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.

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.

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 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.

Autonomic and vascular function testing in collegiate athletes following SARS-CoV-2 infection: an exploratory study.

Introduction: Recent studies suggest that SARS-CoV-2 infection alters autonomic and vascular function in young, otherwise healthy, adults. However, whether these alterations exist in young competitive athletes remains unknown. This study aimed to assess the effects of COVID-19 on cardiac autonomic control and vascular function in collegiate athletes who tested positive for COVID-19, acknowledging the limitations imposed by the early stages of the pandemic. Methods: Sixteen collegiate athletes from various sports underwent a battery of commonly used autonomic and vascular function tests (23 ± 9, range: 12-44 days post-infection). Additionally, data from 26 healthy control participants were included. Results: In response to the Valsalva maneuver, nine athletes had a reduced early phase II blood pressure response and/or reduced Valsalva ratio. A depressed respiratory sinus arrhythmia amplitude was observed in three athletes. Three athletes became presyncopal during standing and did not complete the 10-min orthostatic challenge. Brachial artery flow-mediated dilation, when allometrically scaled to account for differences in baseline diameter, was not different between athletes and controls (10.0% ± 3.5% vs. 7.1% ± 2.4%, p = 0.058). Additionally, no differences were observed between groups when FMD responses were normalized by shear rate (athletes: 0.055% ± 0.026%/s-1, controls: 0.068% ± 0.049%/s-1, p = 0.40). Discussion: Few atypical and borderline responses to autonomic function tests were observed in athletes following an acute SARS-CoV-2 infection. The most meaningful autonomic abnormality being the failure of three athletes to complete a 10-min orthostatic challenge. These findings suggest that some athletes may develop mild alterations in autonomic function in the weeks after developing COVID-19, while vascular function is not significantly impaired.

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.

Effect of Cyclooxygenase Inhibition on Peripheral Venous Distension Reflex in Healthy Humans.

BACKGROUND: Peripheral venous distension evokes a pressor reflex (venous distension reflex). Afferent group III and IV nerves innervating veins are suggested as the afferent arm of the venous distension reflex. Prostaglandins stimulate/sensitize group III/IV nerves. We hypothesized that inhibition of prostaglandin synthesis by local cyclooxygenase blockade would attenuate the muscle sympathetic nerve activity (MSNA) and blood pressure responses to venous distension. METHODS: Nineteen healthy volunteers (age, 27±5 years) participated in the study with 2 visits. To induce venous distension, a volume of solution (saline alone or 9 mg ketorolac tromethamine in saline) was infused into the vein in the antecubital fossa of an arterially occluded forearm. During the procedure, beat-by-beat heart rate, blood pressure and MSNA were recorded simultaneously. The vein size was measured with ultrasound. RESULTS: In both visits, the venous distension procedure significantly increased blood pressure, heart rate, and MSNA (all, P<0.05). The increase in mean arterial pressure and MSNA in the ketorolac visit was significantly lower than in the control visit (∆ mean arterial pressure, 7.0±6.2 versus 13.8±7.7 mm Hg; ∆MSNA, 6.0±7.1 versus 14.8±7.7 bursts/min; both, P<0.05). The increase in vein size induced by the infusion was not different between visits. CONCLUSIONS: The presented data show that cyclooxygenase blockade attenuates the responses in MSNA and blood pressure to peripheral venous distension reflex. The results suggest that cyclooxygenase products play a key role in evoking afferent activation responsible for the venous distension reflex.

Repeated warm water baths decrease sympathetic activity in humans.

Acute whole body heat stress evokes sympathetic activation. However, the chronic effects of repeated moderate heat exposure (RMHE) on muscle sympathetic nerve activity (MSNA) in healthy individuals remain unclear. We performed RMHE with 4 wk (5 days/wk) of warm baths (∼40°C, for 30 min) in nine healthy older (59 ± 2 yr) volunteers. Hemodynamic variables and MSNA were examined before, 1 day after, and 1 wk following 4 wk of RMHE in a laboratory at ∼23°C. Cold pressor test (CPT) and handgrip (HG) exercise were performed during the tests. Under normothermic condition, the resting MSNA burst rate (prior, post, post 1-wk: 31.6 ± 2.0, 25.2 ± 2.0, and 27.7 ± 1.7 bursts/min; P < 0.001) and burst incidence (P < 0.001) significantly decreased after RMHE. Moreover, the resting heart rate significantly decreased after RMHE (62 ± 2, 60 ± 2, and 58 ± 2 beats/min, P = 0.031). The sensitivity of baroreflex control of MSNA and heart rate were not altered by RMHE, although the operating points were reset. The MSNA and hemodynamic responses (i.e., changes) to handgrip exercise or cold pressor test were not significantly altered. These data suggest that the RMHE evoked by warm baths decreases resting sympathetic activity and heart rate, which can be considered beneficial effects. The mechanism(s) should be examined in future studies.NEW & NOTEWORTHY To our knowledge, this is the first study to observe the effects of repeated warm baths on sympathetic nerve activity during rest and stress in healthy middle age and older individuals. The data suggest that the repeated warm baths decreased resting sympathetic activity and heart rate, which can be considered beneficial effects. This study also provides the first evidence that the repeated warm baths did not alter the baroreflex sensitivity and the sympathetic responses to stress.

