Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

The effect of glucose tolerance test on fetoplacental circulation.

OBJECTIVE: Acute hyperglycemia affects the fetoplacental circulation. This study aims to investigate the possible effect of acute hyperglycemia induced by 50 g oral glucose tolerance test (OGTT) on fetoplacental circulation in women between 24 and 28 weeks of gestation. MATERIALS AND METHODS: Between January 2019 and April 2019, a total of 29 women who were between 24 and 28 weeks of gestation with a singleton gestation and were in low-risk group were included in this prospective study. All patients underwent fetal biometric measurements using ultrasonography (USG) and were administered 50 g OGTT. Before and 1 h after the test, Doppler USG was used to measure uterine artery, umbilical artery (UA), middle cerebral artery (MCA), pulsatility index (PI), resistance index (RI), and systolic/diastolic (S/D) ratio. The cerebroplacental ratio (CPR) was calculated as the ratio of the MCA-PI/UA-PI. RESULTS: There was a decline in the MCA-RI (p = 0.008) and UA-PI (p = 0.021) at 1 h after the administration of 50 g OGTT. Z-scores of the mean UA-PI, MCA-PI, and CPR were calculated and a statistically significant increase in the Z-scores of the mean UA-PI was observed (p = 0.028). CONCLUSION: Our study results show that acute hyperglycemia induced by OGTT significantly increases the Z-scores of the UA-PI, affecting the fetoplacental circulation.

Indirect Suppression of Pulsatile LH Secretion by CRH Neurons in the Female Mouse.

Acute stress is a potent suppressor of pulsatile luteinizing hormone (LH) secretion, but the mechanisms through which corticotrophin-releasing hormone (CRH) neurons inhibit gonadotropin-releasing hormone (GnRH) release remain unclear. The activation of paraventricular nucleus (PVN) CRH neurons with Cre-dependent hM3Dq in Crh-Cre female mice resulted in the robust suppression of pulsatile LH secretion. Channelrhodopsin (ChR2)-assisted circuit mapping revealed that PVN CRH neuron projections existed around kisspeptin neurons in the arcuate nucleus (ARN) although many more fibers made close appositions with GnRH neuron distal dendrons in the ventral ARN. Acutely prepared brain slice electrophysiology experiments in GnRH- green fluorescent protein (GFP) mice showed a dose-dependent (30 and 300 nM CRH) activation of firing in ~20% of GnRH neurons in both intact diestrus and ovariectomized mice with inhibitory effects being uncommon (<8%). Confocal GCaMP6 imaging of GnRH neuron distal dendrons in acute para-horizontal brain slices from GnRH-Cre mice injected with Cre-dependent GCaMP6s adeno-associated viruses demonstrated no effects of 30 to 300 nM CRH on GnRH neuron dendron calcium concentrations. Electrophysiological recordings of ARN kisspeptin neurons in Crh-Cre,Kiss1-GFP mice revealed no effects of 30 -300 nM CRH on basal or neurokinin B-stimulated firing rate. Similarly, the optogenetic activation (2-20 Hz) of CRH nerve terminals in the ARN of Crh-Cre,Kiss1-GFP mice injected with Cre-dependent ChR2 had no effect on kisspeptin neuron firing. Together, these studies demonstrate that PVN CRH neurons potently suppress LH pulsatility but do not exert direct inhibitory control over GnRH neurons, at their cell body or dendron, or the ARN kisspeptin neuron pulse generator in the female mouse.

Effects of dexamethasone on foetal Doppler flow velocimetry.

