Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.

A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Quantification of dynamic cerebral autoregulation: welcome to the jungle!

PURPOSE: Patients with dysautonomia often experience symptoms such as dizziness, syncope, blurred vision and brain fog. Dynamic cerebral autoregulation, or the ability of the cerebrovasculature to react to transient changes in arterial blood pressure, could be associated with these symptoms. METHODS: In this narrative review, we go beyond the classical view of cerebral autoregulation to discuss dynamic cerebral autoregulation, focusing on recent advances pitfalls and future directions. RESULTS: Following some historical background, this narrative review provides a brief overview of the concept of cerebral autoregulation, with a focus on the quantification of dynamic cerebral autoregulation. We then discuss the main protocols and analytical approaches to assess dynamic cerebral autoregulation, including recent advances and important issues which need to be tackled. CONCLUSION: The researcher or clinician new to this field needs an adequate comprehension of the toolbox they have to adequately assess, and interpret, the complex relationship between arterial blood pressure and cerebral blood flow in healthy individuals and clinical populations, including patients with autonomic disorders.

On the use and misuse of cerebral hemodynamics terminology using transcranial Doppler ultrasound: a call for standardization.

Cerebral hemodynamics, e.g., cerebral blood flow, can be measured and quantified using many different methods, with transcranial Doppler ultrasound (TCD) being one of the most commonly used approaches. In human physiology, the terminology used to describe metrics of cerebral hemodynamics are inconsistent and in some instances technically inaccurate; this is especially true when evaluating, reporting, and interpreting measures from TCD. Therefore, this perspective article presents recommended terminology when reporting cerebral hemodynamic data. We discuss the current use and misuse of the terminology in the context of using TCD to measure and quantify cerebral hemodynamics and present our rationale and consensus on the terminology that we recommend moving forward. For example, one recommendation is to discontinue the use of the term "cerebral blood flow velocity" in favor of "cerebral blood velocity" with precise indication of the vessel of interest. We also recommend clarity when differentiating between discrete cerebrovascular regulatory mechanisms, namely, cerebral autoregulation, neurovascular coupling, and cerebrovascular reactivity. This will be a useful guide for investigators in the field of cerebral hemodynamics research.

Directional sensitivity of the cerebral pressure-flow relationship in young healthy individuals trained in endurance and resistance exercise.

NEW FINDINGS: What is the central question of this study? Does habitual exercise modality affect the directionality of the cerebral pressure-flow relationship? What is the main finding and its importance? These data suggest the hysteresis-like pattern of dynamic cerebral autoregulation appears present in long-term sedentary and endurance-trained individuals, but absent in resistance-trained individuals. This is the first study to expand knowledge on the directional sensitivity of the cerebral pressure-flow relationship to trained populations. ABSTRACT: Evidence suggests the cerebrovasculature may be more efficient at dampening cerebral blood flow (CBF) variations when mean arterial pressure (MAP) transiently increases, compared to when it decreases. Despite divergent MAP and CBF responses to acute endurance and resistance training, the long-term impact of habitual exercise modality on the directionality of dynamic cerebral autoregulation (dCA) is currently unknown. Thirty-six young healthy participants (sedentary (n = 12), endurance-trained (n = 12), and resistance-trained (n = 12)) undertook a 5-min repeated squat-stand protocol at two forced MAP oscillation frequencies (0.05 and 0.10 Hz). Middle cerebral artery mean blood velocity (MCAv) and MAP were continuously monitored. We calculated absolute (ΔMCAvT /ΔMAPT ) and relative (%MCAvT /%MAPT ) changes in MCAv and MAP with respect to the transition time intervals of both variables to compute a time-adjusted ratio in each MAP direction, averaged over the 5-min repeated squat-stand protocols. At 0.10 Hz repeated squat-stands, ΔMCAvT /ΔMAPT and %MCAvT /%MAPT were lower when MAP increased compared with when MAP decreased for sedentary (ΔMCAvT /ΔMAPT : P = 0.032; %MCAvT /%MAPT : P = 0.040) and endurance-trained individuals (ΔMCAvT /ΔMAPT : P = 0.012; %MCAvT /%MAPT P = 0.007), but not in the resistance-trained individuals (ΔMCAvT /ΔMAPT : P = 0.512; %MCAvT /%MAPT P = 0.666). At 0.05 Hz repeated squat-stands, time-adjusted ratios were similar for all groups (all P > 0.605). These findings suggest exercise training modality does influence the directionality of the cerebral pressure-flow relationship and support the presence of a hysteresis-like pattern during 0.10 Hz repeated squat-stands in sedentary and endurance-trained participants, but not in resistance-trained individuals. In future studies, assessment of elite endurance and resistance training habits may further elucidate modality-dependent discrepancies on directional dCA measurements.

