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.

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.

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.

Head-up tilt does not enhance prostate tumor perfusion or oxygenation in young rats.

Solid tumors contain hypoxic regions that contribute to anticancer therapy resistance. Thus, mitigating tumor hypoxia may enhance the efficacy of radiation therapy which is commonly utilized for patients with prostate cancer. Increasing perfusion pressure in the prostate with head-up tilt (HUT) may augment prostate tumor perfusion and decrease hypoxia. The purpose of this study was to determine if an increase in the vascular hydrostatic gradient via 70° HUT increases tumor perfusion and decreases tumor hypoxia in a preclinical orthotopic model of prostate cancer. Male Copenhagen rats (n = 17) were orthotopically injected with Dunning R-3327 (AT-1) prostate adenocarcinoma cells to induce prostate tumors. After tumors were established, prostate tumor perfusion and hypoxia were measured in rats during level (0°) and 70° HUT positions. To compare the magnitude of the hydrostatic column to that present in humans, ultrasound was used to measure the heart to prostate distance in male human subjects to estimate the prostate vascular hydrostatic pressure with the upright posture. In young rats, no differences were detected in prostate tumor perfusion or prostate tumor hypoxia with 70° HUT versus the level position. However, from the retrospective study, young rats increased prostate vascular resistance to HUT, whereas aged rats lacked this response. Tumor vessels co-opted from existing functional vasculature in young rats may be sufficient to negate increases in perfusion pressure with HUT seen in aged rats. Additionally, in humans, the estimated hydrostatic column at the level of the prostate is five times greater than that of the rat. Therefore, 70° HUT may elicit increases in prostate/prostate tumor blood flow in humans that is not seen in rats.

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.

A bench to bedside perspective on anthracycline chemotherapy-mediated cardiovascular dysfunction: challenges and opportunities. A symposium review.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and the risk of developing CVD is markedly increased following anthracycline chemotherapy treatment. Anthracyclines are an essential component of the cancer treatment regimen used for common forms of cancer in male and female children, adolescents, young adults, and older adults. Increased CVD risk with anthracyclines occurs, in part, due to vascular dysfunction-impaired endothelial function and arterial stiffening. These features of vascular dysfunction also play a major role in other common disorders observed following anthracycline treatment, including chronic kidney disease, dementia, and exercise intolerance. However, the mechanisms by which anthracycline chemotherapy induces and sustains vascular dysfunction are incompletely understood. This budding area of biomedical research is termed cardio-oncology, which presents the unique opportunity for collaboration between physicians and basic scientists. This symposium, presented at Experimental Biology 2022, provided a timely update on this important biomedical research topic. The speakers presented observations made at levels from cells to mice to humans treated with anthracycline chemotherapeutic agents using an array of translational research approaches. The speaker panel included a diverse mix of female and male investigators and unique insight from a cardio-oncology physician-scientist. Particular emphasis was placed on challenges and opportunities in this field as well as mechanisms that could be viewed as therapeutic targets leading to novel treatment strategies.

A Case Series of Diverse Cardiac Abnormalities in Collegiate Athlete with COVID-19: Role for Multimodality Imaging.

Introduction: Since the COVID-19 pandemic there is concern for subclinical cardiac pathology in the absence of clinical symptoms in collegiate athletes, we present 4 cases of abnormal left ventricular global longitudinal strain (LVGLS), a "red-flag" for potential COVID-19 myocardial disease, following diagnosis with diverse abnormalities reported via multimodality imaging weeks into recovery. Methods: Cardiac imaging studies consisting of transthoracic echocardiography (TTE) and cardiovascular magnetic resonance imaging (CMR) were performed 10 days post-COVID-19 diagnosis and several weeks into recovery. Results: Initial TTE revealed abnormal left ventricular global longitudinal strain (LVGLS), an identified "red-flag" for potential COVID-19 myocardial disease. Further CMR imaging revealed potential recent/prior myocarditis in 1 athlete. Follow-up TTE several weeks later revealed a return to normal LVGLS. Conversely, 2 cases with normal CMR imaging had a LVGLS that remained abnormal >30 days into recovery. Conclusions: These individual cases highlight the substantial differences in echocardiographic and CMR abnormalities between athletes with confirmed COVID-19.

