Challenging the Hemodynamic Hypothesis in Heart Failure With Preserved Ejection Fraction: Is Exercise Capacity Limited by Elevated Pulmonary Capillary Wedge Pressure?

BACKGROUND: Exercise intolerance is a defining characteristic of heart failure with preserved ejection fraction (HFpEF). A marked rise in pulmonary capillary wedge pressure (PCWP) during exertion is pathognomonic for HFpEF and is thought to be a key cause of exercise intolerance. If true, acutely lowering PCWP should improve exercise capacity. To test this hypothesis, we evaluated peak exercise capacity with and without nitroglycerin to acutely lower PCWP during exercise in patients with HFpEF. METHODS: Thirty patients with HFpEF (70±6 years of age; 63% female) underwent 2 bouts of upright, seated cycle exercise dosed with sublingual nitroglycerin or placebo control every 15 minutes in a single-blind, randomized, crossover design. PCWP (right heart catheterization), oxygen uptake (breath × breath gas exchange), and cardiac output (direct Fick) were assessed at rest, 20 Watts (W), and peak exercise during both placebo and nitroglycerin conditions. RESULTS: PCWP increased from 8±4 to 35±9 mm Hg from rest to peak exercise with placebo. With nitroglycerin, there was a graded decrease in PCWP compared with placebo at rest (-1±2 mm Hg), 20W (-5±5 mm Hg), and peak exercise (-7±6 mm Hg; drug × exercise stage P=0.004). Nitroglycerin did not affect oxygen uptake at rest, 20W, or peak (placebo, 1.34±0.48 versus nitroglycerin, 1.32±0.46 L/min; drug × exercise P=0.984). Compared with placebo, nitroglycerin lowered stroke volume at rest (-8±13 mL) and 20W (-7±11 mL), but not peak exercise (0±10 mL). CONCLUSIONS: Sublingual nitroglycerin lowered PCWP during submaximal and maximal exercise. Despite reduction in PCWP, peak oxygen uptake was not changed. These results suggest that acute reductions in PCWP are insufficient to improve exercise capacity, and further argue that high PCWP during exercise is not by itself a limiting factor for exercise performance in patients with HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04068844.

Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure.

BACKGROUND: Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT. METHODS: Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5-3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇o2; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples t tests. RESULTS: V̇o2 was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min; P=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL; P=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min; P=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg; P=0.007). CONCLUSIONS: In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.

Exercise intolerance in heart failure with preserved ejection fraction: Causes, consequences and the journey towards a cure.

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases nationwide and continues to rise in its prevalence. The complex, multi-organ involvement of the HFpEF clinical syndrome requires clinicians and investigators to adopt an integrative approach that considers the contribution of both cardiac and non-cardiac function to HFpEF pathophysiology. Thus, this symposium review outlines the key points from presentations covering the contributions of disease-related changes in cardiac function, arterial stiffness, peripheral vascular function, and oxygen delivery and utilization to exercise tolerance in patients with HFpEF. While many aspects of HFpEF pathophysiology remain poorly understood, there is accumulating evidence for a decline in vascular health in this patient group that may be remediable through pharmacological and lifestyle interventions and could improve outcomes and clinical status in this ever-growing patient population.

Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Adrenergic control of skeletal muscle blood flow during chronic hypoxia in healthy males.

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during 1) incremental intra-arterial infusion of phenylephrine to assess α1-adrenergic receptor responsiveness and 2) combined intra-arterial infusion of ß-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-ß-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; +3 ± 18%; P < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; P = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; P = 0.041) doses. Blockade of ß-adrenergic receptors alone had no effect on resting FVC (P = 0.500) and combined α-ß-blockade induced a similar vasodilatory response at SL and HA (P = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA (P = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-ß-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-ß-blockade: +19 ± 23%; P = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-ß-blockade: -23 ± 11%; P = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α1-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.

Assessment of venous pressure by compression sonography of the internal jugular vein during 3 days of bed rest.

