Association between Serum Biomarkers with Postoperative Complications and Delay of Adjuvant Chemotherapy Initiation in Ovarian Cancer Patients Undergoing Primary Cytoreductive Surgery: A Pilot Study.

This study sought to describe and relate the factors associated with complications and delays in adjuvant chemotherapy in patients with ovarian cancer treated with primary cytoreductive surgery. Serum from patients diagnosed with ovarian cancer scheduled for primary cytoreductive surgery were analyzed for prealbumin, 25-OH Vitamin D, intracellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), monocyte chemoattractant protein 2 (MCP-2), macrophage derived chemokine (MDC). Postoperative complications were identified using common terminology criteria for adverse events 4.0 and 30 day after surgery. Delays in adjuvant chemotherapy were defined as >1 week interval between surgery and initiation. Patients with postoperative complications (39.6%) were significantly older, had lower serum prealbumin levels, and higher serum IL-6 and IL-8 than those without. Univariate logistic regression found that age (OR: 1.12, 95%CI: 1.00-1.35) and IL-6 (OR: 1.02, 95%CI: 0.99-1.05) were associated with postoperative complications, whereas age remained significant after multivariate analysis (OR:1.14, 95%CI: 1.00-1.29). Patients with delays in chemotherapy exhibited greater BMI and lower 25-OH Vitamin D than those without. Multivariate analysis found that increasing levels of 25-OH Vitamin D were associated with a lower risk of delayed chemotherapy initiation after controlling for age, body mass index, and tumor grade (OR: 0.93, 95%CI:0.87-0.99). This work suggests that in addition to age being predictive of postoperative complications, serum 25-OH Vitamin D may a provide insight into a patient's risk for postsurgical delays in chemotherapy initiation. These findings should, however, be confirmed in a larger study including robust survival analysis.

In a small cohort, increasing age was associated with postsurgical complications in patients with ovarian cancer following primary cytoreductive surgery.In patients with ovarian cancer following primary cytoreductive surgery delays in adjuvant chemotherapy initiation were inversely associated with serum 25-OH vitamin D status.

Novel mechanosensory role for acid sensing ion channel subtype 1a in evoking the exercise pressor reflex in rats with heart failure.

Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fibre muscle afferents, which, in turn, generates reflex increases in sympathetic nerve activity (SNA) and blood pressure (the exercise pressor reflex; EPR). EPR activation in patients and animals with heart failure with reduced ejection fraction (HF-rEF) results in exaggerated increases in SNA and promotes exercise intolerance. In the healthy decerebrate rat, a subtype of acid sensing ion channel (ASIC) on the sensory endings of thin fibre muscle afferents, namely ASIC1a, has been shown to contribute to the metabolically sensitive portion of the EPR (i.e. metaboreflex), but not the mechanically sensitive portion of the EPR (i.e. the mechanoreflex). However, the role played by ASIC1a in evoking the EPR in HF-rEF is unknown. We hypothesized that, in decerebrate, unanaesthetized HF-rEF rats, injection of the ASIC1a antagonist psalmotoxin-1 (PcTx-1; 100 ng) into the hindlimb arterial supply would reduce the reflex increase in renal SNA (RSNA) evoked via 30 s of electrically induced static hindlimb muscle contraction, but not static hindlimb muscle stretch (model of mechanoreflex activation isolated from contraction-induced metabolite-production). We found that PcTx-1 reduced the reflex increase in RSNA evoked in response to muscle contraction (n = 8; mean (SD) ∫ΔRSNA pre: 1343 (588) a.u.; post: 816 (573) a.u.; P = 0.026) and muscle stretch (n = 6; ∫ΔRSNA pre: 688 (583) a.u.; post: 304 (370) a.u.; P = 0.025). Our data suggest that, in HF-rEF rats, ASIC1a contributes to activation of the exercise pressor reflex and that contribution includes a novel role for ASIC1a in mechanosensation that is not present in healthy rats. KEY POINTS: Skeletal muscle contraction results in exaggerated reflex increases in sympathetic nerve activity in heart failure patients compared to healthy counterparts, which likely contributes to increased cardiovascular risk and impaired tolerance for even mild exercise (i.e. activities of daily living) for patients suffering with this condition. Activation of acid sensing ion channel subtype 1a (ASIC1a) on the sensory endings of thin fibre muscle afferents during skeletal muscle contraction contributes to reflex increases in sympathetic nerve activity and blood pressure, at least in healthy subjects. In this study, we demonstrate that ASIC1a on the sensory endings of thin fibre muscle afferents plays a role in both the mechanical and metabolic components of the exercise pressor reflex in male rats with heart failure. The present data identify a novel role for ASIC1a in evoking the exercise pressor reflex in heart failure and may have important clinical implications for heart failure patients.

Effects of pulmonary hypertension on microcirculatory hemodynamics in rat skeletal muscle.