Early Detection and Correction of Cerebral Desaturation With Noninvasive Oxy-Hemoglobin, Deoxy-Hemoglobin, and Total Hemoglobin in Cardiac Surgery: A Case Series.

Regional cerebral oxygen saturation (rS o2 ) obtained from near-infrared spectroscopy (NIRS) provides valuable information during cardiac surgery. The rS o2 is calculated from the proportion of oxygenated to total hemoglobin in the cerebral vasculature. Root O3 cerebral oximetry (Masimo) allows for individual identification of changes in total (ΔcHbi), oxygenated (Δ o2 Hbi), and deoxygenated (ΔHHbi) hemoglobin spectral absorptions. Variations in these parameters from baseline help identify the underlying mechanisms of cerebral desaturation. This case series represents the first preliminary description of Δ o2 Hbi, ΔHHbi, and ΔcHbi variations in 10 cardiac surgical settings. Hemoglobin spectral absorption changes can be classified according to 3 distinct variations of cerebral desaturation. Reduced cerebral oxygen content or increased cerebral metabolism without major blood flow changes is reflected by decreased Δ o2 Hbi, unchanged ΔcHbi, and increased ΔHHbi Reduced cerebral arterial blood flow is suggested by decreased Δ o2 Hbi and ΔcHbi, with variable ΔHHbi. Finally, acute cerebral congestion may be suspected with increased ΔHHbi and ΔcHbi with unchanged Δ o2 Hbi. Cerebral desaturation can also result from mixed mechanisms reflected by variable combination of those 3 patterns. Normal cerebral saturation can occur, where reduced cerebral oxygen content such as anemia is balanced by a reduction in cerebral oxygen consumption such as during hypothermia. A summative algorithm using rS o2 , Δ o2 Hbi, ΔHHbi, and ΔcHbi is proposed. Further explorations involving more patients should be performed to establish the potential role and limitations of monitoring hemoglobin spectral absorption signals.

A proposed algorithm for combining transcranial Doppler ultrasound monitoring with cerebral and somatic oximetry: a case report.

PURPOSE: Transcranial Doppler (TCD) ultrasound is a non-invasive monitor of cerebral blood velocity that can be used intraoperatively. The purpose of this report is to describe how different patterns seen on TCD can help identify the cause of cerebral desaturation when near-infrared spectroscopy (NIRS) oximetry is used concomitantly. CLINICAL FEATURES: A 69-yr-old male patient undergoing coronary revascularisation and aortic valve replacement developed perioperative complications that were detected using a combination of transtemporal TCD of the middle cerebral artery along with cerebral and somatic NIRS. Initial brain desaturation was secondary to hypocapnia during which TCD-derived blood velocity and somatic NIRS values remained unchanged. After the procedure, a second episode of brain desaturation occurred secondary to a technical issue with the aortic valve prosthesis requiring a return to cardiopulmonary bypass (CPB); there were no high-intensity transient signals (HITS) on TCD. Brain desaturation occurred a third time following the second attempt to separate from CPB at which time TCD detected a significant amount of HITS suggesting air emboli that were associated with acute right ventricular dysfunction; there was also a reduction in somatic NIRS. CONCLUSIONS: Combining TCD with cerebral NIRS allows for the rapid identification of three different mechanisms of brain desaturation. An algorithm is proposed to help identify the origin of NIRS cerebral desaturation. Prospective clinical trials are needed to investigate potential benefits of multimodal brain monitoring and its impact on short and/or long-term clinical outcomes.

