The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Physiological relationship between cardiorespiratory fitness and fitness for surgery: a narrative review.

Epidemiological evidence has highlighted a strong relationship between cardiorespiratory fitness and surgical outcomes; specifically, fitter patients possess heightened resilience to withstand the surgical stress response. This narrative review draws on exercise and surgical physiology research to discuss and hypothesise the potential mechanisms by which higher fitness affords perioperative benefit. A higher fitness, as indicated by higher peak rate of oxygen consumption and ability to sustain metabolic homeostasis (i.e. higher anaerobic threshold) is beneficial postoperatively when metabolic demands are increased. However, the associated adaptations with higher fitness, and the related participation in regular exercise or physical activity, might also underpin the observed perioperative benefit through a process of hormesis, a protective adaptive response to the moderate and intermittent stress of exercise. Potential mediators discussed include greater antioxidant capacity, metabolic flexibility, glycaemic control, lean body mass, and improved mood.

Carotid body hyperexcitability underlies heat-induced hyperventilation in exercising humans.

Physical activity is the most common source of heat strain for humans. The thermal strain of physical activity causes overbreathing (hyperventilation) and this has adverse physiological repercussions. The mechanisms underlying heat-induced hyperventilation during exercise are unknown, but recent evidence supports a primary role of carotid body hyperexcitability (increased tonic activity and sensitivity) underpinning hyperventilation in passively heated humans. In a repeated-measures crossover design, 12 healthy participants (6 female) completed two low-intensity cycling exercise conditions (25% maximal aerobic power) in randomized order, one with core temperature (TC) kept relatively stable near thermoneutrality, and the other with progressive heat strain to +2°C TC. To provide a complete examination of carotid body function under graded heat strain, carotid body tonic activity was assessed indirectly by transient hyperoxia, and its sensitivity estimated by responses to both isocapnic and poikilocapnic hypoxia. Carotid body tonic activity was increased by 220 ± 110% during cycling alone, and by 400 ± 290% with supplemental thermal strain to +1°C TC, and 600 ± 290% at +2°C TC (interaction, P = 0.0031). During exercise with heat stress at both +1°C and +2°C TC, carotid body suppression by hyperoxia decreased ventilation below the rates observed during exercise without heat stress (P < 0.0147). Carotid body sensitivity was increased by up to 230 ± 190% with exercise alone, and by 290 ± 250% with supplemental heating to +1°C TC and 510 ± 470% at +2°C TC (interaction, P = 0.0012). These data indicate that the carotid body is further activated and sensitized by heat strain during exercise and this largely explains the added drive to breathe.NEW & NOTEWORTHY Physical activity is the most common way humans increase their core temperature, and excess breathing in the heat can limit heat tolerance and performance, and may increase the risk of heat-related injury. Dose-dependent increases in carotid body tonic activity and sensitivity with core heating provide compelling evidence that carotid body hyperexcitability is the primary cause of heat-induced hyperventilation during exercise.

Adjunct Methods for the Detection of Patent Foramen Ovale: The Contribution of Transcranial Doppler and the Valsalva Manoeuvre.

A patent foramen ovale (PFO) is present in 25% of the population. In some patients, especially those without traditional stroke risk factors and with no immediately apparent cause, a cryptogenic stroke may be caused by an embolus passing through the PFO to the systemic circulation. The identification, or indeed exclusion, of a PFO is sought in these patients, most commonly using contrast-enhanced transthoracic or transoesophageal echocardiography. Another method for detecting a PFO is transcranial Doppler, which allows the detection of PFO possibly without the need for an echo laboratory, and with arguably improved sensitivity. This review will focus on transcranial Doppler detection of PFO, with a brief summary of echocardiographic techniques and the use of ultrasound contrast agents, and the role of provocations to increase diagnostic accuracy, specifically the Valsalva manoeuvre. We discuss the phases alongside the direct and indirect signs of an adequate Valsalva manoeuvre.

Contribution of the carotid body to thermally mediated hyperventilation in humans.

