068 Morning Cardiovascular Function in Chronic Cannabis Users and Healthy Controls

Introduction In the US cannabis is recreationally legal in 15 states and medically legal in 34 states. Preclinical studies suggest beneficial effects of cannabis on the cardiovascular system (e.g., vasorelaxation). Yet, acute cases of hospitalization after cannabis consumption indicate potential adverse cardiac effects. Vascular endothelial function is a marker of cardiovascular disease and is measured as a change in resting brachial artery diameter (flow-mediated dilation, FMD) during reactive hyperemia. Both resting diameter (positively) and FMD response (negatively) are associated with cardiovascular risk. Resting diameter likely depends on long-term structural changes, and FMD response mostly depends on nitric oxide. Reactive hyperemia is more complex and depends on numerous variables, including adenosine and prostaglandins. FMD is attenuated in the morning when the frequency of adverse cardiovascular events peaks. To begin to understand the effects of chronic cannabis use on the cardiovascular system, in this pilot study, we compared morning measurements of vascular endothelial function, blood pressure, and heart rate between chronic cannabis users and controls while controlling for prior nighttime sleep opportunities. Methods Participants, cannabis non-users (n=5) and users (n=4), 44% female, age 25.4 ± 3.6 years - no demographic differences between groups, kept a consistent 2-week sleep schedule at home followed by an 8h sleep opportunity at their habitual time in the laboratory. Upon-wakening, we measured resting blood pressure, heart rate, baseline diameter, hyperemic response, and FMD. Statistical differences between groups were calculated using a two-tailed t-test. Results Systolic and diastolic blood pressures (p=0.13 and 0.26 respectively), heart rate (p=0.97), and FMD response (p=0.99) did not differ between groups. However, chronic cannabis users had a significantly higher baseline brachial artery diameter (mean difference: 1.04 mm ± 0.26, p=0.005), and lower hyperemic response (mean difference: -7944 iu/s ± 2538, p=0.02) compared to non-users. Conclusion These preliminary findings suggest that chronic cannabis consumption may be associated with adverse structural and functional changes in the vasculature of otherwise healthy young adults. Based on these initial observations, cannabis may act on the cardiovascular system via non-nitric oxide mechanisms. However, it is necessary to increase our sample size to test the robustness of these findings. Support (if any) KL2TR002370, AASM

Role of endothelium-pericyte signaling in capillary blood flow response to neuronal activity

Local blood flow in the brain is tightly coupled to metabolic demands, a phenomenon termed functional hyperemia. Both capillaries and arterioles contribute to the hyperemic response to neuronal activity via different mechanisms and timescales. The nature and specific signaling involved in the hyperemic response of capillaries versus arterioles, and their temporal relationship are not fully defined. We determined the time-dependent changes in capillary flux and diameter versus arteriolar velocity and flow following whisker stimulation using optical microangiography (OMAG) and two-photon microscopy. We further characterized depth-resolved responses of individual capillaries versus capillary networks. We hypothesized that capillaries respond first to neuronal activation, and that they exhibit a coordinated response mediated via endothelial-derived epoxyeicosatrienoates (EETs) acting on pericytes. To visualize peri-capillary pericytes, we used Tie2-GFP/NG2-DsRed mice, and to determine the role of endothelial-derived EETs, we compared cerebrovascular responses to whisker stimulation between wild-type mice and mice with lower endothelial EETs (Tie2-hsEH). We found that capillaries respond immediately to neuronal activation in an orchestrated network-level manner, a response attenuated in Tie2-hsEH and inhibited by blocking EETs action on pericytes. These results demonstrate that capillaries are first responders during functional hyperemia, and that they exhibit a network-level response mediated via endothelial-derived EETs’ action on peri-capillary pericytes.

Using reactive hyperemia to investigate the effect of cupping sizes of cupping therapy on skin blood flow responses

BACKGROUND: Various cupping sizes of cupping therapy have been used in managing musculoskeletal conditions; however, the effect of cupping sizes on skin blood flow (SBF) responses is largely unknown. OBJECTIVE: The objective of this study was to compare the effect of three cupping sizes of cupping therapy on SBF responses. METHODS: Laser Doppler flowmetry (LDF) was used to measure SBF on the triceps in 12 healthy participants in this repeated measures study. Three cup sizes (35, 40 and 45 mm in diameter) were blinded to the participants and were tested at -300 mmHg for 5 minutes. Reactive hyperemic response to cupping therapy was expressed as a ratio of baseline SBF. RESULTS: All three sizes of cupping cups resulted in a significant increase in peak SBF (p< 0.001). Peak SBF of the 45 mm cup (9.41 ± 1.32 times) was significantly higher than the 35 mm cup (5.62 ± 1.42 times, p< 0.05). Total SBF of the 45 mm cup ((24.33 ± 8.72) × 103 times) was significantly higher than the 35 mm cup ((8.05 ± 1.63) × 103 times, p< 0.05). Recovery time of the 45 mm cup (287.46 ± 39.54 seconds) was significantly longer than the 35 mm cup (180.12 ± 1.42 seconds, p< 0.05). CONCLUSIONS: Our results show that all three cup sizes can significantly increase SBF. The 45 mm cup is more effective in increasing SBF compared to the 35 mm cup.