Corticosteroid administration before anticipated preterm birth is a well known antenatal therapy available to improve newborn outcomes. Doppler studies of maternal and foetal vessels provide a way to understand how corticosteroid affects and improves foetal respiratory outcome. This study was registered on 8th of October, 2017 by Menoufia Faculty of Medicine Board with registration number 222-2-10-2017. It included 80 pregnant women divided into two groups. Each group consisted of 40 participants. Group A: participants were between 28 weeks and 34 weeks of gestation and were at risk of preterm labour. Group B: participants were those who had undergone an elective caesarean section (CS) before completing the 39th week of gestation. Each woman had received four doses of Dexamethasone 6 mg intramuscularly, 12 h apart. Doppler studies were performed before the Dexamethasone adminstration and 24 h after the Dexamethasone course. Among both groups, only pregnant women before 34 weeks of gestation showed a significant decrease in middle cerebral artery pulsatility index. However, the other Doppler parameters showed no significant effect. In conclusion, Dexamethasone administration affected only the middle cerebral artery pulsatility index before 34 weeks of gestation.IMPACT STATEMENTWhat is already known on this subject? Preterm births account for 75% of neonatal morbidity and pulmonary dysfunction plays an important role on such morbidities. Also, neonates born after an elective CS have significantly higher rates of respiratory morbidity and neonatal intensive care unit admission. Corticosteroids are wildly used to improve neonatal outcome in women who have expected preterm labour and before an elective CS.What do the results of this study add? Dexamethasone affected blood distribution of foetal brain only before 34 weeks of gestation that had been proved by changes of foetal middle cerebral artery pulsatility index without affecting other Doppler parameters of both groups. With the improvement of foetal respiratory outcome in both groups.What are the implications of these finding for clinical practice and/or further research? Maternal Dexamethasone injection is recommended for mothers at risk of preterm labour, especially if delivery is expected within six days and mothers who will undergo elective CS before completion of 39 weeks of gestation, in terms of improving neonatal respiratory functions and decreasing the possibility of admission to neonatal intensive care unit for transient tachypnoea of the newborn.

To study the changes in maternal hemodynamics with intravenous labetalol or nifedipine in acute severe hypertension.

OBJECTIVE: To study the maternal hemodynamic changes in acute severe hypertension after treatment with intravenous labetalol or oral nifedipine using color doppler ultrasound. STUDY DESIGN: We evaluated thirty pregnant women with gestational age between 28 and 40 weeks in acute severe hypertension (more than or equal to 160/105 mmHg) which were randomly allocated to receive either intravenous labetalol or oral nifedipine until blood pressure was lowered to less than or equal to 140/90 mmHg. Doppler vascular indices namely pulsatility index, resistance index, S/D ratio of bilateral uterine arteries and maternal renal artery were measured baseline at the time of acute severe hypertension and repeated after control of blood pressure, to assess the changes in maternal hemodynamics if any with labetalol or nifedipine. RESULTS: When evaluating right uterine artery Doppler parameters, a trend to increase in PI and RI was observed in those who received labetalol and nifedipine however the difference was not statistically significant. Whereas, while evaluating left uterine artery indices a trend to decrease PI was seen in nifedipine group but the difference was not statistically significant. On intergroup comparison there was no any significant change in any of uterine artery as well as renal artery indices in either group. CONCLUSION: The use of labetalol and nifedipine were not related to any significant changes in maternal Doppler, which is reassuring about the safety of these drugs when treating acute severe hypertension in pregnancy.

Hyperdynamic circulatory syndrome in a mouse model transgenic for SerpinB3.

INTRODUCTION AND OBJECTIVES: SerpinB3 is a cysteine protease inhibitor involved in several biological activities. It is progressively expressed in chronic liver disease, but not in normal liver. The role in vascular reactivity of this serpin, belonging to the same family of Angiotensin II, is still unknown. Our aim was to evaluate the in vivo and in vitro effects of SerpinB3 on systemic and splanchnic hemodynamics. MATERIAL AND METHODS: Different hemodynamic parameters were evaluated by ultrasonography in two colonies of mice (transgenic for human SerpinB3 and C57BL/6J controls) at baseline and after chronic carbon tetrachloride (CCl4) treatment. In vitro SerpinB3 effect on mesenteric microvessels of 5 Wistar-Kyoto rats was analyzed measuring its direct action on: (a) preconstricted arteries, (b) dose-response curves to phenylephrine, before and after inhibition of angiotensin II type 1 receptors with irbesartan. Hearts of SerpinB3 transgenic mice and of the corresponding controls were also analyzed by morphometric assessment. RESULTS: In SerpinB3 transgenic mice, cardiac output (51.6±21.5 vs 30.1±10.8ml/min, p=0.003), hepatic artery pulsatility index (0.85±0.13 vs 0.65±0.11, p<0.001) and portal vein blood flow (5.3±3.2 vs 3.1±1.8ml/min, p=0.03) were significantly increased, compared to controls. In vitro, recombinant SerpinB3 had no direct hemodynamic effect on mesenteric arteries, but it increased their sensitivity to phenylephrine-mediated vasoconstriction (p<0.01). This effect was suppressed by inhibiting angiotensin II type-1 receptors. CONCLUSIONS: In transgenic mice, SerpinB3 is associated with a hyperdynamic circulatory syndrome-like pattern, possibly mediated by angiotensin receptors.