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid-base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. KEY POINTS: Humans over-breathe (hyperventilate) when under heat and cold stress, and though this has detrimental physiological repercussions, the mechanisms underlying this response are unknown. The carotid body, a small organ that is responsible for driving hyperventilation in hypoxia, was assessed under incremental heat and cold strain. The carotid body drive to breathe, as indirectly assessed by transient hyperoxia, increased in a dose-dependent manner with heating, reaching 175% above baseline; cold stress similarly increased the carotid body drive to breathe, but did not show dose-dependency. Carotid body sensitivity, as indirectly assessed by hypoxic ventilatory responses, was profoundly increased by 70-180% with mild and severe heat strain, whereas cooling had no detectable effect. Carotid body hyperactivity and hypersensitivity are two interrelated mechanisms that probably underlie the increased drive to breathe with heat strain, whereas carotid body hyperactivity during mild cooling may play a subsidiary role in cold-induced hyperventilation.

Does the intact nephron hypothesis provide a reasonable model for metformin dosing in chronic kidney disease?

This research explored the intact nephron hypothesis (INH) as a model for metformin dosing in patients with chronic kidney disease (CKD). The INH assumes that glomerular filtration rate (GFR) will account for all kidney drug handling even for drugs eliminated by tubular secretion like metformin. We conducted two studies: (1) a regression analysis to explore the relationship between metformin clearance and eGFR metrics, and (2) a joint population pharmacokinetic analysis to test the relationship between metformin renal clearance and gentamicin clearance. The relationship between metformin renal clearance and eGFR metrics and gentamicin clearance was found to be linear, suggesting that a proportional dose reduction based on GFR in patients with CKD is reasonable.

Influence of the mode of heating on cerebral blood flow, non-invasive intracranial pressure and thermal tolerance in humans.

KEY POINTS: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death. The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment. The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot-water immersion (spa) and exercising in a hot environment. Non-invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP. ABSTRACT: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (Tc ; oesophageal) via passive hot-water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO2 inhalation to prevent heat-induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in Tc and ICP was estimated non-invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end-tidal PCO2 was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum Tc was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain.

Metformin doses to ensure efficacy and safety in patients with reduced kidney function.

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was <5% for most doses and kidney function levels. The lower dose of 500 mg daily was required to maintain concentrations below the safety limits for patients with an eGFR of 15-29 mL/min. Our analysis suggests that a maximum daily dose of 2250, 1700, 1250, 1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b and 4, respectively, will provide a reasonable probability of achieving efficacy and safety. Our results support the cautious of use metformin at appropriate doses in patients with impaired kidney function.

Acute exercise-related cognitive effects are not attributable to changes in end-tidal CO2 or cerebral blood velocity.

PURPOSE: Cognition, cerebral blood flow (CBF) and its major regulator (i.e., arterial CO2), increase with submaximal exercise and decline with severe exercise. These responses may depend on fitness. We investigated whether exercise-related changes in cognition are mediated in part by concomitant changes in CBF and CO2, in ten active (26 ± 3 years) and ten inactive (24 ± 6 years) healthy adults. METHODS: Participants completed two randomised sessions; exercise and a resting CO2-control-wherein end-tidal CO2 (PETCO2) was matched between sessions and clamped across conditions at exercise-associated increases (+ 3 mmHg) and hypercapnia (+ 10 mmHg). Exercise comprised inclined walking at submaximal and severe intensities. CBF was indexed using right middle cerebral artery blood velocity (MCAv). Cognition (visuomotor, switching and inhibitory response time) was measured before, during, and after exercise. RESULTS: MCAv and its inverted-U response to exercise were comparable between groups, whereas visuomotor performance improved during submaximal exercise in the active group only (p = 0.046). Submaximal, but not severe (p = 0.33), exercise increased MCAv (p ≤ 0.03). Hypercapnia increased MCAv during the CO2-control (27 ± 12%) and during submaximal exercise (39 ± 17%; p < 0.01). Despite the acute increases in MCAv, cognition was impaired during both levels of increased PETCO2 (3-6%; p ≤ 0.04), regardless of session. Overall, resting or exercise-related changes in PETCO2 and MCAv did not associate with changes in cognition (r ≤ 0.29 ± 0.34). Fitness ([Formula: see text]O2MAX) was associated with baseline cognition (r ≥ 0.50). CONCLUSION: Acute increases in PETCO2 and MCAv were not associated with improved cognition. In fact, cognitive performance was impaired at both levels of increased PETCO2, regardless of session. Finally, fitter people were found to have better cognition.