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 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.

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.

Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans.

During exercise, ß-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of ß-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular ß1 vs. ß2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that ß1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective ß-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t-tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective ß1 blockade reduce myocardial oxygen demand during exercise, but it also unveils ß2-receptor-mediated coronary exercise hyperemia.NEW & NOTEWORTHY In this study, we evaluated the role of vascular ß1 vs. ß2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary ß1 and ß2 adrenergic receptors in humans.

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.

Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements.

Blood-oxygen-level-dependent magnetic resonance imaging (BOLD MRI) has the potential to quantify skeletal muscle oxygenation with high temporal and high spatial resolution. The purpose of this study was to characterize skeletal muscle BOLD responses during steady-state plantar flexion exercise (i.e., during the brief rest periods between muscle contraction). We used three different imaging modalities (ultrasound of the popliteal artery, BOLD MRI, and near-infrared spectroscopy [NIRS]) and two different exercise intensities (2 and 6 kg). Six healthy men underwent three separate protocols of dynamic plantar flexion exercise on separate days and acute physiological responses were measured. Ultrasound studies showed the percent change in popliteal velocity from baseline to the end of exercise was 151 ± 24% during 2 kg and 589 ± 145% during 6 kg. MRI studies showed an abrupt decrease in BOLD signal intensity at the onset of 2 kg exercise, indicating deoxygenation. The BOLD signal was further reduced during 6 kg exercise (compared to 2 kg) at 1 min (-4.3 ± 0.7 vs. -1.2 ± 0.4%, P < 0.001). Similarly, the change in the NIRS muscle oxygen saturation in the medial gastrocnemius was -11 ± 4% at 2 kg and -38 ± 11% with 6 kg (P = 0.041). In conclusion, we demonstrate that BOLD signal intensity decreases during plantar flexion and this effect is augmented at higher exercise workloads.

Effect of adrenergic agonists on coronary blood flow: a laboratory study in healthy volunteers.

Myocardial oxygen supply and demand mismatch is fundamental to the pathophysiology of ischemia and infarction. The sympathetic nervous system, through α-adrenergic receptors and ß-adrenergic receptors, influences both myocardial oxygen supply and demand. In animal models, mechanistic studies have established that adrenergic receptors contribute to coronary vascular tone. The purpose of this laboratory study was to noninvasively quantify coronary responses to adrenergic receptor stimulation in humans. Fourteen healthy volunteers (11 men and 3 women) performed isometric handgrip exercise to fatigue followed by intravenous infusion of isoproterenol. A subset of individuals also received infusions of phenylephrine (n = 6), terbutaline (n = 10), and epinephrine (n = 4); all dosages were based on fat-free mass and were infused slowly to achieve steady-state. The left anterior descending coronary artery was visualized using Doppler echocardiography. Beat-by-beat heart rate (HR), blood pressure (BP), peak diastolic coronary velocity (CBVpeak), and coronary velocity time integral were calculated. Data are presented as M ± SD Isometric handgrip elicited significant increases in BP, HR, and CBVpeak (from 23.3 ± 5.3 to 34.5 ± 9.9 cm/sec). Isoproterenol raised HR and CBVpeak (from 22.6 ± 4.8 to 43.9 ± 12.4 cm/sec). Terbutaline and epinephrine evoked coronary hyperemia whereas phenylephrine did not significantly alter CBVpeak. Different indices of coronary hyperemia (changes in CBVpeak and velocity time integral) were significantly correlated (R = 0.803). The current data indicate that coronary hyperemia occurs in healthy humans in response to isometric handgrip exercise and low-dose, steady-state infusions of isoproterenol, terbutaline, and epinephrine. The contribution of ß1 versus ß2 receptors to coronary hyperemia remains to be determined. In this echocardiographic study, we demonstrate that coronary blood flow increases when ß-adrenergic receptors are stimulated (i.e., during exercise and different intravenous infusions). Our infusion paradigms and beat-by-beat imaging methodologies can be used in future studies to evaluate age-, sex-, and disease- differences in adrenergic control of coronary blood flow.

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.