Compression sonography has been proposed as a method for non-invasive measurement of venous pressures during spaceflight, but initial reports of venous pressure measured by compression ultrasound conflict with prior reports of invasively measured central venous pressure (CVP). The aim of this study is to determine the agreement of compression sonography of the internal jugular vein (IJVP) with invasive measures of CVP over a range of pressures relevant to microgravity exposure. Ten healthy volunteers (18-55 years, five female) completed two 3-day sessions of supine bed rest to simulate microgravity. IJVP and CVP were measured in the seated position, and in the supine position throughout 3 days of bed rest. The range of CVP recorded was in line with previous reports of CVP during changes in posture on Earth and in microgravity. The correlation between IJVP and CVP was poor when measured during spontaneous breathing (r = 0.29; R2  = 0.09; P = 0.0002; standard error of the estimate (SEE) = 3.0 mmHg) or end-expiration CVP (CVPEE ; r = 0.19; R2  = 0.04; P = 0.121; SEE = 3.0 mmHg). There was a modest correlation between the change in CVP and the change in IJVP for both spontaneous ΔCVP (r = 0.49; R2  = 0.24; P < 0.0001) and ΔCVPEE (r = 0.58; R2  = 0.34; P < 0.0001). Bland-Altman analysis of IJVP revealed a large positive bias compared to spontaneous breathing CVP (3.6 mmHg; SD = 4.0; CV = 85%; P < 0.0001) and CVPEE (3.6 mmHg; SD = 4.2; CV = 84%; P < 0.0001). Assessment of absolute IJVP via compression sonography correlated poorly with direct measurements of CVP by invasive catheterization over a range of venous pressures that are physiologically relevant to spaceflight. However, compression sonography showed modest utility for tracking changes in venous pressure over time. NEW FINDINGS: What is the central question of this study? Compression sonography has been proposed as a novel method for non-invasive measurement of venous pressures during spaceflight. However, the accuracy has not yet been confirmed in the range of CVP experienced by astronauts during spaceflight. What is the main finding and its importance? Our data show that compression sonography of the internal jugular vein correlates poorly with direct measurement of central venous pressures in a range that is physiologically relevant to spaceflight. However, compression sonography showed modest utility for tracking changes in venous pressure over time.

Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high-altitude.

Chronic exposure to hypoxia (high-altitude, HA; >4000 m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (n = 9) at sea-level (SL; 344 m) and following 21-28 days at HA (∼4300 m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF/MAP), and arterial and venous blood sampling (O2 delivery ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ ) and uptake ( V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ )) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local α- and ß-adrenergic blockade (intra-arterial phentolamine and propranolol). HA reduced ΔFBF (25% MVC: SL: 138.3 ± 47.6 vs. HA: 113.4 ± 37.1 ml min-1 ; P = 0.022) and Δ V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (25% MVC: SL: 20.3 ± 7.5 vs. HA: 14.3 ± 6.2 ml min-1 ; P = 0.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SLα-ß blockade : 164.1 ± 71.7 vs. HAα-ß blockade : 185.4 ± 66.6 ml min-1 ; P = 0.947) but resulted in an exaggerated relationship between DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ and V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ / V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ slope: SL: 1.32; HA: slope: 1.86; P = 0.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA. KEY POINTS: In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure. Exposure to chronic hypoxia (altitude, >4000 m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise. In healthy male lowlanders exposed to chronic hypoxia (21-28 days; ∼4300 m), local adrenoreceptor blockade (combined α- and ß-adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise. However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand. This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.

