Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis.Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation.Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor.Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Predictors of 5-year survival in patients with chronic heart failure and reduced left ventricular ejection fraction depending on the presence of type 2 diabetes mellitus

The aim – to determine the predictors of 5-year survival of patients with CHF and reduced LV EF depending on the presence of type 2 diabetes mellitus.Materials and methods. 490 case histories of patients in the period from 2011 to 2018 with CHF, 40–80 years of age (median – 64 years), II–IV NYHA functional class, LVEF ≤ 40 % were analyzed. For the analysis of all patients with CHF and reduced LV EF were divided into two groups: Group I included 338 (69 %) patients without diabetes mellitus type 2, group II consisted of 152 (31 %) patients diagnosed with diabetes mellitus type 2. To measure the values ​​of the independent predictors, we calculated the value of the odds ratio (OR) with a 95 % confidence interval. To determine predictors of mortality/survival of the studied patients, was calculated the Хі-square criterion. Additionally, we calculated the estimate of the frequency difference between the groups, the odds ratio, the confidence interval for the odds ratio, the Pearson correlation coefficient r, for all the calculated characteristics we determined the probability of error of the first kind p. As a result, we formed a final table of indicators-predictors of mortality/survival of patients with CHF with reduced LV EF with and without diabetes mellitus type 2 for which there is a statistical relationship between mortality / survival and the studied indicator.Results and discussion. In patients without diabetes, many indicators are associated with the prognosis of long-term survival. These include hemodynamic parameters (heart rate, the left atrium size (LV) and indexed left ventricular (LV) volumes, LV myocardial mass index, right ventricular size (RV) and LV ejection fraction, renal function parameters (microalbuminuria (UIA), glomerular filtration rate (GFR), urea nitrogen), systemic inflammatory marker (C-reactive protein (CRP)), markers of systemic oxidative stress (myeloperoxidase, citrulline, uric acid) and antioxidant defence – SOD, as well as the N-terminal fragment of the precursor of natriuretic peptide (NT-proBNP), flow-dependent vasodilatory response (FDVR), high-density lipoprotein cholesterol (HDL), insulin and the relative content of lymphocytes in the blood. Patients with diabetes had significantly fewer such predictors: in addition to parameters of intracardiac hemodynamics and heart modeling, other significant predictors of 5-year survival were daily UIA level, CRP, SOD, HDL, insulin and the lymphocyte level.Conclusions. Quantitative predictors of poor 5-year survival prognosis among patients with CHF and reduced LV EF with and without concomitant diabetes mellitus type 2 are parameters of heart remodeling, LV systolic function-EF, UIA level, antioxidant stress marker (SOD), HDL level, blood lymphocytes and the level of circulating insulin. Patients without diabetes are characterized by a wider range of poor long-term survival predictors, which include indicators of renal nitrogen function, markers of systemic oxidative stress (myeloperoxidase, citrulline, uric acid), flow-dependent vasodilatory response and circulating NT-proBNP. The determined quantitative predictors can be used in algorithms of individual prediction of the course of CHF and reduced LV EF, which should be created separately for patients with and without concomitant diabetes mellitus type 2

Sickle Cell Cerebrovascular Reactivity to a CO2 Stimulus Is Both Too Little and Too Slow

