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Sex differences in cardiac vagal reactivation from the end of isometric handgrip exercise and at the onset of muscle metaboreflex isolation

  • Milena Samora
    Affiliations
    NeuroV̇ASQ̇ – Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Brasília, DF, Brazil
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  • André L. Teixeira
    Affiliations
    NeuroV̇ASQ̇ – Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Brasília, DF, Brazil
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  • Jeann L. Sabino-Carvalho
    Affiliations
    NeuroV̇ASQ̇ – Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Brasília, DF, Brazil
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  • Lauro C. Vianna
    Correspondence
    Corresponding author at: NeuroV̇ASQ̇ - Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Darcy Ribeiro Campus, Brasília, Brazil.
    Affiliations
    NeuroV̇ASQ̇ – Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Brasília, DF, Brazil

    Graduate Program in Medical Sciences, Faculty of Medicine, University of Brasília, Brasília, DF, Brazil
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Open AccessPublished:August 13, 2020DOI:https://doi.org/10.1016/j.autneu.2020.102714

      Highlights

      • The rapid fall in heart rate at the onset of post-exercise ischemia (PEI) is mediated by a parasympathetic reactivation.
      • Women presented a slower recovery in heart rate at the cessation of isometric handgrip exercise compared to men.
      • Increases in heart rate variability indexes at the cessation of exercise were lower in women compared to men.
      • There are sex differences in cardiac vagal reactivation at the cessation of isometric handgrip exercise and onset of PEI.

      Abstract

      A parasympathetic reactivation is an underlying mechanism mediating the rapid fall in heart rate (HR) at the onset of post-exercise ischemia (PEI) in humans. Herein, we tested the hypothesis that, compared to men, women present a slower HR recovery at the cessation of isometric handgrip exercise (i.e., onset of PEI) due to an attenuated cardiac vagal reactivation. Forty-seven (23 women) young and healthy volunteers were recruited. Subjects performed 90s of isometric handgrip exercise at 40% of maximal voluntary contraction followed by 3-min of PEI. The onset of PEI was analyzed over the first 30s in 10s windows. Cardiac vagal reactivation was indexed using the HR fall and by HR variability metrics (e.g., RMSSD and SDNN) immediately after the cessation of the exercise. HR was significantly increased from rest during exercise in men and women and increases were similar between sexes. However, following the cessation of exercise, the HR recovery was significantly slower in women compared to men regardless of the time point (women vs. men: ∆-14 ± 8 vs. ∆-18 ± 6 beats.min−1 at 10s; ∆-20 ± 9 vs. ∆-25 ± 8 beats.min−1 at 20s; ∆-22 ± 10 vs. ∆-27 ± 9 beats.min−1 at 30s; P = .027). RMSSD and SDNN increased at the cessation of exercise in greater magnitude in men compared to women. These findings demonstrate that women had a slower HR recovery at the cessation of isometric handgrip exercise and onset of PEI compared to men, suggesting a sex-related difference in cardiac vagal reactivation in healthy young humans.

