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.

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.

Supplemental oxygen administration during mechanical ventilation reduces diaphragm blood flow and oxygen delivery.

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia. Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e., 21% O2) diminishes diaphragm perfusion and O2 delivery in the quiescent diaphragm, the effect of MV with 100% O2 is unknown. We tested the hypothesis that MV supplemented with hyperoxic gas (100% O2) would increase diaphragm vascular resistance and reduce diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (4-6 mo) were randomly divided into two groups: 1) MV + 100% O2 followed by MV + 21% O2 (n = 9) or 2) MV + 21% O2 followed by MV + 100% O2 (n = 10). Diaphragmatic blood flow (mL/min/100 g) and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV + 100% O2, and MV + 21% O2. Compared with SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV + 100% O2 and MV + 21% O2 (all P < 0.05). Medial costal diaphragmatic blood flow was lower with MV + 100% O2 (26 ± 6 mL/min/100 g) versus MV + 21% O2 (51 ± 15 mL/min/100 g; P < 0.05). Second, the addition of 100% O2 during normoxic MV exacerbated the MV-induced reductions in medial costal diaphragm perfusion (23 ± 7 vs. 51 ± 15 mL/min/100 g; P < 0.05) and O2 delivery (3.4 ± 0.2 vs. 6.4 ± 0.3 mL O2/min/100 g; P < 0.05). These data demonstrate that administration of supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a significantly greater degree than normoxic MV. This suggests that prolonged bouts of MV (i.e., 6 h) with hyperoxia may accelerate MV-induced vascular dysfunction in the quiescent diaphragm and potentially exacerbate downstream contractile dysfunction.NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that supplemental oxygen (i.e., 100% O2) during mechanical ventilation (MV) augments the MV-induced reductions in diaphragmatic blood flow and O2 delivery. The accelerated reduction in diaphragmatic blood flow with hyperoxic MV would be expected to potentiate MV-induced diaphragm vascular dysfunction and consequently, downstream contractile dysfunction. The data presented herein provide a putative mechanism for the exacerbated oxidative stress and diaphragm dysfunction reported with prolonged hyperoxic MV.

Prolonged mechanical ventilation increases diaphragm arteriole circumferential stretch without changes in stress/stretch: Implications for the pathogenesis of ventilator-induced diaphragm dysfunction.

INTRODUCTION: Prolonged mechanical ventilation (MV; ≥6 h) results in large, time-dependent reductions in diaphragmatic blood flow and shear stress. We tested the hypothesis that MV would impair the structural and material properties (ie, increased stress/stretch relation and/or circumferential stretch) of first-order arterioles (1A) from the medial costal diaphragm. METHODS: Shear stress was estimated from isolated arterioles and prior blood flow data from the diaphragm during spontaneous breathing (SB) and prolonged MV (6 h MV). Thereafter, female Sprague-Dawley rats (~5 months) were randomly divided into two groups, SB (n = 6) and 6 h MV (n = 6). Following SB and 6 h MV, 1A medial costal diaphragm arterioles were isolated, cannulated, and subjected to stepwise (0-140 cmH2 O) increases in intraluminal pressure in calcium-free Ringer's solution. Inner diameter and wall thickness were measured at each pressure step and used to calculate wall:lumen ratio, Cauchy-stress, and circumferential stretch. RESULTS: Compared to SB, there was a ~90% reduction in arteriolar shear stress with prolonged MV (9 ± 2 vs 78 ± 20 dynes/cm2 ; p ≤ .05). In the unloaded condition (0 cmH2 O), the arteriolar intraluminal diameter was reduced (37 ± 8 vs 79 ± 13 µm) and wall:lumen ratio was increased (120 ± 18 vs 46 ± 10%) compared to SB (p ≤ .05). There were no differences in the passive diameter responses or the circumferential stress/stretch relationship between groups (p > .05), but at each pressure step, circumferential stretch was increased with 6 h MV vs SB (p ≤ .05). CONCLUSION: During prolonged MV, medial costal diaphragm arteriolar shear stress is severely diminished. Despite no change in the material behavior (stress/stretch), prolonged MV resulted in altered structural and mechanical properties (ie, elevated circumferential stretch) of medial costal diaphragm arterioles. This provides important novel mechanistic insights into the impaired diaphragm blood flow capacity and vascular dysfunction following prolonged MV.

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.

Effects of elevated positive end-expiratory pressure on diaphragmatic blood flow and vascular resistance during mechanical ventilation.