Background: By age 30, over 50% of sickle cell disease (SCD) patients have suffered a cerebral infarct. In response to anemia and the reduction in oxygen-carrying capacity, cerebral blood flow (CBF) increases to match metabolic demand. Increased velocity of CBF in major cerebral arteries is a strong risk factor for stroke in SCD children and adolescents. Despite generally increased CBF, silent cerebral infarcts (SCI) can still occur in patients receiving optimal transfusions. This suggests that the increased CBF does not meet metabolic demand and that vasodilatory response is compromised. Hypothesis: In adult patients with SCD, cerebrovascular reactivity (slope of the vasodilatory response to CO2 (CVR) and the steady-state CVR (amplitude) and speed of the vasodilatory response (tau) to a standardized vasodilatory stimulus CO2), are reduced compared to normal subjects. We also explored for possible associations with clinical characteristics. Methods: Functional brain imaging performed as part of routine care in adult (≥18) SCD patients (any phenotype) at the University Health Network Comprehensive Sickle Cell Center (Toronto, Canada) between 2017 and 2018 were reviewed. Patients with known cerebral vasculopathy were excluded. CVR was calculated as the change in CBF measured as the blood oxygenation level dependent (BOLD)-MRI signal, in response to a standard vasoactive stimulus of CO2 (delivered by RespirActTM). To calculate the dynamic (tau) and steady-state CVR (amplitude) components of the BOLD signal response, the PET CO2 waveform was convolved with an exponential decay function. The tau corresponding to the best fit between the convolved CO2 and BOLD signal was defined as the speed of vascular response. The slope of the regression between the convolved CO2 and BOLD signal was defined as amplitude. CVR, amplitude and tau were normalized voxel-wise relative to the mean and standard deviation of the same metric in the corresponding voxels of a previously generated atlas of 42 healthy controls (Z scores). These Z scores were averaged over the vascular territories of the brain for both grey (GM) and white matter (WM). Fisher exact and Pearson correlations were performed to identify possible associations between CVR metrics and SCD comorbid conditions, laboratory parameters, and use of disease-modifying therapy. Associations with univariate P <0.20 were included in the multiple linear regression model. Multi-collinearity was assessed. Results: Fifteen patients were included in the study. The median age was 27 [IQR22-35]. 5/15 (33.3%) were male. 9/15 (60%) were SS or S/b0 and 5/15 (33.3%) were SC. 4/15 (26.7%) were on transfusion. MRI/MRA uncovered Moya moya in 1 patient. SCI were present in 3/15 (21.4%). Compared to the reference atlas of normal subjects, CVR and amplitude were reduced both in GM and WM (mean Z-score for CVR -0.52 [-1.8 - 0.28] and -0.63 [-2.31 - 0.66]; amplitude -0.26 [-2.61 - 0.66] and -0.28 [-2.70 - 0.60] respectively). Tau was lengthened in GM and WM (mean tau Z-score +0.90 [-0.49 - 3.32] and +0.76 [-0.66 - 2.78] respectively). These abnormal metrics were observed with varying severities in all 3 main vascular territories (Figure). CVR decreased linearly with decreasing hematocrit (Hct) (r=0.59, p=0.03). There was also a trend towards lower CVR in SS or S/b0 patients (t=-1.41, p=0.18, d=0.76) and was highly collinear with Hct. Hematocrit was the only significant independent predictor of CVR metrics on multivariable regression. Conclusions: All three measures of cerebrovascular health (CVR, amplitude and tau) in SCD patients were abnormal compared to normal controls. Hematocrit appears to be the strongest independent predictor of these measures. The protocol we applied for measuring CVR provides a standardized reproducible vasodilatory stimulus, enabling comparison against a population of healthy individuals for more accurate assessment of CVR in individual subjects. Furthermore, the stimulus protocol produces rapid changes in arterial CO2 levels within one breath that can be used to measure the speed of response of the vasculature representing a novel metric of vascular performance postulated to represent vessel compliance and functional endothelial integrity. These findings show that CVR methodology represents a promising tool to assess disease state, stroke risk, and therapeutic efficacy in sickle cell patients and merits further investigation. Figure 1 Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer - Global Medical Grants: Research Funding. Sobczyk:Thornhill Research Inc.: Current Employment. Duffin:Thornhill Research Inc.: Current Employment. Fisher:Thornhill Research Inc.: Current equity holder in private company. Mikulis:Thornhill Research Inc.: Current equity holder in private company. Kuo:Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Bluebird Bio: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Apellis: Consultancy; Celgene: Consultancy.

Sex-Related Differences in Rapid-Onset Vasodilation: Impact of Aging

Rapid-onset vasodilation (ROV) in response to a single muscle contraction is attenuated with aging. Moreover, sex-related differences in muscle blood flow and vasodilation during dynamic exercise have been observed in young and older adults. The purpose of the present study was to explore if sex-related differences in ROV exist in young (n=36, 25±1 yr) and older (n=32, 66±1 yr) adults. Subjects performed single forearm contractions at 10%, 20%, and 40% maximal voluntary contraction. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, and forearm vascular conductance (ml·min-1·100 mmHg-1) was calculated from blood flow (ml·min-1) and mean arterial pressure (mmHg) and used as a measure of ROV. Peak ROV was attenuated in women across all relative intensities in the young and older groups (P<0.05). In a subset of subjects with similar absolute workloads (~5 kg and ~11kg), age-related differences in ROV were observed among both women and men (P<0.05). However, only older women demonstrated an attenuated peak ROV compared to men (91±6 vs. 121±11 ml·min-1·100 mmHg-1, P<0.05), a difference not observed in the young group (134±8 vs. 154±11 ml·min-1·100 mmHg-1, P=0.15). Additionally, examining the slope of peak ROV across contraction intensities indicated a blunted response in older women compared to their young counterparts (P<0.05), with no differences observed between older and young men (P=0.38). Our data suggest that sex-related differences in the rapid vasodilatory response to single muscle contractions exist in older but not young adults, such that older women have a blunted response compared to older men.

