiac amyloidosis (ATTR) [1, 2]. The treatment options and prognosis for these two subtypes are different. The AL subtype cardiac amyloidosis is associated with greater than 50 % mortality within 6 months after the diagnosis, while the ATTR subtype has a more favorable prognosis of 98–100 % 2-year survival [3, 4]. Therefore, differentiating the type of cardiac amyloidosis (AL vs. ATTR) is crucial in guiding patient care. Due to its variable clinical symptoms, as well as the nonspecific ECG and echocardiographic presentations, cardiac amyloidosis is a diagnostic challenge and usually underdiagnosed [5, 6]. Endomyocardial biopsy remains the gold standard for diagnosis (Fig. 1). Fig. 1 A 68-year-old male with prostate cancer underwent a bone scan for disease staging. Diffuse cardiac uptake of the bone-seeking radiotracer, Tc-99m MDP (methylene diphosphonate), was incidentally found (arrow, a: bone scan). Given the patient’s ... Perugini et al. [7] demonstrated Tc-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-99m DPD) bone scan findings among patients with cardiac amyloidosis of ATTR (n = 15) and AL (n = 10) subtypes in which cardiac Tc-99m DPD uptake was present in all ATTR patients and absent in all AL patients at visual assessment. Rapezzi et al. [8] evaluated myocardial uptake of Tc-99m DPD in patients with ATTR-related (n = 45, 28 mutant and 17 wild-type) and AL-related (n = 34) cardiac amyloidosis as well as 15 nonaffected controls. On semiquatitative analysis, patients with ATTR had higher visual scoring of cardiac retention (range: score 0, absent cardiac uptake and normal bone uptake; score 1, mild cardiac uptake, inferior to bone uptake; score 2, moderate cardiac uptake accompanied by attenuated bone uptake; score 3, strong cardiac uptake with attenuated bone uptake), with positive and negative predictive values of 88 and 100 % (visual score ≥2). On quantitative analyses, compared to AL and unaffected controls, ATTR patients also had significantly higher (p < 0.0001) heart retention (HR, 7.8 %) and heart-to-whole-body retention ratios (H/WB 10.4), while both unaffected controls (HR 3.5 %; H/WB 5.7) and AL subtypes (HR 4.0 %; H/WB 6.1) were similarly low. Another bone scintigraphic tracer, Tc-99m hydroxymethylene diphosphonate (Tc-99m HDP), has shown high cardiac retention and H/WB ratios in 19 of 30 patients with ATTR cardiac amyloidosis [9]. Bokhari et al. [10] reported that 45 subjects (12 AL, 16 ATTR wild type and 17 ATTR mutants) underwent Tc-99m pyrophosphate (Tc-99m PYP) cardiac imaging. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score (range, 0; no uptake to 3, diffuse uptake) than the AL cohort (2.9 ± 0.06 versus 0.8 ± 0.27; P < 0.0001) as well as a higher quantitative score (1.80 ± 0.04 versus 1.21 ± 0.04; P < 0.0001). Using a heart-to-contralateral-lung ratio of 1.5 on Tc-99m PYP cardiac imaging distinguished ATTR amyloidosis (≥1.5) from AL amyloidosis (<1.5), with 97 % sensitivity and 100 % specificity. Sporadic case reports [11, 12] have shown that Tc-99m MDP radiotracers can accumulate in the heart in patients with cardiac amyloidosis; however, there were no corresponding myocardium tissue biopsy results. Our case demonstrated that intense cardiac uptake of Tc-99m MDP correlates with biopsy-proven ATTR cardiac amyloidosis. We think that the preferential binding of Tc-99m MDP to ATTR is similar to those of Tc-99m PYP, Tc-99m DPD (not available in the USA) and Tc-99m HDP, which may be due to the fact that transthyretin amyloid fibrils have higher calcium contents. Given its universal availability, Tc-99m MDP imaging may serve as a noninvasive adjunct in the differential diagnosis of cardiac amyloid.

