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Background: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) subunit, affects TnI-directed autoimmune pathology of the heart., Methods: TnI-directed autoimmune myocarditis (TnI-AM), a CD4 + T-cell-mediated disease, was induced in mice lacking all 3 immunoproteasome subunits (triple-ip -/- ) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis., Results: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7 -/- mice involved a changed balance between effector and regulatory CD4 + T cells in the spleen, with CD4 + T cells from LMP7 - /- mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14 + monocytes with ONX 0914, diminished proinflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4 + T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing the induction and progression of TnI-AM when self-reactive CD4 + T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, demonstrating the activation of heart-specific autoimmune reactions by ICI therapy., Conclusions: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including patients with ICI-related heart-specific autoimmunity.

Objective: The effect of caffeine on cardiovascular health remains controversial. Patients with long-standing type 1 diabetes are at risk of autonomic failure and sudden cardiac death. We investigated the effects of caffeine on autonomic dysfunction (as assessed by heart rate variability [HRV]) in this high-risk group and in a control population., Research Design and Methods: Using a randomized blinded, placebo-controlled, crossover design trial, we examined 2 weeks of caffeine consumption (250 mg twice daily) on HRV in 20 type 1 diabetic patients and 10 matched healthy volunteers., Results: Baseline HRV was blunted in the diabetic patients (P < 0.0005 vs. control subjects) and markedly increased by caffeine in both groups (+103% in the group with diabetes [P = 0.009] and +38% in control subjects [P = 0.002]). The caffeine-associated increase in HRV was not statistically different between the control and the type 1 diabetes groups (P = 0.16)., Conclusions: Modest amounts of caffeine improved autonomic function in diabetic patients and healthy volunteers. For individuals with abnormal HRV, regular caffeine use may have the potential to reduce the risk of cardiovascular events.

Purpose: This study compared the rate of energy expenditure among six popular exercise machines at intensities corresponding to ratings of perceived exertion (RPE) for fairly light (RPE-11), somewhat hard (RPE-13), and hard (RPE-15) in 9 healthy men and 10 healthy women., Methods: A maximal exercise test on each exercise machine was used to anchor the Borg 15-point category scale. Subjects performed three submaximal exercise tests at selected RPEs on a treadmill, stair-stepper, cycle ergometer, rowing ergometer, cross-country ski simulator, and rider. The submaximal tests on each exercise device were performed in random order and were 6 min in duration with 15-min rest between trials. Oxygen uptake, heart rate, and blood lactate concentration were measured during the final 2 min of each exercise intensity., Results: Energy expenditure at each RPE was highest on the treadmill and ski simulator in men, and on the treadmill, ski simulator, and rowing ergometer in women. Energy expenditure in men and women at all RPEs was lowest on the rider and cycle ergometer. Energy expenditure at a given RPE was greater in men than women on all exercise machines, but men and women used a similar percentage of their machine specific peak oxygen uptake at each RPE on all machines. Heart rate was generally similar among the machines and between both men and women at each RPE., Conclusions: Our results indicated that there are large differences in energy expenditure between exercise machines and between men and women at intensities perceived to be fairly light, somewhat hard, and hard. Consequently, subjects can expend more calories at the same RPE during treadmill and ski simulator exercise, for example, than during exercise with other devices. This may have important implications for the health benefits of different exercises and in promoting long term exercise adherence.