      Keywords

      1. Introduction

      Post-exercise ischemia (PEI) following isometric handgrip exercise is a well-established technique to isolate muscle metaboreflex activation in humans (
      • Alam M.
      • Smirk F.H.
      Observations in man upon a blood pressure raising reflex arising from the voluntary muscles.
      ). While arterial blood pressure (BP) and sympathetic nerve activity remain elevated during PEI, the exercise-induced increase in heart rate (HR) is typically reported to return to resting values (
      • Fisher J.P.
      • Young C.N.
      • Fadel P.J.
      Autonomic adjustments to exercise in humans.
      ). The rapid fall in HR at the end of exercise over the first 30 s of PEI is a confounding and complex response during the transition between exercise and PEI (
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      ). The potential explanation for this observation is a cardiac parasympathetic reactivation, probably due to the loss of central command and muscle mechanoreceptors inputs and/or baroreflex mechanisms, as proposed by others (
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      ;
      • Iellamo F.
      • Pizzinelli P.
      • Massaro M.
      • Raimondi G.
      • Peruzzi G.
      • Legramante J.M.
      Muscle metaboreflex contribution to sinus node regulation during static exercise: insights from spectral analysis of heart rate variability.
      ;
      • O’Leary D.S.
      Autonomic mechanisms of muscle metaboreflex control of heart rate.
      ). To gain more insight into the mechanisms underlying the rapid fall in HR at the onset of PEI,
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      evaluated the autonomic control of HR during the first minute of PEI by employing a pharmacological approach in healthy men. They found that HR rapidly returned towards baseline under both control and sympathetic blockade condition, while the HR fall was slower and less complete under parasympathetic blockade. Thus, this previous study provided strong evidence that rapid fall in HR in the first's seconds at the onset PEI is primarily mediated by cardiac vagal reactivation, which overcomes cardiac sympathetic activation induced by metaboreflex isolation. Although
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      elucidated the autonomic mechanisms whereby HR is regulated by the muscle metaboreflex, the possible sex differences on this rapid cardiac vagal reactivation immediately upon the cessation of the exercise are unknown. This becomes important because alterations in autonomic function contribute to the risk of sudden death, likely related to abnormal HR profiles (
      • Jouven X.
      • Empana J.P.
      • Schwartz P.J.
      • Desnos M.
      • Courbon D.
      • Ducimetiere P.
      Heart-rate profile during exercise as a predictor of sudden death.
      ). For example, delayed HR recovery from exercise (attributed to altered parasympathetic reactivation) has been reported as a powerful independent predictor of mortality in healthy adults (
      • Cole C.R.
      • Blackstone E.H.
      • Pashkow F.J.
      • Snader C.E.
      • Lauer M.S.
      Heart-rate recovery immediately after exercise as a predictor of mortality.
      ;
      • Imai K.
      • Sato H.
      • Hori M.
      • Kusuoka H.
      • Ozaki H.
      • Yokoyama H.
      • Takeda H.
      • Inoue M.
      • Kamada T.
      Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure.
      ).
      The existence of sex differences in cardiac vagal reactivation at the cessation of isometric handgrip exercise is highly plausible given that several previous studies have shown marked sex differences in autonomic function (
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.
      • Joyner M.J.
      Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors.
      ;
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.H.
      • Joyner M.J.
      Sex differences in sympathetic neural-hemodynamic balance: implications for human blood pressure regulation.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Galdino I.
      • Nobrega A.C.
      • Vianna L.C.
      Sex differences in the contribution of blood pressure to acute changes in aortic augmentation index.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Nóbrega A.C.
      • Vianna L.C.
      Cardiovascular response to trigeminal nerve stimulation at rest and during exercise in humans: does sex matter?.
      ;
      • Samora M.
      • Incognito A.V.
      • Vianna L.C.
      Sex differences in blood pressure regulation during ischemic isometric exercise: the role of the beta-adrenergic receptors.
      ;
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ;
      • Teixeira A.L.
      • Ritti-Dias R.
      • Antonino D.
      • Bottaro M.
      • Millar P.J.
      • Vianna L.C.
      Sex differences in cardiac baroreflex sensitivity after isometric handgrip exercise.
      ). We recently demonstrated that muscle metaboreflex interacts with arterial-cardiac baroreflex to the neural control of cardiovascular and hemodynamic adjustments to exercise in a sex-dependent manner (
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ). In this previous study, we demonstrated that spontaneous cardiac baroreflex sensitivity and indexes of HR variability (HRV) related to parasympathetic activity (e.g., RMSSD and HF component) are enhanced during 3-min of PEI in men but not (or less increased) in women. Nevertheless, whether these previous findings about sex differences are already manifested immediately upon the cessation of the exercise, which is known to be primarily mediated by cardiac vagal reactivation, remains to be determined. Thus, the purpose of the present study was to test the hypothesis that women present a slower HR recovery than men at the cessation of isometric handgrip exercise and onset of PEI due to an attenuated cardiac vagal reactivation.