Pulmonary artery pulsatility index predicts prolonged inotrope/pulmonary vasodilator use after implantation of continuous flow left ventricular assist device.

OBJECTIVE: Predictors of right ventricle (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation in children are not well described. We explored the association of preimplantation Pulmonary Artery Pulsatility index (PAPi) and other hemodynamic parameters as predictors of prolonged postoperative inotropes/pulmonary vasodilator use after CF-LVAD implantation. DESIGN: Retrospective chart review. SETTING: Single tertiary care pediatric referral center. PATIENTS: Patients who underwent CF-LVAD implantation from January 2012 to October 2017. INTERVENTIONS: Preimplantation invasive hemodynamic parameters were analyzed to evaluate the association with post-CF-LVAD need for prolonged (>72 hours) use of inotropes/pulmonary vasodilators. MEASUREMENTS AND MAIN RESULTS: Preimplantation cardiac catheterization data was available for 12 of 44 patients who underwent CF-LVAD implant during the study period. Median (IQR) age and BSA of the cohort were 15.3 years (10.2, 18) and 1.74 m2 (0.98, 2.03). Group 1 (n = 6) included patients with need for prolonged inotropes/pulmonary vasodilator use after CF-LVAD implantation and Group 2 (n = 6) included those without. Baseline demographic parameters, cardiopulmonary bypass time, and markers of RV afterload (pulmonary vascular resistance, PA compliance and elastance) were similar among the two groups. PAPi was significantly lower in group 1 compared to group 2 (0.96 vs 3.6, respectively; P = .004). Post-LVAD stay in the intensive care unit was longer for patients in group 1 (46 vs 23 days, P = .52). Brain natriuretic peptide was significantly higher at 3 months after implantation in group 1; P = .01. CONCLUSIONS: The need for inotropes/pulmonary vasodilators in the postoperative period can be predicted by the preimplantation intrinsic RV contractile reserve as assessed by PAPi rather than the markers of RV afterload. Further investigation and correlation with clinical outcomes is needed.

Cerebrovascular reactivity after cessation of menopausal hormone treatment.

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17ß-estradiol, or placebo [PLA]). RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p = 0.029) in the combined MHT group compared with the PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3 years after cessation of hormone treatment.

Psychosomatic symptoms during South East Asian haze crisis are related to changes in cerebral hemodynamics.

