Stefan Neubauer

Persistent breathlessness is common after COVID-19, yet its severity typically correlates weakly with objective clinical measures. This discordance is often attributed to perceptual inference amplified by anxiety. Because breathing involves a closed perception-action loop, breathlessness may also reflect alterations in interoceptive and visceromotor pathways. We acquired 7-tesla resting-state functional MRI in 53 post-COVID patients with varying breathlessness and estimated functional connectivity across 18 pre-defined interoceptive and visceromotor regions. Linear regression identified two connections associated with breathlessness catastrophising: reduced dorsal periaqueductal grey-posterior insula (dPAG-PoI1) and increased basolateral amygdala-dorsal anterior cingulate (BLA-dACC) connectivity. The dPAG-PoI1 association was stronger in patients who had required mechanical ventilation, whereas the BLA-dACC association was attenuated at higher generalised anxiety. These findings are consistent with two potentially separable contributions to symptom burden: weakened interoceptive signalling between brainstem and sensory cortex, and heightened visceromotor influence of threat processing on autonomic control, rather than anxiety-driven misperception alone.

Recent developments in magnetic resonance spectroscopy (MRS) techniques have demonstrated great potential for the quantification of myocardial energy metabolites, enabling an in‐depth glimpse into the energetic state of the heart to better explain the onset and severity of disease states. However, more evidence is required to establish its clinical impact and explanatory power compared to other diagnostic variables. In this study, random forest classification was used on data from 195 subjects to discriminate between healthy vs. obese non‐diabetic, healthy vs. diabetic, healthy vs. non‐obese diabetic, obese non‐diabetic vs. obese diabetic, and non‐obese diabetic vs. obese diabetic patient subgroups using P‐MRS and H‐MRS measurements of cardiac energetics, along with MRI measures of cardiac function, fat volumes, blood pressure, and blood glucose and cholesterol levels. Achieving 78.12%, 88.57%, 85.19%, 90.48%, and 76.47% test accuracies, SHAPs (SHapley Additive exPlanations) feature importances indicate a higher predictive impact of metabolic metrics for classifying the diabetic heart compared to global function metrics, gained through most common imaging techniques. Bayesian networks generated through structure learning of the data further suggests a potential causal association of increased visceral fat, increased LVMass resulting in decreased PCr/ATP, and increased cardiac lipid levels attributed to these disease states. Through the results, we have been able to showcase the importance of MRS measurements, both as strong features separating the diseases with clinically‐relevant accuracy and furthermore its causal connection to other cardiac parameters.

Background and Aims: Adiposity exerts multisystem insults across multiple organs and physiological pathways. This underscores the need for a systems-level framework integrating key organ fat measurements to disentangle the heterogeneous pathways through which adiposity shapes differential cardiometabolic risk profiles. Such an approach could advance mechanistic understanding and enable more precise risk stratification. Methods: In the UK Biobank, 24 935 participants without overt cardiac disease were studied. Six adiposity phenotypic groups were identified using unsupervised clustering of MRI-derived adiposity measures (subcutaneous, visceral, pericardial, liver, pancreatic, and muscle fat). These phenotypes were characterized in terms of body composition, cardiac remodelling, and the development of major cardiometabolic diseases. Results: Each phenotype showed a distinct pattern of fat distribution and body composition. A pancreatic-fat dominant phenotype, marked by visceral adiposity and sarcopenic features, showed a cardiorenal-metabolic risk profile. A muscle-fat dominant phenotype, characterized by subcutaneous adiposity and sarcopenic features, was associated with increased heart failure risk. While pericardial-fat dominant and liver-fat dominant phenotypes did not associate with cardiac disease risk, they exhibited distinctive cardiac remodelling patterns, revealing phenotype-specific metabolic-cardiac interactions. Lastly, normal-weight individuals with mild multi-organ fat showed elevated chronic ischaemic heart disease risk, highlighting the value of phenotype-based risk assessment beyond general weight measures. Conclusions: Distinct patterns of multi-organ fat accumulation were associated with differential body composition, cardiac remodelling, and cardiometabolic disease risk profiles. The identified adiposity phenotypic groups capture clinically meaningful heterogeneity across the cardiorenal-metabolic spectrum and may inform future personalized, multisystem approaches to prevention and management.

