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Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative disease of the myocardium in which extracellular deposits of amyloid cause progressive cardiac impairment.

Objectives: We aimed to evaluate left atrial (LA) deformation and its association with left ventricular (LV) deformation using LA-LV strain loops in patients with ATTR-CM and patients with left ventricular hypertrophy (LVH). We hypothesized that LA strain in ATTR-CM patients is abnormal and more independent of LV strain, compared to LVH patients.

Methods: Retrospective study based on echocardiographic data including 30 patients diagnosed with ATTR-CM based on an end diastolic interventricular septal (IVSd) thickness of ≥14mm, and 29 patients with LVH (IVSd ≥14mm and no ATTR-CM diagnosis) together with 30 controls. LV global longitudinal strain (LV-GLS) and LA strain, assessed as peak atrial longitudinal strain (PALS), were acquired and plotted to construct LA-LV strain loops and using regression line to determine a LA-LV strain slope.

Results: Significantly lower PALS and LA-LV strain slope values were detected in ATTR-CM patients compared to LVH patients (p=0.004 and p=0.014 respectively). A ROC curve demonstrated similar area under the curve (AUC) using PALS (AUC 0.72) and LA-LV slope (AUC 0.71), with both resulting in higher values than recorded for LV-GLS (AUC 0.62).

Conclusions: LA deformation demonstrates an independent ability to differentiate ATTR-CM from LVH. Combining LV strain and LA deformation analysis displays the mechanical LA/LV dissociation in ATTR-CA and potentially unmasks LA amyloid infiltration, this could potentially enable quicker diagnosis and initiation of treatment for ATTR-CM.

BACKGROUND Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR).

METHODS In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.

RESULTS A total of 36 patients received nex-z and completed at least 12 months of followup. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.

CONCLUSIONS In this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels.

Aims: Echocardiography plays an important role in suspecting the presence of transthyretin cardiomyopathy (ATTR-CM) in patients with heart failure, based on parameters proposed as “red flags” for the diagnosis of ATTR-CM. We aimed to validate those measurements in a group of patients with ATTR-CM including ATTRv and ATTRwt.

Methods: We tested a number of echocardiographic red flags in 118 patients with confirmed diagnosis of ATTR-CM. These variables were validated against healthy controls and patients with heart failure with left ventricular hypertrophy (LVH) but not ATTR-CM. The red flag measures outside the proposed cut-off values were also revalidated.

Results: In ATTR-CM, all conventional echocardiographic parameters were significantly abnormal compared to controls. Comparing ATTR-CM and LVH, LV wall thickness, LV diameter, E velocity, and relative apical sparing (RELAPS) were all different. Eighty-three % of ATTR-CM patients had RELAPS >1.0, 73% had RWT >0.6, 72% had LVEF >50%, 24 % had GLS >-13%, 33% had LVEF/GLS >4 and 54% had increased left atrial volume index (LAVI) (>34ml/m²). Forty % of ATTR-CM patients had SVI <30 ml/m² and 52% had CI < 2.5 L/min/m². RELAPS, LVEF and RWT, in order of accuracy, were the three best measures for the presence ATTR-CM in the patient cohort, who all had thick myocardium. The concomitant presence of the three disturbances was found in only 50% but the combination of RELAPS >1.0 and RWT >0.6 was found in 72% of the patient cohort.

Conclusion: Increased relative apical sparing proved the most accurate independent marker of the presence of ATTR-CM followed by normal LV ejection fraction and then increased relative wall thickness. The other proposed red flags for diagnosing ATTR-CM did not feature as reliable disease predictors.

Aims: Echocardiography plays an important role in suspecting the presence of transthyretin cardiomyopathy (ATTR-CM) in patients with heart failure, based on parameters proposed as ‘red flags’ for the diagnosis of ATTR-CM. We aimed to validate those measurements in a group of patients with ATTR-CM including ATTRv and ATTRwt.