Pulmonary hypertension (PH) has previously been characterized as a disease of the pulmonary vasculature that subsequently results in myocardial dysfunction. Heart failure compromises skeletal muscle microvascular function, which contributes to exercise intolerance. Therefore, we tested the hypothesis that such changes might be present in PH. Thus, we investigated skeletal muscle oxygen (O2) transport in the rat model of PH to determine if O2 delivery (Q̇O2) is impaired at the level of the microcirculation as evidenced via reduced red blood cell (RBC) flux, velocity, hematocrit, and percentage of capillaries flowing in quiescent muscle. Adult male Sprague-Dawley rats were randomized into healthy (n = 9) and PH groups (n = 9). Progressive PH was induced via a one-time intraperitoneal injection of monocrotaline (MCT; 50 mg/kg) and rats were monitored weekly via echocardiography. Intravital microscopy in the spinotrapezius muscle was performed when echocardiograms confirmed moderate PH (preceding right ventricular (RV) failure). At 25 ± 9 days post-MCT, PH rats displayed RV hypertrophy (RV/(Left ventricle + Septum): 0.28 ± 0.05 vs. 0.44 ± 0.11), pulmonary congestion, and increased right ventricular systolic pressure (21 ± 8 vs. 55 ± 14 mm Hg) compared to healthy rats (all P < 0.05). Reduced capillary RBC velocity (403 ± 140 vs. 227 ± 84 µm/s; P = 0.01), RBC flux (33 ± 12 vs. 23 ± 5 RBCs/s; P = 0.04) and % of capillaries supporting continuous RBC flux at rest (79 ± 8 vs. 56 ± 13%; P = 0.01) were evident in PH rats compared to healthy rats. When Q̇O2 within a given field of view was quantified (RBC flux x % of capillaries supporting continuous RBC flux), PH rats demonstrated lower overall Q̇O2 (↓ 50%; P = 0.002). These data support that microcirculatory hemodynamic impairments (↓ Q̇O2 and therefore altered Q̇O2-to-V̇O2 matching) may compromise blood-myocyte O2 transport in PH. The mechanistic bases for decreased capillary RBC flux, velocity, and percentage of capillaries supporting RBC flow remains an important topic.

Capillary hemodynamics and contracting skeletal muscle oxygen pressures in male rats with heart failure: Impact of soluble guanylyl cyclase activator.

In heart failure with reduced ejection fraction (HFrEF), nitric oxide-soluble guanylyl cyclase (sGC) pathway dysfunction impairs skeletal muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake (V̇O2) kinetics. Targeting this pathway with sGC activators offers a new treatment approach to HFrEF. We tested the hypotheses that sGC activator administration would increase the O2 delivery (Q̇O2)-to-V̇O2 ratio in the skeletal muscle interstitial space (PO2is) of HFrEF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (fRBC), velocity (VRBC), and capillary hematocrit (Hctcap). HFrEF was induced in male Sprague-Dawley rats via myocardial infarction. After 3 weeks, rats were treated with 0.3 mg/kg of the sGC activator BAY 60-2770 (HFrEF + BAY; n = 11) or solvent (HFrEF; n = 9) via gavage b.i.d for 5 days prior to phosphorescence quenching (PO2is, in contracting muscle) and intravital microscopy (resting) measurements in the spinotrapezius muscle. Intravital microscopy revealed higher fRBC (70 ± 9 vs 25 ± 8 RBC/s), VRBC (490 ± 43 vs 226 ± 35 µm/s), Hctcap (16 ± 1 vs 10 ± 1%) and a greater number of capillaries supporting flow (91 ± 3 vs 82 ± 3%) in HFrEF + BAY vs HFrEF (all P < 0.05). Additionally, PO2is was especially higher during 12-34s of contractions in HFrEF + BAY vs HFrEF (P < 0.05). Our findings suggest that sGC activators improved resting Q̇O2 via increased fRBC, VRBC, and Hctcap allowing for better Q̇O2-to-V̇O2 matching during the rest-contraction transient, supporting sGC activators as a potential therapeutic to target skeletal muscle vasomotor dysfunction in HFrEF.

Inorganic nitrate supplementation may improve diastolic function and the O2 cost of exercise in cancer survivors: a pilot study.

