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BACKGROUND Post-traumatic stress disorder (PTSD) is a public health concern that may elevate the risk for cardiovascular disease (CVD). There are established sex differences in both PTSD risk and CVD risk. PURPOSE To examine sex-specific associations between subclinical PTSD symptom severity and subclinical CVD risk in young men and women. METHODS A total of 61 young adults (women: n = 29, mean age: 26 ± 7 years) completed the post-traumatic stress disorder civilian checklist (PCL) and the Center for Epidemiologic Studies Depression Scale (CES-D). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV). Peripheral vasomotor function was measured as flow-mediated slowing (FMS) of carotid-radial PWV following 5-min forearm occlusion. Heart rate variability was used to assess sympathovagal balance as LF/HF ratio. RESULTS PCL score was positively correlated with CES-D score (r = 0.79, p

A large inter-arm difference (IAD; ≥10 mmHg) in SBP is linked to cardiovascular and peripheral vascular disease, hypertension, and premature mortality. Exercise-induced IAD (eIAD) is related to resting IAD, and acute aerobic activity alters eIAD and reduces IAD in recovery. Isometric handgrip exercise (IHE) affects blood pressure (BP), though the eIAD response to IHE is unknown. Further, the eIAD response may differ between males and females. OBJECTIVES To characterize the eIAD response to IHE in males and females. METHODS On visit 1, participants (16 females and 15 males, aged 18-35 years) completed three maximal voluntary isometric contractions (MVIC) per arm. On visit 2, before IHE, a series of three simultaneous, bilateral BP measures were averaged at rest. During IHE, participants maintained handgrip at 20% of MVIC for 2 minutes (arm randomly assigned), at which time bilateral BP was measured (IHE) during exercise and subsequent recovery (REC1 and REC2). Repeated-measures analysis of variance assessed eIAD and SBP (time × sex). RESULTS IHE increased absolute eIAD (4 mmHg). Differences in relative eIAD were observed at IHE and REC2 based on resting IAD status (P < 0.05). Females only had an exaggerated SBP and pulse pressure response in the working arm. CONCLUSION Acute IHE was shown to augment eIAD. Further eIAD and resting IAD were related. Acute IHE induced different bilateral responses between males and females, though the impact of sex on eIAD warrants further investigation. Future studies should address the effects of repeated bouts of IHE, which may benefit individuals with a large resting IAD.

Background An interarm difference (IAD) in blood pressure (BP) of 10 mmHg or more is a potential cardiovascular risk factor in adults, given its association with cardiovascular events/mortality. In children and adolescents, accurate BP assessment is critical for identifying risk of end organ damage. However, IAD has not been systematically studied in paediatric patients; if present and of significant magnitude, measuring BP in only one arm could lead to misclassification of hypertensive status. Method In 95 children/adolescents with a normal aorta (including 15 with a history of tetralogy of Fallot) aged 7-18 years attending the Royal Children's Hospital, Melbourne, we aimed to determine the magnitude of IAD, frequency of IAD of at least 10 mmHg, difference in BP classification between arms, and influence of repeat measures on IAD in a single visit. After 5 min rest, simultaneous bilateral BP was measured in triplicate with an automated device. Results Absolute systolic IAD was 5.0 mmHg (median, interquartile range 2-8 mmHg) and was 10 mmHg or more in 14%, with no change on repeat measures. In patients with a history of aortic surgery, IAD of 10 mmHg or more occurred in 27% (transposition of the great arteries, n = 15) and 75% (aortic coarctation, n = 8). Differences in BP classification, based on initial left vs. right arm measures, occurred in 25% (normal aorta) and 40%/63% (aortic surgery), or 17% and 33%/50%, respectively if second and third measurements were averaged. Conclusion Substantial interarm BP differences were common, even in apparently healthy children and adolescents: evaluation of IAD may, therefore, be important for BP classification in the paediatric setting.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P 2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

