Joost P. H. Seeger

Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans.

Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.

Exercise training improves physical fitness and vascular function in children with type 1 diabetes

Children with type 1 diabetes mellitus (DM1) show endothelial dysfunction and mild artery wall thickening compared to their age‐matched healthy peers. In this study, we examined the effect of 18‐week exercise training on physical fitness and vascular function and structure in children with DM1. We examined physical fitness, brachial artery endothelial function [flow‐mediated dilation (FMD)], common carotid artery diameter, wall thickness and wall‐to‐lumen ratio before and after 18‐week exercise training in children with DM1 (n = 7). Physical fitness, measured as maximal oxygen consumption, improved after training (p = 0.039). Brachial artery FMD improved from 7.5 ± 4.2 to 12.4 ± 5.2 (p = 0.038). Carotid artery diameter, wall thickness and wall‐to‐lumen ratio did not change significantly (p = 0.26, 0.53 and 0.27, respectively). We showed that exercise training in children with DM1 effectively reverses endothelial dysfunction and improves physical fitness. These data emphasize the important role for physical activity in the management of DM1.

Predictors of cardiac troponin release after a marathon

OBJECTIVES Exercise leads to an increase in cardiac troponin I in healthy, asymptomatic athletes after a marathon. Previous studies revealed single factors to relate to post-race cardiac troponin I levels. Integrating these factors into our study, we aimed to identify independent predictors for the exercise-induced cardiac troponin I release. DESIGN Observational study. METHODS Ninety-two participants participated in a marathon at a self-selected speed. Demographic data, health status, physical activity levels and marathon experience were obtained. Before and immediately after the marathon fluid intake was recorded, body mass changes were measured to determine fluid balance and venous blood was drawn for analysis of high-sensitive cardiac troponin I. Exercise intensity was examined by recording heart rate. We included age, participation in previous marathons, exercise duration, exercise intensity and hydration status (relative weight change) in our model as potential determinants to predict post-exercise cardiac troponin I level. RESULTS Cardiac troponin I increased significantly from 14±12 ng/L at baseline to 94±102 ng/L post-race, with 69% of the participants demonstrating cardiac troponin I levels above the clinical cut-off value (40 ng/L) for an acute myocardial infarction. Linear backward regression analysis identified younger age (β=-0.27) and longer exercise duration (β=0.23) as significant predictors of higher post-race cardiac troponin I levels (total r=0.31, p<0.05), but not participation in previous marathons, relative weight change and exercise intensity. CONCLUSIONS We found that cardiac troponin I levels significantly increased in a large heterogeneous group of athletes after completing a marathon. The magnitude of this response could only be partially explained, with a lower age and longer exercise duration being related to higher post-race cardiac troponin I levels.

Heart failure is associated with exaggerated endothelial ischaemia–reperfusion injury and attenuated effect of ischaemic preconditioning

Background Reperfusion is mandatory after ischaemia, but it also triggers ischaemia–reperfusion (IR)-injury. It is currently unknown whether heart failure alters the magnitude of IR-injury. Ischaemic preconditioning can limit IR-injury. Since ischaemic preconditioning is typically applied in subjects at risk for cardiovascular complications, it is of clinical importance to understand its efficacy in heart failure patients. Objective To examine the magnitude of endothelial IR-injury, and the ability of ischaemic preconditioning to protect against endothelial IR-injury in heart failure. Methods We included 15 subjects with heart failure (67 ± 10 years, New York Heart Association class II/III) and 15 healthy, age- and sex-matched controls (65 ± 9 years). We examined brachial artery endothelial function using flow-mediated dilation before and after arm IR (induced by 5-min ischaemic handgrip exercise +15 min reperfusion). IR was preceded by ischaemic preconditioning (consisting in three cycles of 5-min upper arm cuff inflation to 220 mmHg) or no inflation. Results A significant interaction-effect was found for the change in flow-mediated dilation after IR between groups (two-way ANOVA interaction-effect: p = 0.01). Whilst post-hoc analysis revealed a significantly decline in flow-mediated dilation in both groups (p < 0.05), the decline in flow-mediated dilation in heart failure patients (6.2 ± 3.6% to 3.3 ± 1.8%) was significantly larger than that observed in controls (4.9 ± 2.1 to 4.1 ± 2.0). Neither in heart failure patients nor controls was the decrease in flow-mediated dilation after IR altered by ischaemic preconditioning (three-way ANOVA interaction: p = 0.87). Conclusion We found that patients with heart failure are associated with exaggerated endothelial IR-injury compared with age- and sex-matched, healthy controls, which may contribute to the poor clinical prognosis in heart failure. Furthermore, we found no protective effect of ischaemic preconditioning (3 × 5-min forearm ischaemia) against endothelial IR-injury in heart failure patients.

