BackgroundThree diagnostic scoring systems have been developed to improve the identification of patients with transthyretin cardiac amyloidosis (ATTR-CA) in patients presenting with heart failure with preserved ejection fraction (HFpEF). The ATTR-CM, AMY and T-Amylo scores have been validated, though data comparing their performance are lacking. We sought to compare the diagnostic accuracy of the three scores in an Australian cohort.MethodsWe conducted a retrospective cohort study across two separate healthcare centres from 2018 to 2024 comprising all patients diagnosed with ATTR-CA and all consecutive patients presenting to a HFpEF clinic who were screened for ATTR-CA. All three scores were calculated retrospectively. A multivariable logistic regression model was used to identify significant variables.ResultsA total of 454 patients were included with ATTR-CA being diagnosed in 140 patients (30.8%). The T-Amylo score (area under the curve: 879; 95% CI 0.841 – 0.917) and ATTR-CM score (area under the curve of 0.875; 95% CI 0.840-0.911) both demonstrated very good discriminative capacity for ATTR-CA while the AMY score displayed a moderate discriminative capacity (area under the curve of 0.755; 95% CI 0.705-0.805).ConclusionsBoth the ATTR-CM and T-Amylo scores displayed very good performance in identifying patients at high risk for ATTR-CA in patients with known HFpEF.

Rationale: It is unclear whether carriers of pathogenic variants in PAH-associated genes have a distinct response to PAH treatment. Objectives: To evaluate the effect of genetic variant status on the efficacy of sotatercept and the effect of sotatercept treatment on biomarkers in pulmonary arterial hypertension. Methods: PULSAR (A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension; NCT03496207) was a phase II, randomized controlled study of sotatercept versus placebo added to background therapy for pulmonary arterial hypertension. Participants underwent DNA sequencing at baseline to detect genetic variants in disease-associated genes (ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA3, KCNK3, and SMAD9). Safety (adverse events) and efficacy (pulmonary vascular resistance, 6-min-walk distance) were assessed by variant status and treatment at 24 weeks. Serum concentrations of BMPR2 mRNA and N-terminal prohormone B-type natriuretic peptide were assessed at baseline and 24 weeks by treatment and variant status. Analysis of covariance was used to compare the change from baseline by treatment and variant status. Measurements and Main Results: Among 76 participants included, pathogenic variants were detected in 25 (23 BMPR2, 2 other), and 51 had no variants or variants of uncertain significance. BMPR2 mutation carriers were younger and more frequently on triple therapy but had less severe clinical characteristics at baseline. Changes at 24 weeks in pulmonary vascular resistance and 6-minute-walk distance did not differ by variant status. BMPR2 gene expression varied less than twofold from baseline over time, irrespective of treatment or variant status. The adverse event profile was generally consistent with that seen in the parent PULSAR study. Conclusions: These results suggest consistent safety and clinical efficacy of sotatercept for treatment of pulmonary arterial hypertension, irrespective of BMPR2 variant status.

BACKGROUND:Amyloidosis is a rare, multisystem disorder characterized by extracellular deposition of misfolded protein fibrils. Gastrointestinal (GI) amyloidosis is uncommon but under-recognized due to nonspecific symptoms, but early diagnosis is critical to improve quality of life and prognosis. This comprehensive systematic review aimed to summarize current literature on GI and hepatic manifestations of amyloidosis, highlighting diagnostic and management strategies across the major subtypes of amyloidosis, in particular AL (immunoglobulin light chain), ATTR (transthyretin), and AA (serum amyloid A) amyloidosis. METHODS:A systematic search of MEDLINE, Embase, and PubMed conducted for studies published between January 2014 and December 2024 identified 77 studies meeting inclusion criteria. RESULTS:GI symptoms occur in approximately 1 in 6 patients with amyloidosis, but symptoms correlate poorly with gastrointestinal deposition. Current literature suggests that duodenal biopsy is the most reliable diagnostic site. Fibroscan shows promise in detecting hepatic amyloid involvement. Management is subtype specific. However, supportive care, particularly nutritional intervention, is essential across all subtypes. CONCLUSIONS:GI amyloidosis presents diversely with nonspecific symptoms. Standardized diagnostic algorithms, targeted therapies, and nutritional support can lead to improved outcomes and enhance quality of life.