Although mechanical ventilation (MV) is a life-saving intervention, prolonged MV can lead to deleterious effects on diaphragm function, including vascular incompetence and weaning failure. During MV, positive end-expiratory pressure (PEEP) is used to maintain small airway patency and mitigate alveolar damage. We tested the hypothesis that increased intrathoracic pressure with high levels of PEEP would increase diaphragm vascular resistance and decrease perfusion. Female Sprague-Dawley rats (~6 mo) were randomly divided into two groups receiving low PEEP (1 cmH2O; n = 10) or high PEEP (9 cmH2O; n = 9) during MV. Blood flow, via fluorescent microspheres, was determined during spontaneous breathing (SB), low-PEEP MV, high-PEEP MV, low-PEEP MV + surgical laparotomy (LAP), and high-PEEP MV + pneumothorax (PTX). Compared with SB, both low-PEEP MV and high-PEEP MV increased total diaphragm and medial costal vascular resistance (P ≤ 0.05) and reduced total and medial costal diaphragm blood flow (P ≤ 0.05). Also, during MV medial costal diaphragm vascular resistance was greater and blood flow lower with high-PEEP MV vs. low-PEEP MV (P ≤ 0.05). Diaphragm perfusion with high-PEEP MV+PTX and low-PEEP MV were not different (P > 0.05). The reduced total and medial costal diaphragmatic blood flow with low-PEEP MV appears to be independent of intrathoracic pressure changes and is attributed to increased vascular resistance and diaphragm quiescence. Mechanical compression of the diaphragm vasculature may play a role in the lower diaphragmatic blood flow at higher levels of PEEP. These reductions in blood flow to the quiescent diaphragm during MV could predispose critically ill patients to weaning complications.NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that mechanical ventilation, with low and high positive-end expiratory pressure (PEEP), increases vascular resistance and reduces total and regional diaphragm perfusion. The rapid reduction in diaphragm perfusion and increased vascular resistance may initiate a cascade of events that predispose the diaphragm to vascular and thus contractile dysfunction with prolonged mechanical ventilation.

Impaired diaphragm resistance vessel vasodilation with prolonged mechanical ventilation.

Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4-8 mo, n = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; P ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; P ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; P ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression (P ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; P ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms.NEW & NOTEWORTHY Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.

Prostate cancer cell growth characteristics in serum and prostate-conditioned media from moderate-intensity exercise-trained healthy and tumor-bearing rats.

Physical activity is associated with diminished risk of several cancers, and preclinical studies suggest exercise training may alter tumor cell growth in certain tissue(s) (e.g., adipose). From moderate-intensity exercise-trained rats versus sedentary controls, we hypothesized 1) there will be a decreased prostate cancer cell viability and migration in vitro and, within the prostate, a reduced 5α-reductase 2 (5αR2) and increased caspase-3 expression, and 2) that exercise training in tumor-bearing (TB) animals will demonstrate a reduced tumor cell viability in prostate-conditioned media. Serum and prostate were harvested from sedentary or exercise-trained (treadmill running, 10-11 weeks) immune-competent (Copenhagen; n = 20) and -deficient (Nude; n = 18) rats. AT-1 and PC-3 prostate cancer cells were grown in one or more of the following: serum-supplemented media (SSM), SSM from TB rats (SSM-TB), prostate-conditioned media (PCM) or PCM from TB rats (PCM-TB) for 24-96 h under normoxic (18.6% O2) or hypoxic (5% O2) conditions. Under normoxic condition, there was a decreased AT-1 cell viability in SSM and PCM from the exercise-trained (ET) immune-competent rats, but no difference in PC-3 cell viability in SSM and PCM from ET Nude rats versus the sedentary (SED) group, or in SSM-TB from ET-TB Nude rats versus the SED-TB group. However, there was a decreased PC-3 cell viability in the PCM-TB of the ET-TB group versus SED-TB group. PC-3 cell viability in all conditioned media types was not altered between groups with hypoxia. In the prostate, exercise training did not alter 5αR2 expression levels, but increased caspase-3 expression levels. In conclusion, prior exercise status reduced prostate cancer cell viability in the serum and prostate of trained rats but did not modify several other key prostate tumor cell growth characteristics (e.g., migration, cell cycle except in S phase of PC-3 cells in PCM-TB). Importantly, once the tumor was established, exercise training reduced tumor cell viability in the surrounding prostate, which may help explain the reduced severity of the disease in patients that exercise.