RéSUMé: OBJECTIF: L'échographie par Doppler transcrânien (DTC) est un moniteur non invasif de la vélocité sanguine cérébrale qui peut être utilisé en période peropératoire. L'objectif de ce compte rendu est de décrire comment différents tracés observés sur le DTC peuvent aider l'anesthésiologiste à identifier la cause de la désaturation cérébrale lorsque l'oxymétrie par spectroscopie proche infrarouge (SPIR) est utilisée de manière concomitante. ÉLéMENTS CLINIQUES: Un homme de 69 ans subissant une revascularisation coronarienne et un remplacement de valve aortique a présenté des complications périopératoires détectées grâce à la combinaison d'un DTC trans-temporal de l'artère cérébrale moyenne et d'une SPIR cérébrale et somatique. La désaturation cérébrale initiale était secondaire à une hypocapnie, pendant laquelle la vélocité sanguine dérivée du DTC et les valeurs de SPIR somatique sont demeurées inchangées. Après l'intervention, un deuxième épisode de désaturation cérébrale est survenu suite à un problème technique avec la prothèse de valve aortique, nécessitant un retour sous circulation extracorporelle (CEC); il n'y avait pas de signaux transitoires de haute intensité (HITS) sur le DTC. Il y a eu un troisième épisode de désaturation cérébrale suite à la deuxième tentative de sevrage de la CEC; à ce moment-là, le DTC a détecté une quantité significative de HITS, suggérant des embolies gazeuses associées à une insuffisance ventriculaire droite aiguë; une réduction de la SPIR somatique a également été observée. CONCLUSION: La combinaison du DTC à la SPIR cérébrale a permis d'identifier trois différents mécanismes de désaturation cérébrale. Un algorithme est proposé pour aider le clinicien à déterminer l'origine de la désaturation cérébrale sur la SPIR. Des études cliniques prospectives sont nécessaires afin d'explorer les avantages potentiels d'un monitorage cérébral multimodal et son impact sur les devenirs cliniques à court et à long terme.

HIITing the brain with exercise: mechanisms, consequences and practical recommendations.

The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate-intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high-intensity interval training (HIIT) has since emerged as a more time-efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever-ageing population.

Effect of PPARγ agonist on aerobic exercise capacity in relation to body fat distribution in men with type 2 diabetes mellitus and coronary artery disease: a 1-yr randomized study.

Targeting metabolic determinants of exercise performance with pharmacological agents that would mimic/potentiate the effects of exercise represents an attractive clinical alternative to counterbalance the poor exercise capacity in patients with type 2 diabetes mellitus (T2DM). We examined the effect of 1-yr treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)γ agonist rosiglitazone on aerobic exercise capacity and body fat composition/distribution in men with T2DM and stable coronary artery disease (CAD). One-hundred four men (age: 64 ± 7 yr; body mass index: 30.0 ± 4.4 kg/m2) with T2DM and CAD were randomized to receive rosiglitazone or placebo for 1 yr. Aerobic exercise capacity (exercise duration) was assessed with a maximal treadmill test, and body composition/distribution were assessed by dual-energy X-ray absorptiometry/computed tomography scans. At 1 yr, patients with T2DM under PPARγ agonist treatment showed a reduction in aerobic exercise capacity compared with the control group (exercise duration change, -31 ± 8 versus 7 ± 11 s, P = 0.009). Significant increases in body fat mass (3.1 ± 0.4 kg, 12%), abdominal and mid-thigh subcutaneous adipose tissue (AT) levels, and mid-thigh skeletal muscle fat were found (all P < 0.01), whereas no effect on visceral AT levels was observed (P > 0.05) under treatment. Subcutaneous fat mass gained under PPARγ agonist was the strongest predictor of the worsening in aerobic exercise capacity (P > 0.0001); no association was found with skeletal muscle fat infiltration nor visceral AT. Treatment with the insulin sensitizer PPARγ agonist rosiglitazone in patients with T2DM and CAD is associated with a worsening in aerobic exercise capacity, which seems to be mainly attributable to weight gain and subcutaneous fat mass expansion.