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.

Thromboxane A2 receptors contribute to the exaggerated exercise pressor reflex in male rats with heart failure.

Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fiber muscle afferents and produce reflex increases in sympathetic nerve activity and blood pressure during exercise (i.e., the exercise pressor reflex; EPR). The EPR is exaggerated in patients and animals with heart failure with reduced ejection fraction (HF-rEF) and its activation contributes to reduced exercise capacity within this patient population. Accumulating evidence suggests that the exaggerated EPR in HF-rEF is partially attributable to a sensitization of mechanically activated channels produced by thromboxane A2 receptors (TxA2 -Rs) on those sensory endings; however, this has not been investigated. Accordingly, the purpose of this investigation was to determine the role played by TxA2 -Rs on the sensory endings of thin fiber muscle afferents in the exaggerated EPR in rats with HF-rEF induced by coronary artery ligation. In decerebrate, unanesthetized rats, we found that injection of the TxA2 -R antagonist daltroban (80 µg) into the arterial supply of the hindlimb reduced the pressor response to 30 s of electrically induced 1 Hz dynamic hindlimb muscle contraction in HF-rEF (n = 8, peak ∆MAP pre: 22 ± 3; post: 14 ± 2 mmHg; p = 0.01) but not sham (n = 10, peak ∆MAP pre: 13 ± 3; post: 11 ± 2 mmHg; p = 0.68) rats. In a separate group of HF-rEF rats (n = 4), we found that the systemic (intravenous) injection of daltroban had no effect on the EPR (peak ΔMAP pre: 26 ± 7; post: 25 ± 7 mmHg; p = 0.50). Our data suggest that TxA2 -Rs on thin fiber muscle afferents contribute to the exaggerated EPR evoked in response to dynamic muscle contraction in HF-rEF.

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.

Does wearing a facemask decrease arterial blood oxygenation and impair exercise tolerance?

INTRODUCTION: Concerns have been raised that COVID-19 face coverings compromise lung function and pulmonary gas exchange to the extent that they produce arterial hypoxemia and hypercapnia during high intensity exercise resulting in exercise intolerance in recreational exercisers. This study therefore aimed to investigate the effects of a surgical, flannel or vertical-fold N95 masks on cardiorespiratory responses to incremental exercise. METHODS: This investigation studied 11 adult males and females at rest and while performing progressive cycle exercise to exhaustion. We tested the hypotheses that wearing a surgical (S), flannel (F) or horizontal-fold N95 mask compared to no mask (control) would not promote arterial deoxygenation or exercise intolerance nor alter primary cardiovascular variables during submaximal or maximal exercise. RESULTS: Despite the masks significantly increasing end-expired peri-oral %CO2 and reducing %O2, each ∼0.8-2% during exercise (P < 0.05), our results supported the hypotheses. Specifically, none of these masks reduced sub-maximal or maximal exercise arterial O2 saturation (P = 0.744), but ratings of dyspnea were significantly increased (P = 0.007). Moreover, maximal exercise capacity was not compromised nor were there any significant alterations of primary cardiovascular responses (mean arterial pressure, stroke volume, cardiac output) found during sub-maximal exercise. CONCLUSION: Whereas these results are for young healthy recreational male and female exercisers and cannot be applied directly to elite athletes, older or patient populations, they do support that arterial hypoxemia and exercise intolerance are not the obligatory consequences of COVID-19-indicated mask-wearing at least for cycling exercise.

Influence of muscular contraction on vascular conductance during exercise above versus below critical power.