The UK Biobank Imaging Study, with its dedicated cardiovascular magnetic resonance substudy, has redefined the scale and scope of cardiovascular research, generating high-quality imaging in 100 000 participants with linkage to rich genetic, demographic, lifestyle, and clinical data. The resource has enabled transformative discoveries across genomics, epidemiology, and biomedical engineering and has served as a global blueprint for population imaging studies. Its success has been accelerated by an equitable data access model that fosters international collaboration. The UK Biobank cardiovascular magnetic resonance experience illustrates the power of large-scale imaging cohorts and sets a benchmark for future initiatives aimed at improving cardiovascular health through integrated, collaborative science. Looking ahead, efforts should focus on harmonization across cohorts, adherence to rigorous methodological standards, and multidisciplinary collaboration to drive meaningful clinical translation. This article provides an overview of the UK Biobank and its cardiovascular magnetic resonance substudy, systematically reviews publications to date, discusses limitations and methodological considerations, and highlights future directions.

Background: Previous studies of genotype-phenotype correlations in hypertrophic cardiomyopathy (HCM) have presented inconsistent conclusions, potentially reflecting small studies and non-uniform phenotyping. Objectives: We aimed to identify genotype-phenotype correlations in sarcomeric variant-positive HCM cardiac magnetic resonance (CMR) imaging and adverse outcome data in the National Heart, Lung, and Blood Institute (NHLBI) HCM Registry. Methods: Of 2750 overall patients, 915 sarcomeric variant-positive ones were subgrouped by genotype. CMR measures of left ventricular (LV) hypertrophy, fibrosis and function, and adverse events, were compared. Findings were meta-analyzed with prior studies from systematic review. Results: Patients with pathogenic variants in thick-filament genes had greater hypertrophy than those in thin-filament genes - maximal LV wall thickness (maxLVWT) (21.7 ± 5.0 vs. 20.0 ± 4.4mm, P 2 , P MYBPC3 carriers had greater maxLVWT than MYH7 carriers (22.2 ± 5.2 vs. 20.9 ± 4.5mm, P P 1 disease-linked variants with only 3 (∼0.11%) carrying >1 pathogenic variants. MYBPC3 carriers had lower risk of a multiple event composite than MYH7 carriers. Conclusions: In the largest CMR-based study to date, we identified significant phenotypic differences that characterize disease-gene subgroups and resolved prior discrepancies through systematic review and meta-analysis. However, carriage of >1 sarcomeric variants did not contribute much to variation in phenotypic severity in the general HCM population due to its rarity. Condensed Prior studies of genotype-phenotype correlations in hypertrophic cardiomyopathy have produced inconsistent findings. In the largest study to date with CMR imaging, we identified significant correlations between disease phenotypes and genotype subgroups of sarcomeric variant-positive patients from the NHLBI Hypertrophic Cardiomyopathy Registry. Patients with disease-linked MYBPC3 variants had greater hypertrophy and lower ejection fraction than those with MYH7 variants but also less incidence of clinical outcomes. Patients with multiple variants were strikingly rare (∼1% of all patients). Ultimately, we discovered phenotypic differences that characterize rare genotype subgroups and resolved prior discrepancies through systematic review and meta-analysis.