Hereditary transthyretin amyloidosis (ATTRv) is a clinically important yet under-recognised entity. It develops when inherited genetic mutations synthesise dysfunctional transthyretin protein, which accrues and disrupts organs, typically causing cardiac failure or polyneuropathy. Whilst numerous genotypes have been implicated, this report aims to provide a detailed account of the rare and pathognomonic aspartate to valine amino acid substitution, p.Asp58Val, affecting a 54-year-old Australian female, along with associated clinical manifestations. Genotypic-phenotypic relationships are also examined within index and prior cases. Of note, recurrent syncope formed a predominant symptom affecting our patient, preceding eventual diagnosis, followed by multidisciplinary management to optimise her level of functioning. In summary, progressive neuropathy followed by cardiomyopathy may represent key clinical features associated with p.Asp58Val hereditary transthyretin amyloidosis. Physician vigilance for these symptoms, especially amongst patients with familial cardiomyopathy, may improve detection of this rare disease.

AimsDescribe differences in changes in cardiopulmonary exercise testing after surgery for severe primary mitral regurgitation between class I and class II indications for surgery. Methods Prospective observational study of patients who underwent transthoracic echocardiogram and cardiopulmonary exercise testing pre-operatively and six months after surgery. Results Forty three of the fifty patients recruited between February 2017 and October 2018 were included in per protocol analysis. Seven patients were excluded-two patients did not meet inclusion criteria after further investigation, two patients were unable to perform pre-operative cardiopulmonary exercise testing, two patients had post-operative mortality, one patient declined post-operative cardiopulmonary exercise testing. Median age was 64 years and 15 patients (34.9%) were female. Thirty five patients had impaired post-operative functional capacity defined as post-operative left ventricular ejection fraction on echocardiogram <50% and/or post-operative percentage predicted peak VO2 ≤ 84%). In patients with class I indication for surgery (n = 30), there was no significant change post-operatively in ppVO2 (81 (69-88) % vs. 79 (60-87) %, p = 0.09). In patients with class II indication for surgery (n = 13), there was a significant fall post-operatively in ppVO2 (82 (79-92) % vs. (74 (68-86) %, p < 0.01). In the univariate analysis, pre-operative ppVO2 ≤ 84% (p < 0.01) was a predictor for impaired post-operative functional capacity. Conclusions Patients with class I indication have persistently abnormal exercise performance six months after surgery. Patients with class II indication for surgery have worse exercise performance parameters six months after surgery. Pre-operative ppVO2 ≤84% is an independent predictor of impaired post-operative functional capacity at six months.

BACKGROUND:Sotatercept improves exercise capacity and delays the time to clinical worsening in patients with World Health Organization (WHO) functional class II or III pulmonary arterial hypertension. The effects of add-on sotatercept in patients with advanced pulmonary arterial hypertension and a high risk of death are unclear. METHODS:In this phase 3 trial, we randomly assigned patients with pulmonary arterial hypertension (WHO functional class III or IV) and a high 1-year risk of death (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management Lite 2 risk score, ≥9) who were receiving the maximum tolerated dose of background therapy to receive add-on sotatercept (starting dose, 0.3 mg per kilogram of body weight; escalated to target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension, assessed in a time-to-first-event analysis. RESULTS:A total of 172 patients were included (86 each in the sotatercept and placebo groups). The trial was stopped early on the basis of the efficacy results of a prespecified interim analysis. At least one primary end-point event occurred in 15 patients (17.4%) in the sotatercept group and in 47 patients (54.7%) in the placebo group (hazard ratio, 0.24; 95% confidence interval, 0.13 to 0.43; P<0.001). Death from any cause occurred in 7 patients (8.1%) in the sotatercept group and in 13 patients (15.1%) in the placebo group; lung transplantation in 1 patient (1.2%) and 6 patients (7.0%), respectively; and hospitalization for worsening pulmonary arterial hypertension in 8 patients (9.3%) and 43 patients (50.0%). The most common adverse events with sotatercept were epistaxis and telangiectasia. CONCLUSIONS:Among high-risk adults with pulmonary arterial hypertension who were receiving the maximum tolerated dose of background therapy, treatment with sotatercept resulted in a lower risk of a composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension than placebo. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; ZENITH ClinicalTrials.gov number, NCT04896008.).