      2. Material and methods

      2.1 Participants

      Participants refrained from caffeine/alcohol and physical exercise for at least 12 h prior to testing. All participants were healthy, normotensive, non-smoker and physically active. None had used any controlled medications and had no history or symptoms of cardiopulmonary, metabolic or neurological diseases. All study procedures were approved by the University of Brasília research ethics committee (CAAE 76504017.1.0000.0030) in accordance with the Declaration of Helsinki. All participants read and signed a specific informed consent form before enrolment. Forty-seven participants were enrolled in the present study. Part of this sample has already being tested and used in a previous study from our laboratory that tested a different hypothesis (
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ). All participants were tested at the same time of day in the same quiet, temperature-controlled room (22–24 °C). All women were non-users of oral contraceptive pills for at least six consecutive months and were studied during the early follicular phase of their menstrual cycle (i.e. first five days after menstruation onset). The first visit was for familiarization with all the study equipment and procedures. Weight and height were determined via standard methods, and body mass index (BMI) calculated.

      2.2 Cardiovascular measurements

      Participants performed three maximal efforts each separated by at least 1-min, and the higher value was considered the maximal voluntary contraction (MVC). Participants were in a seated position and resting baseline hemodynamic measures were recorded for the 10-min. HR, systolic, diastolic and mean BP were continuously measured on a beat-to-beat basis by photoplethysmography using a Finometer device (Human NIBP Controller, AD instruments, NSW, Australia), placed at the middle finger of the non-dominant hand, with the hand positioned at heart level. Brachial arterial BP was also measured with an automated digital sphygmomanometer (Dixtal, DX2022, Brazil) for absolute measures of BP to confirm finger measurement accuracy. Respiratory movements were monitored using a pneumatic belt placed around the subjects' abdomen (MLT 1132 Piezo Respiratory Belt Transducer – ADInstruments) to ensure that the subjects did not perform Valsalva maneuver during the protocol. The BP waveform was sampled at 1000 Hz and stored for offline analysis (Powerlab, AD Instruments, Bella Vista, New South Wales, Australia with LabChart 8 software, ADInstruments).

      2.3 Post-exercise ischemia protocol

      Participants performed 90-s of isometric handgrip exercise at 40% of MVC followed by 3-min of PEI to isolate skeletal muscle metaboreflex. The exercise intensity was controlled and maintained by visual feedback of the researcher's computer screen. PEI was achieved by the rapid inflation of a cuff positioned around the exercising arm to supra systolic pressure (240-250 mmHg) 5 s before the end of the exercise. The cuff was released following completion of PEI.

      2.4 Data and statistical analysis

      Five minutes of data segments were used for the calculation of average cardiovascular variables at rest. The exercise response was analyzed using 10s windows average during the last 30s of exercise while the onset of PEI was analyzed during the first 30s immediately upon cessation of exercise. A beat-to-beat RR interval data was used to calculate the HRV in a software developed in Matlab with a graphical interface (SinusCor 1.0.0, Brazil) which was previously validated against standard software (
      • Bartels R.
      • Neumamm L.
      • Peçanha T.
      • Carvalho A.R.S.
      SinusCor: an advanced tool for heart rate variability analysis.
      ). HRV was evaluated in time domain methods providing information on ultra-short variability of the signal as root mean square of successive RR interval differences (RMSSD), the standard deviation of the normal RR intervals (SDNN) and percentage of successive RR intervals that differ by more than 50 ms (pNN50) (
      • Esco M.R.
      • Flatt A.A.
      Ultra-short-term heart rate variability indexes at rest and post-exercise in athletes: evaluating the agreement with accepted recommendations.
      ;
      • Hamilton R.M.
      • McKechnie P.S.
      • Macfarlane P.W.
      Can cardiac vagal tone be estimated from the 10-second ECG?.
      ;
      • Nussinovitch U.
      • Elishkevitz K.P.
      • Katz K.
      • Nussinovitch M.
      • Segev S.
      • Volovitz B.
      • Nussinovitch N.
      Reliability of ultra-short ECG indices for heart rate variability.
      ). All these measurements of ultra-short-term variation estimate high-frequency variations in HR that is primarily mediated by parasympathetic nerve activity and are highly correlated (
      • Task
      Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use.
      ). The normality distribution of the data was verified by the Shapiro-Wilk test. Subjects' characteristics were compared using independent sample t-test. Two-way analysis of variance (ANOVA) for repeated measures followed by Students t-test with Bonferroni correction was used to investigate significant main effects and interactions. Statistical significance was set at P < .05 and values are presented as mean ± S.D. All statistical analyses were conducted using IBM SPSS® Statistics software (version 20) and figures were plotted using Prism, version 8.0 (GraphPad Software Inc., San Diego, United States) for Windows.

