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Effect of Aspirin Supplementation on Hemodynamics in Older Firefighters

LANE-CORDOVA, ABBI D.1; RANADIVE, SUSHANT M.2; YAN, HUIMIN3; KAPPUS, REBECCA M.4; SUN, PENG5; BUNSAWAT, KANOKWAN4; SMITH, DENISE L.6,7; HORN, GAVIN P.7; PLOUTZ-SNYDER, ROBERT8; FERNHALL, BO4

Medicine & Science in Sports & Exercise: December 2015 - Volume 47 - Issue 12 - p 2653–2659
doi: 10.1249/MSS.0000000000000713
APPLIED SCIENCES

Purpose Cardiovascular events are the leading cause of line-of-duty fatality for firefighters. Aspirin reduces the risk of cardiovascular events in men and may reduce fatalities in older (>40 yr) firefighters. We hypothesized that both chronic and acute aspirin supplementation would improve vascular function after live firefighting but that chronic supplementation would also improve resting hemodynamics.

Methods Twenty-four firefighters (40–60 yr) were randomly assigned to acute or chronic aspirin supplementation or placebo in a balanced, crossover design. Arterial stiffness, brachial and central blood pressures, as well as forearm vasodilatory capacity and blood flow were measured at rest and immediately after live firefighting.

Results Total hyperemic blood flow (area under the curve (AUC)) was increased (P < 0.001) after firefighting with no effects for aspirin supplementation or acute versus chronic administration (AUC, from 107 ± 5 to 223 ± 9 in aspirin condition and from 97 ± 5 to 216 ± 7 mL·min−1 per 100-mL forearm tissue for placebo; P < 0.05 for main, and P > 0.05 for interaction). Arterial stiffness/central blood pressure increased (P < 0.04) with no effect of aspirin (from 0.0811 ± 0.001 to 0.0844 ± 0.003 m·s−1·mm Hg−1 in aspirin condition versus 0.0802 ± 0.002 to 0.0858 ± 0.002 m·s−1·mm Hg−1 in placebo condition), whereas peripheral and central systolic and pulse pressures decreased after firefighting across conditions (P < 0.05).

Conclusions Live firefighting resulted in increased AUC and pressure-controlled arterial stiffness and decreased blood pressure in older firefighters, but aspirin supplementation did not affect macro- or microvascular responsiveness at rest or after firefighting.

1Department of Health and Human Physiology, University of Iowa, Iowa City, IA; 2Department of Anesthesiology, Mayo Clinic, Rochester, MN; 3Department of Kinesiology, East Carolina University, Greensboro, NC; 4Department of Kinesiology, Nutrition, and Rehabilitation, University of Illinois at Chicago, Chicago, IL; 5Key Laboratory of Adolescent Health Assessment and Exercise Intervention, East China Normal University, Shanghai, CHINA; 6Department of Health and Exercise Sciences, Skidmore College, Saratoga Springs, NY; 7Illinois Fire Service Institute, Champaign, IL; and 8Division of Space Life Sciences, Universities Space Research Association, Houston, TX

Address for correspondence: Bo Fernhall, Ph.D., Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois at Chicago, 808 South Wood St., CMET 169, Chicago, IL 60612; E-mail: fernhall@uic.edu.

Submitted for publication January 2015.

Accepted for publication May 2015.

Acute, cardiovascular events accounted for approximately 42% of all line-of-duty firefighter deaths in the United States in 2012 (16). Firefighters are 10–100 times more likely to suffer a sudden cardiac event after fire suppression activities than during routine station work (29). This may be because firefighting acts as a trigger for a cardiovascular event in vulnerable individuals because of the combination of strenuous physical work, hyperthermia, smoke and particulate inhalation, and psychological/emotional stress (37). In addition, the risk of cardiac death during firefighting is increased in individuals with traditional cardiovascular risk factors (hypertension and obesity) and those >45 yr old (29,37 29,37). Indeed, firefighting has been shown to increase core temperature and HR and decrease plasma volume and stroke volume (17,25 17,25). Live firefighting also transiently augments arterial stiffness, a predictor of cardiovascular morbidity and precursor to hypertension and end-organ damage (39), which could further increase the risk of major cardiovascular events (15).

