Brock T. Jensen

Exercise Preconditioning Provides Long-Term Protection Against Early Chronic Doxorubicin Cardiotoxicity

Acute doxorubicin (DOX) cardiotoxicity can be attenuated by exercise preconditioning, but little is known of whether this cardioprotection continues beyond 10 days post-DOX administration. The purpose of this study was to determine the effects of exercise preconditioning on early chronic DOX-induced cardiotoxicity. Male rats were randomly assigned to sedentary, treadmill, or wheel running groups. Treadmill and wheel running animals participated in a progressive treadmill training protocol or voluntary wheel running, respectively, for 10 weeks. Following the intervention, animals were further randomized to receive either DOX (sedentary + DOX, treadmill + DOX, wheel running + DOX) or saline (sedentary + saline, treadmill + saline, wheel running + saline). All animals then remained sedentary for 4 weeks. A 22% reduction in fractional shortening was observed in left ventricles from previously sedentary animals receiving DOX when compared with sedentary + saline. This degree of decline was not observed in treadmill + DOX and wheel running + DOX. Sedentary + DOX possessed significantly depressed mitral and aortic valve blood flow velocities when compared with sedentary + saline, but these decrements were not observed in treadmill + DOX and wheel running + DOX. Ex vivo analysis revealed that left ventricular developed pressure and maximal rate of pressure development were significantly lower in sedentary + DOX when compared to sedentary + saline. Treadmill and wheel running prior to DOX treatment protected against these decrements. Exercise cardioprotection was associated with preserved myosin heavy chain but not sarcoendoplasmic reticulum Ca2+ ATPase 2a expression. In conclusion, 10 weeks of prior exercise protected against early chronic DOX cardiotoxicity suggesting that training status may be a determining factor in the degree of late-onset cardiotoxicity experienced by cancer patients undergoing treatment with DOX.

Exercise training mitigates anthracycline-induced chronic cardiotoxicity in a juvenile rat model.

Childhood cancer survivors are at greater risk of cardiovascular complications once they reach adulthood. Anthracyclines may be a major contributor to these delayed‐onset complications, yet their use continues because of favorable clinical outcomes. Exercise has been shown to protect against anthracycline cardiotoxicity, yet it is unclear whether exercise can protect against delayed‐onset cardiotoxicity when treatment is initiated in childhood. The aim of the present study was to determine if exercise training provides cardioprotection in a juvenile rat model of delayed‐onset anthracycline cardiotoxicity.

Rehabilitative exercise in a rat model of doxorubicin cardiotoxicity

The use of exercise to minimize doxorubicin (DOX)-induced cardiotoxicity is gaining attention. However, very few clinically relevant reports exist investigating the effects of exercise performed during and following DOX treatments. The purpose of this study, therefore, was to examine the effects of voluntary wheel running during and following DOX treatment using two models of late-onset DOX cardiotoxicity in the rat. Female Sprague-Dawley rats received either DOX or saline injections using one of two separate treatment regimens. These regimens involved either daily or weekly DOX injections with cumulative doses for both protocols totaling 15 mg/kg. Daily DOX injections were 1 mg/kg and lasted for 15 consecutive days while weekly DOX injections were 2.5 mg/kg and lasted for six consecutive weeks with control animals receiving matched saline injection regimens. Immediately following the initial DOX/saline injection, animals were randomly housed in cages with voluntary running wheels or standard rat cages throughout DOX/saline treatments and continued until reaching 10 weeks. Cardiac function was then assessed using echocardiography and an isolated working heart model, and myosin heavy chain (MHC) isoform distribution was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. When compared wth controls, daily DOX treatment resulted in reduced running wheel distances at weeks 2-10 (P < 0.05), and weekly DOX treatment resulted in reduced running wheel distances at weeks 2, 6 and 10 (P < 0.05). Nonetheless, wheel running during and following daily and weekly DOX dosing protected against DOX-induced cardiotoxicity by preserving maximal mitral and aortic blood flow velocities, left ventricular developed pressure and MHC isoform expression. In conclusion, the overall reduced volume of activity during and following daily and weekly DOX treatments attenuated DOX-induced cardiac dysfunction suggesting that low-volume endurance training may be an effective rehabilitative approach in minimizing DOX cardiotoxicity in cancer patients.