In non-cancer populations, inorganic dietary nitrate (NO3-) supplementation is associated with enhanced cardiorespiratory function but remains untested in patients with a history of cancer. Therefore, this pilot study sought to determine if oral NO3- supplementation, as a supportive care strategy, increases left ventricular (LV) function and exercise performance in survivors of cancer treated with anticancer therapy while simultaneously evaluating the feasibility of the methods and procedures required for future large-scale randomized trials. Two cohorts of patients with a history of cancer treated with anticancer chemotherapy were recruited. Patients in cohort 1 (n = 7) completed a randomized, double-blind, crossover study with 7 days of NO3- or placebo (PL) supplementation, with echocardiography. Similarly, patients in cohort 2 (n = 6) received a single, acute dose of NO3- supplementation or PL. Pulmonary oxygen uptake (VO2), arterial blood pressure, and stroke volume were assessed during exercise. In cohort 1, NO3- improved LV strain rate in early filling (mean difference (MD) [95% CI]: - 0.3 1/s [- 0.6 to 0.06]; P = 0.04) and early mitral septal wall annular velocity (MD [95% CI]: 0.1 m/s [- 0.01 to - 0.001]; P = 0.02) compared to placebo. In cohort 2, NO3- decreased the O2 cost of low-intensity steady-state exercise (MD [95% CI]: - 0.5 ml/kg/min [- 0.9 to - 0.09]; P = 0.01). Resting and steady-state arterial blood pressure and stroke volume were not different between conditions. No differences between conditions for peak VO2 (MD [95% CI]: - 0.7 ml/kg/min [- 3.0 to 1.6]; P = 0.23) were observed. The findings from this pilot study warrant further investigation in larger clinical trials targeting the use of long-term inorganic dietary NO3- supplementation as a possible integrative supportive care strategy in patients following anticancer therapy.

The effects of pulmonary hypertension on skeletal muscle oxygen pressures in contracting rat spinotrapezius muscle.

NEW FINDINGS: What is the central question of this study? Does impairment in the dynamics of O2 transport in skeletal muscle during a series of contractions constitute a potential mechanism underlying reduced exercise capacity in pulmonary hypertension? What is the main finding and its importance? Pulmonary hypertension compromises the dynamic matching of skeletal muscle O2 delivery-to-utilization following contraction onset in the rat spinotrapezius muscle. These results implicate a role for vascular dysfunction in the slow V̇O2 kinetics and exercise intolerance present in pulmonary hypertension. ABSTRACT: Pulmonary hypertension (PH) is characterized by pulmonary vascular dysfunction and exercise intolerance due, in part, to compromised pulmonary and cardiac function. We tested the hypothesis that there are peripheral (i.e., skeletal muscle) aberrations in O2 delivery ( Q̇O2 )-to-O2 utilization ( V̇O2 ) matching and vascular control that might help to explain poor exercise tolerance in PH. Furthermore, we investigated the peripheral effects of nitric oxide (NO) in attenuating these decrements. Male Sprague-Dawley rats (n = 21) were administered monocrotaline (MCT; 50 mg/kg, i.p.) to induce PH. Disease progression was monitored via echocardiography. Phosphorescence quenching determined the O2 partial pressure in the interstitial space ( PO2is ) in the spinotrapezius muscle at rest and during contractions under control (SNP-) and NO-donor (sodium nitroprusside, SNP+) conditions. MCT rats displayed right ventricular (RV) hypertrophy (right ventricle/(left ventricle + septum): 0.44 (0.13) vs. 0.28 (0.05)), pulmonary congestion, increased RV systolic pressure (48 (18) vs. 20 (8) mmHg) and arterial hypoxaemia ( PaO2 : 64 (9) vs. 82 (9) mmHg) compared to healthy controls (HC) (P < 0.05). PO2is was significantly lower in MCT rats during the first 30 s of SNP- contractions. SNP superfusion elevated PO2is in both groups; however, MCT rats demonstrated a lower PO2is throughout SNP+ contractions versus HC (P < 0.05). Thus, for small muscle mass exercise in MCT rats, muscle oxygenation is impaired across the rest-to-contractions transition and exogenous NO does not raise the Q̇O2 -to- V̇O2 ratio in contracting muscle to the same levels as HC. These data support muscle Q̇O2 -to- V̇O2 mismatch as a potential contributor to slow V̇O2 kinetics and therefore exercise intolerance in PH and suggest peripheral vascular dysfunction or remodelling as a possible mechanism.

Health behaviors and patient-practitioner communication in cancer patients and the general population: an analysis of the National Health and Nutrition Examination Survey (NHANES) 2005-2014.

PURPOSE: The purpose of the study was to investigate the prevalence of poor health behaviors (low dietary quality, low physical activity (PA), and high body mass index (BMI)) in cancer patients and the general population and its relationship with receipt of patient-physician recommendations. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2005-2014 to compare 1846 patients with a history of cancer to 16,641 with no cancer history. BMI was measured during physical exam. Dietary quality and PA were obtained from a questionnaire, along with receipt of physician recommendations for each behavior. RESULTS: Cancer patients had dietary quality that "needs improvement," were not meeting PA recommendations, and were overweight. Compared to the general population, dietary quality (54 vs. 54, p = .80), prevalence of physical inactivity (34% vs. 31%, p = .01), and BMI (28 vs. 28, p < .01) were similar. Among cancer patients, prevalence of physician recommendations to improve dietary quality (33.5%), increase PA or exercise (47.7%), and lose or control weight (32.1%) were low. Physicians recommended health behavior change to cancer patients more frequently than the general population (p < .01). Overweight and physically inactive cancer patients were more likely to receive physician recommendations (ps < .01). Physician recommendations were not associated with dietary quality (p = .65). CONCLUSIONS: Prevalence of poor diet, physical inactivity, and obesity is high in both populations with less than 50% of patients receiving physician health behavior recommendations. These findings underscore the need for increased frequency and efficacy of patient-physician health behavior recommendations, especially in cancer patients, to improve patient outcomes.