Low-dose (<325 mg) acetylsalicylic acid (aspirin) use reduces the risk of myocardial infarction in men (i.e., primary prevention (3,42 3,42)). This is because aspirin inhibits cyclooxygenase-1–dependent platelet activation, thereby reducing risk of thrombosis (8). Furthermore, aspirin supplementation has been shown to reliably reduce the risk of serious vascular events (secondary prevention) (2) and effectively attenuate serum levels of inflammation, a modulator of vascular dysfunction (10). In animal and cellular models, aspirin preserves bioavailable nitric oxide (NO), a potent endogenous anticoagulant and vasodilator, and resultant endothelial function (5,28 5,28). However, despite its potential preventive and therapeutic benefits, the use of aspirin for both primary and secondary prevention of cardiovascular disease in adults over age 40 is low (33).

Although there is strong evidence that chronic aspirin supplementation reduces the risk of cardiac events (3), acute supplementation may provide short-term protection via similar mechanisms. Furthermore, acute (immediately before firefighting) versus chronic aspirin supplementation may reduce compliance issues associated with chronic supplementation. Acute aspirin supplementation is also an attractive option because risk of bleeding or other complications associated with long-term use (6) may be reduced or alleviated.

Thus, the aim of this study was to determine the effects of both acute and chronic (2 wk) aspirin supplementation on the vascular and hemodynamic responses to live firefighting drills in firefighters over age 40. We hypothesized that both chronic and acute aspirin supplementation would improve vascular function after live firefighting but that chronic supplementation would also improve resting hemodynamics.

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METHODS

Subjects

Twenty-four subjects age 40–60 yr were recruited from fire departments across Illinois and through the Illinois Fire Services Association. Subjects were excluded if they had contraindications to aspirin therapy, as follows: current nonsteroidal anti-inflammatory, steroid, Clopidogrel, or Warfarin use, history of upper gastrointestinal issues or renal impairment, elevated serum creatinine, hypertension, or cardiac failure. Subjects were excluded if they were currently on aspirin therapy. This study was approved by the University of Illinois institutional review board, and subjects signed an informed consent document before participating.

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Study design

We employed a placebo-controlled, crossover design. Subjects were initially assigned to one of the following two conditions: acute aspirin (81-mg enteric aspirin immediately before firefighting) or placebo supplementation (sugar pill) with a 14- to 60-d washout period between trials. All subjects participated in both conditions, and the order in which they participated in each was randomized. They then completed the chronic supplementation conditions (placebo for 14 d or 81 mg·d−1 of enteric aspirin for 14 d) in the same manner. Thus, all subjects completed four trials: acute aspirin, acute placebo, chronic aspirin, and chronic placebo. Subjects reported for testing after a standard meal, consisting of the following: Ensure Original Shake (220 kcal; 6 g (9%) fat, 33 g (11%) CHO, 10 g (20%) protein) and Clif Bar (240 kcal; 5 g (8%) fat, 43 g (14%) CHO, 9 g (18%) protein) at the same time of the day to control for diurnal variations. They ingested the acute supplement with this meal 60 min before vascular measurements. Resting blood pressure (BP) and vascular measurements were made in the supine position. Next, subjects performed 18 min of high-intensity, live firefighting activities (wearing their personal protective equipment with the self-contained breathing apparatus) in a concrete and steel training structure and then immediately returned for postfirefighting vascular measurements after removal of their personal protective equipment and self-contained breathing apparatus. Vascular measurements were taken less than 10 min after completion of firefighting tasks. The firefighting drills consisted of nine 2-min periods of alternating rest and work, including stair climbing, simulated forcible entry, a simulated search, and simulated hose advance. All drills were completed on the second story of a training building that contained live fires, with trained personnel controlling the temperature by monitoring thermocouple readings, adding small fuel packages to the fire sets sequentially, and adjusting the ventilation conditions in the room. The temperatures at the floor and 1.2 m above the floor were approximately 35°C–41°C and 70°C–82°C, respectively.

