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Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable., (© 2024. The Author(s).)

Treatment of circulatory shock in critically ill patients requires management of blood pressure using invasive monitoring, but uncertainty remains as to optimal individual blood pressure targets. Critical closing pressure, which refers to the arterial pressure when blood flow stops, can provide a fundamental measure of vascular tone in response to disease and therapy, but it has not previously been possible to measure this parameter routinely in clinical care. Here we describe a method to continuously measure critical closing pressure in the systemic circulation using readily available blood pressure monitors and then show that tissue perfusion pressure (TPP), defined as the difference between mean arterial pressure and critical closing pressure, provides unique information compared to other hemodynamic parameters. Using analyses of 5,988 admissions to a modern cardiac intensive care unit, and externally validated with 864 admissions to another institution, we show that TPP can predict the risk of mortality, length of hospital stay and peak blood lactate levels. These results indicate that TPP may provide an additional target for blood pressure optimization in patients with circulatory shock., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)