Background Previous studies indicated that amyloid scintigraphy in combination with free light chain (FLC) assessment yields an excellent diagnostic accuracy for cardiac transthyretin (ATTR) amyloidosis (1). As a consequence, the diagnosis of ATTR amyloidosis is increasingly made without the actual gold-standard method endomyocardial biopsy (EMB). Whether this leads to misdiagnosis in real-world practice is currently underinvestigated. We aimed to describe the diagnostic accuracy of amyloid scintigraphy in a real world setting. Methods Seven tertiary care centers throughout Austria agreed to participate in the study and performed a systematic retrospective medical records search from 2017 to 2020. Patients were included in case of available results of amyloid scintigraphy, FLC assessment and EMB, respectively. Amyloid scintigraphy was performed using a 99m-technetium-labelled tracer. Histological analysis was performed using immunohistochemistry. The number of submitted subjects with complete data per center ranged from 2 to 46. The patient number increased with years, with 15 patients investigated in 2017 and 32 in 2020. Results We enrolled 101 patients (21% women) with a mean age of 73±9 years and median NT-proBNP (IQR) of 2694 (1601–5239) pg/ml (Table 1). An abnormal Perugini Score (ie. grade II or III) was present in 57 patients (56%) and FLC assessment was overall indicative of monoclonal protein in 60 patients (59%). Among patients with abnormal Perugini Score, 29 had FLC assessment indicative of monoclonal protein. The most common histopathological diagnoses were ATTR in 60 patients (59%) and cardiac light chain (AL) amyloidosis in 20 patients (20%). One further patient was diagnosed with concomitant AL and ATTR amyloidosis. Further diagnoses included ApoA4 (n=2) and AA amyloidosis (n=1), while cardiac amyloidosis was ruled out in 17 patients (17%). ATTR was diagnosed in 54 patients with Perugini Score II or III compared with 6 patients with Perugini &amp;lt; II, yielding a sensitivity of abnormal Perugini score for ATTR amyloidosis of 90%. Among patients with abnormal Perugini Score (n=57), ATTR was diagnosed in 55 patients, and AL amyloidosis in 3 (one had concomitant ATTR and AL), yielding a positive predictive value (PPV) of abnormal Perugini Score of 97% (Table 2). Two AL patients had Perugini Score of II and one had Perugini Score of III. When excluding patients with monoclonal gammopathy, the PPV of abnormal Perugini Score was 100%. Conclusion Our data confirm a PPV of abnormal amyloid scintigraphy of 100% for cardiac ATTR amyloidosis when monoclonal gammopathy was excluded. mong patients with monoclonal gammopathy, one of ten patients with abnormal scintigraphy had AL amyloidosis as the underlying condition. Our data underscore that tissue biopsy and histopathological analysis should be performed in every patient with suspected amyloidosis and monoclonal gammopathy even in case of Perugini Score II or III. Funding Acknowledgement Type of funding sources: None.

BackgroundCarpal tunnel syndrome (CTS) is the only known early clinical manifestation of wild-type transthyretin amyloidosis (ATTRwt; formerly known as senile systemic amyloidosis) which causes an amyloid cardiomyopathy. At the UK...

