Justin Lawley

Effect of gravity and microgravity on intracranial pressure

Astronauts have recently been discovered to have impaired vision, with a presentation that resembles syndromes of elevated intracranial pressure on Earth. Gravity has a profound effect on fluid distribution and pressure within the human circulation. In contrast to prevailing theory, we observed that microgravity reduces central venous and intracranial pressure. This being said, intracranial pressure is not reduced to the levels observed in the 90 deg seated upright posture on Earth. Thus, over 24 h in zero gravity, pressure in the brain is slightly above that observed on Earth, which may explain remodelling of the eye in astronauts.

Restoration of Pulsatile Flow Reduces Sympathetic Nerve Activity Among Individuals With Continuous-Flow Left Ventricular Assist Devices

Background— Current-generation left ventricular assist devices provide circulatory support that is minimally or entirely nonpulsatile and are associated with marked increases in muscle sympathetic nerve activity (MSNA), likely through a baroreceptor-mediated pathway. We sought to determine whether the restoration of pulsatile flow through modulations in pump speed would reduce MSNA through the arterial baroreceptor reflex. Methods and Results— Ten men and 3 women (54±14 years) with Heartmate II continuous-flow left ventricular assist devices underwent hemodynamic and sympathetic neural assessment. Beat-to-beat blood pressure, carotid ultrasonography at the level of the arterial baroreceptors, and MSNA via microneurography were continuously recorded to determine steady-state responses to step changes (200–400 revolutions per minute) in continuous-flow left ventricular assist device pump speed from a maximum of 10 480±315 revolutions per minute to a minimum of 8500±380 revolutions per minute. Reductions in pump speed led to increases in pulse pressure (high versus low speed: 17±7 versus 26±12 mm Hg; P<0.01), distension of the carotid artery, and carotid arterial wall tension (P<0.05 for all measures). In addition, MSNA was reduced (high versus low speed: 41±15 versus 33±16 bursts per minute; P<0.01) despite a reduction in mean arterial pressure and was inversely related to pulse pressure (P=0.037). Conclusions— Among subjects with continuous-flow left ventricular assist devices, the restoration of pulsatile flow through modulations in pump speed leads to increased distortion of the arterial baroreceptors with a subsequent decline in MSNA. Additional study is needed to determine whether reduction of MSNA in this setting leads to improved outcomes.

Reversing the Cardiac Effects of Sedentary Aging in Middle Age—A Randomized Controlled Trial: Implications For Heart Failure Prevention

Background: Poor fitness in middle age is a risk factor for heart failure, particularly heart failure with a preserved ejection fraction. The development of heart failure with a preserved ejection fraction is likely mediated through increased left ventricular (LV) stiffness, a consequence of sedentary aging. In a prospective, parallel group, randomized controlled trial, we examined the effect of 2 years of supervised high-intensity exercise training on LV stiffness. Methods: Sixty-one (48% male) healthy, sedentary, middle-aged participants (53±5 years) were randomly assigned to either 2 years of exercise training (n=34) or attention control (control; n=27). Right heart catheterization and 3-dimensional echocardiography were performed with preload manipulations to define LV end-diastolic pressure-volume relationships and Frank-Starling curves. LV stiffness was calculated by curve fit of the diastolic pressure-volume curve. Maximal oxygen uptake (Vo2max) was measured to quantify changes in fitness. Results: Fifty-three participants completed the study. Adherence to prescribed exercise sessions was 88±11%. Vo2max increased by 18% (exercise training: pre 29.0±4.8 to post 34.4±6.4; control: pre 29.5±5.3 to post 28.7±5.4, group×time P<0.001) and LV stiffness was reduced (right/downward shift in the end-diastolic pressure-volume relationships; preexercise training stiffness constant 0.072±0.037 to postexercise training 0.051±0.0268, P=0.0018), whereas there was no change in controls (group×time P<0.001; pre stiffness constant 0.0635±0.026 to post 0.062±0.031, P=0.83). Exercise increased LV end-diastolic volume (group×time P<0.001), whereas pulmonary capillary wedge pressure was unchanged, providing greater stroke volume for any given filling pressure (loading×group×time P=0.007). Conclusions: In previously sedentary healthy middle-aged adults, 2 years of exercise training improved maximal oxygen uptake and decreased cardiac stiffness. Regular exercise training may provide protection against the future risk of heart failure with a preserved ejection fraction by preventing the increase in cardiac stiffness attributable to sedentary aging. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02039154.