Haemodialysis and peritoneal dialysis patients have severely impaired post-occlusive skin forearm vasodilatory response assessed with laser speckle contrast imaging

Background Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage renal disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined skin microcirculation using laser speckle contrast imaging (LSCI) before and after arterial occlusion in ESRD patients undergoing haemodialysis (HD) or peritoneal dialysis (PD). Methods The 38 HD patients were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion and peak perfusion during post-occlusive reactive hyperaemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC and amplitude of the PORH response (i.e. the difference between peak and baseline CVC). Results Baseline perfusion [HD: 46.97 ± 14.6; PD: 49.32 ± 18.07; controls: 42.02 ± 11.94 laser specle perfusion units (LSPU), P = 0.097] and peak post-occlusion perfusion (104.77 ± 28.68 versus 109.04 ± 40.77 versus 116.96 ± 30.96 LSPU, P = 0.238) did not differ significantly between groups. However, the post-occlusive vascular response was completely different since the proportional increase from baseline to peak perfusion (HD: 133 ± 66; PD: 149 ± 125; controls: 187 ± 61%, P = 0.001) was significantly lower in ESRD patients and time to peak response was lower in HD but similar in PD patients compared with controls (HD: 7.24 ± 6.99; PD: 10.68 ± 9.45; controls: 11.11 ± 5.1 s, Kruskal–Wallis P = 0.003; pairwise comparisons: HD versus controls, P = 0.002; HD versus PD, P = 0.154; PD versus controls, P = 0.406). ESRD patients also had lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05 ± 0.3; PD: 1.07 ± 0.44; controls: 1.57 ± 0.52 LSPU/mmHg, P &lt; 0.001), lower proportional increase of CVC at peak (P &lt; 0.001) and lower amplitude of the PORH response, a measure of the difference between baseline and maximum capillary recruitment (P = 0.001). Conclusions Using this novel non-invasive technology, endothelial post-occlusive forearm skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared with controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and nonadrenergic mechanisms

Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.

ACE (Angiotensin-Converting Enzyme) Inhibition Reverses Vasoconstriction and Impaired Dilation of Pial Collaterals in Chronic Hypertension

Leptomeningeal anastomoses (LMAs) are pial collaterals that perfuse the penumbra and important for stroke outcome. We previously showed LMAs from SHRs (spontaneously hypertensive rats) were vasoconstricted compared with normotensive Wistar rats. Here, we investigated mechanisms by which hypertension causes LMA vasoconstriction. SHRs were treated with the ACE (angiotensin-converting enzyme) inhibitor captopril, an Ang II (angiotensin II)–independent antihypertensive agent hydralazine, or vehicle for 5 weeks in drinking water (n=8/group). A group of Wistar rats (n=8) had regular drinking water served as controls. Blood pressure was measured twice weekly by tail-cuff. LMAs were isolated and studied under pressurized conditions. Vasoreactivity of LMAs, including myogenic responses, reactivity to Rho-kinase inhibitor Y-27632, and nitric oxide were measured. Both captopril and hydralazine lowered blood pressure in SHRs similar to Wistar. However, only captopril normalized LMA increased tone compared with untreated SHRs (15±2% versus 50±3%; P <0.01) that was similar to Wistar (16±2%) but not hydralazine (38±6%; P >0.05). Vasodilatory response of LMAs to Y-27632 was impaired in SHRs compared with Wistar (28±3% versus 81±4%; P <0.01) that was restored by captopril (84±5%; P <0.01) and partially hydralazine (59±4%). LMAs from all groups constricted similarly to NOS (NO synthase) inhibition; however, the vasodilatory response of LMAs to the nitric oxide donor sodium nitroprusside was impaired in SHRs compared with Wistar rats (29±4% versus 80±2%; P <0.01) that was restored by captopril (84±4%; P <0.01), not hydralazine (38±8%; P >0.05). These results suggest that ACE inhibition during chronic hypertension reversed vascular dysfunction and hyperconstriction of LMAs that could improve stroke outcome by increasing collateral perfusion.

P0162HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENTS HAVE SEVERELY IMPAIRED ENDOTHELIAL POST-OCCLUSIVE FOREARM VASODILATORY RESPONSE ASSESSED WITH LASER SPECKLE CONTRAST IMAGING

Background and Aims Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage-renal-disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined forearm skin microcirculation using Laser Speckle Contrast Imaging (LSCi) before and after arterial occlusion in ESRD patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) Method 38 patients undergoing HD were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion, and peak perfusion during post-occlusive reactive hyperemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC; and the amplitude of the PORH response (calculated as the difference between peak and baseline CVC). Results Baseline perfusion [HD: 46.97±14.6; PD: 49.32±18.07; controls: 42.02±11.94 Laser-Specle-Perfusion-Units (LSPU), p=0.097] and peak post-occlusion perfusion (104.77±28.68 vs 109.04±40.77 vs 116.96±30.96 LSPU, p=0.238) did not differ between groups. However, the post-occlusive vascular response was completely different, since time to peak response (HD: 7.24±6.99; PD: 10.68±9.45; controls: 11.11±5.1 sec, p=0.003) and the (%) increase from baseline to peak perfusion (HD: 133%±66; PD: 149%±125; controls: 187%±61, p=0.001) was significantly lower in ESRD patients. ESRD patients had also lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05±0.3; PD: 1.07±0.44; controls: 1.57±0.52 LSPU/mmHg, p&lt;0.001), lower % increase of CVC at peak (p=0.001), and lower amplitude of the PORH response (p=0.001) (a measure of the difference between baseline and maximum capillary recruitment). Conclusion Using this novel non-invasive technology endothelial post-occlusive skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared to controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.