Methods and results: We tested a number of echocardiographic red flags in 118 patients with confirmed diagnosis of ATTR-CM. These variables were validated against healthy controls and patients with heart failure with left ventricular hypertrophy (LVH) but not ATTR-CM. The red flag measures outside the proposed cut-off values were also revalidated. In ATTR-CM, all conventional echocardiographic parameters were significantly abnormal compared with controls. Comparing ATTR-CM and LVH, LV wall thickness, LV diameter, E velocity, and relative apical sparing (RELAPS) were all different. Eighty-three per cent of ATTR-CM patients had RELAPS > 1.0, 73% had relative wall thickness (RWT) > 0.6, 72% had LVEF > 50%, 24% had global longitudinal strain (GLS) > −13%, 33% had LVEF/GLS > 4, and 54% had increased left atrial volume index (>34 mL/m2). Forty per cent of ATTR-CM patients had stroke volume index < 30 mL/m2 and 52% had cardiac index < 2.5 L/min/m2. RELAPS, LVEF, and RWT, in order of accuracy, were the three best measures for the presence ATTR-CM in the patient cohort, who all had thick myocardium. The concomitant presence of the three disturbances was found in only 50% but the combination of RELAPS > 1.0 and RWT > 0.6 was found in 72% of the patient cohort.

Conclusion: Increased relative apical sparing proved the most accurate independent marker of the presence of ATTR-CM followed by normal LV ejection fraction and then increased relative wall thickness. The other proposed red flags for diagnosing ATTR-CM did not feature as reliable disease predictors.

Background: Cardiac amyloidosis (CA) is a restrictive and infiltrative cardiomyopathy, characterized by increased biventricular filling pressures and low output. Symptoms are predominantly of right heart origin. The role of right ventricular (RV) myocardial blood flow (MBF) in CA has not been studied.

Objectives: This study aimed to first associate RV MBF measured by using positron emission tomography (PET) with reference standards of RV pressures and then to explore its prognostic value in CA.

Methods: Cardiac PET was performed at rest in 52 patients with CA and 9 healthy control subjects. MBF was quantified from the right and left ventricles by using ¹¹C-acetate, ¹⁵O-water, or both (n = 25). RV pressure was measured invasively or by echocardiography. Associations between biventricular MBF toward symptoms, RV function, and outcome (death or acute heart failure) were studied in patients with CA.

Results: MBF of the right ventricle (MBF_RV) and the ratio of MBF_RV and MBF of the left ventricle (MBF_RV/LV) for the 2 tracers were significantly correlated (r > 0.92). MBF_RV was directly correlated with RV systolic pressures with both tracers (P ≤ 0.005). MBF_LV was inversely correlated with wall thickness (P < 0.0001). MBF_RV/LV was significantly associated with N-terminal pro–B-type natriuretic peptide levels, New York Heart Association functional class, RV pressures, and RV systolic function (all; P < 0.001). Twenty-six cardiac events (25 deaths) occurred during follow-up (median 44 months). MBF_RV/LV higher than 56% was associated with a diagnosis of pulmonary hypertension (AUC: 0.96 [95% CI: 0.91-1.00]; P < 0.0001); and predicted outcome with hazard ratio 9.0 (95% CI: 4.2-14.5), P < 0.0001).

Conclusions: Measurements of MBF_RV using PET are feasible, as confirmed with 2 different tracers. Imbalance between RV and LV myocardial perfusion is associated with increased RV load and adverse events in cardiac amyloidosis.

Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is today more frequently recognized but the rate of progression of cardiac dysfunction is not well established. The aim of this study is to investigate the nature of cardiac structure and function changes, over time, in a retrospective cohort of ATTR-CA patients.

METHODS: Fifty-one patients with ATTR-CA (mean age 78 ± 7 years, 30 females) were compared with 20 patients with heart failure but no amyloidosis (HFnCA) (mean age 76 ± 7 years, 5 females), all with septal thickness >  = 14 mm. All patients underwent DPD scintigraphy and an echocardiogram (Echo 2) which was compared with a previous echocardiographic examination (Echo 1), performed at least 3 years before.

RESULTS: Over the follow-up period, the interventricular septal thickness (IVST) and relative wall thickness (RWT) in ATTR-CA increased from 16 (4) to 18 (5) mm and from 0.51 (0.17) to 0.62 (0.21) respectively, p < 0.001 for both, by a mean increase of 0.4 mm/year and 0.03 mm/year, (p = 0.009 and p = 0.002 compared with HFnCA), respectively. RWT > 0.45 (AUC = 0.77) and RELAPS > 2.0 (AUC 0.86) both predicted positive DPD diagnosis for ATTR-CA.

CONCLUSION: In ATTR-CA patients, the overtime-increase in RWT and IVST was worse than that seen in patients with heart failure but no cardiac amyloidosis. Also, RWT and relative apical sparing predicted diagnosis of ATTR-CA, thus could strengthen the use of follow-up echocardiographic findings as red flag for the diagnosis of ATTR-CA.

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, −6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, −5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).