Potential role of endurance training in altering renal sympathetic nerve activity in CKD

Chronic kidney disease (CKD), is characterized by a progressive loss of renal function and increase in cardiovascular risk. In this review paper, we discuss the pathophysiology of increased sympathetic nerve activity in CKD patients and raise the possibility of endurance exercise being an effective countermeasure to address this problem. We specifically focus on the potential role of endurance training in altering renal sympathetic nerve activity as increased renal sympathetic nerve activity negatively impacts kidney function as well indirectly effects multiple other systems and organs. Recent technological advances in device based therapy have highlighted the detrimental effect of elevated renal sympathetic nerve activity in CKD patients, with kidney function and blood pressure being improved post renal artery nerve denervation in selected patients. These developments provide optimism for the development of alternative and/or complementary strategies to lower renal sympathetic nerve activity. However, appropriately designed studies are required to confirm preliminary observations, as the widespread use of the renal denervation approach to lower sympathetic activity presently has limited feasibility. Endurance training may be one alternative strategy to reduce renal sympathetic nerve activity. Here we review the role of endurance training as a potential alternative or adjunctive to current therapy in CKD patients. We also provide recommendations for future research to assist in establishing an evidence base for the use of endurance training to lower renal sympathetic activity in CKD patients.

Measurement of cerebral blood flow using phase contrast magnetic resonance imaging and duplex ultrasonography

Phase contrast magnetic resonance imaging (PC-MRI) and color-coded duplex ultrasonography (CDUS) are commonly used for measuring cerebral blood flow in the internal carotid (ICA) and vertebral arteries. However, agreement between the two methods has been controversial. Recent development of high spatial and temporal resolution blood vessel wall edge-detection and wall-tracking methods with CDUS increased the accuracy and reliability of blood vessel diameter, hence cerebral blood flow measurement. The aim of this study was to compare the improved CDUS method with 3 T PC-MRI for cerebral blood flow measurements. We found that cerebral blood flow velocity measured in the ICA was lower using PC-MRI than CDUS (left ICA: PC-MRI, 18.0 ± 4.2 vs. CDUS, 25.6 ± 8.6 cm/s; right ICA: PC-MRI, 18.5 ± 4.8 vs. CDUS, 26.6 ± 6.7 cm/s, both p < 0.01). However, ICA diameters measured using PC-MRI were larger (left ICA: PC-MRI, 4.7 ± 0.50 vs. CDUS, 4.1 ± 0.46 mm; right ICA: PC-MRI, 4.5 ± 0.49 vs. CDUS, 4.0 ± 0.45 mm, both p < 0.01). Cerebral blood flow velocity measured in the left vertebral artery with PC-MRI was also lower than CDUS, but no differences in vertebral artery diameter were observed between the methods. Dynamic changes and/or intrinsic physiological fluctuations may have caused these differences in vessel diameter and velocity measurements between the methods. However, estimation of volumetric cerebral blood flow was similar and correlated between the methods despite the presence of large individual differences. These findings support the use of CDUS for cerebral blood flow measurements in the ICA and vertebral artery.