Background SOTERIA ( NCT04796337 ) is an ongoing open-label study evaluating long-term safety, tolerability, and efficacy of sotatercept in participants with pulmonary arterial hypertension (PAH). Methods Eligible adults with PAH on stable background therapy who completed a prior sotatercept study without early discontinuation were enrolled. Participants received subcutaneous sotatercept (≤0.7 mg·kg −1 Q3W). Safety and tolerability (primary objective) were assessed by adverse events (AEs), vital signs, and laboratory assessments. Efficacy (secondary objective) was assessed by 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, WHO functional class (FC), clinical worsening events, and simplified French risk score (SFRS). The data cutoff date was 08NOV2023. Results Altogether, 426 participants were included in the analyses. Mean ( sd ) duration of exposure to sotatercept and follow-up in SOTERIA was 448.6 (172.93) days (range 21–923 days; 523 patient-years). Of 426 participants, 387 (90.8%) experienced AEs, 15 (3.5%) discontinued treatment, 129 (30.3%) had serious AEs, and 11 (2.6%) had serious AEs related to treatment. There were 12 deaths (2.8%). Among AEs of interest, epistaxis (22.1%) and telangiectasia (16.9%) were the most frequently reported individual events. Twenty-two (5.2%) participants had serious bleeding events, including 2 (0.5%) with serious bleeding leading to death (not related to treatment by investigator judgment). Improvements in 6MWD, NT-proBNP, WHO FC, and SFRS achieved from baseline of SOTERIA were largely maintained at one year, including in the placebo-crossed group. Conclusion Interim results of SOTERIA support the favorable benefit-risk of add-on sotatercept treatment in adults with PAH. Follow-up reports from this study will provide additional information on benefit/risk.

Background Acoramidis is an investigational, next-generation, oral, near-complete stabilizer of transthyretin (TTR) for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). The phase 3 ATTRibute-CM study demonstrated robust efficacy on clinical outcomes (all-cause mortality [ACM] and first cardiovascular hospitalization [CVH]) from 2 previously reported analyses: the 2-component, hierarchical Finkelstein-Schoenfeld method (p=0.0182) and the Cox proportional hazards model time to first event analysis (HR 0.645, p=0.0008). However, the previous models do not account for recurrent events. The objective of this post hoc reanalysis is to evaluate the overall effect of acoramidis vs placebo on the combination of ACM and all CVHs as recurrent events. Methods The Andersen-Gill (A-G) model is an extension of the Cox proportional hazards model that allows for handling recurrent events. In this analysis, the model was stratified by randomization stratification factors (genotype [ATTRm-CM vs ATTRwt-CM], baseline NT-proBNP level [≤3000 vs >3000], eGFR level [≥45 vs <45]), with treatment group, baseline 6-minute walk distance, and the number of events that occurred before a given interval included as covariates. Results Of 632 randomized patients, 611 were included in the A-G analysis (efficacy analysis population; acoramidis: 409; placebo: 202). ACM or CVH occurred in 147 (35.9%) and 102 (50.5%) of acoramidis and placebo-treated patients, respectively (Table). Patients treated with acoramidis also experienced fewer recurrent CVH or CVH and ACM events (14.4%) vs placebo (27.7%). The analysis using the A-G methodology demonstrated that acoramidis resulted in fewer ACM or CVH events compared with placebo (HR=0.695; p=0.0008). Conclusion The A-G analysis of time to recurrent event for ACM or CVH in ATTRibute-CM shows a highly significant reduction of singular and multiple, recurrent events in participants treated with acoramidis compared to placebo. These results add to and reinforce the conclusions from the primary analysis of ATTRibute-CM, that acoramidis leads to a significant improvement in clinical outcomes (ACM or CVH) in ATTR-CM patients.

PURPOSE:Pulmonary hypertension (PH) is a chronic complication of sickle cell disease (SCD) with limited known biomarkers, beyond increases in plasma brain natriuretic peptide levels. EXPERIMENTAL DESIGN:We conducted a proof-of-concept study to identify serum protein biomarkers that were differentially expressed in SCD patients with elevated tricuspid regurgitation velocity (TRV-a noninvasive marker of PH). RESULTS:We found 41 out of 92 target proteins that were significantly different between the nonelevated (TRV ≤ 2.6 m/s; N = 35) and highly elevated TRV group (TRV ≥ 2.9 m/s; N = 35, p < 0.05). Six of them passed a Bonferroni correction (p value < 0.0005), including T-cell surface glycoprotein, lymphotactin, SLAM family member 7, galectin-9, TNF-related apoptosis-inducing ligand receptor 2, and tumor necrosis factor receptor superfamily member 11A. We observed up to a 1.2-fold increase in the high TRV group for these six proteins. These six proteins had a strong positive correlation with serum NT-proBNP levels (a positive control marker elevated in PH [r ≥ 0.44]). Additionally, these markers correlated with other clinical parameters of PH in SCD. CONCLUSION:Circulatory protein markers of the immune response are increased in SCD patients with elevated TRV as compared to those without elevated TRV. SUMMARY:This study demonstrates that the circulatory protein markers of the immune response are increased in SCD patients with elevated TRV compared to those without elevated TRV. These biomarkers may be important tools for risk-stratifying patients with SCD or targets for therapeutic intervention.

