Elevated sympathetic-mediated vasoconstriction at rest but intact functional sympatholysis during exercise in heart failure with reduced ejection fraction.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. METHODS: Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (left foot 2-min in -0.5[1] °C water) alone (CPT) and with right handgrip exercise (EX+CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. RESULTS: Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P<0.0001) but not EX+CPT (P=0.449, P=0.199) compared to controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX+CPT in patients with HFrEF (both P<0.0001) and controls (P=0.018, P=0.015), respectively. MAP increased during CPT and EX+CPT in both groups (all P<0.0001). MAP was greater in controls compared to patients with HFrEF during EX+CPT (P=0.025) but not CPT (P=0.209). CONCLUSIONS: Acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Cerebral sympatholysis: experiments on in vivo cerebrovascular regulation and ex vivo cerebral vasomotor control.

Whether cerebral sympathetic-mediated vasomotor control can be modulated by local brain activity remains unknown. This study tested the hypothesis that the application or removal of a cognitive task during a cold pressor test (CPT) would attenuate and restore decreases in cerebrovascular conductance (CVC), respectively. Middle cerebral artery blood velocity (transcranial Doppler) and mean arterial pressure (finger photoplethysmography) were examined in healthy adults (n = 16; 8 females and 8 males) who completed a control CPT, followed by a CPT coupled with a cognitive task administered either 1) 30 s after the onset of the CPT and for the duration of the CPT or 2) at the onset of the CPT and terminated 30 s before the end of the CPT (condition order was counterbalanced). The major finding was that the CPT decreased the index of CVC, and such decreases were abolished when a cognitive task was completed concurrently and restored when the cognitive task was removed. As a secondary experiment, vasomotor interactions between sympathetic transduction pathways (α1-adrenergic and Y1-peptidergic) and compounds implicated in cerebral blood flow control [adenosine, and adenosine triphosphate (ATP)] were explored in isolated porcine cerebral arteries (wire myography). The data reveal α1-receptor agonism potentiated vasorelaxation modestly in response to adenosine, and preexposure to ATP attenuated contractile responses to α1-agonism. Overall, the data suggest a cognitive task attenuates decreases in CVC during sympathoexcitation, possibly related to an interaction between purinergic and α1-adrenergic signaling pathways.NEW & NOTEWORTHY The present study demonstrates that the cerebrovascular conductance index decreases during sympathoexcitation and this response can be positively and negatively modulated by the application or withdrawal of a nonexercise cognitive task. Furthermore, isolated vessel experiments reveal that cerebral α1-adrenergic agonism potentiates adenosine-mediated vasorelaxation and ATP attenuates α1-adrenergic-mediated vasocontraction.

Muscle metaboreflex control of left ventricular systolic function in heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) exhibits exaggerated sympathoexcitation and altered cardiac and vascular responses to muscle metaboreflex activation (MMA). However, left ventricular (LV) responses to MMA are not well studied in patients with HFrEF. The purpose of this study was to examine LV function during MMA using cardiac magnetic resonance imaging (MRI) in patients with HFrEF. Thirteen patients with HFrEF and 18 healthy age-matched controls underwent cardiac MRI during rest and MMA. MMA protocol included 6 min of isometric handgrip exercise followed by 6-min of brachial postexercise circulatory occlusion. LV stroke volume index (SVi), end-systolic volume index (ESVi), end-diastolic volume index (EDVi), and global longitudinal strain (GLS) were measured by two- and four-chamber cine images. Volumes were indexed to body surface area. Heart rate (via ECG) and brachial mean arterial pressure (MAP) were recorded. Cardiac output and total peripheral resistance (TPR) were calculated. SVi decreased during MMA in HFrEF (P = 0.037) but not in controls (P = 0.392). ESVi (P = 0.007) and heart rate (P < 0.001) increased during MMA in HFrEF but not controls (P ≥ 0.170). TPR (P = 0.021) and MAP (P < 0.001) increased during MMA in both groups. Cardiac output (P = 0.946), EDVi (P = 0.177), and GLS (P = 0.619) were maintained from rest to MMA in both groups. Despite similarly maintained cardiac output, LV strain, and increased TPR in HFrEF and control groups, SVi decreased, and heart rate increased during MMA in patients with HFrEF. These findings suggest an impaired contractility reserve in response to increased TPR during MMA in HFrEF.NEW & NOTEWORTHY Stroke volume decreases and end-systolic volume increases during muscle metaboreflex activation in patients with heart failure with reduced ejection fraction (HFrEF), suggesting impaired contractile reserve during muscle metaboreflex activation in patients with HFrEF. Total peripheral resistance increases similarly during muscle metaboreflex activation in patients with HFrEF compared to controls, indicating normal levels of peripheral vasoconstriction during muscle metaboreflex activation in patients with HFrEF.