Lower vascular tone and larger plasma volume in Parkinson's disease with orthostatic hypotension

The pathophysiology of orthostatic hypotension in Parkinsons disease (PD) is incompletely understood. The primary focus has thus far been on failure of the baroreflex, a central mediated vasoconstrictor mechanism. Here, we test the role of two other possible factors: 1) a reduced peripheral vasoconstriction (which may contribute because PD includes a generalized sympathetic denervation); and 2) an inadequate plasma volume (which may explain why plasma volume expansion can manage orthostatic hypotension in PD). We included 11 PD patients with orthostatic hypotension (PD + OH), 14 PD patients without orthostatic hypotension (PD - OH), and 15 age-matched healthy controls. Leg blood flow was examined using duplex ultrasound during 60° head-up tilt. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. In a subset of 9 PD + OH, 9 PD - OH, and 8 controls, plasma volume was determined by indicator dilution method with radiolabeled albumin ((125)I-HSA). The basal leg vascular resistance was significantly lower in PD + OH (0.7 ± 0.3 mmHg·ml(-1)·min) compared with PD - OH (1.3 ± 0.6 mmHg·ml(-1)·min, P < 0.01) and controls (1.3 ± 0.5 mmHg·ml(-1)·min, P < 0.01). Leg vascular resistance increased significantly during 60° head-up tilt with no significant difference between the groups. Plasma volume was significantly larger in PD + OH (3,869 ± 265 ml) compared with PD - OH (3,123 ± 377 ml, P < 0.01) and controls (3,204 ± 537 ml, P < 0.01). These results indicate that PD + OH have a lower basal leg vascular resistance in combination with a larger plasma volume compared with PD - OH and controls. Despite the increase in leg vascular resistance during 60° head-up tilt, PD + OH are unable to maintain their blood pressure.

Heart failure patients demonstrate impaired changes in brachial artery blood flow and shear rate pattern during moderate-intensity cycle exercise.

What is the central question of this study? We explored whether heart failure (HF) patients demonstrate different exercise‐induced brachial artery shear rate patterns compared with control subjects. What is the main finding and its importance? Moderate‐intensity cycle exercise in HF patients is associated with an attenuated increase in brachial artery anterograde and mean shear rate and skin temperature. Differences between HF patients and control subjects cannot be explained fully by differences in workload. HF patients demonstrate a less favourable shear rate pattern during cycle exercise compared with control subjects.

Is delayed ischemic preconditioning as effective on running performance during a 5km time trial as acute IPC

Ischemic preconditioning (IPC) may enhance exercise performance. Cardioprotective effects of IPC are known to re-occur 24h after the stimulus. Whether the delayed effect of IPC has similar effects as IPC on exercise performance is unknown. OBJECTIVES Examine whether IPC applied 24h (24-IPC) before exercise is equally effective as IPC in improving exercise performance. DESIGN Randomized, cross-over study METHODS: 12 healthy participants were randomly exposed to SHAM-session, IPC or 24-IPC before a self-paced 5km running trial on a treadmill. Subjects were blinded for time, speed and heart rate. Furthermore, heart rate, BORG, and the local tissue saturation index were measured during exercise, while lactate levels were determined after running. Using a regression model, we explored whether these parameters predicted the change in running time after IPC and 24-IPC. RESULTS We found no differences in finish time after IPC (SHAM: 1400±105s, IPC: 1381±112s, 24-IPC: 1385±113s; p=0.30). However, we observed a significant positive relation between the change in finish time after IPC and 24-IPC (p=0.016; r=0.677). Using stepwise linear regression, a lower post-exercise blood lactate level after IPC or 24-IPC was significantly related to an improvement in finish time (R2=0.47, β=-0.687, p=0.007). CONCLUSIONS Although no significant effect of IPC or 24-IPC on exercise performance was found, individual finish time after IPC and 24-IPC were strongly correlated. Therefore, our data suggest that, at the individual level, the effects of 24-IPC are closely related to the effects of IPC.