Richard M. Cubbon

Background: Limited heart rate rise contributes to reduced exercise tolerance for people who have heart failure with reduced ejection fraction (HFrEF), yet rate-adaptive pacing does not improve functional capacity due to an attenuated force-frequency relationship (FFR). How the FFR relates to total peripheral resistance and sympathetic tone in HFrEF is unknown. Methods: In a prospective, observational study, participants with HFrEF and controls underwent an incremental pacing protocol, during which heart rate was increased from 50 to 140 beats per minute. At each heart rate increment LV contractility was measured by echocardiography to determine the FFR, as well as continuous beat-to-beat measurement of systolic and diastolic blood pressures with a plethysmography device to determine cardiac output, total peripheral resistance and blood pressure variability (BPV). A microneurography study was then conducted to measure muscle sympathetic nerve activity (MSNA) during incremental pacing. Results: A total of 157 participants with HFrEF and 55 controls (mean age 71.1±1.4 years, 172 (81.1%) male) underwent the pacing protocol. We observed single units in seven of 11 participants who participated in the microneurography study. In both groups, LV contractility and cardiac output increased until the peak of the FFR, after which these declined. We observed a reduction in total peripheral resistance, blood pressure variability, MSNA frequency and incidence coinciding with the peak of the FFR, beyond which these increased. Whilst these relationships were present in both groups, they were more evident in participants with HFrEF. Conclusions: For people with HFrEF there is a bidirectional relationship between heart rate and sympathetic activation, with a nadir of sympathetic tone occurring at the peak of the FFR. Both excessively low and high heart rates are accompanied by greater sympathetic activation. Taken together, these data suggest that optimal heart rate targets for HFrEF are likely to be individual.

Exercise orchestrates an interorgan communication network, in which skeletal muscle releases signaling molecules known as myokines that contribute to exercise training-induced adaptations. We identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a regulator of adipose and hepatic metabolic responses to exercise. Here, we demonstrate that BAIBA regulates muscle metabolism, morphology and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA’s biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.

1. The insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) axis has been implicated in diabetes mellitus and the associated burden of cardiovascular complications. Higher circulating levels of IGFBP-1 and IGFBP-2 have been established as markers of protection from incident type 2 diabetes, yet their associations with cardiovascular disease remain unclear. Utilising the UK Biobank (UKB) resource to integrate disease outcomes, plasma proteomics and MRI data, we examined associations of IGFBP-1 and IGFBP-2 with incident diabetes and cardiovascular disease. Approximately 50,000 UKB participants with plasma proteomic measurements for IGFBP-1 and IGFBP-2 were included. Multivariate Cox regression models revealed that participants in the highest quartiles of IGFBP-1 and IGFBP-2 had a substantially lower risk of incident diabetes (hazard ratio (HR) = 0.31 and 0.32 respectively), but, paradoxically, had increased risks of incident macrovascular disease, all-cause and cardiovascular-related mortality (HR = 1.81 and 2.39). Both proteins were negatively associated with HbA1c levels, triglyceride/HDL ratio and abdominal adiposity, yet positively associated with NT-proBNP, troponin I, cardiac chamber size and aortic dimensions. In summary, negative associations of IGFBP-1 and IGFBP-2 with incident diabetes mellitus did not translate to a reduced cardiovascular risk, suggesting potentially complex actions of IGFBP-1 and IGFBP-2 in the pathophysiology of cardiometabolic disease. Graphical Graphical abstract illustrating the analysis pipeline and aims of this study to identify associations of IGFBP-1 and IGFBP-2 with cardiometabolic disease. Graphical abstract created with BioRender.com . 2. Article highlights: a) The associations of IGFBP-1/-2 with macrovascular disease in cohorts with and without type 2 diabetes are conflicting. b) Can UK Biobank help to clarify the associations of IGFBP-1 and IGFBP-2 with cardiometabolic disease? c) Higher levels of both proteins are associated with a reduced risk of diabetes incidence, but an increased risk of cardiovascular disease. This is the first study to integrate survival analyses with large-scale imaging data, showing consistent associations with a favourable metabolic profile, but novel associations with cardiac measures. d) These findings highlight the limitations of using IGFBP-1 and IGFBP-2 as biomarkers in cardiometabolic disease.

Diabetes mellitus (DM) approximately doubles the risk of atherosclerotic cardiovascular disease (ASCVD) events, but the molecular basis is poorly understood. Using RNA-sequencing data from two arterial sites in >90 people with DM and >330 controls, we defined differentially expressed genes (DEGs) associated with DM. UK Biobank (UKB) was then used to corroborate that DEGs in their plasma protein form were differentially abundant in people with DM and associated with ASCVD events. 619 and 356 DEGs were associated with DM in the thoracic aorta and tibial artery, respectively. Of these, 22 were common to both arteries, all of which were directionally concordant. Of these, 5 were included in the UKB plasma proteomics dataset and we corroborated 4 (ACP5, LEFTY2, LILRA5 and PSME2) as showing concordant differential abundance in people with DM; all were associated with a range of incident ASCVD events. Addition of the 4 proteins to the SCORE2 and SCORE2-Diabetes risk models (for people without and with DM, respectively) improved the population-level discrimination, classification and calibration of these models. These data show that DM is associated with a distinct arterial gene expression profile, hits from which are associated with ASCVD events and add value to risk prediction.