Introduction: Socioeconomic and insurance status are often linked with limited access to health care. Despite several government-funded projects aimed at curtailing these barriers, pediatric orthopaedic patients continue to experience delays in receiving timely care for fracture treatments. This delay has been well-identified within the orthopaedic literature but, to our knowledge, has never been characterized based on timeline. Thus, the goal of this study is to evaluate the role of ethnicity, socioeconomic status, and insurance type on the timeline of pediatric patients to obtain orthopaedic care within our community. Methods: Pediatric patients presenting to our clinic for the treatment of one of 21 most common fractures were included. Patient demographics and the timeline of patient care were collected by retrospective chart review. Results: Government-funded insurance accounted for 60.6% of the 413 patients. These patients experienced significant (P < 0.001) delays in access to care when compared with commercial insurance patients; the time between injury and referral as well as the overall time from injury to orthopaedic evaluation was 2.8 and twofold greater at 4.4 days and 9.2 days, respectively. A strong correlation was established between income levels and insurance type. Discussion: Pediatric patients with a lower socioeconomic status are more likely to rely on government-funded insurance and experience delays in fracture evaluation.

Objective Deer hunting includes various stimuli resulting in augmented sympathetic activity, increased heart rate (HR) response, and rhythm changes. Collectively, these superimposed stresses may increase an individual's risk for cardiovascular events. We undertook this study to evaluate HR and rhythm responses in multiple phases of deer hunting in men and women with and without cardiovascular disease (CVD). Methods Nineteen participants age 38.3 ± 13.8 years (mean ± SD) with body mass index 29.2 ± 6.9 kg/m 2 followed their normal hunting routine. HR and rhythm were recorded continuously during the hunt using a small leadless electrocardiogram (ECG) patch monitor. Results Data were collected on 13 of 19 hunters while hiking. Three hunters recorded HR ≥85% of their age-predicted heart rate maximum (HRmax) for 1 to 2 minutes. Arrhythmias were detected in both participants with CVD and in 8 without CVD. Recorded rhythms included premature atrial, junctional, and ventricular complexes. Six hunters climbed a tree stand; 3 of them recorded HR ≥85% HRmax with sustained elevated HR response for 2 to 3 minutes with premature junctional contractions. Four of 19 participants dragged deer carcasses. During the drag, 1 male hunter recorded an HR of 91% HRmax, and another male hunter without CVD recorded an exercise-induced ischemic ECG. Fifteen of 19 hunters experienced "buck fever" (acute extreme excitation), with 7 reaching ≥85% HRmax for up to 1 minute. Ventricular bigeminy and trigeminy and ventricular couplets were observed in 1 subject during buck fever. Conclusions Men and women with and without CVD recorded substantial increases in HR and clinically relevant arrhythmias while deer hunting.

Background Data addressing risk factors predictive of mortality and reoperation after periprosthetic femur fractures (PPFxs) are lacking. This study examined survivorship and risk ratios for mortality and reoperation after surgical treatment for PPFx and associated clinical risk factors. Methods A retrospective review was performed for 291 patients treated surgically for PPFx between 2004 and 2013. Primary outcomes were death and reoperation. Results Mortality at 1 year was 13%, whereas the rate of reoperation was 12%. Greater span of fixation and revision arthroplasty (vs open reduction internal fixation) trended toward a lower likelihood of reoperation. Conclusion After PPFx, patients have a 24% risk of either death or reoperation at 1 year. Factors contributing to increased mortality are nonmodifiable. Risk of reoperation is minimized with greater span of fixation and performance of revision arthroplasty.