We tested the hypothesis that limb vascular conductance (LVC) would increase during the immediate recovery phase of dynamic exercise above, but not below, critical power (CP) indicating a threshold for muscular contraction-induced impedance of limb blood flow (LBF). CP (115 ± 26 W) was determined in 7 men and 7 women who subsequently performed ∼5 min of near-supine cycling exercise both below and above CP. LVC demonstrated a greater increase during immediate recovery and remained significantly higher following exercise above, compared to below, CP (all p < 0.001). Power output was associated with the immediate increases in LVC following exercise above, but not below, CP (p < 0.001; r = 0.85). Additionally, variance in percent LBF impedance was significantly lower above (CV: 10.7 %), compared to below (CV: 53.2 %), CP (p < 0.01). CP appears to represent a threshold above which the characteristics of LBF impedance by muscular contraction become intensity-dependent. These data suggest a critical level of LBF impedance relative to contraction intensity exists and, once attained, may promote the progressive metabolic and neuromuscular responses known to occur above CP.

Arterial stiffness is associated with cardiovascular and cancer mortality in cancer patients: Insight from NHANESIII.

BACKGROUND: Cancer survivors are at greater risk for cardiovascular disease (CVD) than second malignancy, resulting in a decreased quality of life and increased cost of care. Additional knowledge of CVD prevention by identifying possible risk factors has clinical relevance. Our main objective was to determine the relevance of a clinical index of arterial stiffness, pulse pressure, in predicting CVD mortality in cancer patients, with a second objective to examine its relationship with cancer mortality. METHODS: We retrospectively analyzed 781 cancer patients from Third National Health and Nutrition Examination Survey and Linked Mortality File, including demographic, anthropometric, blood pressure, and cause of death. Kaplan-Meier survival curve and Cox hazard regression analyses were performed to assess the relationship between pulse pressure and cardiovascular, cancer, and all-cause mortality. RESULTS: During a mean follow-up time of 8.1 years, 603 deaths, 257 cancer and 151 CVD, occurred. In unadjusted models, the risk of CVD, cancer, and all-cause mortality were 3.8-fold, 5.3-fold, and 1.6-fold higher, respectively, for pulse pressure ≥70 â€‹mmHg compared to <50 â€‹mmHg. Adjusted analyses revealed a higher CVD mortality in cancer patients <65 years with a pulse pressure 60-70 â€‹mmHg (adjusted hazard ratio, 5.26; 95%CI, 1.12-24.78) when compared to pulse pressure of <50 â€‹mmHg. Pulse pressure was not associated with risk of all-cause, CVD, or cancer in those ≥65 years. CONCLUSION: Pulse pressure, an index of arterial stiffness, is predictive of CVD mortality in cancer patients. Our findings support non-invasive office-setting measurements of arterial stiffness to identify high risk patients.

Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy.

PURPOSE: Cancer patients with a history of radiotherapy are at an increased risk of ischemic heart disease. Preclinical animal studies demonstrate markedly impaired acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation within days to weeks post-irradiation, however, whether microvascular function is affected in the intact human circulation during cancer radiation therapy has yet to be determined. MATERIALS AND METHODS: Using laser-Doppler flowmetry, microvascular endothelium-dependent and independent responses were evaluated through iontophoresis of acetylcholine (ACh) (part 1, n = 7) and sodium nitroprusside (SNP) (part 2, n = 8), respectively, in women currently receiving unilateral chest adjuvant radiation therapy for breast cancer. Measurements were performed at the site of radiation treatment and at a contralateral control, non-radiated site. Cutaneous vascular conductance (CVC) was calculated by normalizing for mean arterial pressure. RESULTS AND CONCULSIONS: In part 1, patients received an average radiation dose of 2104 ± 236 cGy. A significantly lower peak ACh-mediated endothelium-dependent vasodilation was observed within the radiated microvasculature when compared to non-radiated (radiated: 532 ± 167%, non-radiated 1029 ± 263%; P = 0.02). In part 2, the average radiation dose received was 2251 ± 196 cGy. Iontophoresis of SNP elicited a similar peak endothelium-independent vasodilator response in radiated and non-radiated tissue (radiated: 179 ± 58%, non-radiated: 310 ± 158; P = 0.2). The time to 50% of the peak response for ACh and SNP was similar between radiated and non-radiated microvasculature (P < 0.05). These data provide evidence of early endothelium-dependent microvascular dysfunction in cancer patients currently receiving chest radiation and provide the scientific premise for future work evaluating coronary endothelial function and vasomotor reactivity using more detailed and invasive procedures.

