Ninian N. Lang

Background: Cardiovascular disease (CVD) and light chain (AL) amyloidosis are important causes of morbidity and mortality in patients with multiple myeloma (MM). Additionally, MM therapies can have cardiovascular effects. However, the extent to which phase III MM trials account for underlying CVD and amyloidosis through eligibility criteria, screening and reporting remains uncertain. These elements of trial design and reporting are essential for accurate interpretation of cardiovascular safety signals. Objectives: To examine practice-changing MM trials with respect to amyloidosis and CVD eligibility criteria, assessment for cardiac amyloidosis, reporting of baseline cardiovascular characteristics and cardiovascular adverse events (CVAE). Methods: Systematic review of phase III randomised controlled trials of MM drug therapies published in English between 2015 and 2025, identified by searching MEDLINE, Embase and Cochrane Library. Eligible trials enrolled adults aged ≥18 years with MM and included ≥100 patients per treatment group; non-randomised, subgroup and abstract-only reports were excluded. Results: 41 trials enrolling 20 144 participants were included. Amyloidosis was an exclusion criterion in 30 trials typically using non-specific definitions. No trial reported active screening for amyloidosis or assessment of cardiac involvement. Baseline cardiovascular investigations were common but were not used to identify cardiac amyloidosis. At least one cardiovascular exclusion criterion was present in 98% of trials, most commonly heart failure and recent myocardial infarction. Baseline cardiovascular characteristics were reported in only one trial. CVAEs were investigator-reported, inconsistently defined and not centrally adjudicated. Conclusions: Phase III MM trials frequently incorporate amyloidosis and CVD exclusion criteria. However, the prevalence of cardiac amyloidosis and other CVD within these practice-changing MM trials remains poorly defined and CVAE reporting remains suboptimal. These limitations may bias safety and efficacy outcomes and reduce trial generalisability. PROSPERO registration number: CRD420251125097.

Aims: Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence and has limited treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular hypertrophy, collectively resulting in enhanced morbidity and mortality. The transcription factor RUNX1 has recently been identified as a mediator of pathological changes in multiple cardiac diseases; however, its role in HFpEF remained unknown. Methods and results: Here, we show that inhibition of Runx1 limits adverse cardiac remodelling in a mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducible Runx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targeting Runx1 in HFpEF by using gene transfer or small-molecule inhibitor Ro5-3335 improves diastolic function and reduces pulmonary oedema, both in female and male mice. Conclusion: Overall, this work enhances our understanding of RUNX1 in cardiac disease and presents a novel translational target for the treatment of HFpEF.

Background and Aims: Many patients with cancer develop heart failure (HF), and many patients with HF develop cancer. Inter-relationships between their natural histories are rarely reported. Methods: Health records were obtained for a Scottish region. People aged >50 years were classified by the presence or absence of HF, loop diuretics (a pharmacological marker of congestion), and cancer. Incident cancer, mortality, and cause of death were recorded. Results: Of 317 178 people aged >50 years, 11 268 (3.6%) had HF of whom 6276 were prescribed loop diuretics; a further 19 044 (6.0%) received loop diuretics. Thus, 30 312 (9.6%) people met an expanded definition of heart failure (HFexp). Annual cancer incidence was slightly higher for those with HFexp (incidence rate ratio 1.10; P < .001), varying amongst cancer types. For people with neither cancer nor HFexp, mortality was <3% annually; most deaths were cardiovascular. For those with cancer but not HFexp, annual mortality was 6.3% for women and 9.0% for men; most died of cancer. For those with HFexp but not cancer, annual mortality ranged from 6.6% to 18.4% depending on sex and HFexp criteria applied; most deaths were cardiovascular. For those with both cancer and HFexp, annual mortality ranged from 14.5% to 28.4%; cardiovascular and cancer mortality rates were similar. Few patients died at home (∼20%). Conclusions: Patients with HFexp have a slightly higher risk of cancer overall, but this may vary according to cancer type. Patients with both cancer and HFexp have a poor prognosis with a similar proportion of deaths attributed to cancer and cardiovascular disease.