Doxorubicin (DOX) is a potent and widely used antineoplastic agent. Despite the efficacy of DOX, its clinical use is limited by a dose-dependent cardiotoxicity. Chronic exercise training has been shown to protect against DOX-induced cardiotoxicity. It is less clear whether short-term exercise can attenuate DOX-induced dysfunction. The purposes of this study were to determine if short-term wheel running and treadmill exercise training can attenuate the cardiac dysfunction that accompanies DOX treatment and to investigate possible mechanisms that may be involved with any protective effects of exercise. Male Sprague-Dawley rats engaged in a short-term 5-day voluntary wheel running (WR) or treadmill exercise (TM) regimen. Following the exercise preconditioning period, animals received either 10 or 15 mg/kg of DOX or an equivalent volume of saline (SAL). Five days after DOX/SAL exposure, cardiac function was examined. Western immunoblotting was used to quantify left ventricular sarcoendoplasmic reticulum calcium-ATPase 2a (SERCA2a) protein expression. Exercise preconditioning attenuated in vivo and ex vivo cardiac dysfunction observed with DOX treatment alone. Specifically, short-term treadmill exercise (TM + DOX10, 56 ± 4 %; TM + DOX15, 48 ± 5 %) and voluntary wheel running (WR + DOX10, 51 ± 5 %; WR + DOX15, 45 ± 3 %) consistently preserved fractional shortening when compared to sedentary (SED) animals treated with DOX (SED + DOX10, 48 ± 4 %; SED + DOX15, 39 ± 6 %). Likewise, both exercise protocols preserved left ventricular developed pressure (TM + DOX10, 115 ± 6 mmHg; TM + DOX15, 85 ± 5 mmHg; WR + DOX10, 92 ± 12 mmHg; WR + DOX15, 91 ± 8 mmHg) when compared to SED animals treated with DOX (SED + DOX10, 79 ± 6 mmHg; SED + DOX15, 69 ± 7 mmHg). SERCA2a expression was also preserved in TM + DOX and WR + DOX. These findings suggest that short-term exercise prior to DOX treatment may be a valuable adjuvant therapy to offset acute cardiotoxicities and that maintaining calcium handling in cardiomyocytes may be responsible, in part, for the preservation in cardiac function.

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.

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 (Pmax which was significantly greater than men (37±36%; Ppeak corresponded to 90±6% and 99±7%, respectively, of their measured HRmax via GXT (Pmean between men and women during the drag tests. The results from this study indicate that hunting includes high-intensity exercise, with a greater relative stress placed on women. Deer hunters should exercise caution and adequately prepare for the potential demands of this activity.

Objectives To identify medical professionals’ specific insights to implementing a transitions of care (TOC) clinic in a federally qualified health center (FQHC). Design The investigators conducted focus groups during the structured 1-hour provider meetings that take place at each clinic. Each meeting was split into two 30-minute group sessions that consisted of licensed providers and of other health care team members. During the focus groups, investigators explored past experiences of care provided to patients recently discharged from hospitalizations, and the perceived benefits, barriers, and workflow for a TOC clinic. Questions used were based on the consolidated framework for implementation research (CFIR). Transcriptions were coded with the use of qualitative research data analysis software by 2 investigators independently. Initial codes were based on the CFIR constructs to identify themes in responses while remaining adaptable for any themes or discussion that the participants found important. Setting and participants Participants were selected via purposive sampling within FQHCs of northwest Indiana. Participants included physicians, nurse practitioners, team care nurses, pharmacists, and behavioral health consultants. Results A total of 40 participants took part in 8 focus groups. Major themes identified were inaccessibility to patient information, apprehension about implementation, lack of familiarity with transitions of care service, and FQHC patient-centered factors. Aspects of each of the 5 CFIR constructs are discussed. Conclusion Participants provided numerous factors that may affect the success of this patient care intervention in an FQHC. Proper external communication with other health care providers, comprehensive assessment of patient access to necessary resources, and collaboration at the site are the most crucial factors. Many FQHCs work with scarce resources and high patient volumes; being able to develop appropriate processes for a patient care service as encompassing and important as a TOC will affect both patient and provider experience in primary care.

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.

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.

