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Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Since their development, patisiran (siRNA), vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN, and early data suggest these drugs may have efficacy in treating ATTR-CM. An ongoing phase 3 clinical trial will evaluate the efficacy of eplontersen (ASO) in the treatment of both ATTR-PN and ATTR-CM, and a recent phase 1 trial demonstrated the safety of novel in vivo CRISPR-Cas9 gene-editing therapy in patients with ATTR amyloidosis. Recent results from trials of gene silencer and gene-editing therapies suggest these novel therapeutic agents have the potential to substantially alter the landscape of treatment for ATTR amyloidosis. Their success has already changed the perception of ATTR amyloidosis from a universally progressive and fatal disease to one that is treatable through availability of highly specific and effective disease-modifying therapies. However, important questions remain including long-term safety of these drugs, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.

Systemic amyloidosis encompasses a debilitating, under-diagnosed but increasingly recognized group of disorders characterized by the extracellular deposition of misfolded proteins in one or more organs. Cardiac amyloid deposition leads to an infiltrative or restrictive cardiomyopathy and is the major contributor to poor prognosis in patients with systemic amyloidosis. In total, >30 proteins can form amyloid fibrils, but the two main types of amyloid that can infiltrate the heart are monoclonal immunoglobulin light-chain amyloid and transthyretin amyloid. Cardiac amyloidosis can be acquired in older individuals or inherited from birth. Given the nonspecific symptoms of these disorders, a high index of suspicion is paramount in making the correct diagnosis, which can involve the use of non-invasive imaging methods such as echocardiography, bone scintigraphy and cardiovascular MRI. In the past decade, the use of cardiovascular MRI with tissue characterization and bone scintigraphy to diagnose cardiac amyloidosis has revolutionized our understanding of the disease, leading to changes in patient care. However, a need remains for improved awareness and expertise, and greater clinical suspicion, because the initial clues provided by electrocardiography and echocardiography might not be typical. With specific treatments now available, timely diagnosis of cardiac amyloidosis is more important than ever. In this Review, we discuss the current and novel approaches for the diagnostic imaging of cardiac amyloidosis.Cardiac amyloidosis is a life-threatening cause of restrictive cardiomyopathy that is often underdiagnosed or misdiagnosed. This Review summarizes the latest non-invasive imaging techniques used to diagnose cardiac amyloidosis, including echocardiography, bone scintigraphy and cardiac MRI.

A two-step process, in which circulating levels of amyloid P are reduced and then anti–serum amyloid P antibody is given to activate macrophage clearance mechanisms of tissue deposits, appears to reduce amyloid deposits in liver and some other organs. In systemic amyloidosis, the extracellular deposition of normally soluble plasma proteins as insoluble amyloid fibrils damages the structure and function of tissues and organs. 1 Current treatment consists of support or replacement of failing organs and measures to reduce the abundance of the amyloid fibril precursor protein. 1 , 2 A sufficient reduction of precursor supply arrests the accumulation of amyloid and can reduce morbidity and mortality. However, amyloid regression is very slow and often does not occur at all, in contrast to the usually swift clearance of other extracellular debris and efficient tissue remodeling — for example, after trauma. At least 65% . . .

Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Antibody-Associated Cardiac Amyloid RegressionThe investigators describe antibodies that bound amyloid in three patients with transthyretin amyloidosis. Spontaneous regression of cardiomyopathy occurred in all three patients.

Myocardial extracellular volume (ECV) is elevated in fibrosis or infiltration and can be quantified by measuring the haematocrit with pre and post contrast T1 at sufficient contrast equilibrium. Equilibrium CMR (EQ-CMR), using a bolus-infusion protocol, has been shown to provide robust measurements of ECV using a multibreath-hold T1 pulse sequence. Newer, faster sequences for T1 mapping promise whole heart coverage and improved clinical utility, but have not been validated. Multibreathhold T1 quantification with heart rate correction and single breath-hold T1 mapping using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) were used in equilibrium contrast CMR to generate ECV values and compared in 3 ways. Firstly, both techniques were compared in a spectrum of disease with variable ECV expansion (n=100, 50 healthy volunteers, 12 patients with hypertrophic cardiomyopathy, 18 with severe aortic stenosis, 20 with amyloid). Secondly, both techniques were correlated to human histological collagen volume fraction (CVF%, n=18, severe aortic stenosis biopsies). Thirdly, an assessment of test:retest reproducibility of the 2 CMR techniques was performed 1 week apart in individuals with widely different ECVs (n=10 healthy volunteers, n=7 amyloid patients). More patients were able to perform ShMOLLI than the multibreath-hold technique (6% unable to breath-hold). ECV calculated by multibreath-hold T1 and ShMOLLI showed strong correlation (r2=0.892), little bias (bias -2.2%, 95%CI -8.9% to 4.6%) and good agreement (ICC 0.922, range 0.802 to 0.961, p<0.0001). ECV correlated with histological CVF% by multibreath-hold ECV (r2= 0.589) but better by ShMOLLI ECV (r2= 0.685). Inter-study reproducibility demonstrated that ShMOLLI ECV trended towards greater reproducibility than the multibreath-hold ECV, although this did not reach statistical significance (95%CI -4.9% to 5.4% versus 95%CI -6.4% to 7.3% respectively, p=0.21). ECV quantification by single breath-hold ShMOLLI T1 mapping can measure ECV by EQ-CMR across the spectrum of interstitial expansion. It is procedurally better tolerated, slightly more reproducible and better correlates with histology compared to the older multibreath-hold FLASH techniques.

