Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide

Background

Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function.

Methods and Findings

In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4±0.4 and SMase: 2.1±0.1 mN/mm; n = 10), that were virtually absent in WKY vessels (DMS: 0.0±0.0 and SMase: 0.6±0.1 mN/mm; n = 9, p<0.05). Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA₂, cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42±4%; n = 7), but not in WKY (−12±10%; n = 6). Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691±42 vs. 419±27 pmol, n = 3–5 respectively, p<0.05). These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513±19 pmol WKY vs. 645±25 pmol SHR, n = 6–12, p<0.05). Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade) in plasma from humans with essential hypertension (185±8 pmol vs. 252±23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05).

Conclusions

Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone.     

Super,Red Palm and Palm Oleins Improve the Blood Pressure,Heart Size,Aortic Media Thickness and Lipid Profile in Spontaneously Hypertensive Rats

Background

Oleic acid has been shown to lower high blood pressure and provide cardiovascular protection. Curiosity arises as to whether super olein (SO), red palm olein (RPO) and palm olein (PO), which have high oleic acid content, are able to prevent the development of hypertension.

Methodology/Principal Findings

Four-week-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were fed 15% SO, RPO or PO supplemented diet for 15 weeks. After 15 weeks of treatment, the systolic blood pressure (SBP) of SHR treated with SO, RPO and PO were 158.4±5.0 mmHg (p<0.001), 178.9±2.7 mmHg (p<0.001) and 167.7±2.1 mmHg (p<0.001), respectively, compared with SHR controls (220.9±1.5 mmHg). Bradycardia was observed with SO and PO. In contrast, the SBP and heart rate of treated WKY rats were not different from those of WKY controls. The SO and PO significantly reduced the increased heart size and thoracic aortic media thickness observed in untreated SHR but RPO reduced only the latter. No such differences, however, were observed between the treated and untreated WKY rats. Oil Red O enface staining of thoracic-abdominal aorta did not show any lipid deposition in all treated rats. The SO and RPO significantly raised serum alkaline phosphatase levels in the SHR while body weight and renal biochemical indices were unaltered in both strains. Serum lipid profiles of treated SHR and WKY rats were unchanged, with the exception of a significant reduction in LDL-C level and total cholesterol/HDL ratio (atherogenic index) in SO and RPO treated SHR compared with untreated SHR.

Conclusion

The SO, RPO and PO attenuate the rise in blood pressure in SHR, accompanied by bradycardia and heart size reduction with SO and PO, and aortic media thickness reduction with SO, RPO and PO. The SO and RPO are antiatherogenic in nature by improving blood lipid profiles in SHR.     

Excess Salt Increases Infarct Size Produced by Photothrombotic Distal Middle Cerebral Artery Occlusion in Spontaneously Hypertensive Rats

Cerebral circulation is known to be vulnerable to high salt loading. However, no study has investigated the effects of excess salt on focal ischemic brain injury. After 14 days of salt loading (0.9% saline) or water, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to photothrombotic middle cerebral artery occlusion (MCAO), and infarct volume was determined at 48 h after MCAO: albumin and hemoglobin contents in discrete brain regions were also determined in SHR. Salt loading did not affect blood pressure levels in SHR and WKY. After MCAO, regional cerebral blood flow (CBF), determined with two ways of laser-Doppler flowmetry (one-point measurement or manual scanning), was more steeply decreased in the salt-loaded group than in the control group. In SHR/Izm, infarct volume in the salt-loaded group was 112±27 mm³, which was significantly larger than 77±12 mm³ in the control group (p = 0.002), while the extents of blood-brain barrier disruption (brain albumin and hemoglobin levels) were not affected by excess salt. In WKY, salt loading did not significantly increase infarct size. These results show the detrimental effects of salt loading on intra-ischemic CBF and subsequent brain infarction produced by phototrhombotic MCAO in hypertensive rats.     