Objective To estimate the burden of transthyretin cardiac amyloidosis (ATTR-CA) through a cross- sectional ‘snapshot’ of Australian Amyloidosis Network (AAN) and New Zealand (NZ) specialist amyloidosis clinics. Design, Setting & Participants A prospective survey was performed of seven AAN/ specialist amyloidosis clinics across Australia and NZ. All centres were invited to contribute data; participating centres provided clinical and demographic data for patients with ATTR-CA reviewed in the 2022 calendar year. Patients with new or previously confirmed ATTR-CA reviewed in the 2022 calendar year were included. Diagnosis was established through a positive cardiac scintigraphy scan in the absence of a monoclonal gammopathy or through a cardiac biopsy staining positive with transthyretin (TTR). Results A total of 515 patients were reviewed across seven sites. A total of 302/515 (59%) were wild type TTR (ATTRwt), 63/515 (12%) were variant ATTR (ATTRv) and the remaining 150 (29%) had not undergone genetic testing at the time of data collection. A total of 455/515 (88%) patients were male. Compared to ATTRwt, patients with ATTRv had smaller left ventricular (LV) wall thickness (IVSd 14±3 mm vs 16±3mm, p<0.001), and better LV systolic function (LVGLS -15.4±5% vs -11.7±3%, p<0.001). Most patients, 387/515 (75%) were on at least one ATTR specific treatment, including EGCG (157), diflunisal (139), doxycycline (68) and tafamidis (78), acoramidis (33) and gene silencer therapies or monoclonal antibodies (23). Conclusion A significant number of patients with ATTR-CA are seen in specialist amyloidosis clinics across Australia and NZ. Most patients received specific amyloidosis therapy, thorough enrollment in clinical trials. With increased recognition of amyloidosis and newer therapies becoming available, the volume of patients seen in these clinics is likely to increase.

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

The utility of serum free light chain measurements (SFLC) to predict renal outcome, to optimize prognosis and avoid dialysis, was investigated in myeloma patients with renal impairment treated with carfilzomibdexamethasone. We found a significant correlation between the change in involved SFLC at Cycle 2 with renal function, from which a threshold to change therapy is proposed to avoid suboptimal outcome. Disease response and survival were favorable but there was significant toxicity including cardiac impairment and infections. Background and Purpose: Renal impairment (RI) confers adverse prognosis in myeloma; its reversal and avoidance of dialysis are crucial. We investigated whether serum free light chain (SFLC) measurements can predict renal outcome, to enable change in therapy to optimize prognosis and avoid dialysis. Patients and Methods: We investigated 36 myeloma patients (17 newly diagnosed [ND]; 19 relapsed refractory [RR]; with median of 5 prior lines) with eGFR 15-40 ml/min treated with carfilzomib (Cfz)-dexamethasone to determine whether SFLC kinetics can predict renal outcomes, and assess efficacy and tolerability. Results: The change in involved SFLC at Cycle 2 Day 1 was significantly correlated with renal function; for every one log10 reduction in involved SFLC, eGFR increased by 9.0-15.0 mL/min at cycles 2-4, with SFLC reduction of 54%-78%. At a median follow-up of 30.6 months, renal outcomes were favorable-CRrenal 25%, MRrenal 36%. Disease responses (ND 100%, RR 75%), progression-free survival (ND 32.2 months, RR 11.1 months) and overall survival (ND not reached, RR 42.0 months) were comparable to patients without RI. There was significant toxicity, including Cfz-related cardiac impairment of 20% within a cohort with high co-morbidity, and a high incidence of infections. Conclusion: We propose that one log10 reduction in involved SFLC at Cycle 2 Day 1 is an appropriate target for reducing the risk of dialysis in myeloma patients with RI; below this threshold patients may benefit from a change in therapy. While Cfz-dexamethasone achieved favorable renal and disease outcomes, toxicity can be significant in this vulnerable cohort.

In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplantineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% con fidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumabcontaining arm showed a signi ficant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% ( P = .0002); 24 months, 36% vs 52% ( P = .0001); and 30 months, 27% vs 41% ( P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were signi ficantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).

Over the past 5 years, early diagnosis of and new treatments for cardiac amyloidosis (CA) have emerged that hold promise for early intervention. These include non-invasive diagnostic tests and disease modifying therapies. Recently, CA has been one of the first types of cardiomyopathy to be treated with gene editing techniques. Although these therapies are not yet widely available to patients in Australia and New Zealand, this may change in the near future. Given the rapid pace with which this field is evolving, it is important to view these advances within the Australian and New Zealand context. This Consensus Statement aims to update the Australian and New Zealand general physician and cardiologist with regards to the diagnosis, investigations, and management of CA.