Longhi, Simone

Abstract Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light-chain CM (AL-CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone-tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut-offs overall and by carpal tunnel syndrome (CTS), defined an age-based "gray zone" (74–83 years), and evaluated risk modifiers for AL-CM and transthyretin CM (ATTR-CM). We built a points-based algorithm for "gray-zone" patients. Clinical utility was assessed using decision-curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal-protein subgroup, ATTR-CM accounted for 49%, AL-CM for 30%, and neither ATTR- nor AL-CM for 21%. Age ≤73 years was the Youden-optimal threshold favoring AL-CM (sensitivity 66%, specificity 78%), whereas age >84 years made AL-CM unlikely (sensitivity 98%, negative predictive value 94%), defining a "gray zone" (n=261; ATTR-CM 63%, AL-CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light-chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) favored AL-CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT-proBNP favored ATTR-CM. Penalized models achieved cross-validated area under the curves of 0.87 (AL-CM) and 0.94 (ATTR-CM). A two-score algorithm identified small gray-zone subsets enriched for AL-CM (positive predictive value 81.5%, specificity 98%) or ATTR-CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score- and model-based strategies versus treat-all/treat-none across clinically relevant threshold probabilities, with consistent patterns across regions. Conclusions In patients with suspected amyloid CM and a monoclonal protein, age- and CTS-anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre-biopsy probabilities and may help prioritize urgent biopsy and AL-directed work-up while definitive tissue typing is pursued.For image description, please refer to the figure legend and surrounding text.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild–type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO–B study. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ–OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, –3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6–MWT and KCCQ–OS were observed across predefined patient subgroups. Time to first event of all–cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all–cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO–B open–label extension.

Abstract Background Transthyretin-mediated (ATTR) amyloidosis is a rapidly progressive, debilitating, and fatal disease caused by misfolded TTR accumulating in multiple organs and tissues. Patients with hereditary (hATTR) amyloidosis (also known as ATTRv amyloidosis) or wild-type (wtATTR) amyloidosis with cardiomyopathy exhibit decreased survival. Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, was approved for the treatment of hATTR amyloidosis with polyneuropathy. Exploratory analyses of a predefined cardiac subpopulation in the APOLLO study demonstrated the potential for patisiran to improve the manifestations of cardiomyopathy in patients with hATTR amyloidosis with polyneuropathy. Objective To investigate the safety and efficacy of patisiran in patients with ATTR amyloidosis with cardiomyopathy in the ongoing APOLLO-B study (NCT03997383). Material & Methods Patients were 18–85 years of age with evidence of cardiac amyloidosis by echocardiography (end-diastolic interventricular wall thickness &gt;12 mm), and either ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy. Patients had a medical history of heart failure (HF) due to ATTR amyloidosis with at least 1 prior hospitalization for HF, or current clinical evidence of HF. Patients were randomized (1:1) to receive patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. After the double-blind, placebo-controlled period, all patients may receive patisiran in an open-label extension period for up to 36 months. The primary endpoint was change from baseline in 6-MWT at Month 12 with patisiran treatment, compared with placebo. Secondary endpoints evaluated the effect of patisiran vs placebo at Month 12 on QOL (KCCQ-OS score) as well as two sets of composite endpoints: 1) All-cause mortality, frequency of CV events (CV hospitalizations and urgent HF visits) and change from baseline in 6-MWT; and 2) All-cause mortality and frequency of all-cause hospitalizations and urgent HF visits. The pharmacodynamic effect of patisiran on serum TTR level (change from baseline through Month 12) was also assessed. Results & Discussion Enrollment completed (359 patients) in May 2021. About 80% of patients have wtATTR amyloidosis. Primary and secondary endpoint data will be presented, including change in 6-MWT and KCCQ-OS score at Month 12, in addition to safety data. Summary & Conclusion The primary results of the APOLLO-B study will inform the potential of patisiran as a treatment for the cardiomyopathy of ATTR amyloidosis. APOLLO-B will continue to investigate the efficacy and safety of patisiran on ATTR amyloidosis in an open-label extension period.