Angiotensin restores atrial natriuretic factor-induced decrease of baroreceptor sensitivity in normotensive rats, but not in spontaneously hypertensive rats

The effect of atrial natriuretic factor (ANF) on baroreflex sensitivity was determined in unanesthetized normotensive (Wistar-Kyoto, WKY) or spontaneously hypertensive rats (SHR) during acute hypertensive stimuli (phenylephrine) or hypotensive stimuli (sodium nitroprusside). The i.v. dose of rat ANF [( Ser99,Tyr126]ANF) was 50 ng/min per rat, sufficient to decrease mean arterial blood pressure (ABP) by about 6 mmHg (1 mmHg = 133.3 Pa) in WKY. SHR showed no change in ABP with this ANF dose. During a control infusion of physiological saline, the mean heart rate (HR) response to increases in ABP was -1.30 +/- 0.27 beats/min (bpm)/mmHg in WKY and -0.37 +/- 0.22 in SHR (p less than 0.05). These values were not affected significantly by ANF. However, ANF blunted chronotropic responses to ABP decreases. The control values of the delta HR/delta ABP slope in WKY and SHR were -2.34 +/- 0.57 and -2.01 +/- 0.37 bpm/mmHg, respectively. In the presence of ANF, the slope changed to -0.36 +/- 0.43 (i.e., bradycardia in response to hypotension) in WKY and to +0.20 +/- 0.21 in SHR (p less than 0.005 for the difference from control for both). This ANF-induced loss of baroreflex sensitivity was reversed in WKY by the addition of angiotensin I (sufficient to increase ABP by 5 mmHg in control rats). Angiotensin did not restore baroreflex sensitivity in ANF-infused SHR, and ANF had no effect on the ABP increase caused by angiotensin in either group. The data suggest that ANF does not act on baroreceptor structures directly, but inhibits mechanisms involved in efferent sympathetic activation. Parasympathetic responses do not appear to be compromised.     

Apnea-Induced Cortical BOLD-fMRI and Peripheral Sympathoneural Firing Response Patterns of Awake Healthy Humans

End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35±4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29±6 (rest) to 49±6 (BH) and 47±6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.     

Queckenstedt's Test Affects More than Jugular Venous Congestion in Rat

Jugular venous compression by the Queckenstedt''s test (Q-test) increases the intracranial pressure, but the effects of isolated jugular venous congestion are not well known. Intraventricular pressure (IVP) was compared during direct obstruction of the common jugular veins (bilateral CJV clipping) and during external compression of bilateral CJV flows (Q-test) in a rat model. Intracerebroventricular catheters were inserted into the right lateral ventricle of nine male Sprague-Dawley rats (371.1±44.8 g, 82.2±12.0 days old). The initial mean IVP, arterial pressure (MAP), and pulse rate were 2.8±1.3 mmHg, 88.8±12.7 mmHg, and 348.3±69.1 beats/min, respectively. The mean IVP increment and MAP decrement were 6.5±2.5 and 13.5±5.7 mmHg, respectively, during the Q-test, compared to 2.3±1.5 and 7.3±3.8 mmHg, respectively, during bilateral CJV clipping (all p = 0.008). The IVP increment and MAP decrement were greater during the Q-test than during bilateral CJV clipping (p = 0.008 and p = 0.038). Although the Q-test and bilateral CJV clipping showed similar effects, the response with the Q-test was greater. Thus, the Q-test appears to obstruct other collateral cerebral veins in addition to bilateral CJV flows. Since this model revealed significant differences between the manual Q-test and bilateral CJV clipping, the finding should be taken into account in future studies on the Q-test in SD rats.     

Burnt Sugarcane Harvesting – Cardiovascular Effects on a Group of Healthy Workers,Brazil

Background

Brazil is the world''s largest producer of sugarcane. Harvest is predominantly manual, exposing workers to health risks: intense physical exertion, heat, pollutants from sugarcane burning.

Design

Panel study to evaluate the effects of burnt sugarcane harvesting on blood markers and on cardiovascular system.

Methods

Twenty-eight healthy male workers, living in the countryside of Brazil were submitted to blood markers, blood pressure, heart rate variability, cardiopulmonary exercise testing, sympathetic nerve activity evaluation and forearm blood flow measures (venous occlusion plethysmography) during burnt sugarcane harvesting and four months later while they performed other activities in sugar cane culture.