The systemic amyloidoses are a group of uncommon diseases in which the common factor is infiltration of one or more organs with a noncellular, extracellular proteinaceous material with specific light microscopic staining characteristics [1]. Significant advances in treatment have been made over the past decade, particularly in AL amyloidosis in which the precursor protein is derived from immunoglobulin light chain fragments [2]. Transthyretin (TTR)-derived amyloidosis has also been the subject of intensive investigation, and several new therapeutic approaches have completed, or are approaching, preliminary clinical testing [3–7]. Refinements in immunohistochemical and proteomic techniques have permitted precise definition of the amyloid type, a prerequisite for initiating appropriate (and avoiding inappropriate) therapies [8]. In 2005, the Bologna group published data from 25 patients with amyloidosis (17 of whom had TTR-related amyloidosis) suggesting the bone-scanning agent Tc3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) was preferentially taken up by the heart in patients with TTR amyloidosis, whereas it showed no uptake in AL amyloidosis or in controls without the disease [9]. This appeared to be isotope specific, as Tc-methylene diphosphonate (MDP) showed no uptake in 11 patients who showed distinct myocardial uptake with Tc-DPD. The authors have now expanded their original observations and, while confirming the tracer is avidly taken up in the TTR amyloid patients, they now also describe a mild to moderate uptake in one third of AL patients, thereby reducing the specificity of the test for TTR amyloidosis alone but still rendering it an interesting and informative technique [10]. Uptake of technetium-based bone imaging traces by the heart in cardiac amyloidosis is not a newly described phenomenon. As pointed out by Rapezzi and coauthors and recently reviewed in detail [11], several other nuclear imaging modalities have been proposed for imaging cardiac amyloidosis, such as Tc-aprotinin [12] and I-metaiodobenzylguanidine (MIBG) [13]. Over 25 years ago the uptake of technetium pyrophosphate (then used as a myocardial infarction imaging agent) was described in both AL and TTR amyloidosis, although the sensitivity of the imaging was subject to debate [14–16]. The type of technetium-based isotope was believed to be significant, as Tc-MDP showed little consistency for imaging amyloid cardiomyopathy, despite occasional case reports of cardiac uptake [17]. With the rapid advances in echocardiography and the echocardiographic descriptions of amyloid cardiomyopathy, technetium pyrophosphate cardiac imaging for possible amyloid cardiomyopathy became obsolete, limited to a radiologic curiosity when incidentally seen on a scan performed for other reasons such as for the evaluation of metastatic disease. Echocardiography still remains the mainstay for the initial suspicion/diagnosis of cardiac amyloidosis [1] (and was also a component of the “gold standard” used in this study), and is nowadays often complemented by cardiac MRI which R. H. Falk : S. Dorbala Cardiac Amyloidosis Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

> Gregory: “Is there any other point to which you would wish to draw my attention?” > > Holmes: “To the curious incident of the dog in the night-time.” > > Gregory: “The dog did nothing in the night-time.” > > Holmes: “That was the curious incident.” > > —Arthur Conan Doyle, “Silver Blaze” in The Memoirs of Sherlock Holmes Cardiac amyloidosis is caused by the aggregation and deposition of misfolded proteins in the extracellular space of the myocardium. The heart is one of multiple organs that may be involved in systemic amyloidosis and is usually the main cause of significant morbidity and mortality. Transthyretin amyloidosis (ATTR), one of the most common forms of cardiac amyloidosis, is increasingly recognized as an important cause of heart failure with preserved ejection fraction.1 It is generally believed that for heart failure to occur, the severity of amyloid deposition in a diseased heart has to be great enough to cause abnormal wall thickening, which is easily identifiable by echocardiography. See Article by Dungu et al ATTR is caused either by wild-type transthyretin (TTR), a disease limited to the heart and predominantly of elderly males, or by mutant TTR, a disease with autosomal dominant inheritance, which may cause an isolated cardiomyopathy, isolated neuropathy, or combined disease. Numerous variants of TTR have been identified, among which is the substitution of isoleucine for valine at position 122 (V122I). This mutation has a prevalence of 3.4% in the North American population of African descent and is generally recognized as causing an infiltrative–restrictive cardiomyopathy, usually in the seventh decade and above.2 In this issue of Circulation: Heart Failure , Dungu et al3 provide data that further substantiate the importance of the V122I allele as a cause of heart failure in …

