Effects of acute hyperoxia on autonomic function and coronary tone in patients with peripheral artery disease.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD.NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Association between right ventricular global longitudinal strain and mortality in intermediate-risk pulmonary embolism.

BACKGROUND: Right ventricular (RV) systolic dysfunction has been identified as a prognostic marker for adverse clinical events in patients presenting with acute pulmonary embolism (PE). However, challenges exist in identifying RV dysfunction using conventional echocardiography techniques. Strain echocardiography is an evolving imaging modality which measures myocardial deformation and can be used as an objective index of RV systolic function. This study evaluated RV Global Longitudinal Strain (RVGLS) in patients with intermediate risk PE as a parameter of RV dysfunction, and compared to traditional echocardiographic and CT parameters evaluating short-term mortality. METHODS: Retrospective single center cohort study of 251 patients with intermediate-risk PE between 2010 and 2018. The primary outcome was all-cause mortality at 30 days. Statistical analysis evaluated each parameter comparing survivors versus non-survivors at 30 days. Receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used for comparison of the two cohorts. RESULTS: Altogether 251 patients were evaluated. Overall mortality rate was 12.4%. Utilizing an ROC curve, an absolute cutoff value of 17.7 for RVGLS demonstrated a sensitivity of 93% and specificity of 70% for observed 30-day mortality. Individuals with an RVGLS ≤17.7 had a 25 times higher mortality rate than those with RVGLS above 17.7 (HR 25.24, 95% CI = 6.0-106.4, p < .001). Area under the curve was (.855), RVGLS outperformed traditional echocardiographic parameters, CT findings, and cardiac biomarkers on univariable and multivariable analysis. CONCLUSIONS: Reduced RVGLS values on initial echocardiographic assessment of patients with intermediate-risk PE identified patients at higher risk for mortality at 30 days.

Limited Memory-Based Random-Weighted Kalman Filter.

The Kalman filter is an important technique for system state estimation. It requires the exact knowledge of system noise statistics to achieve optimal state estimation. However, in practice, this knowledge is often unknown or inaccurate due to uncertainties and disturbances involved in the dynamic environment, leading to degraded or even divergent filtering solutions. To address this issue, this paper presents a new method by combining the random weighting concept with the limited memory technique to accurately estimate system noise statistics. To avoid the influence of excessive historical information on state estimation, random weighting theories are established based on the limited memory technique to estimate both process noise and measurement noise statistics within a limited memory. Subsequently, the estimated system noise statistics are fed back into the Kalman filtering process for system state estimation. The proposed method improves the Kalman filtering accuracy by adaptively adjusting the weights of system noise statistics within a limited memory to suppress the interference of system noise on system state estimation. Simulations and experiments as well as comparison analysis were conducted, demonstrating that the proposed method can overcome the disadvantage of the traditional limited memory filter, leading to im-proved accuracy for system state estimation.

Aortic blood pressure and pulse wave indices responses to exercise in peripheral artery disease.

Peripheral artery disease (PAD) refers to obstructed blood flow in peripheral arteries typically due to atherosclerotic plaques. How PAD alters aortic blood pressure and pressure wave propagation during exercise is unclear. Thus, this study examined central blood pressure responses to plantar flexion exercise by investigating aortic pulse wave properties in PAD. Thirteen subjects with PAD and 13 healthy [age-, sex-, body mass index (BMI) matched] subjects performed rhythmic plantar flexion for 14 min or until fatigue (20 contractions/min; started at 2 kg with 1 kg/min increment up to 12 kg). Brachial (oscillometric cuff) and radial (SphygmoCor) blood pressure and derived-aortic waveforms were analyzed during supine rest and plantar flexion exercise. At rest, baseline augmentation index (P = 0.0263) and cardiac wasted energy (P = 0.0321) were greater in PAD due to earlier arrival of the reflected wave (P = 0.0289). During exercise, aortic blood pressure (aMAP) and aortic pulse pressure showed significant interaction effects (P = 0.0041 and P = 0.0109, respectively). In particular, PAD had a greater aMAP increase at peak exercise (P = 0.0147). Moreover, the tension time index was greater during exercise in PAD (P = 0.0173), especially at peak exercise (P = 0.0173), whereas the diastolic time index (P = 0.0685) was not different between the two groups. Hence, during exercise, the subendocardial viability ratio was lower in PAD (P = 0.0164), especially at peak exercise (P = 0.0164). The results suggest that in PAD, the aortic blood pressure responses and myocardial oxygen demand during exercise are increased compared with healthy controls.