Transthyretin amyloidosis (ATTR) is a condition caused by TTR protein misfolding and amyloid deposition, particularly in the heart and nervous system, leading to organ dysfunction. Advances in therapeutic strategies have revolutionised the management of ATTR amyloidosis. Treatments available in clinical practice include TTR stabilisers (tafamidis and acoramidis), which prevent the dissociation of TTR tetramer into monomers and oligomers that subsequently form amyloid fibrils, and gene-silencing therapies (patisiran, inotersen and vutrisiran), which suppress the hepatic synthesis of TTR, which is the amyloid precursor protein. Novel treatment strategies that are at various stages of development include Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 gene-editing technology (nexiguran ziclumeran), which, if successful, offers the prospect of a single-dose treatment, and monoclonal (cormitug and ALXN220) and pan-amyloid antibodies (AT-02) that seek to target and remove amyloid fibrils that have deposited in the myocardium. Amyloid removal remains a significant unmet clinical need, and hence, the ability to promote amyloid degradation and clearance through the use of antiamyloid therapies would represent a groundbreaking advancement in the treatment of ATTR amyloidosis. The success of ATTR-specific disease-modifying therapies has already altered the treatment landscape and changed the perception of ATTR amyloidosis from a progressive and fatal disease to one that is treatable through the availability of highly effective disease-modifying therapies. However, important questions remain, including the long-term safety of these drugs, whether combining therapies with different mechanisms of action has an additive prognostic benefit and how best to monitor the treatment response.

Background Quantitative cardiovascular magnetic resonance (CMR) T1 and T2 mapping are used to detect diffuse disease such as myocardial fibrosis or edema. However, post gadolinium contrast mapping often lacks visual contrast needed for assessment of focal scar. On the other hand, late gadolinium enhancement (LGE) CMR which nulls the normal myocardium has excellent contrast between focal scar and normal myocardium but has poor ability to detect global disease. The objective of this work is to provide a calculated bright-blood (BB) and dark-blood (DB) LGE based on simultaneous acquisition of T1 and T2 maps, so that both diffuse and focal disease may be assessed within a single multi-parametric acquisition. Methods The prototype saturation recovery-based SASHA T1 mapping may be modified to jointly calculate T1 and T2 maps (known as multi-parametric SASHA) by acquiring additional saturation recovery (SR) images with both SR and T2 preparations. The synthetic BB phase sensitive inversion recovery (PSIR) LGE may be calculated from the post-contrast T1, and the DB PSIR LGE may be calculated from the post-contrast joint T1 and T2 maps. Multi-parametric SASHA maps were acquired free-breathing (45 heartbeats). Protocols were designed to use the same spatial resolution and achieve similar signal-to-noise ratio (SNR) as conventional motion corrected (MOCO) PSIR. The calculated BB and DB LGE were compared with separate free breathing (FB) BB and DB MOCO PSIR acquisitions requiring 16 and 32 heart beats, respectively. One slice with myocardial infarction (MI) was acquired with all protocols within 4 min. Results Multiparametric T1 and T2 maps and calculated BB and DB PSIR LGE images were acquired for patients with subendocardial chronic MI (n = 10), acute MI (n = 3), and myocarditis (n = 1). The contrast-to-noise (CNR) between scar (MI and myocarditis) and remote was 26.6 ± 7.7 and 20.2 ± 7.4 for BB and DB PSIR LGE, and 31.3 ± 10.6 and 21.8 ± 7.6 for calculated BB and DB PSIR LGE, respectively. The CNR between scar and the left ventricualr blood pool was 5.2 ± 6.5 and 29.7 ± 9.4 for conventional BB and DB PSIR LGE, and 6.5 ± 6.0 and 38.6 ± 11.6 for calculated BB and DB PSIR LGE, respectively. Conclusions A single free-breathing acquisition using multi-parametric SASHA provides T1 and T2 maps and calculated BB and DB PSIR LGE images for comprehensive tissue characterization.

Purpose of ReviewThis review will explore the role of cardiac imaging in guiding treatment in the two most commonly encountered subtypes of cardiac amyloidosis (immunoglobulin light-chain amyloidosis [AL] and transthyretin amyloidosis [ATTR]).Recent FindingsAdvances in multi-parametric cardiac imaging involving a combination of bone scintigraphy, echocardiography and cardiac magnetic resonance imaging have resulted in earlier diagnosis and initiation of treatment, while the evolution of techniques such as longitudinal strain and extracellular volume quantification allow clinicians to track individuals’ response to treatment. Imaging developments have led to a deeper understanding of the disease process and treatment mechanisms, which in combination result in improved patient outcomes.SummaryThe rapidly expanding treatment regimens for cardiac amyloidosis have led to an even greater reliance on cardiac imaging to help establish an accurate diagnosis, monitor treatment response and aid the adjustment of treatment strategies accordingly.