Body temperature was continuously measured with a monitor and silicone-coated gastrointestinal core temperature capsule (Mini Mitter, VitalSense; Philips Respironics, Bend, OR). Subjects swallowed a small disposable core temperature sensor capsule 6–12 hours before the study was conducted. Heart rate (HR) was measured with a commercially-available HR monitor (Vantage XL; Polar Electro, Inc., Lake Success, NY).

Compliance during the chronic supplementation phase was encouraged by providing each subject with a 14-d pill case with separate treatment for each day, which was returned upon completion of each subject’s treatment.

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Brachial BP

Resting systolic BP (SBP) and diastolic BP (DBP) were measured in duplicate, 1 min apart, with the upper arm at heart level using an automated oscillometric cuff (HEM-907 XL; Omron, Shimane, Japan) after a 10-min supine resting period in a quiet room. If the two values of either SBP or DBP were not within 5 mm Hg of each other, another measurement was taken until two values within 5 mm Hg of each other were obtained. Two values within 5 mm Hg of each other were averaged and used for analyses. Mean arterial pressure (MAP) was calculated as (SBP + 2 × DBP)/3.

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Pulse contour analysis

Radial artery pressure waveforms were obtained in the supine position from a 10-s epoch using applanation tonometry and a high-fidelity strain transducer (Millar Instruments, Houston, TX) and calibrated using the brachial SBP and DBP. A validated transfer function was used to determine aortic BP (aortic SBP, aDBP, aMAP, and pulse pressure [aPP]). This method has been shown to be reliable both at rest and during exercise (23,36 23,36).

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Pulse wave velocity

Central pulse wave velocity (cPWV) was measured using techniques described in detail elsewhere (41). Briefly, the distance from the carotid artery to the suprasternal notch was measured and subtracted from the distance from the suprasternal notch to the common femoral artery. A high-fidelity strain transducer was used to record arterial pressure waveforms at both the common carotid and common femoral arteries. PWV was derived from the distances between the measured points and the measured time delay between 10 proximal and distal waveforms (SphygmoCor; AtCor Medical). The peak of the R wave from the ECG was used as a timing marker. As cPWV is a pressure-driven measure of arterial stiffness, we also analyzed cPWV/aMAP to account for the effect of changes in pressure on cPWV.

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Microvascular function–forearm resistance artery vasodilatory capacity

Microvascular reactivity and forearm blood flow (FBF) were measured via plethysmography (EC-4; D E Hokanson, Inc., Bellevue, WA) as previously described by our group (15). A strain gauge was placed around the widest part of the forearm, and a cuff designed to inhibit venous flow was placed around the upper arm, and a standard BP, around wrist. The cuff on the wrist was inflated to 250 mm Hg for 1 min before and during the readings. FBF was recorded by inflating the upper cuff to 50 mm Hg for 7 s followed by an 8-s deflation. An average of six of these 15-s plethysmographic cycles was used for resting FBF. FBF was expressed as milliliters per minute per 100 mL of forearm tissue.

Peak blood flow was determined by inflating an additional, rapid-release BP cuff around the upper arm and inflating it for 5 min. During the last minute, the wrist cuff was also inflated as previously described. After rapid release of the upper cuff, 15-s cycles were recorded for 3 min, as previously described (13 cycles). The highest reading was reported as peak flow, and all 13 readings were plotted into a curve, and the area under the curve (AUC) represents total hyperemic response.

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Rate pressure product

We calculated rate pressure product (RPP), a surrogate for myocardial demand, as HR × SBP.