OBJECTIVES: Forest fires in South Asia lead to widespread haze, where many healthy individuals develop psychosomatic symptoms. We investigated the effects of haze exposure on cerebral hemodynamics and new symptoms. We hypothesised that vasoactive substances present in the haze, would lead to vasodilation of cerebral vasculature, thereby altering cerebral hemodynamics, which in turn may account for new psychosomatic symptoms. METHODS: Seventy-four healthy volunteers were recruited, and serial transcranial Doppler (TCD) ultrasonography was performed to record blood flow parameters of bilateral middle cerebral arteries (MCA). The first TCD was performed in an air-conditioned environment. It was repeated outdoors after the participants spent 30-minutes in the haze environment. The prevailing level of pollutant standards index (PSI) was recorded. Appropriate statistical analyses were performed to compare cerebral hemodynamics at baseline and after haze exposure in all participants. Subgroup analyses were then employed to compare the findings between symptomatic and asymptomatic participants. RESULTS: Study participants' median age was 30 years (IQR 26-34), and new psychosomatic symptoms were reported by 35 (47.3%). There was a modest but significant decrease in pulsatility index (PI) and resistivity index (RI) in the left MCA after haze exposure (PI: p = 0.026; RI: p = 0.021). When compared to baseline parameters, haze exposure resulted in significantly lower mean PI (p = 0.001) and RI (p = 0.001) in symptomatic patients, but this difference was not present in asymptomatic patients (PI: p = 0.919; RI: p = 0.970). CONCLUSION: Haze causes significant alterations in cerebral hemodynamics in susceptible individuals, probably responsible for various psychosomatic symptoms. The prognostic implications and health effects of haze require evaluation in a larger study.

Non-pulsatile blood flow is associated with enhanced cerebrovascular carbon dioxide reactivity and an attenuated relationship between cerebral blood flow and regional brain oxygenation.

BACKGROUND: Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon-especially when CO2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2 reactivity (CVR) and regional brain oxygenation (rSO2). METHODS: In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2 was determined during step changes of PaCO2 between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2 alterations were determined for each flow mode. Each patient served as her own control. RESULTS: MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO2 slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8-16.9] and 10.4 cm/s/mmHg [CI 7.9-13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg, p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO2 and ΔMCAv was less pronounced during non-pulsatile flow. CONCLUSIONS: Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO2/ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed. TRIAL REGISTRATION: The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury.

BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

Uterine artery flow velocity waveform, arterial flow indices, follicular dynamics, and sex hormones during preovulatory period in synchronized ovulatory cycle of Bos indicus beef cows.

A greater understanding of the uterine artery's (UtA) biology is essential to the increase in female reproductive abilities. The UtA flow velocity waveform, blood flow volume (BFV), pulsatility and resistance indices (PI and RI), blood flow velocities, dynamics of the dominant follicle (DF), and estradiol (E2) and progesterone (P4) levels in an induced ovulatory cycle were evaluated in Thai native cattle. Twenty cows were induced with synchronized ovulation through a P4-releasing device, from Day -9 to Day -4, concurrent with the administration of two doses of a gonadotropin-releasing hormone on Day -9 and Day -1, and two doses of prostaglandin F2α on Day -4 and 8 h later. Day 0 was designated as the day of ovulation. The cows underwent Doppler sonographic determination and blood collection from Day -4 to Day 0. The cows were classified in the non-ovulating (n = 5) and ovulating groups (n = 15). The ovulating cows presented higher BFV values, blood flow velocities, DF growth rates, and E2 levels; yet lower PI values and P4 concentrations, than those of the non-ovulating cows. The BFV values and the blood flow velocities were greater, but the RI and PI values were lower in the ovulatory side UtA than in the contraovulatory side UtA. The BFV values were positively correlated with blood flow velocities, DF growth rates and E2 concentrations in the ovulating cows; confirming the importance of UtA blood flow, follicular growth, and E2-vasodilation during preovulatory phase in the induced ovulatory cycle of Bos indicus beef cows.

Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin.

Context: Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely. Objective: To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA. Design: Nonrandomized, interventional trial. Setting: Academic clinical research unit. Participants: Ten adolescent girls with HA. Intervention: The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed. Main Outcome Measure: Metformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level]. Results: Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use. Conclusion: Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.

Acute impact of drinking coffee on the cerebral and systemic vasculature.