Aims: Right ventricular pacing (RVP) is associated with left ventricular systolic dysfunction (LVSD) and heart failure (HF). We investigated the prevalence and predictors of LVSD and adverse HF outcomes in patients undergoing de novo or replacement RVP for bradycardia. Methods and results: Prospective data were collected from 1024 patients receiving de novo (2014–2017, n = 514) or generator replacement (2008–2011, n = 510) RVP at a UK tertiary centre. Logistic regression models were used to identify predictors of LVSD, defined as left ventricular ejection fraction (LVEF) < 50%, and subsequent HF hospitalization (HFH) and all-cause mortality. Overall, 61% were male; mean age 76 ± 11 years. De novo patients were more often male (66% vs. 56%) and more likely to have ischaemic heart disease (IHD; 31% vs. 14%) and diabetes (24% vs. 6%), but less likely to have atrial fibrillation (AF; 25% vs. 33%) than replacement patients (all P < 0.01). LVSD was present in 344 (37%) and was more frequent in de novo than replacement cases (20% vs. 17%, P < 0.01). Independent predictors of LVSD were IHD [odds ratio (OR) = 2.56, confidence interval (CI): 1.58–4.13] and ventricular pacing burden >80% (OR = 2.13, CI: 1.29–3.52). Over a median 30 (IQR: 16–42) months, 341 (33%) experienced HFH or death, more commonly after replacement than de novo RVP (25% vs. 8%, P < 0.01). Predictors of adverse outcomes included replacement status [hazard ratio (HR) = 2.27, CI: 1.78–4.16], older age, AF, and LVEF <50%. Conclusion: LVSD is common in RVP recipients and largely driven by comorbidities rather than pacing burden. Screening and targeted therapy in high-risk patients may improve outcomes and optimize resource use.

Objective: Diabetes mellitus (DM) approximately doubles the risk of atherosclerotic cardiovascular disease (ASCVD) events, but the molecular basis is poorly understood. We aimed to define arterial differentially expressed genes (DEGs) associated with DM, validate hits as plasma proteins, and ascertain whether these complement ASCVD risk prediction tools. Research design and methods: RNA-sequencing data from the Genotype-Tissue Expression (GTEx) cohort was used to define DEGs associated with DM in two arterial sites in >90 people with DM and >330 controls. UK Biobank (UKB) was used to corroborate that DEGs in their plasma protein form were differentially abundant in people with DM and associated with ASCVD events. Finally, we assessed if including these plasma proteins improved performance of the SCORE2 and SCORE2-Diabetes ASCVD risk models. Results: 619 and 356 DEGs were associated with DM in the thoracic aorta and tibial artery, respectively. Of these, 22 were common to both arteries, all of which were directionally concordant. Of these, 5 were included in the UKB plasma proteomics dataset and we corroborated 4 (ACP5, LEFTY2, LILRA5 and PSME2) as showing concordant differential abundance in people with DM; all demonstrated associations with a range of incident ASCVD events. Addition of the 4 proteins to SCORE2 and SCORE2-Diabetes (for people without and with DM, respectively) improved the population-level discrimination, classification and calibration of these models. Conclusions: DM is associated with a distinct arterial gene expression profile, hits from which are associated with ASCVD events and add value to risk prediction. Visual

Diabetes mellitus (DM) and obesity frequently coexist. Both are associated with adipose dysfunction, yet the contribution of DM remains uncertain. Using bulk transcriptomics of subcutaneous and visceral adipose tissue (SAT and VAT, respectively), we show that DM is associated with shared and distinct patterns of differential gene expression in these depots. Gene ontology analysis of hits across depots highlighted extracellular matrix, inflammatory pathways, metabolism, axon guidance and endoplasmic reticulum stress. Histology revealed larger SAT adipocytes in people with DM, but only in the overweight category. Body mass index (BMI)-stratified transcriptomic analyses of SAT identified DM-associated hits present only in the overweight group. These were validated in plasma protein form using UK Biobank, informing our development of an adipose risk score that predicted incident DM in overweight people beyond a clinical risk score. Hence, molecular signatures of diabetic SAT can define high-risk adiposity, which may aid the targeting of clinical interventions.

Cardiology remains one of the most competitive medical specialties in the UK. This article provides practical guidance for aspiring cardiologists preparing for Higher Specialty Training applications. It outlines strategies to maximize portfolio scores, prepare effectively for interviews and adapt to recent changes in the scoring framework. The guidance also simultaneously supports the development of core skills essential for a successful career in cardiology.