Moderate whole body heating attenuates the exercise pressor reflex responses in older humans.

Prior reports show that whole body heat stress attenuates the pressor response to exercise in young healthy subjects. The effects of moderate whole body heating (WBH; e.g., increase in internal temperature Tcore of ∼0.4°C-0.5°C) or limb heating on sympathetic and cardiovascular responses to exercise in older healthy humans remain unclear. We examined the muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), and heart rate (HR) in 14 older (62 ± 2 yr) healthy subjects during fatiguing isometric handgrip exercise and postexercise circulatory occlusion (PECO). The protocol was performed under normothermic, moderate WBH, and local limb (i.e., forearm) heating conditions during three visits. During the mild WBH stage (increase in Tcore of <0.3°C), HR increased, whereas BP and MSNA decreased from baseline. Under the moderate WBH condition (increase in Tcore of ∼0.4°C), BP decreased, HR increased, and MSNA was unchanged from baseline. Compared with the normothermic trial, the absolute MAP during fatiguing exercise and PECO was lower during the WBH trial. Moreover, MSNA and MAP responses (i.e., changes) to fatiguing exercise were also less than those seen during the normothermic trial. Limb heating induced a similar increase in forearm muscle temperature to that seen in the WBH trial (∼0.7°C-1.5°C). Limb heating did not alter resting MAP, HR, or MSNA. The MSNA and hemodynamic responses to exercise in the limb heating trial were not different from those in the normothermic trial. These data suggest that moderate WBH attenuates MSNA and BP responses to exercise in older healthy humans.

Systemic and regional hemodynamic response to activation of the exercise pressor reflex in patients with peripheral artery disease.

Patients with peripheral artery disease (PAD) have an accentuated exercise pressor reflex (EPR) during exercise of the affected limb. The underlying hemodynamic changes responsible for this, and its effect on blood flow to the exercising extremity, are unclear. We tested the hypothesis that the exaggerated EPR in PAD is mediated by an increase in total peripheral resistance (TPR), which augments redistribution of blood flow to the exercising limb. Twelve patients with PAD and 12 age- and sex-matched subjects without PAD performed dynamic plantar flexion (PF) using the most symptomatic leg at progressive workloads of 2-12 kg (increased by 1 kg/min until onset of fatigue). We measured heart rate, beat-by-beat blood pressure, femoral blood flow velocity (FBV), and muscle oxygen saturation (SmO2) continuously during the exercise. Femoral blood flow (FBF) was calculated from FBV and baseline femoral artery diameter. Stroke volume (SV), cardiac output (CO), and TPR were derived from the blood pressure tracings. Mean arterial blood pressure and TPR were significantly augmented in PAD compared with control during PF. FBF increased during exercise to an equal extent in both groups. However, SmO2 of the exercising limb remained significantly lower in PAD compared with control. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal TPR response, which augments redistribution of blood flow to the exercising extremity, leading to an equal rise in FBF compared with controls. However, this increase in FBF is not sufficient to normalize the SmO2 response during exercise in patients with PAD.NEW & NOTEWORTHY In this study, peripheral artery disease (PAD) patients and healthy control subjects performed graded, dynamic plantar flexion exercise. Data from this study suggest that previously reported exaggerated exercise pressor reflex in patients with PAD is driven by greater vasoconstriction in nonexercising vascular territories which also results in a redistribution of blood flow to the exercising extremity. However, this rise in femoral blood flow does not fully correct the oxygen deficit due to changes in other mechanisms that require further investigation.

