Abstract Aims To characterize the pattern of chronotropic incompetence (CI) response to exercise in patients with heart failure (HF) across distinct phenotypes of the left ventricular ejection fraction and to explore the extent to which heart rate (HR) response should be prioritized as a therapeutic target within personalized HF management strategies. Methods Patients with HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF), and healthy controls underwent incremental exercise testing with simultaneous gas exchange and echocardiography assessments. Stroke volume (SV), HR, cardiac output (CO), and arteriovenous oxygen difference [C(a–v)O2] were assessed from rest to peak exercise. Graphical analyses explored relationships amongst determinants of oxygen uptake (V̇O2). Results Both HF phenotypes exhibited CI and a blunted increase in CO during exercise compared with controls. Peak HR was similarly reduced by 20% in HFpEF and 23% in HFrEF. HFpEF, however, exhibited a steeper HR-VO2 relationship. HFrEF demonstrated a greater compensatory increase in peripheral O2 extraction, with peak C(a–v)O2 73% higher than controls and 21% higher than HFpEF. In contrast, HFpEF showed limited ability to augment C(a–v)O2 and presented the lowest relative peak V̇O2 (−39% vs. controls and −16% vs. HFrEF), despite similar peak V̇O2%pred between HF phenotypes. Conclusion CI can contribute to exercise intolerance in both HF phenotypes, with distinct compensatory mechanisms. An integrated cardiopulmonary exercise testing–echocardiography approach may support identifying phenotype-specific physiological profiles that might address therapeutic strategies targeting CI, SV reserve, and peripheral O2 utilization to improve functional capacity in HF. Addressing the kinetics of HR slope and ΔHR metrics seems relevant to implement knowledge on the fundamental CI contribution in HF phenotypes.
AIMS Sodium-glucose cotransporter-2 (SGLT2) inhibitors are agents originally developed as glucose-lowering drugs but now widely used to improve cardiorenal outcomes, including in patients with heart failure and chronic kidney disease regardless of diabetes status. However, their exact mode of action remains unclear. Here, we investigated the association of loss-of-function (LoF) and other rare coding variants in the SLC5A2 gene, as a genetic model of altered SGLT2 function, with 13 cardiometabolic and renal traits and clinical outcomes. METHODS AND RESULTS A total of 442 570 European ancestry participants from the UK Biobank with exome sequence and phenotype data were included. We applied SAIGE-GENE+ for gene-based and single-variant association tests in the full study population and in individuals with heart failure, renal failure, and type 2 diabetes (T2D). A total of 52 LoF variants in SLC5A2 were identified. Rare variants in SLC5A2 were associated with decreased uric acid (PCauchy = 4.98 × 10-13) and with increased haematocrit (PCauchy = 1.67 × 10-5), haemoglobin (PCauchy = 1.60 × 10-5), and estimated glomerular filtration rate (PCauchy = 9.88 × 10-4). One frameshift variant (rs267607067) was significantly associated with increased haemoglobin (β = 0.33 [95% CI 0.15-0.51]; P-value = 2.40 × 10-4) and another (rs768095044) with decreased uric acid (β = -0.31 [95% CI -0.49 to -0.13]; P-value = 4.22 × 10-4). In patients with T2D, the rare variants within SLC5A2 were also associated with a lower probability of having heart failure (PCauchy = 4.00 × 10-4). CONCLUSION Rare genetic variants in SLC5A2 were associated with increased haemoglobin and decreased uric acid. These variants were also associated with a lower probability of heart failure among participants with T2D, providing tentative genetic support for a cardioprotective effect of SGLT2 inhibition.
Abstract Cardiometabolic diseases increasingly manifest as interconnected dysfunction across the heart, vasculature, kidneys, liver, and metabolic system. The global rise in obesity, insulin resistance, and diabetes, together with therapies benefiting multiple organs, has reshaped the epidemiology and understanding of cardiometabolic disease, exposing the limitations of organ-specific or single-stage approaches. The cardioVascular–kidney–liver–metabolic (CVKLM) framework is a multidimensional staging system in which cardiac, vascular, kidney, liver, and metabolic involvement are graded independently from absent to advanced. Analogous to tumour–node–metastasis staging, it provides a standardized language describing disease severity within each organ and its distribution across organs. Rather than replacing existing classifications, CVKLM integrates universal heart failure stages, validated vascular risk assessment, KDIGO chronic kidney disease stratification, contemporary metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced liver disease criteria, and current definitions of diabetes and clinical obesity. Unlike hierarchical frameworks assigning a single overall stage, CVKLM preserves organ-specific information and records coexisting abnormalities across domains. Intended for clinical and research phenotyping and staging rather than as a validated global risk score, it may facilitate systematic recognition of concomitant organ disease, support existing organ-specific diagnostic, referral, and treatment pathways, and provide a standardized taxonomy for observational studies and clinical trials. The prognostic significance of CVKLM profiles, their incremental value beyond established risk tools, and their clinical utility remain to be established. By integrating these domains within a common architecture, CVKLM offers a pragmatic framework spanning the full spectrum of cardiometabolic disease, from preclinical involvement to advanced multiorgan failure.