One-Year Committed Exercise Training Reverses Abnormal Left Ventricular Myocardial Stiffness in Patients With Stage B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular (LV) hypertrophy and elevated cardiac biomarkers in middle age are at increased risk for the development of heart failure with preserved ejection fraction. Prolonged exercise training reverses the LV stiffening associated with healthy but sedentary aging; however, whether it can also normalize LV myocardial stiffness in patients at high risk for heart failure with preserved ejection fraction is unknown. In a prospective, randomized controlled trial, we hypothesized that 1-year prolonged exercise training would reduce LV myocardial stiffness in patients with LV hypertrophy. METHODS: Forty-six patients with LV hypertrophy (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomly assigned to either 1 year of high-intensity exercise training (n=30) or attention control (n=16). Right-heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using both lower body negative pressure and rapid saline infusion to define the LV end-diastolic pressure-volume relationship. A constant representing LV myocardial stiffness was calculated from the following: P=S×[Exp {a (V-V0)}-1], where "P" is transmural pressure (pulmonary capillary wedge pressure - right atrial pressure), "S" is the pressure asymptote of the curve, "V" is the LV end-diastolic volume index, "V0" is equilibrium volume, and "a" is the constant that characterizes LV myocardial stiffness. RESULTS: Thirty-one participants (exercise group [n=20]: 54±6 years, 65% male; and controls (n=11): 51±6 years, 55% male) completed the study. One year of exercise training increased max by 21% (baseline 26.0±5.3 to 1 year later 31.3±5.8 mL·min-1·kg-1, P<0.0001, interaction P=0.0004), whereas there was no significant change in max in controls (baseline 24.6±3.4 to 1 year later 24.2±4.1 mL·min-1·kg-1, P=0.986). LV myocardial stiffness was reduced (right and downward shift in the end-diastolic pressure-volume relationship; LV myocardial stiffness: baseline 0.062±0.020 to 1 year later 0.031±0.009), whereas there was no significant change in controls (baseline 0.061±0.033 to 1 year later 0.066±0.031, interaction P=0.001). CONCLUSIONS: In patients with LV hypertrophy and elevated cardiac biomarkers (stage B heart failure with preserved ejection fraction), 1 year of exercise training reduced LV myocardial stiffness. Thus, exercise training may provide protection against the future risk of heart failure with preserved ejection fraction in such patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03476785.

Global Reach 2018: sympathetic neural and hemodynamic responses to submaximal exercise in Andeans with and without chronic mountain sickness.

Andeans with chronic mountain sickness (CMS) and polycythemia have similar maximal oxygen uptakes to healthy Andeans. Therefore, this study aimed to explore potential adaptations in convective oxygen transport, with a specific focus on sympathetically mediated vasoconstriction of nonactive skeletal muscle. In Andeans with (CMS+, n = 7) and without (CMS-, n = 9) CMS, we measured components of convective oxygen delivery, hemodynamic (arterial blood pressure via intra-arterial catheter), and autonomic responses [muscle sympathetic nerve activity (MSNA)] at rest and during steady-state submaximal cycling exercise [30% and 60% peak power output (PPO) for 5 min each]. Cycling caused similar increases in heart rate, cardiac output, and oxygen delivery at both workloads between both Andean groups. However, at 60% PPO, CMS+ had a blunted reduction in Δtotal peripheral resistance (CMS-, -10.7 ± 3.8 vs. CMS+, -4.9 ± 4.1 mmHg·L-1·min-1; P = 0.012; d = 1.5) that coincided with a greater Δforearm vasoconstriction (CMS-, -0.2 ± 0.6 vs. CMS+, 1.5 ± 1.3 mmHg·mL-1·min-1; P = 0.008; d = 1.7) and a rise in Δdiastolic blood pressure (CMS-, 14.2 ± 7.2 vs. CMS+, 21.6 ± 4.2 mmHg; P = 0.023; d = 1.2) compared with CMS-. Interestingly, although MSNA burst frequency did not change at 30% or 60% of PPO in either group, at 60% Δburst incidence was attenuated in CMS+ (P = 0.028; d = 1.4). These findings indicate that in Andeans with polycythemia, light intensity exercise elicited similar cardiovascular and autonomic responses compared with CMS-. Furthermore, convective oxygen delivery is maintained during moderate-intensity exercise despite higher peripheral resistance. In addition, the elevated peripheral resistance during exercise was not mediated by greater sympathetic neural outflow, thus other neural and/or nonneural factors are perhaps involved.NEW & NOTEWORTHY During submaximal exercise, convective oxygen transport is maintained in Andeans suffering from polycythemia. Light intensity exercise elicited similar cardiovascular and autonomic responses compared with healthy Andeans. However, during moderate-intensity exercise, we observed a blunted reduction in total peripheral resistance, which cannot be ascribed to an exaggerated increase in muscle sympathetic nerve activity, indicating possible contributions from other neural and/or nonneural mechanisms.

Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia.

RATIONALE: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. OBJECTIVE: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. METHODS AND RESULTS: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+ß adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. CONCLUSIONS: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia.

KEY POINTS: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. ABSTRACT: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.

Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF. METHODS: Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion. RESULTS: There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure - right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028). CONCLUSIONS: LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

BACKGROUND: Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. METHODS: Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .

The role of systolic-diastolic coupling in distinguishing impaired diastolic recoil in healthy aging and heart failure with preserved ejection fraction.

BACKGROUND: Age-related changes to left ventricular (LV) early diastolic recoil confound the diagnostic value of e' velocity in heart failure with preserved ejection fraction (HFpEF). Systolic-diastolic coupling quantifies passive left ventricular elastic recoil and may be superior to e' in differentiating abnormal diastolic recoil in HFpEF from healthy aging. This study aims to determine the effect of healthy aging and HFpEF on systolic-diastolic coupling. METHODS: Healthy adults (n = 141, aged 20-90 years) underwent right heart catheterization (RHC) to quantify LV filling pressure and tissue Doppler echocardiography to define peak velocities and excursion (velocity time integral) of the mitral annulus. Separately, HFpEF patients (n = 12, age 67 ± 5 years) and controls (n = 12, age 68 ± 5 years) underwent RHC and echocardiography. Systolic-diastolic coupling was measured as early diastolic excursion (EDexc ) divided by systolic excursion (Sexc ). RESULTS: In healthy adults, EDexc / Sexc declined by 15% per decade of life (r2  = 0.53, P < .001). EDexc /Sexc was significantly lower in HFpEF compared with controls (0.43 ± 0.11 vs 0.56 ± 0.11, P = .011), while e' was similar (6.2 ± 1.5 vs 6.8 ± 1.3 cm/s, P = .33). Using ROC analysis, EDexc /Sexc had an AUC to detect HFpEF of 0.82 (0.61-0.95, P = .007), which was superior to e' alone (AUC 0.60(0.39-0.80), P = .39; P = .026 for difference). CONCLUSIONS: Systolic-diastolic coupling, quantified by the EDexc /Sexc ratio, declined linearly with healthy aging. The EDexc /Sexc ratio was further reduced in HFpEF and able to predict HFpEF more accurately than e' alone. Systolic-diastolic coupling may be a useful diagnostic tool to detect HFpEF.

Acute and Chronic Citrulline Malate Supplementation on Muscle Contractile Properties and Fatigue Rate of the Quadriceps.

This study compared the acute and chronic impact of citrulline malate (CM) supplementation on muscle contractile properties and fatigue rate of the quadriceps. Eighteen recreationally trained males consumed both a placebo (PL) and CM treatment for two separate dosing periods. The first experimental testing session for each dosing period was considered the baseline day, the second session the acute day, and the third session the chronic day, which followed seven consecutive days of supplementation. All testing sessions included exercising on a cycle ergometer at 50%-60% of their max power output for 30 min followed by performing the Thorstensson test on an isokinetic dynamometer. A two-way (Supplement × Time) analysis of variance with repeated measures resulted in no significant interactions (p > .05) (PL: baseline day, acute day, chronic day vs. CM: baseline day, acute day, chronic day) for peak power (in watts) (469 ± 81, 490 ± 97, 502 ± 99 vs. 464 ± 85, 480 ± 103, 501 ± 81); peak torque (in newton meters) (150 ± 26, 157 ± 32, 161 ± 31 vs. 149 ± 27, 156 ± 33, 161 ± 26); fatigue rate (in percentage) (57 ± 9, 57 ± 10, 58 ± 9 vs. 57 ± 10, 56 ± 9, 58 ± 9); and heart rate (in beats per minute) (156 ± 17, 146 ± 13, 146 ± 9 vs. 155 ± 11, 146 ± 11, 146 ± 9). The results of this study suggest that neither acute nor chronic supplementation of CM had an effect on recovery or fatigue rate of the quadriceps.

KIR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.