Results

Mean participant age was 31±6.3 years, and had worked for 9.8±8.4 years on sugarcane work. Work during the harvest period was associated with higher serum levels of Creatine Kinase – 136.5 U/L (IQR: 108.5–216.0) vs. 104.5 U/L (IQR: 77.5–170.5), (p = 0.001); plasma Malondialdehyde–7.5±1.4 µM/dl vs. 6.9±1.0 µM/dl, (p = 0.058); Glutathione Peroxidase – 55.1±11.8 Ug/Hb vs. 39.5±9.5 Ug/Hb, (p<0.001); Glutathione Transferase– 3.4±1.3 Ug/Hb vs. 3.0±1.3 Ug/Hb, (p = 0.001); and 24-hour systolic blood pressure – 120.1±10.3 mmHg vs. 117.0±10.0 mmHg, (p = 0.034). In cardiopulmonary exercise testing, rest-to-peak diastolic blood pressure increased by 11.12 mmHg and 5.13 mmHg in the harvest and non-harvest period, respectively. A 10 miliseconds reduction in rMSSD and a 10 burst/min increase in sympathetic nerve activity were associated to 2.2 and 1.8 mmHg rises in systolic arterial pressure, respectively.

Conclusion

Work in burnt sugarcane harvesting was associated with changes in blood markers and higher blood pressure, which may be related to autonomic imbalance.     

The essential role of carotid body chemoreceptors in sleep apnea

Sleep apnea is attributable, in part, to an unstable ventilatory control system and specifically to a narrowed "CO2 reserve" (i.e., the difference in P(a)CO2 between eupnea and the apneic threshold). Findings from sleeping animal preparations with denervated carotid chemoreceptors or vascularly isolated, perfused carotid chemoreceptors demonstrate the critical importance of peripheral chemoreceptors to the ventilatory responses to dynamic changes in P(a)CO2. Specifically, (i) carotid body denervation prevented the apnea and periodic breathing that normally follow transient ventilatory overshoots; (ii) the CO2 reserve for peripheral chemoreceptors was about one half that for brain chemoreceptors; and (iii) hypocapnia isolated to the carotid chemoreceptors caused hypoventilation that persisted over time despite a concomitant, progressive brain respiratory acidosis. Observations in both humans and animals are cited to demonstrate the marked plasticity of the CO2 reserve and, therefore, the propensity for apneas and periodic breathing, in response to changing background ventilatory stimuli.     

Effects of Aging on Genioglossus Motor Units in Humans

The genioglossus is a major upper airway dilator muscle thought to be important in obstructive sleep apnea pathogenesis. Aging is a risk factor for obstructive sleep apnea although the mechanisms are unclear and the effects of aging on motor unit remodeled in the genioglossus remains unknown. To assess possible changes associated with aging we compared quantitative parameters related to motor unit potential morphology derived from EMG signals in a sample of older (n = 11; >55 years) versus younger (n = 29; <55 years) adults. All data were recorded during quiet breathing with the subjects awake. Diagnostic sleep studies (Apnea Hypopnea Index) confirmed the presence or absence of obstructive sleep apnea. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which estimated a MUP template from each extracted motor unit potential train (MUPT) for both the selective concentric needle and concentric needle macro (CNMACRO) recorded EMG signals. 2074 MUPTs from 40 subjects (mean±95% CI; older AHI 19.6±9.9 events/hr versus younger AHI 30.1±6.1 events/hr) were extracted. MUPs detected in older adults were 32% longer in duration (14.7±0.5 ms versus 11.1±0.2 ms; P  =  0.05), with similar amplitudes (395.2±25.1 µV versus 394.6±13.7 µV). Amplitudes of CNMACRO MUPs detected in older adults were larger by 22% (62.7±6.5 µV versus 51.3±3.0 µV; P<0.05), with areas 24% larger (160.6±18.6 µV.ms versus 130.0±7.4 µV.ms; P<0.05) than those detected in younger adults. These results confirm that remodeled motor units are present in the genioglossus muscle of individuals above 55 years, which may have implications for OSA pathogenesis and aging related upper airway collapsibility.     