CP55940-induced vasorelaxation is endothelial-dependent and mediated by the CB1R through NOS, COX and EDHF pathways in porcine cerebral arteries.

Using swine as an experimental model, we examined whether the cannabinoid receptors (CB1R and CB2R) modulated vasomotor tone in isolated pial arteries. It was hypothesized that the CB1R would mediate cerebral artery vasorelaxation in an endothelial-dependent manner. First-order pial arteries were isolated from female Landrace pigs (age = 2 months; N = 27) for wire and pressure myography. Arteries were pre-contracted with a thromboxane A2 analogue (U-46619) and vasorelaxation in response to the CB1R and CB2R receptor agonist CP55940 was examined in the following conditions: 1) untreated; 2) inhibition of the CB1R (AM251); or 3) inhibition of the CB2R receptor (AM630). The data revealed that CP55940 elicits a CB1R-dependent relaxation in pial arteries. CB1R expression was confirmed using immunoblot and immunohistochemical analyses. Subsequently, the role of different endothelial-dependent pathways in the CB1R-mediated vasorelaxation was examined using: 1) denudation (removal of the endothelium); 2) inhibition of cyclooxygenase (COX; Naproxen); 3) inhibition of nitric oxide synthase (NOS; L-NAME); and 4) combined inhibition of COX + NOS. The data revealed CB1R-mediated vasorelaxation was endothelial-dependent, with contributions from COX-derived prostaglandins, NO, and endothelium-dependent hyperpolarizing factor (EDHF). Pressurized arteries underwent myogenic curves (20-100 mmHg) under the following conditions: 1) untreated; 2) inhibition of the CB1R. The data revealed CB1R inhibition increased basal myogenic tone, but not myogenic reactivity. As the vascular responses were assessed in isolated pial arteries, this work reveals that the CB1R modulates cerebrovascular tone independently of changes in brain metabolism.

Left ventricle chest compression improves ETCO2, blood pressure, and cerebral blood velocity in a swine model of cardiac arrest and cardiopulmonary resuscitation.

Introduction: During cardiopulmonary resuscitation (CPR), high quality chest compressions are critical to organ perfusion, especially the brain. Yet, the optimal location for chest compressions is unclear. It was hypothesized that compared with the standard chest compression (SCC) location, left ventricle chest compressions (LVCCs) would result in greater ETCO2, blood pressure (BP), and cerebral blood velocity (CBV) during CPR in swine. Methods: Female Landrace swine (N = 32; 35 ± 2 kg) underwent two mins of untreated asphyxiated cardiac arrest (CA). Thereafter, swine were treated with three 2-min cycles of either SCC or LVCC mechanical basic life support CPR (LUCAS 3). ETCO2 (in-line sampling), BP (arterial catheter line), and CBV (transcranial Doppler) were measured during the pre-CA, untreated-CA, and CPR-treated phases. Results: ETCO2, BP, and CBV were similar between groups at pre- and during untreated-CA (P ≥ 0.188). During CPR, ETCO2 (36 ± 6 versus 24 ± 10 mmHg, P < 0.001), mean arterial BP (MAP; 49 ± 9 versus 37 ± 9 mmHg, P = 0.002), and CBV (11 ± 5 versus 5 ± 2 cm/s, P < 0.001) were significantly greater in the LVCC versus SCC group. Moreover, a greater proportion of animals obtained targets for ETCO2 (ETCO2 ≥ 20 mmHg; 52 % (17/33) versus 100 % (32/32), P < 0.001) and diastolic BP (DBP ≥ 25 mmHg; 82 % (33/40) versus 97 % (48/49), P = 0.020) in the LVCC versus SCC group. Conclusion: Indicators of cardiac output, BP, and cerebral perfusion during CPR were greatest in the LVCC group, suggesting the quality of chest compressions during BLS CPR may be improved by performing compressions over the left ventricle compared to the centre of the chest.

Cerebral haemodynamics during arrhythmia in health, ischaemic heart disease and heart failure with reduced ejection fraction, and in a preclinical swine model.

