BackgroundDiagnosis of apical HCM utilizes conventional wall thickness criteria. The normal left ventricular wall thins towards the apex such that normal values are lower in the apical versus the basal segments. The impact of this on the diagnosis of apical hypertrophic cardiomyopathy has not been evaluated.MethodsWe performed a retrospective review of 2662 consecutive CMR referrals, of which 75 patients were identified in whom there was abnormal T-wave inversion on ECG and a clinical suspicion of hypertrophic cardiomyopathy. These were retrospectively analyzed for imaging features consistent with cardiomyopathy, specifically: relative apical hypertrophy, left atrial dilatation, scar, apical cavity obliteration or apical aneurysm. For comparison, the same evaluation was performed in 60 healthy volunteers and 50 hypertensive patients.ResultsOf the 75 patients, 48 met conventional HCM diagnostic criteria and went on to act as another comparator group. Twenty-seven did not meet criteria for HCM and of these 5 had no relative apical hypertrophy and were not analyzed further. The remaining 22 patients had relative apical thickening with an apical:basal wall thickness ratio > 1 and a higher prevalence of features consistent with a cardiomyopathy than in the control groups with 54% having 2 or more of the 4 features. No individual in the healthy volunteer group had more than one feature and no hypertension patient had more than 2.ConclusionA cohort of individuals exist with T wave inversion, relative apical hypertrophy and additional imaging features of HCM suggesting an apical HCM phenotype not captured by existing diagnostic criteria.

Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal systems to varying degrees. Its underlying cause is a plasma cell dyscrasia characterized by misfolding of monoclonal immunoglobulin light chains which leads to aggregation and deposition of insoluble amyloid fibrils in target organs. Prognosis is primarily dependent on extent of cardiac involvement and depth of hematologic response to treatment. To facilitate development of new therapies, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify novel/composite end points and analytic strategies to expedite clinical trials for development of new therapies for the primary hematologic disorder and organ system manifestations. Specialized working groups identified organ-specific end points; additional working groups reviewed health-related quality of life measures and statistical approaches to data analysis. Each working group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Agency, and pharmaceutical companies. This review summarizes the proceedings and recommendations of the Cardiac Working Group. Using a modified Delphi method, the group identified, reviewed, and prioritized cardiac end points relevant to immunoglobulin light chain amyloidosis in the context of an antiplasma cell therapy. Prioritized cardiovascular end points included overall survival, hospitalization, N-terminal pro-B-type natriuretic peptide level, 6-minute walk test, Kansas City Cardiac Questionnaire, and cardiac deterioration progression-free survival. These recommended components will be further explored through evaluation of clinical trial datasets and formal guidance from regulatory authorities.

INTRODUCTION Treatment outcomes in AL amyloidosis are dependent on the hematological response to chemotherapy translating into organ responses. Cardiac biomarker, N-terminal brain pro-natriuretic peptide (NT-proBNP), is the main determinant of cardiac response in AL amyloidosis. Strongly supported by the amyloidosis community, the FDA is considering use of NT-proBNP as the primary end point for clinical trials. A number of questions on the exact details on NT-proBNP in AL remain unanswered - rate of decrease over time, timing of NT-proBNP measurement (6 months or 12 months) and values to use as a baseline. We report the use of serial NT-proBNP measurements for cardiac response assessment at 6 months and 12 months addressing some of these questions. PATIENTS AND METHODS All patients (n=650) recruited in the ALChemy study (a prospective observational study of all patients with AL amyloidosis undergoing chemotherapy) at the UK National Amyloidosis Centre from Sept 2009 to Jan 2014 with a minimum follow of 12 months and available NT-proBNP at 0, 6 and 12 months were included in this study. Organ involvement and hematologic/amyloidotic organ responses were assessed according to 2010 amyloidosis consensus criteria. The primary outcome measure was cardiac response as defined by NT-proBNP (Palladini et al JCO 2012). Correlation with 6 minute walk test was done where available. RESULTS A total of 343 patients were identified. The median age was 64 yrs. Organ involvement was: cardiac - 72%, renal - 73% and liver - 12% (median - 2 organs). The median creatinine was 90 _mol/L, median dFLC was 150 mg/L (range 10-15898 mg/L). The median NT-proBNP was 966 ng/L (range 33-30872 ng/L). The Mayo disease stage was: stage 1 - 26%, stage 2 - 47% and stage 3 Ð 27%. Serial six minute walk test results were available in 71 patients. Treatment was: thalidomide based regimes (mainly CTD) 56%, CyBorD Ð 30%, Melphalan-Dexamethasone - 5% and SCT 1%. A total of 204 patients had baseline NT-proBNP >650 ng/L (the threshold defined for NT-proBNP to be assessable for cardiac response) and were included in response analysis. Partial hematological response (or better) was seen in 92%, ³ VGPR in 66% and 22 (8%) were non-responders. The median decrease in dFLC was 85% over baseline at six months. The median NT-proBNP at baseline (for the response assessable group n=204) was 2669 ng/L. At six months, the median NT-proBNP had increased significantly to a median 3258ng/L (p<0.0001). At 12 months, there was a significant decrease in the NT-proBNP to a median of 2097 pMol/L (p=0.014). There was a discordance in NT-proBNP response at 6 and 12 months in 42 (44%) of patients (Figure 1). At six months, 52 (25%) patients had achieved NT-proBNP response and at 12 months 94 patients (46%) achieved an NT-proBNP response. When NT-proBNP at the 6 month time point was used as a baseline for response assessment, at 12 months, 106 (52%) patients met the criteria for a cardiac response. There was no significant difference in the median six minute walk test at baseline, 6 m and 12 months was 390m, 370m and 400 m. The six minute walk distance improved by greater than 10% over baseline at 6 and 12 months in 12% and 20% patients, worsened by more than 10% in 32% and 27% patients with change of less than 10% in the remainder. The median survival for this cohort has not been reached at 5 years with 60% survival at 7 years. Contrary to published data, NT-proBNP response at six months had a non-significant impact on survival whilst the NT-proBNP response at 12 months significantly impacted survival (median not reached for responders vs. 67 months for the non-responders; p<0.0001). CONCLUSIONS This study shows the median NT-proBNP increased at six months over the baseline. There was a marked discrepancy in NT-proBNP at 6 months and 12 months Ð with a clear mis-classification of nearly half of all eventual cardiac responders. Consequently, the NTproBNP measurements at six months did not have a significant impact on survival whilst there was a marked impact at 12 months. NT-proBNP, as a primary end point, measure too early has potential for giving false negative results as a trial end point. This study highlights the critical importance of the timing of NT-proBNP measurements in response assessment for AL amyloidosis for clinical trials to avoid false negative results. FIgure 1 FIgure 1. Disclosures Wechalekar: Janssen: Honoraria; Celgene: Honoraria; Glaxo Smith Kline: Honoraria; Takeda: Honoraria.