Morphological characteristics and peptidergic innervation in the carotid body of spontaneously hypertensive rats

We examined morphological characteristics of the carotid body of spontaneously hypertensive rats (SHR), those of age-matched normotensive Wistar rats (NWR), and age-matched genetically comparable Wistar Kyoto rats (WKY). We examined the distribution and abundance of four different regulatory neuropeptides: substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) in the carotid bodies of these three strains of rats. The carotid bodies of SHR were larger than those of NWR and WKY. The values of the long axis of the carotid bodies of SHR were significantly larger (1.3 times) than those of NWR and WKY. In the carotid bodies of SHR, the percentage of relatively large vessels was similar to that of the carotid bodies of WKY, although the carotid bodies themselves were significantly larger than in WKY. The density of VIP varicose fibers in the carotid bodies of SHR was lower than in the carotid bodies of WKY, although the density of SP, CGRP and NPY fibers was similar to that of the carotid bodies of NWR and WKY. These findings suggested that VIP was unrelated to enlargement of the carotid body of SHR, but it might modify the sensitivity of chemoreceptors in the carotid body.     

Cerebral Oxygen Saturation: Graded Response to Carbon Dioxide with Isoxia and Graded Response to Oxygen with Isocapnia

Background

Monitoring cerebral saturation is increasingly seen as an aid to management of patients in the operating room and in neurocritical care. How best to manipulate cerebral saturation is not fully known. We examined cerebral saturation with graded changes in carbon dioxide tension while isoxic and with graded changes in oxygen tension while isocapnic.

Methodology/Principal Findings

The study was approved by the Research Ethics Board of the University Health Network at the University of Toronto. Thirteen studies were undertaken in healthy adults with cerebral oximetry by near infrared spectroscopy. End-tidal gas concentrations were manipulated using a model-based prospective end-tidal targeting device. End-tidal carbon dioxide was altered ±15 mmHg from baseline in 5 mmHg increments with isoxia (clamped at 110±4 mmHg). End-tidal oxygen was changed to 300, 400, 500, 80, 60 and 50 mmHg under isocapnia (37±2 mmHg). Twelve studies were completed. The end-tidal carbon dioxide versus cerebral saturation fit a linear relationship (R² = 0.92±0.06). The end-tidal oxygen versus cerebral saturation followed log-linear behaviour and best fit a hyperbolic relationship (R² = 0.85±0.10). Cerebral saturation was maximized in isoxia at end-tidal carbon dioxide of baseline +15 mmHg (77±3 percent). Cerebral saturation was minimal in isocapnia at an end-tidal oxygen tension of 50 mmHg (61±3 percent). The cerebral saturation during normoxic hypocapnia was equivalent to normocapnic hypoxia of 60 mmHg.

Conclusions/Significance

Hypocapnia reduces cerebral saturation to an extent equivalent to moderate hypoxia.     

Antibacterial Responses by Peritoneal Macrophages Are Enhanced Following Vitamin D Supplementation

Patients with chronic kidney disease (CKD), who usually display low serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are at high risk of infection, notably those undergoing peritoneal dialysis (PD). We hypothesized that peritoneal macrophages from PD patients are an important target for vitamin D-induced antibacterial activity. Dialysate effluent fluid was obtained from 27 non-infected PD patients. Flow cytometry indicated that PD cells were mainly monocytic (37.9±17.7% cells CD14⁺/CD45⁺). Ex vivo analyses showed that PD cells treated with 25D (100 nM, 6 hrs) or 1,25D (5 nM, 6 hrs) induced mRNA for antibacterial cathelicidin (CAMP) but conversely suppressed mRNA for hepcidin (HAMP). PD cells from patients with peritonitis (n = 3) showed higher baseline expression of CAMP (18-fold±9, p<0.05) and HAMP (64-fold±7) relative to cells from non-infected patients. In 12 non-infected PD patients, oral supplementation with a single dose of vitamin D₂ (100,000 IU) increased serum levels of 25D from 18±8 to 41±15 ng/ml (p = 0.002). This had no significant effect on PD cell CD14/CD45 expression, but mRNA for HAMP was suppressed significantly (0.5-fold, p = 0.04). Adjustment for PD cell CD14/CD45 expression using a mixed linear statistical model also revealed increased expression of CAMP (mRNA in PD cells and protein in effluent) in vitamin D-supplemented patients. These data show for the first time that vitamin D supplementation in vitro and in vivo promotes innate immune responses that may enhance macrophage antibacterial responses in patients undergoing PD. This highlights a potentially important function for vitamin D in preventing infection-related complications in CKD.     