Vascular ATP-sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport.

KEY POINTS: Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP-sensitive K+ (KATP ) channels to increase insulin release. However, KATP channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity ( V̇ O2 max) and submaximal exercise tolerance (i.e. speed-duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than V̇ O2 max but did not alter resting cardiac output. Vascular KATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO2 during twitch contractions reflecting impaired O2 delivery-to-utilization matching. Our findings demonstrate that systemic KATP channel inhibition reduces V̇ O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V̇ O2 , especially within fast-twitch oxidative skeletal muscle. ABSTRACT: Vascular ATP-sensitive K+ (KATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic KATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic KATP channel inhibition via glibenclamide (GLI; 10 mg kg-1 i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( V̇ O2 max) and the speed-duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local KATP channel inhibition (5 mg kg-1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO2 is; phosphorescence quenching) and convective and diffusive O2 transport ( Q̇ O2 and DO2 , respectively; Fick Principle and Law of Diffusion) in contracting fast-twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s-1 ) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P < 0.05) while cardiac output remained unaltered (219 ± 64 vs. 197 ± 39 ml min-1 , P > 0.05). During exercise, GLI reduced V̇ O2 max (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg-1 min-1 ) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min-1 , both P < 0.05). Local KATP channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min-1 100 g tissue-1 ) and PO2 isnadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG V̇ O2 was reduced via impaired Q̇ O2 and DO2 (P < 0.05 for each). Collectively, these data support that vascular KATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, KATP channel inhibition may exacerbate exercise intolerance.

Microvascular blood flow during vascular occlusion tests assessed by diffuse correlation spectroscopy.

NEW FINDINGS: What is the central question of this study? What are the characteristics of the time courses of blood flow in the brachial artery and microvascular beds of the skin and skeletal muscle following transient ischaemia? What is the main finding and its importance? Skeletal muscle blood flow was significantly slower than the transient increase in the cutaneous tissue, suggesting mechanistic differences between cutaneous and muscular blood flow distribution after transient ischaemia. These results challenge the use of the cutaneous circulation as globally representative of vascular function. ABSTRACT: Vascular function can be assessed by measuring post-occlusion hyperaemic responses along the arterial tree (vascular occlusion test; VOT). It is currently unclear if responses are similar across vascular beds following cuff release, given potential differences in compliance. To examine this, we compared laser Doppler-derived blood flux in the cutaneous circulation (LDFcut ) and skeletal muscle microvascular blood flux (BFI) using diffuse correlation spectroscopy (DCS), to brachial artery blood flow (BABF) during VOT. We hypothesized that during a VOT following cuff release, (1) BFI response would be delayed compared to the brachial artery response, and (2) time to peak blood flux in the cutaneous vasculature would be slower than both brachial artery and skeletal muscle responses. Seven healthy men (26 ± 4 years) performed three trials of a brachial artery VOT protocol with 10 min of rest between trials. A combined DCS and near-infrared spectroscopy probe provided BFI and oxygenation characteristics (total-[haem]), respectively, of skeletal muscle. BABF was determined via Doppler ultrasound and microvascular cutaneous blood flux was determined via LDFcut . Following cuff release, time to peak of BFI (32.3 ± 6.0 s) was significantly longer than BABF (7.3 ± 2.5 s), LDFcut (10.0 ± 6.4 s) and total-[haem] (14.2 ± 8.3 s) (all P < 0.001). However, time to peak of BABF, LDFcut and total-[haem] were not significantly different (P > 0.05). These results suggest mechanistic differences in control of cutaneous and muscular blood flow distribution after transient ischaemia.

No effect of endoperoxide 4 or thromboxane A2 receptor blockade on static mechanoreflex activation in rats with heart failure.