Cardiac remodeling after six weeks of high-intensity interval training to exhaustion in endurance-trained men.

High-intensity interval training (HIIT) improves physical performance of endurance athletes, although studies examining its cardiovascular effects are sparse. We evaluated the impact of HIIT on blood pressure, heart rate, and cardiac cavities' size and function in endurance-trained adults. Seventeen endurance-trained men underwent 24-h ambulatory blood pressure monitoring and Doppler echocardiography at baseline and after 6 wk of HIIT. Participants were divided into 2 groups [85% maximal aerobic power (HIIT85), n = 8 and 115% maximal aerobic power (HIIT115), n = 9] to compare the impact of different HIIT intensities. Ambulatory blood pressure monitoring and cardiac chambers' size and function were similar between groups at baseline. HIIT reduced heart rate (55 ± 8 vs. 51 ± 7 beats/min; P = 0.003), systolic blood pressure (121 ± 11 vs. 118 ± 9 mmHg; P = 0.01), mean arterial pressure (90 ± 8 vs. 89 ± 6 mmHg; P = 0.03), and pulse pressure (52 ± 6 vs. 49 ± 5 mmHg; P = 0.01) irrespective of training intensity. Left atrium volumes increased after HIIT (maximal: 50 ± 14 vs. 54 ± 14 mL; P = 0.02; minimal: 15 ± 5 vs. 20 ± 8 mL; P = 0.01) in both groups. Right ventricle global longitudinal strain lowered after training in the HIIT85 group only (20 ± 4 vs. 17 ± 3%, P = 0.04). In endurance-trained men, 6 wk of HIIT reduced systolic blood pressure and mean arterial pressure and increased left atrium volumes irrespective of training intensity, whereas submaximal HIIT deteriorated right ventricle systolic function.NEW & NOTEWORTHY The novel findings of this study are that 6 wk of high-intensity interval training increases left atrial volumes irrespective of training intensity (85 or 115% maximal aerobic power), whereas the submaximal training decreases right ventricular systolic function in endurance-trained men. These results may help identify the exercise threshold for potential toxicity of intense exercise training for at-risk individuals and ideal exercise training regimens conferring optimal cardiovascular protection and adapted endurance training for athletes.

Implications of habitual endurance and resistance exercise for dynamic cerebral autoregulation.

NEW FINDINGS: What is the central question of this study? Does habitual resistance and endurance exercise modify dynamic cerebral autoregulation? What is the main finding and its importance? To the authors' knowledge, this is the first study to directly assess dynamic cerebral autoregulation in resistance-trained individuals, and potential differences between exercise training modalities. Forced oscillations in blood pressure were induced by repeated squat-stands, from which dynamic cerebral autoregulation was assessed using transfer function analysis. These data indicate that dynamic cerebral autoregulatory function is largely unaffected by habitual exercise type, and further document the systemic circulatory effects of regular exercise. ABSTRACT: Regular endurance and resistance exercise produce differential but desirable physiological adaptations in both healthy and clinical populations. The chronic effect of these different exercise modalities on cerebral vessels' ability to respond to rapid changes in blood pressure (BP) had not been examined. We examined dynamic cerebral autoregulation (dCA) in 12 resistance-trained (mean ± SD, 25 ± 6 years), 12 endurance-trained (28 ± 9 years) and 12 sedentary (26 ± 6 years) volunteers. The dCA was assessed using transfer function analysis of forced oscillations in BP vs. middle cerebral artery blood velocity (MCAv), induced via repeated squat-stands at 0.05 and 0.10 Hz. Resting BP and MCAv were similar between groups (interaction: both P ≥ 0.544). The partial pressure of end-tidal carbon dioxide ( PETCO2 ) was unchanged (P = 0.561) across squat-stand manoeuvres (grouped mean for absolute change +0.6 ± 2.3 mmHg). Gain and normalized gain were similar between groups across all frequencies (both P ≥ 0.261). Phase showed a frequency-specific effect between groups (P = 0.043), tending to be lower in resistance-trained (0.63 ± 0.21 radians) than in endurance-trained (0.90 ± 0.41, P = 0.052) and -untrained (0.85 ± 0.38, P = 0.081) groups at slower frequency (0.05 Hz) oscillations. Squat-stands induced mean arterial pressure perturbations differed between groups (interaction: P = 0.031), with greater changes in the resistance (P < 0.001) and endurance (P = 0.001) groups compared with the sedentary group at 0.05 Hz (56 ± 13 and 49 ± 11 vs. 35 ± 11 mmHg, respectively). The differences persisted at 0.1 Hz between resistance and sedentary groups (49 ± 12 vs. 33 ± 7 mmHg, P < 0.001). These results indicate that dCA remains largely unaltered by habitual endurance and resistance exercise with a trend for phase to be lower in the resistance exercise group at lower fequencies.