Background Isolated cardiac amyloidosis (CA) is a complex diagnostic scenario, highlighting the need for physician awareness in differential diagnosis. Among the different types of amyloidosis, nearly all cases of CA are caused by light chain (AL) and transthyretin amyloidosis (ATTR). Patients with suspect CA without monoclonal components (MC) in both serum and urine and normal free light chain (FLC) ratio can have a non-biopsy diagnosis of ATTR amyloidosis with bone scintigraphy (1). However, in all suspected CA with a MC (approximately 20% of patients with ATTR amyloidosis), amyloid typing is mandatory. Thus, the diagnostic pathway of CA diverges based on MC-studies. We aim to assess if different sequence of diagnostic tests can affect outcomes in patients with cardiac AL amyloidosis. Methods Pavia Amyloidosis prospectively maintained database was searched for patients with isolated cardiac AL amyloidosis referred to our Centre from January 2016 to December 2020. Patients with a known monoclonal gammopathy (MG) and with multiple organ involvement were excluded. We searched for the date of symptom onset and first suspect of CA (i.e. recognition of clinical, imaging or laboratory signs of CA). In addition, we recorded the date of the different diagnostic tests performed: i.e. echocardiogram; serum and urine immunofixation and FLC measurement (MC-study); bone scintigraphy and cardiac magnetic resonance (defined as advanced cardiac imaging). We calculated the interval between those time-points and the final diagnosis: (a) from symptom onset to diagnosis, (b) from first suspect to final diagnosis, (c) from first suspect to MC-study and (d) to advanced cardiac imaging tests. We then searched for possible intervals of time amongst those, that were able to predict death at 3 months, by means of a ROC analysis. Results A total of 94 patients were included in the analysis (25% of all patients with cardiac AL amyloidosis diagnosed in the study period). Six (6%) patients died &amp;lt;1 month from diagnosis, and 27 (29%) died &amp;lt;3 months. Median overall survival (OS) of the whole cohort was 8 months, and the median follow-up of living patients was 39 months (range 16-73). The median time from symptom onset to diagnosis was 9 months (range 1-44) and the median time from the first suspect to diagnosis was 2 months (range 0-9). An interval from the first suspect to MC-study ≥6 weeks was the only predictor of death at 3 months. None of the other tested periods were associated with a significant ability to predict survival. A delay in MC-study ≥6 weeks identified patients with more advanced cardiac stage (50% vs. 25% were stage IIIb, P=0.02) and was associated with a significantly worse outcome (median survival 13 months vs. 4 months, P=0.012). In the whole cohort, a total of 76 (81%) patients underwent at least one advanced imaging examination. Amongst those, 37 (49%) performed the imaging tests before MC-study with a higher percentage of patients who had a delay in MC-studies evaluation (69% vs. 27%; P&amp;lt;0.001). Conclusion In patients who present with isolated cardiac AL amyloidosis with previously unknown MG, a relatively short delay in identifying the amyloid MC results in a considerable reduction of survival. A delay in MC-study was associated with more advanced cardiac stage. MC studies should be the first step in the work-up of patients with suspected CA to guide biopsy vs. non-biopsy diagnostic approach.

CARDIAC AA AMYLOIDOSIS SECONDARY TO FAMILIAL MEDITERRANEAN FEVER PRESENTING AS INTERMITENT COMPLETE HEART BLOCK: A RARE CASE WITH LITERATURE REVIEW

AimsCongo red staining of an endomyocardial biopsy is the diagnostic gold-standard in suspected cardiac amyloidosis (CA), but the procedure is associated with the risk, albeit small, of serious complications, and delay in diagnosis due to the requirement for technical expertise. In contrast, abdominal fat pad fine needle aspiration (FPFNA) is a simple, safe and well-established procedure in systemic amyloidosis, but its diagnostic sensitivity in patients with suspected CA remains unclear.Methods and resultsWe assessed the diagnostic sensitivity of FPFNA in 600 consecutive patients diagnosed with CA [216 AL amyloidosis, 113 hereditary transthyretin (ATTRm), and 271 wild-type transthyretin (ATTRwt) amyloidosis] at our Centre. Amyloid was detected on Congo red staining of FPFNAs in 181/216 (84%) patients with cardiac AL amyloidosis, including 100, 97, and 78% of those with a large, moderate, and small whole-body amyloid burden, respectively, as assessed by serum amyloid P (SAP) component scintigraphy (P < 0.001); the deposits were successfully typed as AL by immunohistochemistry in 102/216 (47%) cases. Amyloid was detected in FPFNAs of 51/113 (45%) patients with ATTRm CA, and only 42/271 (15%) cases with ATTRwt CA.ConclusionsFPFNA has reasonable diagnostic sensitivity in cardiac AL amyloidosis, particularly in patients with a large whole-body amyloid burden. Although the diagnostic sensitivity of FPFNA is substantially lower in transthyretin CA, particularly ATTRwt, it may nevertheless sometimes obviate the need for endomyocardial biopsy.