Constrained Unscented Particle Filter for SINS/GNSS/ADS Integrated Airship Navigation in the Presence of Wind Field Disturbance.

Due to the disturbance of wind field, it is difficult to achieve precise airship positioning and navigation in the stratosphere. This paper presents a new constrained unscented particle filter (UPF) for SINS/GNSS/ADS (inertial navigation system/global navigation satellite system/atmosphere data system) integrated airship navigation. This approach constructs a wind speed model to describe the relationship between airship velocity and wind speed using the information output from ADS, and further establishes a mathematical model for SINS/GNSS/ADS integrated navigation. Based on these models, it also develops a constrained UPF to obtain system state estimation for SINS/GNSS/ADS integration. The proposed constrained UPF uses the wind speed model to constrain the UPF filtering process to effectively resist the influence of wind field on the navigation solution. Simulations and comparison analysis demonstrate that the proposed approach can achieve optimal state estimation for SINS/GNSS/ADS integrated airship navigation in the presence of wind field disturbance.

A SINS/SRS/GNS Autonomous Integrated Navigation System Based on Spectral Redshift Velocity Measurements.

In order to meet the requirements of autonomy and reliability for the navigation system, combined with the method of measuring speed by using the spectral redshift information of the natural celestial bodies, a new scheme, consisting of Strapdown Inertial Navigation System (SINS)/Spectral Redshift (SRS)/Geomagnetic Navigation System (GNS), is designed for autonomous integrated navigation systems. The principle of this SINS/SRS/GNS autonomous integrated navigation system is explored, and the corresponding mathematical model is established. Furthermore, a robust adaptive central difference particle filtering algorithm is proposed for this autonomous integrated navigation system. The simulation experiments are conducted and the results show that the designed SINS/SRS/GNS autonomous integrated navigation system possesses good autonomy, strong robustness and high reliability, thus providing a new solution for autonomous navigation technology.

A Strap-Down Inertial Navigation/Spectrum Red-Shift/Star Sensor (SINS/SRS/SS) Autonomous Integrated System for Spacecraft Navigation.

This paper presents a new Strap-down Inertial Navigation System/Spectrum Red-Shift/Star Sensor (SINS/SRS/SS) system integration methodology to improve the autonomy and reliability of spacecraft navigation using the spectrum red-shift information from natural celestial bodies such as the Sun, Jupiter and the Earth. The system models for SINS/SRS/SS integration are established. The information fusion of SINS/SRS/SS integration is designed as the structure of the federated Kalman filter to fuse the local estimations of SINS/SRS and SINS/SS integrated subsystems to generate the global state estimation for spacecraft navigation. A new robust adaptive unscented particle filter is also developed to obtain the local state estimations of SINS/SRS and SINS/SS integrated subsystems in a parallel manner. The simulation results demonstrate that the proposed methodology for SINS/SRS/SS integration can effectively calculate navigation solutions, leading to strong autonomy and high reliability for spacecraft navigation.

Microbial transformation of pseudoprotodioscin by Gibberella fujikuroi.

Three new (6, 9, and 12) and nine known steroidal saponins were obtained from the fermentation broth of pseudoprotodioscin (PPD) incubated with a fungus Gibberella fujikuroi CGMCC 3.4663. Structures of the metabolites were elucidated by 1-D (1H, 13C), 2-D (HMBC, HSQC, NOESY) NMR, and HR-MS analyses. The biotransformation pathway of pseudoprotodioscin by Gibberella fujikuroi CGMCC 3.4663 was proposed. Compounds 1-11 were tested in vitro for their cytotoxic activities against two human cancer cell lines (HepG2 and Hela). Compounds 1, 6, 9, and 10 exhibited cytotoxic activity against HepG2 cells. Compound 10 exhibited cytotoxicity to Hela cells.

Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease.

BACKGROUND: Peripheral arterial disease (PAD) is an atherosclerotic vascular disease that affects over 200 million people worldwide. The hallmark of PAD is ischemic leg pain and this condition is also associated with an augmented blood pressure response to exercise, impaired vascular function, and high risk of myocardial infarction and cardiovascular mortality. In this study, we tested the hypothesis that coronary exercise hyperemia is impaired in PAD. METHODS: Twelve patients with PAD and no overt coronary disease (65 ± 2 years, 7 men) and 15 healthy control subjects (64 ± 2 years, 9 men) performed supine plantar flexion exercise (30 contractions/min, increasing workload). A subset of subjects (n = 7 PAD, n = 8 healthy) also performed isometric handgrip exercise (40% of maximum voluntary contraction to fatigue). Coronary blood velocity in the left anterior descending artery was measured by transthoracic Doppler echocardiography; blood pressure and heart rate were monitored continuously. RESULTS: Coronary blood velocity responses to 4 min of plantar flexion exercise (PAD: Δ2.4 ± 1.2, healthy: Δ6.0 ± 1.6 cm/sec, P = 0.039) and isometric handgrip exercise (PAD: Δ8.3 ± 4.2, healthy: Δ16.9 ± 3.6, P = 0.033) were attenuated in PAD patients. CONCLUSION: These data indicate that coronary exercise hyperemia is impaired in PAD, which may predispose these patients to myocardial ischemia.

Impaired coronary and retinal vasomotor function to hyperoxia in Individuals with Type 2 diabetes.

PURPOSE: Adults with diabetes are at a high risk of developing coronary heart disease. The purpose of this study was to assess coronary artery vascular function non-invasively in individuals with and without Type 2 diabetes and to compare these coronary responses to another microvascular bed (i.e. retina). We hypothesized that individuals with diabetes would have impaired coronary reactivity and that these impairments would be associated with impairments in retinal reactivity. METHODS: Coronary blood velocity (Transthoracic Doppler Echocardiography) and retinal diameters (Dynamic Vessel Analyzer) were measured continuously during five minutes of breathing 100% oxygen (i.e. hyperoxia) in 15 persons with Type 2 diabetes and 15 age-matched control subjects. Using fundus photographs, retinal vascular calibers were also measured (central retinal arteriole and venule equivalents). RESULTS: Individuals with diabetes compared to controls had impaired coronary (-2.34±16.64% vs. -14.27±10.58%, P=0.03) and retinal (arteriole: -0.04±3.34% vs. -3.65±5.07%, P=0.03; venule: -1.65±3.68% vs. -5.23±5.47%, P=0.05) vasoconstrictor responses to hyperoxia, and smaller central arteriole-venule equivalent ratios (0.83±0.07 vs. 0.90±0.07, P=0.014). Coronary reactivity was associated with central retinal arteriole equivalents (r=-0.516, P=0.005) and retinal venular reactivity (r=0.387, P=0.034). CONCLUSION: Diabetes impairs coronary and retinal microvascular function to hyperoxia. Impaired vasoconstrictor responses may be part of a systemic diabetic vasculopathy, which may contribute to adverse cardiovascular events in individuals with diabetes.

Unusual microbial lactonization and hydroxylation of asiatic acid by Umbelopsis isabellina.

Asiatic acid (1) is a natural triterpenoid isolated from Centella asiatica. This paper reports the microbial transformation of asiatic acid by an endophytic fungus Umbelopsis isabellina to obtain derivatives potentially useful for further studies. Incubation of asiatic acid with U. isabellina afforded two derivatives 2α,3ß,7ß, 23-tetrahydroxyurs-12-ene-28-oic acid (2) and 2α,3ß,7ß,23-tetrahydroxyurs-11-ene-28,13-lactone (3). The structures of these compounds were elucidated by spectral data. Compound 3 has formed an unusual lactone. These two products are new compounds. The possible transformation passway was also discussed.