KEY POINTS: During exercise, blood flow to working skeletal muscle increases in parallel with contractile activity such that oxygen delivery is sufficient to meet metabolic demand. K+ released from active skeletal muscle fibres could facilitate vasodilatation in proportion to the degree of muscle fibre recruitment. Once released, K+ stimulates inwardly rectifying K+ (KIR ) channels on the vasculature to elicit an increase in blood flow. In the present study, we demonstrate that KIR channels mediate the rapid vasodilatory response to an increase in exercise intensity. We also show that KIR channels augment vasodilatation during exercise which demands greater muscle fibre recruitment independent of the total amount of work performed. These results suggest that K+ plays a key role in coupling the magnitude of vasodilatation to the degree of contractile activity. Ultimately, the findings from this study help us understand the signalling mechanisms that regulate muscle blood flow in humans. ABSTRACT: Blood flow to active skeletal muscle is augmented with greater muscle fibre recruitment. We tested whether activation of inwardly rectifying potassium (KIR ) channels underlies vasodilatation with elevated muscle fibre recruitment when work rate is increased (Protocol 1) or held constant (Protocol 2). We assessed forearm vascular conductance (FVC) during rhythmic handgrip exercise under control conditions and during local inhibition of KIR channels (intra-arterial BaCl2 ). In Protocol 1, healthy volunteers performed mild handgrip exercise for 3 min, then transitioned to moderate intensity for 30 s. BaCl2 eliminated vasodilatation during the first contraction at the moderate workload (ΔFVC, BaCl2 : -1 ± 17 vs. control: 30 ± 28 ml min-1  100 mmHg-1 ; n = 9; P = 0.004) and attenuated the 30 s area under the curve by 56 ± 14% (n = 9; P < 0.0001). In Protocol 2, participants performed two exercise bouts in which muscle fibre recruitment was manipulated while total contractile work was held constant via reciprocal changes in contraction frequency: (1) low fibre recruitment, with contractions at 12.5% maximal voluntary contraction once every 4 s and (2) high fibre recruitment, with contractions at 25% maximal voluntary contraction once every 8 s. Under control conditions, steady-state FVC was augmented in high vs. low fibre recruitment (211 ± 90 vs. 166 ± 73 ml min-1 ⋅100 mmHg-1 ; n = 10; P = 0.0006), whereas BaCl2 abolished the difference between high and low fibre recruitment (134 ± 59 vs. 134 ± 63 ml min-1  100 mmHg-1 ; n = 10; P = 0.85). These findings demonstrate that KIR channel activation is a key mechanism linking local vasodilatation with muscle fibre recruitment during exercise.

Augmentation of endothelium-dependent vasodilatory signalling improves functional sympatholysis in contracting muscle of older adults.

KEY POINTS: The ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction (functional sympatholysis) is critical for maintaining blood flow during exercise-mediated sympathoexcitation. Functional sympatholysis and endothelial function are impaired with ageing, resulting in compromised blood flow and oxygen delivery to contracting skeletal muscle during exercise. In the present study, intra-arterial infusion of ACh or ATP to augment endothelium-dependent signalling during exercise attenuated α1 -adrenergic vasoconstriction in the contracting muscle of older adults. The vascular signalling mechanisms capable of functional sympatholysis are preserved in healthy ageing, and thus the age-related impairment in functional sympatholysis probably results from the loss of a functional signal (e.g. plasma [ATP]) as opposed to an intrinsic endothelial dysfunction. ABSTRACT: The ability of contracting skeletal muscle to attenuate sympathetic α-adrenergic vasoconstriction ('functional sympatholysis') is impaired with age. In young adults, increasing endothelium-dependent vasodilatory signalling during mild exercise augments sympatholysis. In the present study, we tested the hypothesis that increasing endothelium-dependent signalling during exercise in older adults can improve sympatholysis. In 16 older individuals (Protocol 1, n = 8; Protocol 2, n = 8), we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of phenylephrine (PE; α1 -agonist) during (i) infusion of an endothelium-dependent vasodilator alone (Protocol 1: ACh or Protocol 2: low dose ATP); (ii) mild handgrip exercise (5% maximum voluntary contraction; MVC); (iii) moderate handgrip exercise (15% MVC); and (iv) mild or moderate handgrip exercise + infusion of ACh or ATP to augment endothelium-dependent signalling. PE caused robust vasoconstriction in resting skeletal muscle during control vasodilator infusions (ΔFVC: ACh: -31 ± 3 and ATP: -30 ± 4%). PE-mediated vasoconstriction was not attenuated by mild or moderate intensity exercise (ΔFVC: 5% MVC: -30 ± 9; 15% MVC: -33 ± 8%; P > 0.05 vs. control ACh and ATP), indicative of impaired sympatholysis, and ACh or ATP infusion during mild exercise did not impact this response. However, augmentation of endothelium-dependent signalling via infusion of ACh or ATP during moderate intensity exercise attenuated PE-mediated vasoconstriction (ΔFVC: -13 ± 1 and -19 ± 5%, respectively; P < 0.05 vs. all conditions). Our findings demonstrate that, given a sufficient stimulus, endothelium-dependent sympatholysis remains intact in older adults. Strategies aimed at activating such pathways represent a viable approach for improving sympatholysis and thus tissue blood flow and oxygen delivery in older adults.