The role of the endothelium in the hyperemic response to passive leg movement: looking beyond nitric oxide

Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite NO synthase (NOS) inhibition. Therefore, in 9 young healthy men (25±4 yrs), this investigation aimed to determine if the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement) when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl L-arginine (L-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P450 (CYP450) by L-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF (LBFAUC) response to both PLM (control: 456±194, L-NMMA: 168±127 ml, p<0.01) and sPLM (control: 185±171, L-NMMA: 62±31 ml, p=0.03). The combined inhibition of NOS, COX, and CYP450 (i.e. L-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271±97 ml, p>0.05) or sPLM (LBFAUC: 72±45 ml, p>0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent, hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.

Intracoronary Saline‐Induced Hyperemia During Coronary Thermodilution Measurements of Absolute Coronary Blood Flow: An Animal Mechanistic Study

Background Absolute hyperemic coronary blood flow and microvascular resistances can be measured by continuous thermodilution with a dedicated infusion catheter. We aimed to determine the mechanisms of this hyperemic response in animal. Methods and Results Twenty open chest pigs were instrumented with flow probes on coronary arteries. The following possible mechanisms of saline‐induced hyperemia were explored compared with maximal hyperemia achieve with adenosine by testing: (1) various infusion rates; (2) various infusion content and temperature; (3) NO production inhibition with L‐arginine methyl ester and endothelial denudation; (4) effects of vibrations generated by rotational atherectomy and of infusion through one end‐hole versus side‐holes. Saline infusion rates of 5, 10 and 15 mL/min did not reach maximal hyperemia as compared with adenosine. Percentage of coronary blood flow expressed in percent of the coronary blood flow after adenosine were 48±17% at baseline, 57±18% at 5 mL/min, 65±17% at 10 mL/min, 82±26% at 15 mL/min and 107±18% at 20 mL/min. Maximal hyperemia was observed during infusion of both saline at body temperature and glucose 5%, after endothelial denudation, l‐ arginine methyl ester administration, and after stent implantation. The activation of a Rota burr in the first millimeters of the epicardial artery also induced maximal hyperemia. Maximal hyperemia was achieved by infusion through lateral side‐holes but not through an end‐hole catheter. Conclusions Infusion of saline at 20 mL/min through a catheter with side holes in the first millimeters of the epicardial artery induces maximal hyperemia. The data indicate that this vasodilation is related neither to the composition/temperature of the indicator nor is it endothelial mediated. It is suggested that it could be elicited by epicardial wall vibrations.

P4502Noninvasively assessed mitochondrial function estimated by skin fluorescence is abnormal in coronary artery disease

Mitochondrial NADH undergoes oxygenation to NAD+ and NADH molecules, activated by ultraviolet light, start to emit fluorescence at a wavelength 460nm. This phenomenon can be measured to non-invasively assess mitochondrial function in the forearm epidermis at rest, during transient ischaemia, and afterward reperfusion assuming that it reflects abnormal microvascular circulation. We hypothesized that flow-dependent skin fluorescence (FDSF) is abnormal in patients with coronary atherosclerosis. Methods Prototype device manufactured by Angionica (Poland) was used to quantify FDSF recorded in forearm before, during and after 100 s of brachial artery occlusion in 63 individuals (26 with coronary artery disease (CAD) and 37 healthy volunteers. The absolute value of baseline FDSF (BASE), maximum FDSF (MAX), minimal FDSF (MIN), percentage ischemic response (IR) and hyperemic response (HR) were measured. Age, lipid profile, fasting glucose, HbA1c, C-reactive protein (CRP), systolic and diastolic blood pressure, pulse wave velocity (PWV), augmentation index, time domain heart rate variability parameters (SDNN, rMSSD) and estimated apnea/hypopnea index -eAHI (Holter ECG based), BMI, intima-media thickness (IMT), left ventricle systolic and diastolic function were determined in all study participants to search for potential correlations with FDSF. Results Measurements were feasible in all study subjects and examination duration was 9±1min. Hyperemic response (HR) was significantly lower in patients with CAD vs controls: 10,4 vs. 14,36 vs 14,73 – p=0,025. Other parameters: BASE, MAX, MIN, and IR were not significantly different between groups (p>0,05). In the entire group, HR was correlated with age (r=−0,23 p=0,037), and with total or LDL cholesterol (r=0,37 p=0,001 and r=0,36 p=0,001). Interestingly, HR was also positively correlated with SDNN (r=0,26 p=0,044) and rMSSD (r=0,29 p=0,026). Mode of FDSF examination Conclusion Abnormal mitochondrial function probably secondary to microcirculatory disorder is detectable by noninvasive skin fluorescence test as decreased hyperemic response in patients with coronary disease. Age and cholesterol concentration as well as autonomic balance Holter indices are correlated with hyperemic response. Acknowledgement/Funding POIR.01.01.01.0540/15-00

Serum Phosphate and Microvascular Function in a Population-Based Cohort

Background and objectivesHigher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking.Design, setting, participants, & measurementsWe performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light–induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light–induced retinal arteriolar, and venular dilation.ResultsThe mean age of the cohort was 59±8 years, 48% were women, 7% had an eGFR <60 ml/min per 1.73 m2, and the mean serum phosphate concentration was 3.2±0.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, −10.0% to −0.1%). Results were similar for capillary recruitment with venous congestion (−4.5%; 95% CI, −9.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, −0.44% to −0.02%). A higher serum phosphate was not associated with change in flicker light–induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (−149% [95% CI, −260 to −38] per 1 mg/dl higher serum phosphate) but not women (P interaction, 0.01).ConclusionsHigher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_20_CJN02610319.mp3