ß-Adrenergic receptor blockade impairs coronary exercise hyperemia in young men but not older men.

Patients with coronary artery disease have attenuated coronary vasodilator responses to physiological stress, which is partially attributed to a ß-adrenergic receptor (ß-AR)-mediated mechanisms. Whether ß-ARs contribute to impaired coronary vasodilation seen with healthy aging is unknown. The purpose of this study was to investigate the role of ß-ARs in coronary exercise hyperemia in healthy humans. Six young men (26 ± 1 yr) and seven older men (67 ± 4 yr) performed isometric handgrip exercise at 30% maximal voluntary contraction for 2 min after receiving intravenous propranolol, a ß-AR antagonist, and no treatment. Isoproterenol, a ß-AR agonist, was infused to confirm the ß-AR blockade. Blood pressure and heart rate were monitored continuously, and coronary blood flow velocity (CBV, left anterior descending artery) was measured by transthoracic Doppler echocardiography. Older men had an attenuated ΔCBV to isometric exercise (3.8 ± 1.3 vs. 9.7 ± 2.1 cm/s, P = 0.02) compared with young men. Propranolol decreased the ΔCBV at peak handgrip exercise in young men (9.7 ± 2.1 vs. 2.7 ± 0.9 cm/s, P = 0.008). However, propranolol had no effect on ΔCBV in older men (3.8 ± 1.3 vs. 4.2 ± 1.9 cm/s, P = 0.9). Older men also had attenuated coronary hyperemia to low-dose isoproterenol. These data indicate that ß-AR control of coronary blood flow is impaired in healthy older men.

Coronary responses to cold air inhalation following afferent and efferent blockade.

Cardiac ischemia and angina pectoris are commonly experienced during exertion in a cold environment. In the current study we tested the hypotheses that oropharyngeal afferent blockade (i.e., local anesthesia of the upper airway with lidocaine) as well as systemic ß-adrenergic receptor blockade (i.e., intravenous propranolol) would improve the balance between myocardial oxygen supply and demand in response to the combined stimulus of cold air inhalation (-15 to -30°C) and isometric handgrip exercise (Cold + Grip). Young healthy subjects underwent Cold + Grip following lidocaine, propranolol, and control (no drug). Heart rate, blood pressure, and coronary blood flow velocity (CBV, from Doppler echocardiography) were continuously measured. Rate-pressure product (RPP) was calculated, and changes from baseline were compared between treatments. The change in RPP at the end of Cold + Grip was not different between lidocaine (2,441 ± 376) and control conditions (3,159 ± 626); CBV responses were also not different between treatments. With propranolol, heart rate (8 ± 1 vs. 14 ± 3 beats/min) and RPP responses to Cold + Grip were significantly attenuated. However, at peak exercise propranolol also resulted in a smaller ΔCBV (1.4 ± 0.8 vs. 5.3 ± 1.4 cm/s, P = 0.035), such that the relationship between coronary flow and cardiac metabolism was impaired under propranolol (0.43 ± 0.37 vs. 2.1 ± 0.63 arbitrary units). These data suggest that cold air breathing and isometric exercise significantly influence efferent control of coronary blood flow. Additionally, ß-adrenergic vasodilation may play a significant role in coronary regulation during exercise.

ß-Adrenergic blockade enhances coronary vasoconstrictor response to forehead cooling.