Previous studies have suggested that the risk of ischemic stroke increases immediately after drinking coffee. Indeed, drinking coffee, that is, caffeine, acutely increases arterial stiffness as well as blood pressure and peripheral vascular resistance. On the other hand, it has been reported that arterial stiffening is associated with elevation in the pulsatility index (PI) of cerebral blood flow (CBF), which increases the risk of brain disease. However, the effect of drinking coffee on the PI of the CBF and its interaction with arterial stiffness remain unknown. Against this background, we hypothesized that an acute increase in arterial stiffness induced by drinking coffee augments cerebral pulsatile stress. To test this hypothesis, in 10 healthy young men we examined the effects of drinking coffee on the PI of middle cerebral artery blood velocity (MCAv) and brachial-ankle pulse wave velocity (baPWV) as indices of cerebral pulsatile stress and arterial stiffness, respectively. Mean arterial blood pressure and baPWV were higher (P < 0.01 and P = 0.02), whereas mean MCAV and mean cerebrovascular conductance index were lower upon drinking coffee (P = 0.02 and P < 0.01) compared with a placebo (decaffeinated coffee). However, there was no difference in the PI of MCAv between drinking coffee and the placebo condition. These findings suggest that drinking coffee does not increase cerebral pulsatile stress acutely despite an elevation in arterial stiffness in the systemic circulation.

Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy.

PURPOSE: To investigate the effect of cilostazol on ocular hemodynamics and to determine whether the administration of cilostazol increases the ocular blood flow in patients with diabetic retinopathy. METHODS: This prospective observational study investigated the effect of orally administered cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment. RESULTS: Twenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 ± 4.6 µL/sec vs. 19.6 ± 6.2 µL/sec, p < 0.001) after administration of cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 ± 5.6 cm/sec vs. 26.0 ± 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007). CONCLUSIONS: Cilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation.

Metformin and sulodexide restore cardiac microvascular perfusion capacity in diet-induced obese rats.

BACKGROUND: Disturbances in coronary microcirculatory function, such as the endothelial glycocalyx, are early hallmarks in the development of obesity and insulin resistance. Accordingly, in the present study myocardial microcirculatory perfusion during rest and stress was assessed following metformin or sulodexide therapy in a rat model of diet-induced obesity. Additionally, the effect of degradation of the glycocalyx on myocardial perfusion was assessed in chow-fed rats. METHODS: Rats were fed a high fat diet (HFD) for 8 weeks and were divided into a group without therapy, and groups that received the anti-diabetic drug metformin or the glycocalyx-stabilizing drug sulodexide in their drinking water during the last 4 weeks of the feeding period. Myocardial microvascular perfusion was determined using first-pass perfusion MRI before and after adenosine infusion. The effect of HFD on microcirculatory properties was also assessed by sidestream darkfield (SDF) imaging of the gastrocnemius muscle. In an acute experimental setting, hyaluronidase was administered to chow-fed control rats to determine the effect of enzymatical degradation of the glycocalyx on myocardial perfusion. RESULTS: HFD-rats developed central obesity and insulin sensitivity was reduced as evidenced by the marked reduction in insulin-induced phosphorylation of Akt in both cardiac and gastrocnemius muscle. We confirmed our earlier findings that the robust increase in myocardial perfusion in chow-fed rats after an adenosine challenge (+56%, p = 0.002) is blunted in HFD rats (+8%, p = 0.68). In contrast, 4-weeks treatment with metformin or sulodexide partly restored the increase in myocardial perfusion during adenosine infusion in HFD rats (+81%, p = 0.002 and +37%, p = 0.02, respectively). Treating chow-fed rats acutely with hyaluronidase, to enzymatically degrade the glyocalyx, completely blunted the increase in myocardial perfusion during stress. CONCLUSIONS: In early stages of HFD-induced insulin resistance myocardial perfusion becomes compromised, a process that can be countered by treatment with both metformin and sulodexide. The adverse effect of acute glycocalyx degradation and protective effect of long-term sulodexide administration on myocardial perfusion provides indirect evidence, suggesting a role for the glycocalyx in preserving coronary microvascular function in pre-diabetic animals.

Aortic Waveform Analysis to Individualize Treatment in Heart Failure.