NEW FINDINGS: What is the central question of this study? Do endoperoxide 4 and thromboxane A2 receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF-rEF)? What is the main finding and its importance? The data do not support a role for endoperoxide 4 receptors or thromboxane A2 receptors in the chronic mechanoreflex sensitization in HF-rEF rats. ABSTRACT: We investigated the role of cyclooxygenase metabolite-associated endoperoxide 4 receptors (EP4-R) and thromboxane A2 receptors (TxA2 -R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the EP4-R antagonist L-161,982 (1 µg) or the TxA2 -R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF-rEF rats but not sham-operated control rats (SHAM). Ejection fraction was significantly reduced in HF-rEF (45 ± 11%) compared to SHAM (83 ± 6%; P < 0.01) rats. In SHAM and HF-rEF rats, we found that the EP4-R antagonist had no effect on the peak increase in mean arterial pressure (peak ΔMAP SHAM n = 6, pre: 15 ± 7, post: 15 ± 9, P = 0.99; HF-rEF n = 9, pre: 30 ± 11, post: 32 ± 15 mmHg, P = 0.84) or peak increase in RSNA (peak ΔRSNA SHAM pre: 33 ± 14, post: 47 ± 31%, P = 0.94; HF-rEF, pre: 109 ± 47, post: 139 ± 150%, P = 0.76) response to stretch. Similarly, in SHAM and HF-rEF rats, we found that the TxA2 -R antagonist had no effect on the peak ΔMAP (SHAM n = 7, pre: 13 ± 7, post: 19 ± 14, P = 0.15; HF-rEF n = 14, pre: 24 ± 13, post: 21 ± 13 mmHg, P = 0.47) or peak ΔRSNA (SHAM pre: 52 ± 43, post: 57 ± 67%, P = 0.94; HF-rEF, pre: 108 ± 93, post: 88 ± 72%, P = 0.30) response to stretch. The data do not support a role for EP4-Rs or TxA2 -Rs in the chronic mechanoreflex sensitization in HF-rEF.

Central and peripheral factors mechanistically linked to exercise intolerance in heart failure with reduced ejection fraction.

Exercise intolerance is a primary symptom of heart failure (HF); however, the specific contribution of central and peripheral factors to this intolerance is not well described. The hyperbolic relationship between exercise intensity and time to exhaustion (speed-duration relationship) defines exercise tolerance but is underused in HF. We tested the hypotheses that critical speed (CS) would be reduced in HF, resting central functional measurements would correlate with CS, and the greatest HF-induced peripheral dysfunction would occur in more oxidative muscle. Multiple treadmill-constant speed runs to exhaustion were used to quantify CS and D' (distance coverable above CS) in healthy control (Con) and HF rats. Central function was determined via left ventricular (LV) Doppler echocardiography [fractional shortening (FS)] and a micromanometer-tipped catheter [LV end-diastolic pressure (LVEDP)]. Peripheral O2 delivery-to-utilization matching was determined via phosphorescence quenching (interstitial Po2, Po2 is) in the soleus and white gastrocnemius during electrically induced twitch contractions (1 Hz, 8V). CS was lower in HF compared with Con (37 ± 1 vs. 44 ± 1 m/min, P < 0.001), but D' was not different (77 ± 8 vs. 69 ± 13 m, P = 0.6). HF reduced FS (23 ± 2 vs. 47 ± 2%, P < 0.001) and increased LVEDP (15 ± 1 vs. 7 ± 1 mmHg, P < 0.001). CS was related to FS (r = 0.72, P = 0.045) and LVEDP (r = -0.75, P = 0.02) only in HF. HF reduced soleus Po2 is at rest and during contractions (both P < 0.01) but had no effect on white gastrocnemius Po2 is (P > 0.05). We show in HF rats that decrements in central cardiac function relate directly with impaired exercise tolerance (i.e., CS) and that this compromised exercise tolerance is likely due to reduced perfusive and diffusive O2 delivery to oxidative muscles.NEW & NOTEWORTHY We show that critical speed (CS), which defines the upper boundary of sustainable activity, can be resolved in heart failure (HF) animals and is diminished compared with controls. Central cardiac function is strongly related with CS in the HF animals, but not controls. Skeletal muscle O2 delivery-to-utilization dysfunction is evident in the more oxidative, but not glycolytic, muscles of HF rats and is explained, in part, by reduced nitric oxide bioavailability.

Cyclooxygenase inhibition does not impact the pressor response during static or dynamic mechanoreflex activation in healthy decerebrate rats.

Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex independent of contraction-induced metabolite production. Cyclooxygenase (COX) metabolites, however, are produced by skeletal muscle stretch in vitro and have been found to impact various models of mechanoreflex activation. Whether COX metabolites influence the decerebrate rat triceps surae muscle stretch mechanoreflex model remains unknown. We examined the effect of rat triceps surae muscle stretch on the interstitial concentration of the COX metabolite prostaglandin E2 (PGE2). Interstitial PGE2 concentration was increased above baseline values by 4 min of both static (38% increase, P = 0.01) and dynamic (56% increase, P < 0.01) triceps surae muscle stretch (n = 10). The 4-min protocol was required to collect enough microdialysis fluid for PGE2 detection. The finding that skeletal muscle stretch in vivo was capable of producing COX metabolites prompted the hypothesis that intra-arterial administration of the COX inhibitor indomethacin (1 mg/kg) would reduce the pressor and cardioaccelerator responses evoked during 30 s (the duration most commonly used in the rat mechanoreflex model) of static and dynamic rat triceps surae muscle stretch. We found that indomethacin had no effect (P > 0.05, n = 9) on the pressor or cardioaccelerator response during 30 s of either static or dynamic stretch. We conclude that, despite the possibility of increased COX metabolite concentration, COX metabolites do not activate or sensitize thin-fiber muscle afferents stimulated during 30 s of static or dynamic hindlimb skeletal muscle stretch in healthy rats.