Refinement of a protocol to induce reliable muscle cramps in the abductor hallucis.

OBJECTIVE: To test the reliability of immediate replication of muscle cramp characteristics induced with different electrical stimulation protocols. APPROACH: Five (age 33.8 ± 5.7 y, 60% male) and ten (age 47.4 ± 11.7 y, 60% male) participants completed independent discovery and validation cohorts, respectively. This was to identify a protocol that resulted in consistent muscle cramp characteristics (discovery), and to examine the test-retest reliability of the identified protocol (validation). Electrical stimulation (150 burst) at abductor hallucis motor-point was used to induce muscle cramps with 4 Hz increments in stimulation frequency (8-32 Hz) or until muscle cramp was first evident, followed by refinement (2 and 1 Hz) until at least two muscle cramps occurred. This defined the cramp threshold frequency, and concurrent electromyogram activity and duration of the cramp were quantified. The discovery cohort involved three separate randomised sessions where intervals between stimulation was 60, 90, and 120 s respectively. In each session, four randomised electrical stimulation protocols were completed. Stimulation current was fixed at 10, 20, and 30% higher than m-wave stimulation current (protocols 1-3 respectively), or randomised within 4 Hz steps (protocol 4) to minimise any order effect. MAIN RESULTS: We were able to immediately replicate tolerable muscle cramp at least twice. Discovery cohort demonstrated (i) incremental changes in stimulation frequency (protocols 1-3 vs. protocol 4, i.e. order effect), and (ii) changes in stimulation current with differing protocols did not significantly alter the prevailing muscle cramp characteristics, and (iii) defining the muscle cramp characteristics elicits good-to-excellent inter-observer reliability. The validation cohort's test-retest reliability and the minimum detectable change were improved for all muscle cramp characteristics when immediately replicated more than twice at the lowest stimulation frequency. SIGNIFICANCE: This study provides evidence for a reliable method for inducing repeatable muscle cramps in abductor hallucis.

Cerebrovascular haemodynamics during isometric resistance exercise with and without the Valsalva manoeuvre.

PURPOSE: To examine the interactive effects of VM and isometric resistance exercise on cerebral haemodynamics. METHODS: Eleven healthy participants (mean ± SD 28 ± 9 years; 2 females) completed 20-s bilateral isometric leg extension at 50% of maximal voluntary contraction with continued ventilation (RE), a 20-s VM at mouth pressure of 40 mmHg (VM), and a combination (RE + VM), in randomised order. Mean beat-to-beat blood velocity in the posterior (PCAvmean) and middle cerebral arteries (MCAvmean), vertebral artery blood flow, end-tidal partial pressure of CO2 and mean arterial pressure (MAP) were measured. RE data were time aligned to RE + VM and analysed according to standard VM phases. RESULTS: Interaction effects (VM phase × condition) were observed for MCAvmean, PCAvmean, vertebral artery blood flow and MAP (all ≤ 0.010). Phase I MCAvmean was greatest for RE [88 ± 19, vs. 71 ± 11 and 78 ± 12 cm s-1 for VM (P = 0.008) and RE + VM (P = 0.021), respectively]. Greater increases in MCAvmean than PCAvmean occurred in phase I of RE only (24 ± 15% vs. 16 ± 16%, post hoc P = 0.044). In phase IIb, MAP was lower in RE than RE + VM (115 ± 15 vs. 138 ± 21 mmHg, P = 0.004), but did not reduce MCAvmean (78 ± 8 vs. 79 ± 9 cm s-1, P = 0.579) or PCAvmean (45 ± 11 vs .46 ± 11 cm s-1, P = 0.617). Phase IIb MCAvmean and PCAvmean was lowest in VM (66 ± 6 and 39 ± 8 cm s-1, respectively, all P < 0.001), whereas in Phase IV, MCAvmean, PCAvmean and MAP were greater in VM than in RE and RE + VM (all P < 0.020). CONCLUSION: RE and RE + VM produce similar cerebrovascular responses despite different MAP profiles. However, the VM produced the greatest cerebrovascular challenge afterward.