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Statistics

Given the completely within-subject experimental design, with all subjects participating in all conditions and repeated observations before and after firefighting, we analyzed our outcomes using mixed-effects linear regression methods (known as HLM or MLM methods). These recent extensions to repeated-measures ANOVA are better able to incorporate missing data and potential heterogeneous effects among subjects. Because we did experience occasional missing observations owing to difficulty obtaining data (although missing data accounted for <5% of all observations), mixed-effects analysis was particularly applicable. We evaluated each of our primary outcomes in separate fully factorialized mixed models with fixed effect parameters for the main effects of aspirin (versus placebo), firefighting (versus prefirefighting), and acute (versus chronic) supplementation and all interactions involving these factors. We included random y-intercept terms to accommodate the within-subject experimental design and considered random intercepts where patterns of residuals suggested heterogeneous effects. Our study statistician tested model assumptions before hypothesis testing, and in no cases was it necessary to incorporate random slope terms; however, we did experience one overly influential outlier in each of three separate analyses (cPWV, cPWV/aMAP, and AUC). Once eliminated, our model assumptions were met, leading to the results reported in the following section. Data are represented as mean ± SEM.

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RESULTS

Subjects

Subjects’ descriptive data are shown in Table 1. There was no difference between acute and chronic aspirin supplementation on resting or postfirefighting temperature, BP, or other hemodynamic characteristics (P > 0.05 for all). We included data for all four conditions in Table 2 to illustrate this point. For this reason, we combined the chronic and acute aspirin conditions for the presentation of our results.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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BP

After acute, live firefighting, there was a significant overall reduction in SBP (P < 0.002), from 134 ± 3 to 125 ± 3 mm Hg in the aspirin condition and from 131 ± 3 to 125 ± 2 mm Hg in the control conditions with no difference between aspirin and control conditions (P > 0.05). Brachial MAP (P < 0.03 for main effect of firefighting; from 99 ± 2 to 92 ± 3 mm Hg and from 97 ± 2 to 94 ± 2 mm Hg in the aspirin and control conditions, respectively), PP (P < 0.01; from 52 ± 2 to 46 ± 2 mm Hg and from 50 ± 2 to 46 ± 2 mm Hg in the aspirin and control conditions), aortic SBP (P < 0.01; from 116 ± 2 to 108 ± 2 mm Hg and from 114 ± 2 to 109 ± 1 mm Hg in the aspirin and control conditions), and aPP (P < 0.01; from 35 ± 1 to 29 ± 1 mm Hg and from 33 ± 1 to 29 ± 1 mm Hg in the aspirin and control conditions) were all decreased after firefighting without any effects of aspirin or acute versus chronic supplementation (P > 0.05 for interaction effects for all). aDBP was reduced after firefighting, from 82 ± 1 to 80 ± 1 in the aspirin and from 82 ± 1 to 80 ± 1 mm Hg in the placebo conditions (P < 0.01 for main effect of firefighting), with no effect of aspirin (P > 0.05 for interaction effects). DBP (from 81 ± 1 to 78 ± 1 mm Hg in aspirin conditions and from 81 ± 1 to 79 ± 1 mm Hg in placebo condition) and aMAP (from 97 ± 1 to 93 ± 1 mm Hg in aspirin and from 96 ± 1 to 94 ± 1 mm Hg in placebo conditions) were unchanged after firefighting, although there was a strong trend (P = 0.051 for main effect of firefighting) toward decrease in aMAP; there was no effect of acute/chronic supplementation on these measures (P > 0.05 for all).

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Arterial stiffness

Aspirin had no effect on cPWV, nor did firefighting (P > 0.05 for main and interaction effects) (Table 2). However, when we considered the reduction in BP, pressure-controlled arterial stiffness (cPWV/aMAP) increased after firefighting (P < 0.04), with no effects of either type of aspirin supplementation (Fig. 1).

FIGURE 1

FIGURE 1

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Forearm vasodilatory capacity

Resting FBF was increased after firefighting, from 4.3 ± 0.3 to 14.6 ± 0.5 mL·min−1 per 100-mL forearm tissue in the aspirin conditions and from 3.9 ± 0.3 to 15.9 ± 0.5 mL·min−1 per 100 mL of forearm tissue in the placebo conditions (P < 0.001 for main firefighting effect and P > 0.05 for interaction effect). Total hyperemic blood flow (AUC) increased significantly after firefighting (P < 0.001) (Fig. 2). There was no effect of acute firefighting or aspirin on peak FBF (from 26.0 ± 1.0 to 29.8 ± 1 in aspirin and from 28.3 ± 1 to 30.3 ± 1 mL·min−1 per 100-mL forearm tissue in placebo conditions; P > 0.05 for main and interaction effects).