Background 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. Procedure At 25 days of age, male Sprague–Dawley rat pups were subjected to a treatment regimen with the anthracycline doxorubicin (DOX). Pups received DOX at 2 mg/kg on 7 consecutive days (cumulative dose 14 mg/kg) or saline as a control. At the time DOX treatment began, pups remained sedentary or were allowed to voluntarily exercise. Ten weeks after the initiation of exercise, cardiac function was assessed both in vivo and ex vivo. Results DOX treatment stunted normal growth and significantly impaired cardiac function. While voluntary exercise did not offset changes in the growth curve, it did provide significant cardioprotection against DOX-induced cardiotoxicity. Conclusions Exercise training, initiated at the time treatment begins, can protect against delayed-onset anthracycline-induced cardiotoxicity in adult rats that were treated with anthracyclines as juveniles. Pediatr Blood Cancer 2012; 59: 149–154. © 2011 Wiley Periodicals, Inc.

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.

The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg) to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C.) which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient) or genetic (permanent) inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.

A high-fat diet has been shown to exacerbate the cardiotoxicity associated with the chemotherapy drug doxorubicin (DOX); however, it is unknown whether switching from a high-fat diet to a low-fat diet can attenuate the intensified DOX cardiotoxicity. The purpose of this study was to investigate the effects of a low-fat diet on DOX-induced cardiotoxicity in rats previously fed a high-fat diet.Male rats were randomly assigned to consume a Western diet or a low-fat diet for 6 weeks. Western diet-fed rats were then further randomized to switch to the low-fat diet (WD-LF) or continue with the Western diet (WD). One week later, WD-LF and WD received 1 mg/kg DOX per day for 10 consecutive days and continued with their diets (WD-LF + DOX, WD + DOX). LF was further randomized to receive 1 mg/kg DOX per day for 10 consecutive days (LF + DOX) or saline injections as a control (LF + SAL). Four weeks following the first injection, cardiac function was analyzed, and left ventricles were analyzed for cardiotoxicity indices.When compared to LF + SAL and LF + DOX, WD + DOX exhibited an enhanced cardiotoxicity as evidenced by reduced septal wall thickness, fractional shortening, and sarco-endoplasmic reticulum Ca(2+) ATPase expression as well as increased left ventricular cavity dimensions, lipid peroxidation, and β-myosin heavy-chain expression. This exacerbated cardiotoxicity was not observed in WD-LF + DOX.Switching to a low-fat diet 1 week prior to, during, and following DOX treatment attenuated the exacerbated cardiotoxicity observed in the previously Western diet-fed rats.

Each year, approximately two million people in the United States suffer eye injuries that require treatment [1]. Although it is suggested that blast overpressure can cause serious eye injuries, there is no clear evidence in the literature to support this injury mechanism. Conversely, projectile impacts have been shown to cause serious eye injuries [2, 3]. The critical question is whether blast overpressure alone can cause eye injury or if injuries are caused solely by projected material. Therefore, the purpose of the current study is to measure the intraocular pressure (IOP) of postmortem human eyes during blasts and assess injuries sustained in order to more fully understand the effect of blast overpressure on the eye.Copyright © 2012 by ASME

Doxorubicin (DOX) and goserelin acetate (GA), when administered individually, can lead to impaired cardiac function via different mechanisms. Combining GA and DOX (GA + DOX), however, could potentially exacerbate cardiac dysfunction when compared to GA and DOX treatments administered individually. Therefore, the first purpose of this study was to investigate the effects of GA + DOX on cardiac function. Additionally, since exercise training has been shown to protect against GA- and DOX-induced cardiac dysfunction when administered individually, the second purpose of this study was to examine the effects of exercise during GA + DOX on cardiac function. Female rats were randomly assigned to control (CON), GA, DOX, GA + DOX, or exercise training during GA + DOX (EX GA + DOX). Following 56 days, cardiac function was analyzed in vivo using echocardiography and ex vivo using an isolated working heart model. GA + DOX had significantly lower mitral valve maximal and mean blood flow velocities and aortic valve maximal blood flow velocity than CON (in vivo analysis, P