Aerobic Exercise Supplemented With Muscular Endurance Training Improves Onset of Blood Lactate Accumulation.

Farrell III, JW, Lantis, DJ, Ade, CJ, Cantrell, GS, and Larson, RD. Aerobic exercise supplemented with muscular endurance training improves onset of blood lactate accumulation. J Strength Cond Res 32(5): 1376-1382, 2018-Studies have shown that when aerobic exercise is supplemented with muscular endurance training metabolic adaptions occur that result in the delay of the onset of blood lactate accumulation (OBLA). However, previous studies have not explored any submaximal cardiorespiratory adaptations that may result from this training protocol. The aim of the current investigation was to evaluate the effect of supplementing an aerobic exercise training program with a muscular endurance training program on various cardiorespiratory and metabolic measurements. Fourteen aerobically active men performed an incremental exercise test to determine the OBLA, gas exchange threshold (GET), and maximal oxygen uptake (V[Combining Dot Above]O2max). Maximal strength was measured using 1 repetition maximum (1RM) for leg press (LP), leg curl (LC), and leg extension (LE). Eight subjects supplemented their aerobic activity (experimental [EX] group) with 8 weeks of muscular endurance training, while 6 continued their regular aerobic activity (control [CON] group). No significant group differences were observed for all pretraining variables. After 8 weeks of training, no significant differences in body mass, GET, and V[Combining Dot Above]O2max were observed for either group. However, the EX group showed a significant improvement for both absolute and relative V[Combining Dot Above]O2 at OBLA compared with the CON group. Leg curl and LE 1RM assessments for the EX group showed a significant improvement compared with CON group. Muscular endurance training did not improve GET and V[Combining Dot Above]O2max, but significantly increased V[Combining Dot Above]O2 at OBLA, LP, and LC. These findings suggest that this training protocol maybe useful in the development of submaximal aerobic performance and leg strength for endurance athletes.

The effects of exercise-induced muscle damage on critical torque.

OBJECTIVE: Exercise-induced muscle damage (EIMD) has been shown to reduce endurance exercise performance. This study examined the effects of EIMD on critical torque (CT) and the sum of the torque integral above CT during (∫ T total) during a 5-min all-out, intermittent isometric knee extension exercise. METHODS: CT was determined in eight participants prior to and 48-h following EIMD. EIMD was induced using electrically stimulated eccentric knee extensions until maximal voluntary strength (MVC) was reduced by 40%. EIMD was assessed by changes in MVC and ratings of muscle soreness using a VAS scale. EMG and near-infrared spectroscopy (NIRS) were collected from the vastus lateralis and vastus medialis, respectively, during the CT test to assess neuromuscular electrical activity and microvascular circulation. RESULTS: MVC decreased 22% (p = 0.006) and soreness increased from 2.1 ± 1.9 to 50.4 ± 31.5 mm (p = 0.002) 48-h following eccentric exercise. CT declined from 61.6 ± 17.8 to 52.0 ± 14.1 Nm (-14%; p = 0.005) post-EIMD. ∫ T total declined 33% (p = 0.0006) post-EIMD. No changes were observed in neuromuscular electrical activity (p = 0.95 for EMG RMS and p = 0.57 for EMG median frequency) or any parameter of microvascular circulation (p = 0.60 for tissue saturation index, p = 0.27 for total hemoglobin and myoglobin, p = 0.51 for oxyhemoglobin, and p = 0.26 for deoxyhemoglobin) between conditions. CONCLUSIONS: Our finding that EIMD-reduced CT may explain the decrements in endurance performance following EIMD observed in the previous studies. The disproportionate reduction in ∫ T total compared to MVC and CT is suggestive of a more rapid depletion of anaerobic energy stores and/or accumulation of metabolic by-products leading to fatigue following EIMD.

The effect of resting blood flow occlusion on exercise tolerance and W'.

