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In a cohort study, 3856 black Americans were genotyped for the amyloidogenic V122I transthyretin variant; 124 were variant carriers. At a median follow-up of 21.5 years, carriers did not differ significantly from noncarriers in mortality but had a higher risk of incident heart failure. Amyloid heart disease leads to an increase in ventricular wall thickness and stiffness of the heart. 1 Abnormalities of transthyretin, a transport protein synthesized mainly by the liver, may lead to hereditary transthyretin-related amyloidosis. 2 This disorder can be caused by any one of more than 100 point mutations in the transthyretin gene ( TTR ); the V122I variant, in which isoleucine is substituted for valine at position 122, is the most frequent mutation and occurs in 3 to 4% of black Americans. 3 – 5 V122I reduces the stability of transthyretin tetramers, causing cardiac deposition of misfolded transthyretin monomers and resulting in an . . .

TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans. Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography. At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥70 beats/min, baseline stroke volume, left ventricular ejection fraction <50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort. In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.

To evaluate the prevalence of monoclonal gammopathy (MG) in patients with wild-type transthyretin amyloidosis (ATTRwt) (formerly known as senile amyloidosis). We retrospectively analyzed the serum protein electrophoresis and serum immunofixation results, free light chain (FLC) levels, and renal function of 113 consecutive patients with ATTRwt seen at the Brigham and Women's Hospital's Cardiac Amyloidosis Program between February 21, 2006, and November 9, 2016. Monoclonal gammopathy was defined as a monoclonal protein present in the serum. Light chain MG was defined as an abnormal serum FLC κ/λ ratio with an elevated FLC level in the absence of a monoclonal protein. In patients with renal dysfunction, the renal FLC reference range was used. The mean age of the population was 75 years, 3 of the 113 patients (3%) were female, and 110 (97%) were white. Monoclonal gammopathy was present in 26 patients (23%), 24 of whom had monoclonal protein present and 2 others who met criteria for light chain MG. Most clones (12 of 20 [60%]) were λ restricted. Another 7 patients had an abnormal FLC κ/λ ratio in the setting of renal dysfunction. In this study, MG was present in 23% of patients with ATTRwt. The finding of MG or an abnormal FLC κ/λ ratio in an elderly man may cause diagnostic confusion during subtyping of amyloidosis. A high degree of clinical suspicion for ATTRwt and precise tissue typing using mass spectrometry may overcome such diagnostic challenges.

The diagnosis of cardiac amyloidosis (CA) often necessitates invasive myocardial biopsy. We sought to evaluate whether late gadolinium enhancement (LGE) of the atrial myocardium by cardiac magnetic resonance imaging was associated with impaired left atrial (LA) function and whether the extent of LA LGE may enhance diagnostic differentiation of CA from other cardiomyopathies. Twenty-two patients with biopsy-proven CA, 37 with systemic hypertension (SH), and 22 with nonischemic dilated cardiomyopathy (NIDC) underwent cardiac magnetic resonance imaging and echocardiographic evaluation. Patients with CA had greater minimal LA volume (57 ± 53 vs 24 ± 18 in SH and 19 ± 25% in NIDC, p = 0.003), and significantly lower total LA emptying function (19 ± 14 vs 40 ± 14 in SH and 33 ± 20% in NIDC, p = 0.0006). The mean proportion of atrial enhancement (LGELA%) was significantly greater in patients with CA than with SH and NIDC (59 ± 36% vs 7.4 ± 2.1 and 2.9 ± 9.0%, p <0.0001, respectively). There was also a strong inverse correlation between both active and total atrial emptying (r = −0.69, p = 0.001; r = −0.67, p = 0.01, respectively) with LGELA% for patients with CA. In multivariate regression analysis, LGELA% was the strongest adjusted predictor for CA diagnosis. Using receiver operating characteristic analysis, LGELA% ≥33% produced the greatest diagnostic utility for CA (sensitivity 76%, specificity 94%). Patients with CA may have extensive LGE of the LA myocardium, which is associated with marked reduction in LA emptying function. The extent of LA LGE was highly predictive for the diagnosis of CA.

