Alberto Aimo

Protein misfolding diseases impose a substantial and often under-recognized burden on both the heart and vasculature. In this Review, we outline how the failure of proteostasis drives oligomer toxicity, amyloid deposition and inflammation in cardiovascular tissues as well as microvascular injury and thrombosis, which culminate in cardiovascular dysfunction. We define the cardiovascular hallmarks of protein misfolding diseases, focusing on transthyretin amyloidosis and immunoglobulin light chain amyloidosis, and the disease-specific organ tropisms. We examine neurodegenerative proteinopathies affecting the heart-vascular-brain axis, highlighting how amyloid-β and α-synuclein accumulation contribute to dysautonomia, vascular dysfunction and adverse outcomes. We summarize diagnostic pathways and clinical indicators for early diagnosis of cardiovascular involvement in protein misfolding diseases and review established and emerging biomarkers of vascular stress and proteotoxic load. We also map the current therapeutic landscape for protein misfolding diseases, including strategies to reduce the synthesis of precursor proteins or promote the stabilization of mature proteins as well as fibril-directed therapies, and discuss remaining challenges, such as residual cardiovascular risk, that support the development of mechanism-informed therapeutic approaches. Finally, we propose a research roadmap that prioritizes systematic cardiovascular screening in at-risk populations, harmonized methods for vascular phenotyping, biomarker-anchored mechanistic clinical trials across protein misfolding diseases, and artificial intelligence-based approaches and precision medicine frameworks that integrate genotype or distinct protein conformational strain patterns, organ tropism and dynamic proteostasis measures.

Cardiomyopathies are increasingly managed with disease-modifying and phenotype-specific therapies, creating a need for imaging biomarkers that can reliably capture treatment response over time. Cardiovascular magnetic resonance (CMR) is uniquely suited to this role because it combines highly reproducible assessment of cardiac structure and function with detailed tissue characterization. Cine imaging enables serial evaluation of ventricular volumes, mass, and ejection fraction; late gadolinium enhancement identifies focal replacement fibrosis and arrhythmogenic substrate; and native T1/T2 mapping with extracellular volume quantification provides quantitative markers of diffuse fibrosis, oedema, inflammation, and infiltrative burden. In this review, we discuss the role of CMR in therapy monitoring across the spectrum of cardiomyopathies. In dilated cardiomyopathy, CMR tracks reverse remodelling and helps identify persistent scar and non-response despite guideline-directed therapy or cardiac resynchronization. In non-dilated and arrhythmogenic cardiomyopathies, serial tissue characterization helps refine dynamic arrhythmic risk. In hypertrophic cardiomyopathy, CMR documents structural and interstitial changes during treatment with myosin inhibitors and after septal reduction. In amyloid and metabolic/storage cardiomyopathies, mapping techniques are particularly useful for demonstrating stabilization or regression of myocardial disease under targeted treatments. Overall, CMR offers a framework for standardized longitudinal follow-up and for the development of biologically meaningful surrogate endpoints in clinical trials. Wider harmonization of acquisition, analysis, and reporting will be essential to fully integrate CMR into individualized therapeutic decision-making.

Aims: Photon-counting computed tomography (PCCT) enables simultaneous assessment of left ventricular morphology, function, and myocardial tissue characterization. Whether sex influences PCCT findings across hypertrophic phenotypes remains uncertain. Methods and results: We studied consecutive adults with a left ventricular hypertrophic phenotype undergoing PCCT. Patients were classified as hypertrophic cardiomyopathy (HCM), transthyretin amyloid cardiomyopathy (ATTR-CM), or secondary left ventricular hypertrophy (LVH). Sex differences in PCCT-derived left ventricular mass index, volumes, ejection fraction (EF), late iodine enhancement (LIE), and extracellular volume (ECV) were assessed overall and by aetiology. In patients with clinically indicated cardiovascular magnetic resonance (CMR) within ±12 months, sex effects on CT-CMR agreement were also evaluated. Among 182 patients, 50 were women and 132 were men; 83 had paired PCCT-CMR data. In the overall cohort, women had lower left ventricular mass index, smaller left ventricular volumes, higher EF, slightly lower ECV, and lower LIE extent than men. In HCM, women and men showed similar wall thickness, left ventricular mass, LIE burden, and ECV. In secondary LVH, women had smaller volumes and higher EF, without meaningful differences in tissue markers. In ATTR-CM, women appeared less remodelled and less infiltrative, although only four women were included. CT-CMR agreement for wall thickness, left ventricular mass, EF, scar extent, and ECV was similar in women and men. Diagnostic ECV thresholds were also consistent across sexes. Conclusion: Sex influences PCCT hypertrophic phenotypes mainly through remodelling and functional adaptation rather than major differences in tissue characterization. CT-CMR agreement and diagnostic ECV thresholds appear robust across sexes.

Background: Cardiac amyloidosis (CA) is an under-recognized cause of heart failure. Its prevalence in screening studies, and the extent to which selective confirmatory testing affects prevalence estimates, remain uncertain across clinical settings. Methods: We systematically searched PubMed/MEDLINE and EMBASE up to 10 August 2025. Two reviewers independently screened studies and extracted data. We grouped studies by clinical setting and combined prevalence estimates using random-effects meta-analysis. For each study, we calculated CA prevalence in 1) the whole enrolled cohort and 2) the subgroup who underwent confirmatory testing. Results: Eighty-three studies were included. Pooled CA prevalence (whole cohort; tested subgroup) was highest in left ventricular hypertrophy/hypertrophic cardiomyopathy [LVH/HCM] (15.1%; 35.4%), followed by heart failure [HF]—mainly HF with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF)—(12.6%; 13.6%) and aortic stenosis [AS] (9.6%; 11.6%). Orthopedic cohorts were lower overall (4.1%) but higher in tested subgroups (12.4%); “no specific red flags” showed 1.8% vs. 7.8%; non-cardiac bone scintigraphy was 0.49% in both denominators. Across settings, transthyretin CA predominated over light-chain CA. Several studies approached systematic screening in the general elderly; however, they were few and still applied referral criteria to second-level examinations. Conclusion: This meta-analysis shows that CA is relatively frequent in HFpEF/HFmrEF, severe AS, and LVH/HCM. To obtain reliable population estimates, future studies should test either all eligible participants or a predefined random sample, rather than only those with suspected disease. In clinical practice, screening strategies should clearly define which higher-risk individuals are referred for second-level tests, balancing diagnostic yield with feasibility.