FIGURE 2

FIGURE 2

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RPP

RPP was increased after firefighting (P < 0.001), with no effect of aspirin or chronic versus placebo supplementation (P > 0.05) (Table 2.

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DISCUSSION

The main findings of this study are as follows: i) acute, live firefighting caused an increase in FBF in firefighters over 40 yr old, ii) aortic and brachial SBP, PP, brachial MAP, and aDBP decreased whereas cPWV controlled for BP increased after firefighting in our cohort, and iii) aspirin use (acute and/or chronic versus placebo) did not affect forearm vasodilatory capacity, BP, or arterial stiffness at rest or after firefighting, indicating that hemodynamics was not affected by aspirin supplementation in this study.

In the Firefighters and Their Endothelium study, hyperemic velocity, not flow mediated dilation, was a risk factor for cardiovascular outcomes in older firefighters (1). Hence, finding interventions to augment blood flow may be especially relevant to this population. Previous work from our group has shown that FBF and conductance are increased after live firefighting in young, male firefighters (15). Aspirin did not further augment blood flow and endothelial responsiveness in our current group of older firefighters. However, because aspirin has been shown to offer both primary and secondary prevention of major cardiac events in adults over 40 yr old (2), it may still be a useful tool for the prevention of line-of-duty fatalities. Indeed, Hostler et al. (27) reported that daily aspirin use blunted platelet aggregation in firefighters after heat stress, underscoring its usefulness in this population.

Despite our equivocal findings, the vasculoprotective effects of aspirin are numerous and not restricted to its effect on platelet activation and the cyclooxygenase pathways (40). Aspirin has been shown to improve endothelial function by protecting endothelial cells from oxidative damage, thereby preserving NO (43). In addition, in cell and animal models, chronic aspirin supplementation may improve vascular relaxation and offer protection to endothelial cells via NO-dependent activation of the cyclic guanylyl monophosphate pathway because of aspirin’s stimulatory effect on endothelial NO synthase (18). These pathways linking aspirin use with NO availability did not result in improvement in FBF in our study. This is not completely surprising, as earlier work demonstrated that chronic low-dose aspirin therapy in humans did not improve cutaneous dilation or NO-dependent cutaneous dilation in response to heat stress (12,24 12,24).

The augmentation of pressure-controlled arterial stiffness after firefighting provides a potential mechanistic link between firefighting and cardiac events. In contrast to moderate-intensity physical activity, which decreases central stiffness (11,21 11,21), the near-maximal nature of the stimulus (HRmax reached during firefighting in our study, 172.3 ± 11.9 bpm, which was equal to the age-predicted HRmax for this age group; average HR during firefighting, 145.3 ± 16.2 bpm) and accompanying emotional stress are both potential contributors to this response (37). It is important to consider changes in arterial stiffness in this context, as cPWV is a pressure-dependent measure (13). Thus, acute (or chronic) changes in PWV may be masked or misinterpreted if evaluated without considering BP. These hemodynamic changes after firefighting resemble the responses to acute resistance or maximal exercise: heightened central stiffness and increased blood flow to the periphery due to peripheral vasodilation (14). The increased peripheral vasodilation in our study, which presumably aided in cooling and augmentation of muscle blood flow, also most likely contributes to the decrease in BP (9). The extreme temperature stress experienced by firefighters placed additional demand on the heart as RPP increased. However, Bruning et al. (4) reported a reduction in skin blood flow but no change in central hemodynamics during exercise with heat stress with aspirin therapy. However, their study population was older and included both men and women and their exercise stimulus was submaximal in nature, which may account for the differences in findings. We have previously shown that prolonged firefighting (3 h) in young firefighters produced reduced systolic and diastolic function, resulting in reduced stroke volume during recovery after firefighting activities (16). Furthermore, we have also shown that acute firefighting decreases arterioventricular coupling (44), likely as a result of reduced ventricular function coupled with increase in central artery stiffness.