BACKGROUND: Afterload reduction is a cornerstone in the management of patients with heart failure (HF) and reduced ejection fraction. However, arterial load and the effect of HF therapies on afterload might vary between individuals. Tailoring vasoactive medicines to patients with HF based upon better understanding of arterial afterload may enable better individualization of therapy. METHODS AND RESULTS: Subjects with HF and reduced ejection fraction underwent aggressive titration of vasoactive HF therapies with assessment of central aortic waveforms analyzed using pulse wave, wave separation, and arterial reservoir models. Clinical response to treatment was assessed using the 6-minute walk test distance, which increased in 25 subjects and decreased or remained unchanged in 13. Subjects with improvement on therapy displayed higher aortic pressure wave pulsatility (central pulse pressure [PP], reflected pressure wave, and reservoir pressure) at study entry compared with subjects without improvement (all P<0.05). Parameters derived by the arterial analysis methods were strongly correlated with one another and displayed similar ability to predict improvement. Aortic pressure pulsatility significantly decreased in subjects with functional improvement, whereas no change was observed in patients without functional improvement (P for interaction <0.05). These differences in arterial load at baseline and on therapy were not apparent from conventional brachial artery cuff pressure assessments. CONCLUSIONS: Increased aortic pressure wave pulsatility and greater decrease in pulsatility on treatment are associated with functional improvement in patients with HF and reduced ejection fraction receiving aggressive vasodilator titration. These differences are not identifiable using brachial cuff pressures. Central aortic waveform analysis may enable better individualization of vasoactive therapies in chronic HF and reduced ejection fraction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00588692.

Estrogen Preserves Pulsatile Pulmonary Arterial Hemodynamics in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is caused by extensive pulmonary vascular remodeling that increases right ventricular (RV) afterload and leads to RV failure. PAH predominantly affects women; paradoxically, female PAH patients have better outcomes than men. The roles of estrogen in PAH remain controversial, which is referred to as "the estrogen paradox". Here, we sought to determine the role of estrogen in pulsatile pulmonary arterial hemodynamic changes and its impact on RV functional adaption to PAH. Female mice were ovariectomized and replenished with estrogen or placebo. PAH was induced with SU5416 and chronic hypoxia. In vivo hemodynamic measurements showed that (1) estrogen prevented loss of pulmonary vascular compliance with limited effects on the increase of pulmonary vascular resistance in PAH; (2) estrogen attenuated increases in wave reflections in PAH and limited its adverse effects on PA systolic and pulse pressures; and (3) estrogen maintained the total hydraulic power and preserved transpulmonary vascular efficiency in PAH. This study demonstrates that estrogen preserves pulmonary vascular compliance independent of pulmonary vascular resistance, which provides a mechanical mechanism for ability of estrogen to delay disease progression without preventing onset. The estrogenic protection of pulsatile pulmonary hemodynamics underscores the therapeutic potential of estrogen in PAH.

High-flavanol and high-theobromine versus low-flavanol and low-theobromine chocolate to improve uterine artery pulsatility index: a double blind randomized clinical trial.

OBJECTIVE: To evaluate the impact of high-flavanol and high-theobromine (HFHT) chocolate in women at risk of preeclampsia (PE). STUDY DESIGN: We conducted a single-center randomized controlled trial including women with singleton pregnancy between 11 and 14 weeks gestation who had bilateral abnormal uterine artery (UtA) waveforms (notching) and elevated pulsatility index (PI). Participants were randomized to either HFHT or low-flavanol and low-theobromine (LFLT) chocolate (30 grams daily for a total of 12 weeks). UtA PI, reported as multiple of medians (MoM) adjusted for gestational age, was assessed at baseline and 12 weeks after randomization. RESULTS: One hundred thirty-one women were randomized with mean gestational age of 12.4 ± 0.6 weeks and a mean UtA PI of 1.39 ± 0.31 MoM. UtA PI adjusted for gestational age significantly decreased from baseline to the second visit (12 weeks later) in the two groups (p < 0.0001) but no significant difference was observed between the groups (p = 0.16). CONCLUSIONS: Compared with LFLT chocolate, daily intake of HFHT chocolate was not associated with significant changes of UtA PI. Nevertheless, the improvement observed in both groups suggests that chocolate could improve placental function independently of flavanol and/or theobromine content.