Exaggerated sympathetic and cardiovascular responses to dynamic mechanoreflex activation in rats with heart failure: Role of endoperoxide 4 and thromboxane A2 receptors.

The primary purpose of this investigation was to determine the role played by endoperoxide 4 receptors (EP4-R) and thromboxane A2 receptors (TxA2-R) during isolated dynamic muscle mechanoreflex activation in rats with heart failure with reduced ejection fraction (HF-rEF) and sham-operated healthy controls. We found that injection of the EP4-R antagonist L-161,982 (1 µg) into the arterial supply of the hindlimb had no effect on the peak pressor response to dynamic hindlimb muscle stretch in HF-rEF (n = 6, peak ∆MAP pre: 27 ± 7; post: 27 ± 4 mm Hg; P = 0.99) or sham (n = 6, peak ∆MAP pre: 15 ± 3; post: 13 ± 3 mm Hg; P = 0.67) rats. In contrast, injection of the TxA2-R antagonist daltroban (80 µg) into the arterial supply of the hindlimb reduced the pressor response to dynamic hindlimb muscle stretch in HF-rEF (n = 11, peak ∆MAP pre: 28 ± 4; post: 16 ± 2 mm Hg; P = 0.02) but not sham (n = 8, peak ∆MAP pre: 17 ± 3; post: 16 ± 3; P = 0.84) rats. Our data suggest that TxA2-Rs on thin fibre muscle afferents contribute to the exaggerated mechanoreflex in HF-rEF.

Effects of high-intensity training on prostate cancer-induced cardiac atrophy.

BACKGROUND: Recent evidence suggests prostate cancer independent of treatment has atrophic effects on whole heart and left ventricular (LV) masses, associated with reduced endurance exercise capacity. In a pre-clinical model, we tested the hypothesis that high-intensity training could prevent cardiac atrophy with prostate cancer and alter cardiac protein degradation mechanisms. METHODS: Dunning R-3327 AT-1 prostate cancer cells (1×105) were injected into the ventral prostate lobe of 5-6 mo immunocompetent Copenhagen rats (n=24). These animals were randomized into two groups, tumor-bearing exercise (TBEX, n=15) or tumor bearing sedentary (TBS, n=9). Five days after surgery, TBEX animals began exercise on a treadmill (25 m/min, 15° incline) for 45-60 min/day for 18±2 days. Pre-surgery (Pre), and post-exercise training (Post) echocardiographic evaluation (Vivid S6, GE Health Care), using the parasternal short axis view, was used to examine ventricle dimensions. Markers of protein degradation (muscle atrophy F-box, Cathepsin B, Cathepsin L) in the left ventricle were semi-quantified via Western Blot. RESULTS: There were no significant differences in tumor mass between groups (TBEX 3.4±0.7, TBS 2.8±0.6 g, P=0.3), or body mass (TBEX 317±5, TBS 333±7 g, P=0.2). Heart-to-body mass ratio was lower in TBS group compared to TBEX (2.3±0.1 vs. 2.5±0.1 mg/g, P<0.05). LV/body mass ratio was also lower in the TBS group (1.6±0.1 vs. 1.8±0.1 mg/g, P<0.05). From Pre-Post, TBEX had significant increases in SV (~20% P<0.05) whereas TBS had no significant change. There were no significant differences between groups for markers of protein degradation. CONCLUSION: This study suggests that high-intensity exercise can improve LV function and increase LV mass concurrent with prostate cancer development, versus sedentary counterparts. Given cardiac dysfunction often manifests with conventional anti-cancer treatments, a short-term high-intensity training program, prior to treatment, may improve cardiac function and fatigue resistance in cancer patients.