Beat-to-beat blood pressure measurement using a cuffless device does not accurately reflect invasive blood pressure.

BACKGROUND: The availability of an accurate continuous cuffless blood pressure (BP) monitor would provide an alternative to both invasive continuous BP and 24-h intermittent cuff-based BP monitors. We investigated the accuracy of a cuffless beat to beat (BtB) device compared to both invasive BP (iBP) and brachial cuff BP (cBP) measurements. METHODS: Patients undergoing clinically indicated coronary angiography (CA) and/or percutaneous coronary intervention (PCI) were recruited. After calibration to an initial cBP reading, BP was measured simultaneously using a BtB device (SOMNOtouch NIBP), brachial artery iBP, and cBP at two time points. RESULTS: The study was terminated early due to a significant bias. Recordings from 14 participants (11 males, mean age 68.4 years) were analysed. Readings from BtB BP were higher than iBP. The bias between BtB BP and iBP was 34.3 mmHg (95%CI: 27.0, 41.5) and 23.6 mmHg (95%CI: 16.8, 30.4) for SBP and DBP respectively. A similar bias was seen between BtB BP and cBP, but cBP and iBP were largely in agreement. CONCLUSIONS: In patients undergoing CA/PCI, significant differences were detected between BtB BP and both invasively measured and cuff BP. The non-invasive BtB BP measurement device tested is not suitable for clinical or research use.

Review: Detection of patient foramen ovale using transcranial Doppler or standard echocardiography.

A patent foramen ovale (PFO) is a common remnant of fetal circulation present in up to 25% of the worldwide adult population. Paradoxical embolism occurs when venous blood crosses the PFO into the arterial system, bypassing the pulmonary circulation. This allows for the direct passage of microemboli into cerebral blood vessels, increasing the risk of cryptogenic stroke. This review investigates the current diagnostic procedures used to detect and grade a PFO, including transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE) and transcranial Doppler (TCD). Only a few studies have directly compared the use of TTE with TCD for PFO detection but several have compared TTE and TCD independently against the clinical gold standard TOE. Known pitfalls of TTE and TCD are also discussed, including the difficulty of differentiating between intracardiac shunts and intrapulmonary shunts. This review also discusses methods to optimise imaging, such as performing an adequate Valsalva manoeuvre, the role of abdominal compression and the choice of the injection site for the contrast agent and how these may increase the diagnostic success of detecting a right-to-left shunt when prompted by a clinician.

Swimming-related effects on cerebrovascular and cognitive function.

Both acute and regular exercise influence vascular and cognitive function. Upright aquatic exercise increases mean middle cerebral artery blood velocity (MCAvmean ) and has been suggested as favorable for cerebrovascular adaptations. However, MCAvmean has not been reported during swimming. Thus, we examined the cerebrovascular and cognitive effects of swimming. Ten land-based athletes (22 ± 5 years) and eight swimmers (19 ± 1 years) completed three cognitive tasks and four conditions that were used to independently and collectively delineate the swimming-related factors (i.e., posture, immersion, CO2 retention [end-tidal CO2 ; PETCO2 ], and motor involvement). Measurements of MCAvmean and PETCO2 were taken throughout each condition. Prone posture increased MCAvmean by 11% (P < 0.01 vs. upright land). Water immersion independently increased MCAvmean when upright (12%; P < 0.01) but not prone (P = 0.76). The consequent rise in PETCO2 during head-out, breast-stroke swimming (50% heart rate range) independently increased MCAvmean by 14% (P < 0.01), while the motor involvement of swimming per se did not significantly change MCAvmean (P = 0.32). While accounting for sex, swimmers had ~17% lower MCAvmean during all rest conditions (P ≤ 0.05). However, in a subset of participants, both groups had similar internal carotid artery diameters (P = 0.99) and velocities (P = 0.97). Water immersion per se did not alter cognition (P ≥ 0.15), but 20 min of moderate-intensity swimming improved visuomotor performance by 4% (P = 0.03), regardless of athlete group (P = 0.12). In conclusion, breast-stroke swimming increased MCAvmean mostly due to postural and PETCO2 effects, with minimal contributions from water immersion or motor activity. Lastly, swimming improved cognitive functioning acutely, regardless of athlete group. Future research should explore the chronic effects of swimming on cerebrovascular function and cognition, particularly in aging.