It has previously been postulated that the anaerobic work capacity (W') may be utilized during resting blood flow occlusion in the absence of mechanical work. We tested the hypothesis that W' would not be utilized during an initial range of time following the onset of resting blood flow occlusion, after which W' would be utilized progressively more. Seven men completed blood flow occlusion constant power severe intensity handgrip exercise to task failure following 0, 300, 600, 900, and 1,200 s of resting blood flow occlusion. The work performed above critical power (CP) was not significantly different between the 0-, 300-, and 600-s conditions and was not significantly different from the total W' available. Significantly less work was performed above CP during the 1,200-s condition than the 900-s condition (P < 0.05), while both conditions were significantly less than the 0-, 300-, and 600-s conditions (P < 0.05). The work performed above CP during these conditions was significantly less than the total W' available (P < 0.05). The utilization of W' during resting blood flow occlusion did not begin until 751 ± 118 s, after which time W' was progressively utilized. The current findings demonstrate that W' is not utilized during the initial ∼751 s of resting blood flow occlusion, but is progressively utilized thereafter, despite no mechanical work being performed. Thus, the utilization of W' is not exclusive to exercise, and a constant amount of work that can be performed above CP is not the determining mechanism of W'.

The effects of short-term fish oil supplementation on pulmonary function and airway inflammation following a high-fat meal.

INTRODUCTION: Many environmental and dietary influences can cause immune cells to produce biological mediators that increase airway inflammation. A high-fat meal (HFM) is one stimulus that increases airway inflammation in healthy individuals. Supplementation with omega-3 fatty acids can reduce inflammation systemically and may be beneficial to the airways. PURPOSE: To determine if omega-3 fatty acid supplementation via fish oil would mitigate the airway inflammatory response induced by a single HFM. METHODS: Seventeen non-asthmatic men (22 ± 2 years.) were supplemented with 3,000 mg × day(-1) fish oil or a placebo for 3 weeks. Fractional exhaled nitric oxide (FENO; a marker of airway inflammation), impulse oscillometry (a measure of respiratory impedance), pulmonary function, and triglycerides were measured prior to and 2 h following a HFM. RESULTS: Following a HFM, triglycerides increased in both fish oil and placebo groups compared to pre-HFM (~59 and ~49 %, respectively, p < 0.05). The percent increase in FENO was greater in the placebo group compared to the fish oil group (25.7 ± 16.7 vs. -1.99 ± 10.5 %, respectively, p < 0.05). A significant correlation was observed between blood triglycerides and FENO in the placebo group (r = 0.61; p < 0.05), but not the fish oil group (p = 0.21). CONCLUSION: A single HFM increases airway inflammation and omega-3 fatty acid supplementation via fish oil protects against HFM associated changes in airway health.

Influence of exercise intensity on respiratory muscle fatigue and brachial artery blood flow during cycling exercise.

PURPOSE: During high intensity exercise, both respiratory muscle fatigue and cardiovascular reflexes occur; however, it is not known how inactive limb blood flow is influenced. The purpose of this study was to determine the influence of moderate and high exercise intensity on respiratory muscle fatigue and inactive limb muscle and cutaneous blood flow during exercise. METHODS: Twelve men cycled at 70 and 85 % [Formula: see text] for 20 min. Subjects also performed a second 85 % [Formula: see text] test after ingesting 1,800 mg of N-acetylcysteine (NAC), which has been shown to reduce respiratory muscle fatigue (RMF). Maximum inspiratory pressures (P Imax), brachial artery blood flow (BABF), cutaneous vascular conductance (CVC), and mean arterial pressure were measured at rest and during exercise. RESULTS: Significant RMF occurred with 85 % [Formula: see text] (P Imax, -12.8 ± 9.8 %), but not with 70 % [Formula: see text] (P Imax, -5.0 ± 5.9 %). BABF and BA vascular conductance were significantly lower at end exercise of the 85 % [Formula: see text] test compared to the 70 % [Formula: see text] test. CVC during exercise was not different (p > 0.05) between trials. With NAC, RMF was reduced (p < 0.05) and BABF was significantly higher (~30 %) compared to 85 % [Formula: see text] (p < 0.05). CONCLUSIONS: These data suggest that heavy whole-body exercise at 85 % [Formula: see text] leads to RMF, decreases in inactive arm blood flow, and vascular conductance, but not cutaneous blood flow.