A Practical Approach to Cerebro-Somatic Near-Infrared Spectroscopy and Whole-Body Ultrasound.

Near-infrared spectroscopy (NIRS) is an emerging noninvasive monitoring modality based on chromophore absorption of infrared light. Because NIRS provides instantaneous information on cerebral and somatic tissue oxygenation, it becomes mandatory to identify rapidly the etiology of impaired regional oxygenation and thus perfusion. To do so, the use of whole-body ultrasound (WHOBUS) represents a significant advance in the management of patients experiencing cerebral or somatic desaturation. This narrative review describes the authors' experience since 2002 in the use of combined NIRS and WHOBUS. A practical approach in the use of both modalities and their respective limitations is described.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

BACKGROUND: The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. METHODS: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. RESULTS: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). CONCLUSIONS: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Rosiglitazone lowers resting and blood pressure response to exercise in men with type 2 diabetes: A 1-year randomized study.

AIMS: We aimed to determine the effect of 1-year treatment with the insulin sensitizer peroxisome proliferator-activated receptor (PPAR)-γ agonist rosiglitazone on exercise capacity and blood pressure (BP) response to exercise in men with coronary artery disease (CAD) and type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 116 men (age, 64 ± 7 years; body mass index, 30.0 ± 4.4 kg/m2 ) with CAD and T2D were randomized to receive rosiglitazone or placebo for 1 year. Exercise capacity (VO2peak ) and BP response to exercise were assessed with a maximal treadmill test, prior to the intervention and at 1-year follow-up. Exercise-induced hypertension (EIH) was defined as maximal systolic BP ≥ 220 mm Hg and/or diastolic BP ≥ 100 mm Hg. RESULTS: PPAR-γ agonist-treated patients showed improvements in fasting glucose, HbA1c and insulin sensitivity (Homeostasis model assessment of insulin resistance [HOMA-IR]) (all P < .05). Resting BPs, maximal exercise diastolic BP and resting rate-pressure product (RPP) were all reduced in the PPAR-γ agonist group (P < .05). Maximal exercise duration was unchanged. T2D patients who displayed the greatest improvement in insulin sensitivity (HOMA-IR) under PPAR-γ agonist treatment experienced a greater reduction in exercise BP and RPP (P < .05). The proportion of men with EIH decreased in the PPAR-γ agonist group during follow-up (39.00% ± 0.06% vs 21.00% ± 0.05%). In the subgroup with EIH that was treated with a PPAR-γ agonist, resting and exercise diastolic BP, as well as resting RPP, were all reduced at 1-year follow-up (P < .05). CONCLUSIONS: The insulin sensitizer rosiglitazone has a beneficial effect on resting and BP response to exercise in men with CAD and T2D, especially in those with an exaggerated BP response to exercise.