Ocular Hypertension: General Characteristics and Estimated Cerebrospinal Fluid Pressure. The Beijing Eye Study 2011

Purpose

To examine characteristics of ocular hypertensive subjects and potential associations with estimated cerebrospinal fluid pressure (estCSFP).

Methods

The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years. Ocular hypertension was defined as intraocular pressure (IOP) >21 mmHg, normal optic nerve head appearance and normal retinal nerve fiber layer thickness. IOP was corrected for its dependence on central corneal thickness (CCT) and corneal curvature radius. Estimated CSFP was calculated as CSFP [mmHg] = 0.44×Body Mass Index [kg/m²]+0.16×Diastolic Blood Pressure [mmHg]−0.18×Age [Years]−1.91. Estimated trans-lamina cribrosa pressure difference (estTLCPD) was IOP–estCSFP.

Results

EstCSFP (10.5±3.6 mmHg versus 9.0±3.7 mmHg; P = 0.003) and estTLCPD (12.0±4.4 mmHg versus 5.4±3.8 mmHg; P<0.001) were higher in the ocular hypertensive group than in the normotensive group. In binary regression analysis, ocular hypertension was associated with increased estCSFP (P = 0.03; odds ratio (OR): 1.08; 95% confidence interval (CI): 1.01, 1.17) after adjusting for prevalence of arterial hypertension (P = 0.07; OR: 1.79; 95%CI: 0.96, 3.34), retinal nerve fiber layer thickness (P = 0.03; OR: 0.97; 95%CI: 0.95, 0.997) and blood glucose concentration (P = 0.006; OR: 1.17; 95%CI: 1.04, 1.30).

Conclusions

Ocular hypertensive subjects (with IOP correction for CCT and corneal curvature) as compared to ocular normotensive subjects had a significantly higher estCSFP in univariate analysis and in multivariate analysis. Despite of a higher estCSFP, estTLCPD was still markedly higher in ocular hypertensive eyes than in ocular normotensive eyes.     

Antihypertensive treatment differentially affects vascular sphingolipid biology in spontaneously hypertensive rats

Background

We have previously shown that essential hypertension in humans and spontaneously hypertensive rats (SHR), is associated with increased levels of ceramide and marked alterations in sphingolipid biology. Pharmacological elevation of ceramide in isolated carotid arteries of SHR leads to vasoconstriction via a calcium-independent phospholipase A₂, cyclooxygenase-1 and thromboxane synthase-dependent release of thromboxane A₂. This phenomenon is almost absent in vessels from normotensive Wistar Kyoto (WKY) rats. Here we investigated whether lowering of blood pressure can reverse elevated ceramide levels and reduce ceramide-mediated contractions in SHR.

Methods and Findings

For this purpose SHR were treated for 4 weeks with the angiotensin II type 1 receptor antagonist losartan or the vasodilator hydralazine. Both drugs decreased blood pressure equally (SBP untreated SHR: 191±7 mmHg, losartan: 125±5 mmHg and hydralazine: 113±14 mmHg). The blood pressure lowering was associated with a 20–25% reduction in vascular ceramide levels and improved endothelial function of isolated carotid arteries in both groups. Interestingly, losartan, but not hydralazine treatment, markedly reduced sphingomyelinase-induced contractions. While both drugs lowered cyclooxygenase-1 expression, only losartan and not hydralazine, reduced the endothelial expression of calcium-independent phospholipase A₂. The latter finding may explain the effect of losartan treatment on sphingomyelinase-induced vascular contraction.