AL amyloidosis is the consequence of clonal production of amyloidogenic immunoglobulin light chain (LC) proteins, often resulting in a rapidly progressive and fatal amyloid cardiomyopathy. Recent work has found that amyloidogenic LC directly initiate a cardio‐toxic response underlying the pathogenesis of the cardiomyopathy; however, the mechanisms that contribute to this proteotoxicity remain unknown. Using human amyloidogenic LC isolated from patients with amyloid cardiomyopathy, we reveal that dysregulation of autophagic flux is critical for mediating amyloidogenic LC proteotoxicity. Restoration of autophagic flux by pharmacological intervention using rapamycin protected against amyloidogenic light chain protein‐induced pathologies including contractile dysfunction and cell death at the cellular and organ level and also prolonged survival in an in vivo zebrafish model of amyloid cardiotoxicity. Mechanistically, we identify impaired lysosomal function to be the major cause of defective autophagy and amyloidogenic LC‐induced proteotoxicity. Collectively, these findings detail the downstream molecular mechanisms underlying AL amyloid cardiomyopathy and highlight potential targeting of autophagy and lysosomal dysfunction in patients with amyloid cardiomyopathy. Synopsis Cardiomyocyte dysfunction associated with immunoglobulin abnormal light chain protein (AL‐LC) proteotoxicity is found to be caused by a dysregulation in autophagy. Genetic or pharmacological restoration of autophagy protects against AL‐ LC proteotoxicity and the development of AL amyloid cardiomyopathy. Impaired lysosomal function and autophagic flux are early and critical steps in amyloidogenic light chain‐induced proteotoxicity. Downregulation of the transcription factor TFEB underlies lysosomal dysfunction with light chain proteotoxicity. Treatment with the small molecule rapamycin restored autophagic flux and protected against amyloidogenic light chain‐induced proteotoxicity. Rapamycin may hold therapeutic promise for the treatment of AL amyloid cardiomyopathy. Graphical Abstract Cardiomyocyte dysfunction associated with immunoglobulin abnormal light chain protein (AL‐LC) proteotoxicity is found to be caused by a dysregulation in autophagy. Genetic or pharmacological restoration of autophagy protects against AL‐LC proteotoxicity and the development of AL amyloid cardiomyopathy.

Transthyretin (TTR) mutations known to cause cardiac amyloidosis include V122I, found almost exclusively in African Americans at a prevalence of 3-3.9%. This retrospective study describes TTR V122I–associated cardiac amyloid disease (ATTR) in a major amyloid referral clinic population. Self-identified African Americans with amyloidosis (n = 156) were screened for TTR V122I by serum isoelectric focusing; mutant TTR was confirmed by DNA sequencing or mass spectrometry. Cardiac findings in ATTR V122I and immunoglobulin light chain (AL) amyloidoses were compared. TTR V122I was identified in 36/156 (23.1%) of evaluated patients and included 5 homozygotes; the allele frequency was 0.013. One compound heterozygote (F44L/V122I) and 4 patients who had AL and the mutant TTR allele were characterized. In patients negative for V122I, AL was the most frequent diagnosis (86/120). Cardiomyopathy was present in 100% of patients with ATTR and 84% of patients with AL ( P = .01). In patients with dominant cardiac involvement, better survival occurred in ATTR (n = 30) compared to AL (n = 31), (27 vs 5 months, P < .01) although the mean age in ATTR was higher (70.3 vs 56.2 years, P < .01). Congestive heart failure symptoms and electrocardiographic findings were similar in ATTR and AL, but significant differences in echocardiographic measurements were observed. ATTR V122I and AL are equally prevalent as the cause of cardiomyopathy in African Americans referred for a diagnosis of amyloidosis. Available therapy for AL underscores the need for early and accurate determination of amyloid type.

Background In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. Methods Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [ 89 Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [ 89 Zr]Zr-dezamizumab cardiac uptake assessed via PET. Results Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [ 89 Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. Conclusions Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

PurposeThe Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis.MethodsPatients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction.ResultsRevusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events.ConclusionsCauses for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded.Clinical Trial RegistrationNCT02319005.

A 54-year-old male athlete was evaluated at this hospital because of exertional dyspnea and chest pain. Physical examination revealed jugular venous distention and Kussmaul’s sign. A diagnosis was made.