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

Purpose: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. Methods: Sprague–Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. Results: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. Conclusions: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Voluntary wheel running in growing rats does not protect against doxorubicin-induced osteopenia.

There is growing concern regarding the long-term negative side effects of chemotherapy in childhood cancer survivors. Doxorubicin (DOX) is commonly used in the treatment of childhood cancers and has been shown to be both cardiotoxic and osteotoxic. It is unclear whether exercise can attenuate the negative skeletal effects of this chemotherapy. Rat pups were treated with saline or DOX. Animals remained sedentary or voluntarily exercised. After 10 weeks, femoral bone mineral content and bone mineral density were measured using dual-energy x-ray absorptiometry. Cortical and cancellous bone architecture was then evaluated by microcomputed tomography. DOX had a profound negative effect on all measures of bone mass and cortical and cancellous bone architecture. Treatment with DOX resulted in shorter femora and lower femoral bone mineral content and bone mineral density, lower cross-sectional volume, cortical volume, marrow volume, cortical thickness, and principal (IMAX, IMIN) and polar (IPOLAR) moments of inertia in the femur diaphysis, and lower cancellous bone volume/tissue volume, trabecular number, and trabecular thickness in the distal femur metaphysis. Exercise failed to protect bones from the damaging effects of DOX. Other modalities may be necessary to mitigate the deleterious skeletal effects that occur in juveniles undergoing treatment with anthracyclines.

Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin.

Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX-induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg·(kg body mass)(-1)·d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective.

Effects of voluntary wheel running on goserelin acetate-induced bone degeneration

A common treatment option for many breast and prostate cancer patients is the use of a luteinizing hormone-releasing hormone agonist such as goserelin acetate (GA) which reduces sex hormone levels. This treatment, however, is associated with bone degeneration, and exercise has been suggested as a means of preventing this side effect. Little is known about the effects of low intensity, low volume exercise on GA-induced bone loss. The purpose of this study, therefore, was to investigate the effects of voluntary wheel running on bone architecture in growing male (M) and female (F) rats receiving GA treatment. Rats received an 8-week GA treatment or placebo (CON) and were either housed in cages equipped with voluntary running wheels (WR) or remained sedentary (SED) in standard cages throughout the experimental period. Following treatments, tibiae were excised and analyzed for cortical bone (cross-sectional volume, cortical volume, marrow volume, cortical thickness) and cancellous bone (bone volume/total volume, trabecular number, trabecular thickness, trabecular spacing) using micro-computed tomography. Treatment with GA resulted in a significant reduction in running wheel distances in both sexes throughout the study period (P<0.05). GA treatment had no effect on cortical bone architecture in neither sex (P>0.05). Cancellous bone degeneration, however, was observed in M and F SED+GA (P<0.05). No significant differences were observed in M WR+GA animals in bone volume/total volume, trabecular number and trabecular spacing when compared to M SED+CON (P>0.05). In F WR+GA, trabecular thickness did not differ from that of F SED+CON (P>0.05), and trabecular spacing was found to be significantly lower than F SED+GA (P<0.05). The current report indicates that 8 weeks of GA treatment promotes cancellous bone degeneration, and voluntary wheel running provides no clear osteoprotection in growing male and female rats.