Conclusion

In summary, this study corroborates the importance of sphingolipid biology in blood pressure control and specifically shows that blood pressure lowering reduces vascular ceramide levels in SHR and that losartan treatment, but not blood pressure lowering per se, reduces ceramide-mediated arterial contractions.     

Total Beta-Adrenoceptor Knockout Slows Conduction and Reduces Inducible Arrhythmias in the Mouse Heart

Introduction

Beta-adrenoceptors (β-AR) play an important role in the neurohumoral regulation of cardiac function. Three β-AR subtypes (β₁, β₂, β₃) have been described so far. Total deficiency of these adrenoceptors (TKO) results in cardiac hypotrophy and negative inotropy. TKO represents a unique mouse model mimicking total unselective medical β-blocker therapy in men. Electrophysiological characteristics of TKO have not yet been investigated in an animal model.

Methods

In vivo electrophysiological studies using right heart catheterisation were performed in 10 TKO mice and 10 129SV wild type control mice (WT) at the age of 15 weeks. Standard surface ECG, intracardiac and electrophysiological parameters, and arrhythmia inducibility were analyzed.

Results

The surface ECG of TKO mice revealed a reduced heart rate (359.2±20.9 bpm vs. 461.1±33.3 bpm; p<0.001), prolonged P wave (17.5±3.0 ms vs. 15.1±1.2 ms; p = 0.019) and PQ time (40.8±2.4 ms vs. 37.3±3.0 ms; p = 0.013) compared to WT. Intracardiac ECG showed a significantly prolonged infra-Hisian conductance (HV-interval: 12.9±1.4 ms vs. 6.8±1.0 ms; p<0.001). Functional testing showed prolonged atrial and ventricular refractory periods in TKO (40.5±15.5 ms vs. 21.3±5.8 ms; p = 0.004; and 41.0±9.7 ms vs. 28.3±6.6 ms; p = 0.004, respectively). In TKO both the probability of induction of atrial fibrillation (12% vs. 24%; p<0.001) and of ventricular tachycardias (0% vs. 26%; p<0.001) were significantly reduced.

Conclusion

TKO results in significant prolongations of cardiac conduction times and refractory periods. This was accompanied by a highly significant reduction of atrial and ventricular arrhythmias. Our finding confirms the importance of β-AR in arrhythmogenesis and the potential role of unspecific beta-receptor-blockade as therapeutic target.     

The Effect of pH and Ion Channel Modulators on Human Placental Arteries

Chorionic plate arteries (CPA) are located at the maternofetal interface where they are able to respond to local metabolic changes. Unlike many other types of vasculature, the placenta lacks nervous control and requires autoregulation for controlling blood flow. The placental circulation, which is of low-resistance, may become hypoxic easily leading to fetal acidosis and fetal distress however the role of the ion channels in these circumstances is not well-understood. Active potassium channel conductances that are subject to local physicochemical modulation may serve as pathways through which such signals are transduced. The aim of this study was to investigate the modulation of CPA by pH and the channels implicated in these responses using wire myography. CPA were isolated from healthy placentae and pre-contracted with U46619 before testing the effects of extracellular pH using 1 M lactic acid over the pH range 7.4 - 6.4 in the presence of a variety of ion channel modulators. A change from pH 7.4 to 7.2 produced a 29±3% (n = 9) relaxation of CPA which increased to 61±4% at the lowest pH of 6.4. In vessels isolated from placentae of women with pre-eclampsia (n = 6), pH responses were attenuated. L-methionine increased the relaxation to 67±7% (n = 6; p<0.001) at pH 6.4. Similarly the TASK 1/3 blocker zinc chloride (1 mM) gave a maximum relaxation of 72±5% (n = 8; p<0.01) which compared with the relaxation produced by the TREK-1 opener riluzole (75±5%; n = 6). Several other modulators induced no significant changes in vascular responses. Our study confirmed expression of several ion channel subtypes in CPA with our results indicating that extracellular pH within the physiological range has an important role in controlling vasodilatation in the human term placenta.     