Associations of Cerebrovascular Regulation and Arterial Stiffness With Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Cerebral small vessel disease (cSVD) is a major contributing factor to ischemic stroke and dementia. However, the vascular pathologies of cSVD remain inconclusive. The aim of this systematic review and meta-analysis was to characterize the associations between cSVD and cerebrovascular reactivity (CVR), cerebral autoregulation, and arterial stiffness (AS). METHODS AND RESULTS: MEDLINE, Web of Science, and Embase were searched from inception to September 2023 for studies reporting CVR, cerebral autoregulation, or AS in relation to radiological markers of cSVD. Data were extracted in predefined tables, reviewed, and meta-analyses performed using inverse-variance random effects models to determine pooled odds ratios (ORs). A total of 1611 studies were identified; 142 were included in the systematic review, of which 60 had data available for meta-analyses. Systematic review revealed that CVR, cerebral autoregulation, and AS were consistently associated with cSVD (80.4%, 78.6%, and 85.4% of studies, respectively). Meta-analysis in 7 studies (536 participants, 32.9% women) revealed a borderline association between impaired CVR and cSVD (OR, 2.26 [95% CI, 0.99-5.14]; P=0.05). In 37 studies (27 952 participants, 53.0% women) increased AS, per SD, was associated with cSVD (OR, 1.24 [95% CI, 1.15-1.33]; P<0.01). Meta-regression adjusted for comorbidities accounted for one-third of the AS model variance (R2=29.4%, Pmoderators=0.02). Subgroup analysis of AS studies demonstrated an association with white matter hyperintensities (OR, 1.42 [95% CI, 1.18-1.70]; P<0.01). CONCLUSIONS: The collective findings of the present systematic review and meta-analyses suggest an association between cSVD and impaired CVR and elevated AS. However, longitudinal investigations into vascular stiffness and regulatory function as possible risk factors for cSVD remain warranted.

Cardiac changes in collegiate athletes following SARS-CoV-2 infection and quarantine: a prospective Case-Control study.

OBJECTIVE: Athletes are susceptible to acute respiratory tract infections, including SARS-CoV-2, which can affect cardiovascular function. We aimed to evaluate the impact of COVID-19 infection and quarantine on cardiac function in male and female collegiate athletes. METHODS: We conducted a single-center, prospective, case-control study and performed transthoracic echocardiography in a diverse group of convalescent SARS-CoV-2-positive athletes following a 10-14-day quarantine, matched to non-SARS-CoV-2 athletes. Data collection occurred from August 1, 2020, to May 31, 2021. RESULTS: We evaluated 61 SARS-CoV-2-positive athletes (20 ± 1 years, 39% female) and 61 controls (age 20 ± 2 years, 39% female). Echocardiography in SARS-CoV-2-positive athletes was performed on average 40 ± 38 days after infection diagnosis. All SARS-CoV-2-positive athletes had clinically normal systolic left ventricular function (LVEF > 50%). However, SARS-CoV-2-positive athletes exhibited mildly lower LVEF compared to controls (65 ± 6% vs. 72 ± 8%, respectively, p < 0.001), which remained significant when evaluated separately for female and male athletes. Sub-analysis revealed these differences occurred only when imaging occurred within a mean average of 27 days of infection, with a longer recovery period (≥27 days) resulting in no differences. SARS-CoV-2-positive male athletes exhibited higher left ventricular end-diastolic volume and mitral filling velocities compared to male controls. CONCLUSION: Our study reveals unique sex-specific cardiac changes in collegiate athletes following SARS-CoV-2 infection and quarantine compared to controls. Despite a mild reduction in LVEF, which was only observed in the first weeks following infection, no clinically significant cardiac abnormalities were observed. Further research is required to understand if the changes in LVEF are directly attributed to the infection or indirectly through exercise restrictions resulting from quarantine.

Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction.

Background: 5-fluorouracil (5-FU) is the second most common cancer chemotherapy associated with short- and long-term cardiotoxicity. Although the mechanisms mediating these toxicities are not well understood, patients often present with symptoms suggestive of microvascular dysfunction. We tested the hypotheses that patients undergoing cancer treatment with 5-FU based chemotherapy regimens would present with impaired microvascular reactivity and that these findings would be substantiated by decrements in endothelial nitric oxide synthase (eNOS) gene expression in 5-FU treated human coronary artery endothelial cells (HCAEC). Methods: We first performed a cross-sectional analysis of 30 patients undergoing 5-FU based chemotherapy treatment for cancer (5-FU) and 32 controls (CON) matched for age, sex, body mass index, and prior health history (excluding cancer). Cutaneous microvascular reactivity was evaluated by laser Doppler flowmetry in response to endothelium-dependent (local skin heating; acetylcholine iontophoresis, ACh) and -independent (sodium nitroprusside iontophoresis, SNP) stimuli. In vitro experiments in HCAEC were completed to assess the effects of 5-FU on eNOS gene expression. Results: 5-FU presented with diminished microvascular reactivity following eNOS-dependent local heating compared to CON (P = 0.001). Iontophoresis of the eNOS inhibitor L-NAME failed to alter the heating response in 5-FU (P = 0.95), despite significant reductions in CON (P = 0.03). These findings were corroborated by lower eNOS gene expression in 5-FU treated HCAEC (P < 0.01) compared to control. Peak vasodilation to ACh (P = 0.58) nor SNP (P = 0.39) were different between groups. Conclusions: The present findings suggest diminished microvascular function along the eNOS-NO vasodilatory pathway in patients with cancer undergoing treatment with 5-FU-based chemotherapy regimens and thus, may provide insight into the underlying mechanisms of 5-FU cardiotoxicity.