Pathophysiological features of hypertrophic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, and myocardial energy deficiency. Depletion of cardiomyocyte copper I ions leads to impaired mitochondrial function, a state associated with left ventricular hypertrophy. Unbound or loosely bound copper II ions activate profibrotic pathways. Trientine dihydrochloride improves intracellular copper I ion trafficking and availability, and chelates copper II ions. In preclinical studies, trientine improved myocardial mitochondrial function and reduced left ventricular hypertrophy and fibrosis. The efficacy and safety of trientine in persons with hypertrophic cardiomyopathy are unknown. In this multicentre, placebo-controlled phase 2 trial, adults with hypertrophic cardiomyopathy, a left ventricular wall thickness of 15 mm or greater, and who were in New York Heart Association class I to III were randomly assigned to receive trientine 400 mg twice daily or placebo for 52 weeks. Patients with any left ventricular outflow tract (LVOT) gradient were eligible. The primary endpoint was the change in left ventricular mass indexed to body surface area measured using cardiovascular magnetic resonance. A total of 154 patients underwent randomization. The mean age was 53.4 years, median maximum left ventricular wall thickness was 20.0 mm, median maximum LVOT gradient was 6.0 mmHg, 18.6% of patients had a resting LVOT gradient ≥30 mmHg, and 61.7% were in New York Heart Association class I. At 52 weeks, the mean change in the left ventricular mass indexed to body surface area was -4.4 ± 7.7 g/m2 in the trientine group and -1.5 ± 6.1 g/m2 in the placebo group (between-group difference -3.2 g/m2; 95% confidence interval -5.6 to -0.8; P = .009). The efficacy of trientine increased at higher levels of baseline left ventricular mass (baseline left ventricular mass indexed to body surface area by treatment allocation interaction P = .015). The effect of trientine was mediated via a reduction in myocardial cellular mass (average causal mediated effect -3.9 g/m2; 95% confidence interval -6.8 to -0.9). The incidence of adverse events was similar in the two groups. Among patients with hypertrophic cardiomyopathy, treatment with trientine resulted in a significantly greater reduction in left ventricular mass indexed to body surface area than placebo. (Funded by NIHR; TEMPEST ClinicalTrials.gov number, NCT04706429).

Aims: The cardiac phosphocreatine-to-ATP ratio (PCr/ATP) is the principal non-invasive biomarker of myocardial energetic status and is measured by phosphorus magnetic resonance spectroscopy (31P-MRS). However, studies of cardiac energetics are typically from single centres with relatively small numbers of patients, leading to unknown generalizability. Methods and results: Here, we use systematic review and meta-analysis of all available studies reporting cardiac PCr/ATP ratios to show pooled reference values across populations (databases searched: Embase, Medline, CENTRAL). We collected data on differing methodological factors to enable adjustment. We included 176 studies comprising 7843 individual participant magnetic resonance examinations between 1987 and 2025. The pooled PCr/ATP ratio was 1.96 for healthy volunteers (n = 2988), 1.54 for heart failure with reduced ejection fraction (n = 575; a 21% reduction), and 1.60 for heart failure with preserved ejection fraction (n = 146; an 18% reduction) with further reductions seen across other disease states including valvular disease and diabetes. Methodological factors, including field strength, sequence type, and voxel location significantly, influenced measurements, though adjustment had minimal effect on pooled estimates. Body mass index and natriuretic peptides negatively correlated with PCr/ATP, whilst left ventricular systolic function showed positive correlation. Conclusion: This comprehensive meta-analysis provides reference PCr/ATP values across cardiac conditions, implicating energetic impairment as a common pathway spanning myocardial diseases of diverse aetiology, and suggests that methodological heterogeneity does not fully account for the observed between-group differences. Registration: PROSPERO (CRD420251081946).

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM. METHODS: We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning. RESULTS: We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels. CONCLUSIONS: This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.

Recent advances in CT technology have led to the advent of the photon-counting detector CT (PCD-CT). The technology has shown significant improvements in CT image quality with high spatial resolution, more accurate differentiation of coronary plaque components, and radiation reductions compared to the energy-integrating detector-CT (EID-CT). However, limited experience exists, and little has been published on the decision-making process for PCD-CT coronary scanning protocols and parameters in clinical practice. In this pictorial review, we showcase our experience in the use of PCD-CT coronary CT angiogram through a step-by-step guide in the form of a decision tree, a series of clinical cases, and a detailed discussion of each scanning protocol to aid the operator in making decisions in commonly encountered clinical scenarios. The guide should also help the operator in setting up a PCD-CT cardiac imaging service.