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and nonadrenergic mechanisms.

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and ß-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min-1·100 mmHg-1; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.

The Effect of Aspartate and Sodium Bicarbonate Supplementation on Muscle Contractile Properties Among Trained Men.

Farney, TM, MacLellan, MJ, Hearon, CM, Johannsen, NM, and Nelson, AG. The effect of aspartate and sodium bicarbonate supplementation on muscle contractile properties among trained men. J Strength Cond Res 34(3): 763-770, 2020-The focus of this investigation was to examine the effects of aspartate and NaHCO3 supplementation on muscle contractile properties within trained men. Eleven men (21.9 ± 1.5 years) ingested supplementation as 4 conditions all separated by 1 week and included the following: placebo (PLA), L-aspartate (12.5 mg) (ASP), NaHCO3 (0.3 g·kg) (SBC), or combination of ASP and SBC (CBO). For each day of testing, participants performed 1 high-intensity exercise session along with a pre- and postexercise (pre- or postex) isometric mid thigh pull test to measure peak force (PF) production and rate of force development (RFD). Blood was collected for all testing sessions before and after the high-intensity exercise to determine ammonia accumulation (AMM). Exercise sessions consisted of 4 exercises: barbell thrusters, squat jumps, lunge jumps, and forward jumps, with the total amount of work being equated for all 4 exercises across all 4 testing sessions. Participants performed the exercises in the aforementioned order, which was designated as 1 round. Each participant performed 3 rounds, with the work-to-rest ratio being 20-second work, 30-second rest. A 1-minute rest was given between the rounds. There were no treatment effects (p > 0.05) for PF, RFD, or AMM. However, there was a significant main effect for supplement consumption for the total time of work with the ASP, SBC, and CBO treatments having a lower time to completion compared with the PLA treatment. Ammonia was significantly elevated postexercise (p = 0.004), whereas there were no differences from preexercise to postexercise for PF or RFD (p > 0.05). The only significant treatment × time interaction was for RFD (p = 0.03) with CBO increasing postexercise, with the other 3 treatments all decreasing postexercise. The combination of ASP and SBC together may have the potential to reduce fatigue by mitigating the effects of metabolic by-product accumulation.

The Effect of Vinegar Supplementation on High-Intensity Cycling Performance within Recreationally Trained Individuals.

Background and objectives: To investigate the effects of vinegar ingestion upon high-intensity cycle performance in recreationally trained individuals. Materials and methods: Twenty-two participants consumed one of the following in a randomized order on four separate visits: (1) 29 mL of vinegar along with 451 mL of water, (2) 39 g of sucrose along with 441 mL of water, (3) 29 mL of vinegar and 39 g of sucrose along with 412 mL of water, or (4) 480 mL of water alone. For each of the experimental testing sessions, all participants completed in order: (1) high-intensity cycle test 1, (2) fatiguing cycle test, (3) high-intensity cycle test 2, (4) supplement consumption, (5) 90 min rest period, and (6) high-intensity cycle test 3. Total time to exhaustion (TTE) and average heart rate (HR) for each set of sprints was used in analysis. Results: There was no supplement by time interaction or significant main treatment effect observed (p > 0.05) for either TTE or HR. However, there was a main time effect observed, with TTE (p = 0.0001) being lower for cycle test 2 than both cycle test 1 and cycle test 3, and cycle test 3 being lower than cycle test 1. HR (p = 0.0001) was lower for cycle test 3 than both cycle test 1 and cycle test 2, but HR for cycle test 1 did not differ significantly from HR for cycle test 2. Conclusions: The addition of vinegar or sucrose alone, or in combination, was ineffective in improving cycle sprinting TTE when performing three cycle tests.