Ventricular arrhythmias are associated with neurological impairment and could represent a source of cerebral hypoperfusion. In the present study, data from healthy individuals (n = 11), patients with ischaemic heart disease (IHD; ejection fraction >40%; n = 9) and patients with heart failure with reduced ejection fraction (HFrEF; EF = 31 (5)%, n = 11), as well as data from swine surgeries, where spontaneous ventricular arrhythmias were observed during cerebrovascular examination (transcranial Doppler ultrasound in humans and laser Doppler in swine) were analysed retrospectively to investigate the effect of arrhythmia on cerebral microvascular haemodynamics. A subset of participants also completed the Montreal Cognitive Assessment (MoCA). Middle cerebral artery mean blood velocity (MCAVmean ) decreased during premature ventricular contraction (PVC) in all groups, and data from swine indicate PVCs reduced cerebral microvascular perfusion. Overall MCAVmean was decreased in the HFrEF vs. control group. Further, %∆MCAVmean /%∆mean arterial pressure during the PVC was greater in the HFrEF vs. control group and was correlated with decreased MoCA scores. Subanalysis of HFrEF data revealed that during bigeminy MCAVmean decreased owing to reductions during irregular beats only. During non-sustained ventricular tachycardia, MCAVmean decreased but recovered above baseline upon return to sinus rhythm. Also, haemodynamic perturbations during and following the PVC were greater in the brachial artery vs. the MCA. Therefore, ventricular arrhythmias decreased indices of cerebral perfusion irrespective of IHD or HFrEF. The relative magnitude of arrhythmia-induced haemodynamic perturbations appears to be population specific and arrhythmia type and organ dependent. The cumulative burden of arrhythmia-induced deficits may exacerbate existing cerebral hypoperfusion in HFrEF and contribute to neurological abnormalities in this population. KEY POINTS: Irregular heartbeats are often considered benign in isolation, but individuals who experience them frequently have a higher prevalence of cerebrovascular and/or cognitive associated disorders. How irregular heartbeats affect blood pressure and cerebral haemodynamics in healthy and cardiovascular disease patients, those with and without reduced ejection fraction, remains unknown. Here it was found that in the absence of symptoms associated with irregular heartbeats, such as dizziness or hypotension, single, multiple non-sustained and sustained irregular heartbeats influence cerebral haemodynamics in a population-specific, arrhythmia-type and organ-dependent manner. Relative deficits in the index of cerebral blood flow normalized to relative deficits in blood pressure were greatest in patients with heart failure with reduced ejection and inversely related with cognitive performance. Chronic arrhythmias may exacerbate existing cerebral hypoperfusion in heart failure with reduced ejection fraction, thereby providing a mechanistic link between otherwise benign irregular heartbeats and cognitive dysfunction, independent of embolism.

Performance of an automated ultrasound device in identifying and tracing the heart in porcine cardiac arrest.

BACKGROUND: While intra-arrest echocardiography can be used to guide and monitor chest compression quality, it is not currently feasible on the scene of out-of-hospital cardiac arrests. Rapid and automated sonographic localization of the heart may provide first-responders guidance to an optimal area of compression without requiring them to interpret ultrasound images. In this proof-of-concept porcine study, we sought to describe the performance of an automated ultrasound device in correctly identifying and tracing the borders of the heart in three distinct states: pre-arrest, arrest, and late arrest. METHODS: An automated ultrasound device (bladder scanner) was placed on the chests of 7 swine, along the left sternal border (4th-8th intercostal spaces). Scanner-generated images were recorded for each space during pre-arrest, arrest, and finally late arrest. 828 images of the LV and LV outflow tract were randomized and 150 (50/state) selected for analysis. Scanner tracings of the heart were then digitally obscured to facilitate tracing by expert reviewers who were blinded to the physiologic state. Reviewer tracings were compared to bladder scanner tracings; with concordance between these images determined via Sørensen-Dice index (SDI). RESULTS: When compared to human reviewers, the bladder scanner was able to identify and trace the borders during cardiac arrest. The bladder scanner performed best at the time of arrest (SDI 0.900 ± 0.059). As resuscitation efforts continued and time from initial arrest increased, the scanner's performance decreased dramatically (SDI 0.597 ± 0.241 in late arrest). CONCLUSION: An automated ultrasound device (bladder scanner) reliably traced porcine hearts during cardiac arrest. It is possible a device could be developed to indicate where compressions should be performed without requiring the operator to interpret ultrasound images. Further investigation into rapid, automated, sonographic localization of the heart to identify the area of compression in out-of-hospital cardiac arrest is warranted.