Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between cardiac diseases, comorbidities and ageing. HFpEF is characterised by the activation of neurohormonal axes, namely of the renin-angiotensin-aldosterone system and the sympathetic nervous system, although to a lesser extent compared with heart failure with reduced ejection fraction. This provides a rationale for neurohormonal modulation as a therapeutic approach for HFpEF. Nonetheless, randomised clinical trials have failed to demonstrate a prognostic benefit from neurohormonal modulation therapies in HFpEF, with the sole exception of patients with left ventricular ejection fraction in the lower range of normality, for whom the American guidelines suggest that such therapies may be considered. In this review, the pathophysiological rationale for neurohormonal modulation in HFpEF is summarised and the clinical evidence on pharmacological and nonpharmacological approaches backing current recommendations discussed.

Haemodynamic forces (HDFs), which represent the forces exchanged between blood and surrounding tissues, are critical in regulating the structure and function of the left ventricle (LV). These forces can be assessed on cardiac magnetic resonance or transthoracic echocardiography exams using specialized software, offering a non-invasive alternative for measuring intraventricular pressure gradients. The analysis of HDFs can be a valuable tool in improving our understanding of cardiovascular disease and providing insights beyond traditional diagnostic and therapeutic approaches. For instance, HDF analysis has the potential to identify early signs of adverse remodelling and cardiac dysfunction, which may not be detected by standard imaging methods such as bidimensional or speckle-tracking echocardiography. This review aims to summarize the principles of HDF analysis and to reappraise its possible applications to cardiac disorders.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease where, despite recent advances, accurate diagnosis, risk stratification, and personalized treatment remain challenging. Artificial intelligence (AI) offers a transformative approach to HCM by enabling rapid, precise analysis of complex data. This article reviews the current and potential applications of AI in HCM. AI enhances diagnostic accuracy by analysing electrocardiograms, echocardiography, and cardiac magnetic resonance images, differentiating HCM from other forms of left ventricular hypertrophy, identifying subtle phenotypic variations, and standardizing myocardial fibrosis assessment. Multimodal AI-driven approaches improve risk stratification, therapeutic decision-making, and monitoring of both established and novel therapies, such as cardiac myosin inhibitors. Emerging AI-driven in silico trials and digital twin platforms highlight the potential of combining data-driven and knowledge-based AI with biophysical models to simulate patient-specific disease trajectories, supporting preclinical evaluation and personalized care. As a multidisciplinary case study, the SMASH-HCM consortium is presented to illustrate how digital twin technologies and hybrid modelling can bring AI into clinical practice. Integration of genetic data further enhances AI's ability to identify at-risk individuals and predict disease progression. However, widespread AI applications raise concerns regarding data privacy, ethical considerations, and the risk of biases. Guidelines for researchers and developers—e.g. on trustworthy AI, regulatory frameworks, and transparent policies—are essential to address these possible pitfalls. As AI rapidly evolves, it has the potential to revolutionize drug discovery, disease management, and the patient journey in HCM, making interventions more precise, timely, and patient-centred.

Aims: The positron emission tomography (PET) tracer 18F-florbetaben is a promising diagnostic tool for light-chain cardiac amyloidosis (AL-CA). A greater cardiac uptake might signal more amyloid burden and a worse outcome. We aimed to assess the prognostic significance of 18F-florbetaben uptake in AL-CA. Methods and results: Consecutive patients with AL-CA underwent 18F-florbetaben PET scans. Total amyloid burden (TAB; calculated as mean standardized uptake value multiplied by molecular volume) was assessed in the left and right ventricles (LV/RV) in early (5–15′) and late (50–60′) acquisitions. The endpoint was all-cause mortality. Forty patients (median age 69 years, 73% males, Mayo 2004 Stage III in 80%) underwent 18F-florbetaben PET with a median time from tissue biopsy of 21 days (interquartile range, IQR 7–83). Late LV TAB, but not early LV TAB, correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity (hs)-troponin T. Over 13 months after the PET scan (IQR 5–21), 65% of patients died. A late LV TAB ≥273 cm3 (cut-off derived from spline curve analysis) predicted 18 and 24 month all-cause mortality independently from baseline variables, including NT-proBNP, hs-troponin T, and Mayo 2004 stage. Late RV TAB ≥135 cm3 independently predicted 18 and 24 month all-cause mortality. Patients with both late LV and RV TAB ≥ cut-offs had a shorter survival than those with only LV TAB ≥ cut-off and those with TAB in both ventricles < cut-offs (Log-rank 16.52, P < 0.001). Conclusion: 18F-florbetaben PET imaging offers valuable prognostic information in AL-CA. Values of late TAB measured in the LV and RV are strong predictors of all-cause mortality.

Heart failure (HF) and cardiac amyloidosis (CA) are significant clinical challenges, with evolving epidemiological patterns reshaping the understanding of these conditions. Traditionally linked with HF with preserved ejection fraction, CA is increasingly recognised for its specific characteristics, including a considerable subset of patients presenting with reduced left ventricular ejection fraction. This review explores how the neurohormonal activation observed in CA impacts on disease progression and management strategies. Historically, neurohormonal antagonists were considered contraindicated in CA owing to concerns about autonomic dysfunction and chronotropic incompetence. However, recent evidence suggests a paradigm shift, indicating that such agents may offer therapeutic benefits even in these patients. By examining these developments, this review provides a comprehensive overview of current therapeutic approaches, the role of neurohormonal modulation and the need for personalised care strategies to address the complexities of HF in the context of CA.