Preload-corrected dynamic Starling mechanism in patients with heart failure with preserved ejection fraction

The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume (SV) because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. The purpose of this study was to test whether the LVEDP-SV relationship remained impaired in heart failure with preserved ejection fraction (HFpEF) patients after normalization of LVEDP. Right heart catheterization and model-flow analysis of the arterial pressure waveform were performed while preload was manipulated using lower-body negative pressure to alter LVEDP. The DSM was compared at similar levels of LVEDP between HFpEF patients ( n = 10) and age-matched healthy controls ( n = 12) (HFpEF vs. CONTROLS 10.9 ± 3.8 vs. 11.2 ± 1.3 mmHg, P = 1.00). Transfer function analysis between diastolic pulmonary artery pressure (PAD) representing dynamic changes in LVEDP vs. SV index was applied to obtain gain and coherence of the DSM. The DSM gain was significantly lower in HFpEF patients than in the controls, even at a similar level of LVEDP (0.46 ± 0.19 vs. 0.99 ± 0.39 ml·m-2·mmHg-1, P = 0.0018). Moreover, the power spectral density of PAD, the input variability, was greater in the HFpEF group than the controls (0.75 ± 0.38 vs. 0.28 ± 0.26 mmHg2, P = 0.01). Conversely, the power spectral density of SV index, the output variability, was not different between the groups ( P = 0.97). There was no difference in the coherence, which confirms the reliability of the linear transfer function between the two groups (0.71 ± 0.13 vs. 0.77 ± 0.19, P = 0.87). The DSM gain in HFpEF patients is impaired compared with age-matched controls even at a similar level of LVEDP, which may reflect intrinsic LV diastolic dysfunction and incompetence of ventricular-arterial coupling. NEW & NOTEWORTHY The beat-to-beat dynamic Starling mechanism (DSM), the dynamic modulation of stroke volume because of breath-by-breath changes in left-ventricular end-diastolic pressure (LVEDP), reflects ventricular-arterial coupling. Although the DSM gain is impaired in heart failure with preserved ejection fraction (HFpEF) patients, it is not clear whether this is because of higher LVEDP or left-ventricular diastolic dysfunction. The DSM gain in HFpEF patients is severely impaired, even at a similar level of LVEDP, which may reflect intrinsic left-ventricular diastolic dysfunction.

Lower body negative pressure to safely reduce intracranial pressure

During long‐term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure ‘unloading’ associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non‐linear dose–response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non‐invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension.

Augmented venoarteriolar response with ageing is associated with morning blood pressure surge

What is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied. What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age‐related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning.

Integrative Blood Pressure Response to Upright Tilt Post Renal Denervation

BACKGROUND Whether renal denervation (RDN) in patients with resistant hypertension normalizes blood pressure (BP) regulation in response to routine cardiovascular stimuli such as upright posture is unknown. We conducted an integrative study of BP regulation in patients with resistant hypertension who had received RDN to characterize autonomic circulatory control. METHODS Twelve patients (60 ± 9 [SD] years, n = 10 males) who participated in the Symplicity HTN-3 trial were studied and compared to 2 age-matched normotensive (Norm) and hypertensive (unmedicated, HTN) control groups. BP, heart rate (HR), cardiac output (Qc), muscle sympathetic nerve activity (MSNA), and neurohormonal variables were measured supine, and 30° (5 minutes) and 60° (20 minutes) head-up-tilt (HUT). Total peripheral resistance (TPR) was calculated from mean arterial pressure and Qc. RESULTS Despite treatment with RDN and 4.8 (range, 3-7) antihypertensive medications, the RDN had significantly higher supine systolic BP compared to Norm and HTN (149 ± 15 vs. 118 ± 6, 108 ± 8 mm Hg, P < 0.001). When supine, RDN had higher HR, TPR, MSNA, plasma norepinephrine, and effective arterial elastance compared to Norm. Plasma norepinephrine, Qc, and HR were also higher in the RDN vs. HTN. During HUT, BP remained higher in the RDN, due to increases in Qc, plasma norepinephrine, and aldosterone. CONCLUSION We provide evidence of a possible mechanism by which BP remains elevated post RDN, with the observation of increased Qc and arterial stiffness, as well as plasma norepinephrine and aldosterone levels at approximately 2 years post treatment. These findings may be the consequence of incomplete ablation of sympathetic renal nerves or be related to other factors.