Cerebrovascular regulation is not blunted during mental stress.

NEW FINDINGS: What is the central question of the study? What are the effects of acute mental stress on the mechanisms regulating cerebral blood flow? What is the main finding and its importance? The major new findings are as follows: (i) high mental stress and hypercapnia had an interactive effect on mean middle cerebral artery blood velocity; (ii) high mental stress altered the regulation of cerebral blood flow; (iii) the increased cerebrovascular hypercapnic reactivity was not driven by changes in mean arterial pressure alone; and (iv) this increased perfusion with mental stress appeared not to be justified functionally by an increase in oxygen demand (as determined by near-infrared spectroscopy-derived measures). ABSTRACT: In this study, we examined the effects of acute mental stress on cerebrovascular function. Sixteen participants (aged 23 ± 4 years; five female) were exposed to low and high mental stress using simple arithmetic (counting backwards from 1000) and more complex arithmetic (serial subtraction of 13 from a rapidly changing four-digit number), respectively. During consecutive conditions of baseline, low stress and high stress, end-tidal partial pressure of CO2 ( PET,CO2 ) was recorded at normocapnia (37 ± 3 mmHg) and clamped at two elevated levels (P < 0.01): 41 ± 1 and 46 ± 1 mmHg. Mean right middle cerebral artery blood velocity (MCAvmean ; transcranial Doppler ultrasound), right prefrontal cortex haemodynamics (near-infrared spectroscopy) and mean arterial blood pressure (MAP; finger photoplethysmography) were measured continuously. Cerebrovascular hypercapnic reactivity (ΔMCAvmean /Δ PET,CO2 ), cerebrovascular conductance (CVC; MCAvmean /MAP), CVC CO2 reactivity (ΔCVC/Δ PET,CO2 ) and total peripheral resistance (MAP/cardiac output) were calculated. Acute high mental stress increased MCAvmean by 7 ± 7%, and more so at higher PET,CO2 (32 ± 10%; interaction, P = 0.03), illustrating increased sensitivity to CO2 (i.e. its major regulator). High mental stress also increased MAP (17 ± 9%; P ≤ 0.01), coinciding with increased near-infrared spectroscopy-derived prefrontal haemoglobin volume and saturation measures. High mental stress elevated both cerebrovascular hypercapnic and conductance reactivities (main effect of stress, P ≤ 0.04). These findings indicate that the cerebrovascular response to acute high mental stress results in a coordinated regulation between multiple processes.

Sympathetic overactivity in dialysis patients-Underappreciated and clinically consequential.

Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population.

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection-A Proof-of-Concept Study.

INTRODUCTION: Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. METHODS: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. RESULTS: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 95% CI [-47, -8]) were reduced. Mean ambulatory BP (systolic: -24 mm Hg, 95% CI [-42, -5] and diastolic: -13 mm Hg, 95% CI [-22, -4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: -25 mm Hg, 95% CI [-45, -5] and diastolic: -13 mm Hg, 95% CI [-24, -1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. DISCUSSION: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

ß-Adrenergic Responsiveness in the Type 2 Diabetic Heart: Effects on Cardiac Reserve.

Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). PURPOSE: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to ß-adrenergic stimulation. METHODS: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and V˙O2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental ß-adrenergic stimulation (dobutamine). RESULTS: V˙O2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. CONCLUSIONS: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to ß-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.