Evidence for hysteresis in the cerebral pressure-flow relationship in healthy men.

The cerebrovasculature is more efficient at compensating for pharmacologically induced transient hypertension versus transient hypotension. Whether this phenomenon exists during nonpharmacologically induced hypertension and hypotension is currently unknown. We compared the percent change in mean velocity in the middle cerebral artery (MCAvmean) per percent change in mean arterial pressure (MAP) (%ΔMCAVmean/%ΔMAP) during transient hypertension and hypotension induced during squat-stand maneuvers performed at 0.05 Hz (20-s cycles) and 0.10 Hz (10-s cycles) in 58 male volunteers. %ΔMCAvmean/%ΔMAP was attenuated by 25% (P = 0.03, 0.05 Hz) and 47% (P < 0.0001, 0.10 Hz) during transient hypertension versus hypotension. Thus, these findings indicate that the brain in healthy men is better adapted to compensate for physiologically relevant transient hypertension than hypotension.NEW & NOTEWORTHY The novel finding of this study is that the change in middle cerebral artery mean flow velocity is attenuated during hypertension compared with hypotension physiologically induced by oscillations in blood pressure in men. These results support that the human brain is more effective at compensating for transient hypertension than hypotension.

Sympathetic Vasoconstrictor Responsiveness of the Leg Vasculature During Experimental Endotoxemia and Hypoxia in Humans.

OBJECTIVE: Sympathetic vasoconstriction regulates peripheral circulation and controls blood pressure, but sepsis is associated with hypotension. We evaluated whether apparent loss of sympathetic vasoconstrictor responsiveness relates to distended smooth muscles or to endotoxemia and/or hypoxia. DESIGN: Prospective descriptive study. SETTING: Hospital research laboratory. SUBJECTS: Ten healthy young men (age [mean ± SD], 31 ± 8 yr; body weight, 83 ± 10 kg) participated in the study. INTERVENTIONS: Leg blood flow and mean arterial pressure were determined, whereas leg vascular conductance was calculated during 1) adenosine infusion (vasodilator control), 2) hypoxia (FIO2 = 10%), 3) endotoxemia, and 4) endotoxemia + hypoxia. Leg sympathetic vasoconstrictor responsiveness (reduction in leg vascular conductance) was evaluated by femoral artery tyramine infusion. MEASUREMENTS AND MAIN RESULTS: Endotoxemia increased body temperature from 36.9 ± 0.4°C to 38.6 ± 0.5°C (p < 0.01) and plasma tumor necrosis factor-α from 6 pg/mL (3-8 pg/mL) to 391 pg/mL (128-2258 pg/mL) (p < 0.01; median [range]). Mean arterial pressure decreased similarly during endotoxemia (-11% ± 16%) and endotoxemia + hypoxia (-10% ± 15%; both p < 0.05). Leg blood flow and leg vascular conductance were not affected by endotoxemia, whereas both were elevated by adenosine infusion (leg blood flow, +94% ± 61%; leg vascular conductance, +97% ± 57%), hypoxia (leg blood flow: +93% ± 58%; leg vascular conductance, +100% ± 115%), and endotoxemia + hypoxia (leg blood flow, +67% ± 120%; leg vascular conductance, +65% ± 57%; p < 0.05). Endotoxemia lessened the tyramine-induced reduction in leg vascular conductance (-28% ± 13%) compared with the reduction during adenosine infusion (-47% ± 5%; p < 0.05). Also, endotoxemia + hypoxia (-17% ± 21%) attenuated the tyramine-induced reduction in leg vascular conductance compared with both adenosine infusion and hypoxia (-45% ± 13%; p < 0.05). CONCLUSIONS: Both endotoxemia and combined hypoxia and endotoxemia blunted sympathetic vasoconstrictor responsiveness. Furthermore, tyramine normalized the doubled leg vascular conductance during administration of adenosine, suggesting that distension of vascular smooth muscles does not explain blunted sympathetic vasoconstrictor responsiveness during endotoxemia.