Heart Rate Responses to Autonomic Challenges in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is accompanied by structural alterations and dysfunction in central autonomic regulatory regions, which may impair dynamic and static cardiovascular regulation, and contribute to other syndrome pathologies. Characterizing cardiovascular responses to autonomic challenges may provide insights into central nervous system impairments, including contributions by sex, since structural alterations are enhanced in OSA females over males. The objective was to assess heart rate responses in OSA versus healthy control subjects to autonomic challenges, and, separately, characterize female and male patterns. We studied 94 subjects, including 37 newly-diagnosed, untreated OSA patients (6 female, age mean±std: 52.1±8.1 years; 31 male aged 54.3±8.4 years), and 57 healthy control subjects (20 female, 50.5±8.1 years; 37 male, 45.6±9.2 years). We measured instantaneous heart rate with pulse oximetry during cold pressor, hand grip, and Valsalva maneuver challenges. All challenges elicited significant heart rate differences between OSA and control groups during and after challenges (repeated measures ANOVA, p<0.05). In post-hoc analyses, OSA females showed greater impairments than OSA males, which included: for cold pressor, lower initial increase (OSA vs. control: 9.5 vs. 7.3 bpm in females, 7.6 vs. 3.7 bpm in males), OSA delay to initial peak (2.5 s females/0.9 s males), slower mid-challenge rate-of-increase (OSA vs. control: −0.11 vs. 0.09 bpm/s in females, 0.03 vs. 0.06 bpm/s in males); for hand grip, lower initial peak (OSA vs. control: 2.6 vs. 4.6 bpm in females, 5.3 vs. 6.0 bpm in males); for Valsalva maneuver, lower Valsalva ratio (OSA vs. control: 1.14 vs. 1.30 in females, 1.29 vs. 1.34 in males), and OSA delay during phase II (0.68 s females/1.31 s males). Heart rate responses showed lower amplitude, delayed onset, and slower rate changes in OSA patients over healthy controls, and impairments may be more pronounced in females. The dysfunctions may reflect central injury in the syndrome, and suggest autonomic deficiencies that may contribute to further tissue and functional pathologies.     

Regular Cocaine Use Is Associated with Increased Systolic Blood Pressure,Aortic Stiffness and Left Ventricular Mass in Young Otherwise Healthy Individuals

Background

The cardiovascular impact of cocaine use in otherwise healthy individuals who consider themselves ‘social’ users is not well established.

Methods/Results

Twenty regular cocaine users and 20 control subjects were recruited by word-of-mouth. Cardiovascular magnetic resonance was performed to assess cardiac and vascular structure and function. Cocaine users had higher systolic blood pressure compared to non-users (134±11 vs 126±11 mmHg, p = 0.036), a finding independent of age, body surface area, smoking and alcohol consumption. Cocaine use was associated with increased arterial stiffness - reflected by reduced aortic compliance (1.3±0.2 vs 1.7±0.5 cm²×10⁻².mmHg⁻¹, p = 0.004), decreased distensibility (3.8±0.9 vs 5.1±1.4 mmHg⁻¹.10⁻³, p = 0.001), increased stiffness index (2.6±0.6 vs 2.1±0.6, p = 0.005), and higher pulse wave velocity (5.1±0.6 vs 4.4±0.6 m.s⁻¹, p = 0.001). This change in aortic stiffness was independent of vessel wall thickness. Left ventricular mass was 18% higher in cocaine users (124±25 vs 105±16 g, p = 0.01), a finding that was independent of body surface area, and left atrial diameter was larger in the user group than controls (3.8±0.6 vs 3.5±0.3 cm, p = 0.04). The increased left ventricular mass, systolic blood pressure and vascular stiffness measures were all associated with duration and/or frequency of cocaine use. No late gadolinium enhancement or segmental wall motion abnormalities were seen in any of the subjects.

Conclusions

Compared with the non-user control cohort, cocaine users had increased aortic stiffness and systolic blood pressure, associated with greater left ventricular mass. These measures are all well known risk factors for premature cardiovascular events, highlighting the dangers of cocaine use, even in a ‘social’ setting, and have important public health implications.