Forehead cooling activates the sympathetic nervous system and can trigger angina pectoris in susceptible individuals. However, the effect of forehead cooling on coronary blood flow velocity (CBV) is not well understood. In this human experiment, we tested the hypotheses that forehead cooling reduces CBV (i.e., coronary vasoconstriction) and that this vasoconstrictor effect would be enhanced under systemic ß-adrenergic blockade. A total of 30 healthy subjects (age range, 23-79 years) underwent Doppler echocardiography evaluation of CBV in response to 60 s of forehead cooling (1°C ice bag on forehead). A subset of subjects (n = 10) also underwent the procedures after an intravenous infusion of propranolol. Rate pressure product (RPP) was used as an index of myocardial oxygen demand. Consistent with our first hypothesis, forehead cooling reduced CBV from 19.5 ± 0.7 to 17.5 ± 0.8 cm/s (P < 0.001), whereas mean arterial pressure increased by 11 ± 2 mmHg (P < 0.001). Consistent with our second hypothesis, forehead cooling reduced CBV under propranolol despite a significant rise in RPP. The current studies indicate that forehead cooling elicits a sympathetically mediated pressor response and a reduction in CBV, and this effect is augmented under ß-blockade. The results are consistent with sympathetic activation of ß-receptor coronary vasodilation in humans, as has been demonstrated in animals.

Artificial neural network based on strong track and square root UKF for INS/GNSS intelligence integrated system during GPS outage.

When INS/GNSS (inertial navigation system/global navigation satellite system) integrated system is applied, it will be affected by the insufficient number of visible satellites, and even the satellite signal will be lost completely. At this time, the positioning error of INS accumulates with time, and the navigation accuracy decreases rapidly. Therefore, in order to improve the performance of INS/GNSS integration during the satellite signals interruption, a novel learning algorithm for neural network has been presented and used for intelligence integrated system in this article. First of all, determine the input and output of neural network for intelligent integrated system and a nonlinear model for weighs updating during neural network learning has been established. Then, the neural network learning based on strong tracking and square root UKF (unscented Kalman filter) is proposed for iterations of the nonlinear model. In this algorithm, the square root of the state covariance matrix is used to replace the covariance matrix in the classical UKF to avoid the filter divergence caused by the negative definite state covariance matrix. Meanwhile, the strong tracking coefficient is introduced to adjust the filter gain in real-time and improve the tracking capability to mutation state. Finally, an improved calculation method of strong tracking coefficient is presented to reduce the computational complexity in this algorithm. The results of the simulation test and the field-positioning data show that the proposed learning algorithm could improve the calculation stability and robustness of neural network. Therefore, the error accumulation of INS/GNSS integration is effectively compensated, and then the positioning accuracy of INS/GNSS intelligence integrated system has been improved.

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Background: Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. Objective: We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Methods: Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Results: Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Conclusion: Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing.

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and ß-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and ß-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Distension of central great vein decreases sympathetic outflow in humans.

Classic canine studies suggest that central great vein distension evokes an autonomic reflex tachycardia (Bainbridge reflex). It is unclear whether central venous distension in humans is a necessary and sufficient stimulus to evoke a reflex increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Prior work from our laboratory suggests that limb venous distension evokes a reflex increase in BP and MSNA in humans. We hypothesized that in humans, compared with the limb venous distension, inferior vena cava (IVC) distension would evoke a less prominent increase in HR and MSNA. IVC distension (monitored with ultrasonography) was induced by two methods: 1) head-down tilt (HDT, N = 13); and 2) lower-body positive pressure (LBPP, N = 10). Two minutes of HDT induced IVC distension (Δ2.6 ± 0.2 mm, P < 0.001, ~27% in cross-sectional area), slightly increased mean BP (Δ2.3 ± 0.7 mmHg, P = 0.005), decreased MSNA (Δ5.2 ± 0.8 bursts/min, P < 0.001, N = 10), and did not alter HR (P = 0.37). LBPP induced similar IVC distension, increased BP (Δ2.0 ± 0.7 mmHg, P < 0.01), and did not alter HR (P = 0.34). Thus central venous distension leads to a rapid increase in BP and a subsequent fall in MSNA. Central venous distension does not evoke either bradycardia or tachycardia in humans. The absence of a baroreflex-mediated bradycardia suggests that the Bainbridge reflex is engaged. Clearly, this reflex differs from the powerful sympathoexcitation peripheral venous distension reflex described in humans.