Dynamic heart rate response to deer hunting in men and women

The purpose of the present study was to examine the heart rate response and force tension associated with deer hunting activities in men and women. Fifteen men and women (body mass index: 25.6±5.2 kg/m2; age: 27±9 years) participated in this study. Subjects performed a maximal graded exercise test (GXT) to determine maximal heart rate (HRmax). Subjects completed a 0.8 km hike over typical hunting terrain. Following a short rest, subjects completed a 0.4 km drag using a fake deer weighing 56 kg (123 pounds, the weight of the average field dressed deer in Pennsylvania, USA) over similar terrain. HR was measured during the activities using a Polar Heart Rate Monitor. Force tension (TNmean) while dragging the deer was measured using a cable tensiometer. Women on average completed the 0.4 km drag course in 13±3 min, where men on average only needed 6±2 min to complete the drag. Women spent significantly more time ≥85% HRmax (9±4 min), than men (2±3 min) during the drag (P<0.05). Women, on average, completed 71...

An acute bout of aerobic exercise alters interarm systolic blood pressure difference

Background Clinically, when a difference of at least 10 mmHg in systolic blood pressure (SBP) between arms exists, it is identified as an interarm systolic blood pressure difference (ISBPD). At rest, ISBPD is linked with hypertension, peripheral vascular disease, and increased premature mortality. Exercise may reveal underlying cardiovascular pathologies otherwise absent at rest. However, there have been no investigations to examine the effect of exercise on ISBPD. Aim The aim of this investigation was to determine whether exercise may alter ISBPD when detected at rest or reveal ISBPD when it was not observed in the resting condition. Methods An experienced investigator sequentially measured SBP using standard auscultation in each arm (alternating order) in 85 normotensive individuals (22±6 years, 39 male, 46 female). ISBPD was quantified before exercise (PRE). Participants then completed a three-stage protocol on a cycle ergometer. A cadence of 50 rpm was maintained at a workload of 3 (EX-3; light) and 6 (EX-6; moderate) METS and during an active recovery (REC). At each stage, SBP was measured upon achieving steady-state heart rate. A logistic regression analysis was used to determine the change in odds ratio of ISBPD when exposed to exercise. Results Thirteen percent (n=11) of patients presented with ISBPD during PRE and the degree of ISBPD was lower (3.81 mmHg; P<0.05) in REC than PRE. In individuals who did not present with ISBPD during PRE (n=74), progression from EX-3 to EX-6 significantly increased the odds of developing ISBPD (4.31; P<0.05). Conclusion In individuals with ISBPD at PRE, active recovery from exercise attenuated the difference between interarm SBP. Moderate-intensity exercise resulted in ISBPD not otherwise present at rest.

Using a novel assessment of procedural proficiency provides medical educators insight into blood pressure measurement.

Objective This investigation was performed to determine how students in a health sciences program utilize and explain techniques within blood pressure measurement using a novel assessment, and changes associated with greater curricular exposure. Methods An exploratory, qualitative and quantitative study was conducted using a ‘Think Aloud’ design with protocol analysis. Following familiarization, participants performed the task of measuring blood pressure on a reference subject while stating their thought processes. A trained practitioner recorded each participant’s procedural proficiency using a standardized rubric. There were 112 participants in the study with varying levels of curricular exposure to blood pressure measurement. Results Four trends are noted. Specifically, a trend was observed wherein a marked increase in procedural proficiency with a plateau occurred (e.g. released cuff pressure 2-4 mmHg, 10%, 60%, 83%, 82%). Secondly, a trend was observed with improvement across groups (e.g. cuff placed snugly/smoothly on upper arm, 20%, 60%, 81%, and 91%). Other trends included a marked improvement with subsequent decrease, and an improvement without achieving proficiency (e.g. palpation of the brachial pulse, 5%, 90%, 81%, 68%, appropriate size cuff, 17%, 40%, 33%, 41%, respectively). Qualitatively, transcript interpretation resulted in a need for clarification in the way blood pressure procedure is instructed in the curriculum. Conclusions The current investigation provides a snapshot of proficiency in blood pressure assessment across a curriculum and highlights considerations for best instructional practices, including the use of Think Aloud. Consequently, medical educators should use qualitative and quantitative assessments concurrently to determine achievement of blood pressure skill proficiency.