This concomitant drop in BP and increased cPWV could affect myocardial energetics and at least partially explain line-of-duty cardiac deaths. Decreased DBP may result in decreased coronary perfusion, whereas increased arterial stiffness may increase the oxygen demand on the heart (30). Thus, the composite response to live firefighting (reduced DBP coupled with increased in arterial stiffness) may predispose firefighters, especially older firefighters, to myocardial ischemia. In light of this information, the anticoagulatory effects of aspirin may be particularly important for the prevention of these cardiac events.

In an earlier study conducted in young (mean age, 28 yr) firefighters, we reported augmented microvascular function and arterial stiffness but unchanged postfirefighting BP (15) This is in contrast to BP and pressure-controlled cPWV changes in the older cohort in this study. The small reduction in BP in older firefighters may be a classic postexercise BP reduction in response to physical exertion (19) that masked real changes in arterial stiffness. A postexercise drop in BP occurs because the increase in cardiac output (mediated primarily by an increase in HR) cannot offset the decrease in peripheral resistance caused by dilatation of the peripheral vascular beds (31). This effect is more pronounced in individuals with higher resting BP, which may explain why older firefighters could be more likely than younger firefighters to experience a reduction in BP after exertion (31). However, we emphasize that comparisons between these two studies should be cautiously made because the live firefighting stimuli were of different durations in these studies.

In addition, reduced postexercise BP may be important for recovering the plasma volume lost by strenuous exercise (20). Experimental inhibition of postexercise hypotension ameliorated the exercise-induced expansion of plasma volume (20). This is because plasma albumin plays a role in the expansion of plasma volume after exercise, and when BP decreases, more albumin stays in the intravascular space and draws additional fluid in from the extravascular space (20). Facilitation of plasma volume expansion may explain the small reduction in this study, as a similar bout of firefighting activity was shown to reduce plasma volume by almost 15% (38). Acute reductions in BP may be a more significant concern during longer-duration firefighting, where dehydration is increasingly prevalent (26).

Alternatively, the reduction in BP we observed in older firefighters may reflect an age-associated alteration of circulatory control in response to the combined heat and mental stress to which the firefighters were subjected. Heat stress causes tandem increases in HR and vasodilation; thus, BP remains constant (35). In contrast, mental stress is associated with augmented muscle sympathetic nerve activity and BP (7). Mental stress and perceived stress also cause increased forearm vasodilation, and this vasodilation is reported to be directly proportional to the level of perceived stress (34). However, older adults exhibited impaired forearm vasodilation to mental stress (22) , and this may be particularly relevant to our population.

The addition of mental stress to heat stress further alters neural control of the circulation (32); despite heightened muscle sympathetic nerve activity, the rise in MAP is blunted during combined heat and mental stress. Ultimately, this perturbation of neural regulation of the circulation may predispose susceptible individuals to bouts of syncope after activities characterized by both heat and mental stress, i.e., firefighting activities (32). Our observations of increased blood flow without increased MAP in older firefighters are consistent with this interpretation. Taken together, these results suggest that encouraging an “active cooldown” protocol to encourage venous return and maintain BP after firefighting may be beneficial, especially for older firefighters.

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Limitations

Our study used noninvasive measurements. However, the methods used have been validated and have been shown to be reliable compared with invasive measurements (23,36,41 23,36,41 23,36,41). We did not study firefighters before and after an actual emergency event, but our study used a state-of-the-art training facility with live fires to mimic an actual firefighting scenario, and we believe it was a realistic, although slightly conservative, representation of actual firefighting activities.

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CONCLUSIONS

Acute, live firefighting increases FBF and pressure-controlled arterial stiffness and decreases BP in older firefighters. Acute and/or chronic aspirin supplementation did not affect macro- or microvascular function in firefighters older than 40 yr, and its use as a preventive strategy warrants further consideration.

This study was funded by the Department of Homeland Security: EMW-2009-FP-00544, awarded to G. P. H.

The clinical trial registration for this study is NCT01276691.

The results of the study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

BLOOD FLOW; ANTICOAGULANT; FIREFIGHTING; ARTERIAL STIFFNESS

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