      3. Results

      The subject's characteristics are presented in Table 1. Women and men were matched for BMI, however, men had higher weight, height, and MVC than women (all P < .05).
      Table 1Subjects characteristics.
      Men (n = 24)Women (n = 23)P value
      Age (years)21 ± 223 ± 30.04
      Height (m)1.78 ± 0.061.63 ± 0.07<0.001
      Weight (kg)78 ± 1062 ± 10<0.001
      BMI (kg/m2)24.6 ± 2.823.1 ± 2.60.06
      MVC (N)615 ± 140401 ± 73<0.001
      Value represents means ± S.D. BMI, body mass index; MVC, maximum voluntary contraction.
      P value is derived from an independent sample t-test.
      The hemodynamics responses at rest and during isometric handgrip exercise are presented in Table 2.
      Table 2Hemodynamic variables and heart rate variability at rest and during isometric handgrip exercise.
      MenWomenP value
      SexTimeInteraction
       Systolic BP, mmHg
      Rest115 ± 8100 ± 5
      P < .05 vs men.
      <0.001<0.0010.001
      Exercise164 ± 21
      p < .05 vs rest within group.
      131 ± 16
      P < .05 vs men.
      p < .05 vs rest within group.
      Δ50 ± 2032 ± 14
      P < .05 vs men.
      0.001
       Diastolic BP, mmHg
      Rest59 ± 857 ± 50.015<0.0010.037
      Exercise88 ± 13
      p < .05 vs rest within group.
      79 ± 9
      P < .05 vs men.
      p < .05 vs rest within group.
      Δ28 ± 1122 ± 9
      P < .05 vs men.
      0.038
       Mean BP, mmHg
      Rest77 ± 771 ± 5
      P < .05 vs men.
      <0.001<0.0010.014
      Exercise113 ± 14
      p < .05 vs rest within group.
      98 ± 10
      P < .05 vs men.
      p < .05 vs rest within group.
      Δ36 ± 1327 ± 10
      P < .05 vs men.
      0.013
       Heart rate, beats.min−1
      Rest71 ± 974 ± 90.893<0.0010.148
      Exercise96 ± 1393 ± 13
      Δ24 ± 1219 ± 120.156
       RR interval, ms
      Rest856 ± 127827 ± 1010.840<0.0010.121
      Exercise639 ± 96658 ± 86
      Δ−217 ± 108−169 ± 1030.121
      Heart rate variability
       RMSSD, ms
      Rest50.49 ± 22.9347.82 ± 18.820.846<0.0010.450
      Exercise25.91 ± 17.5226.71 ± 10.84
      Δ−24.58 ± 13.93−21.11 ± 17.170.448
       SDNN, ms
      Rest67.38 ± 25.7459.93 ± 18.480.473<0.0010.200
      Exercise31.75 ± 19.5231.84 ± 14.50
      Δ−35.62 ± 20.62−28.09 ± 19.030.200
       pNN50, %
      Rest27.04 ± 15.5925.91 ± 13.470.840<0.0010.783
      Exercise7.79 ± 12.697.55 ± 7.49
      Δ−19.25 ± 10.12−18.36 ± 11.920.784
      Value represents means ± S.D. BP, blood pressure; RMSSD, root mean square of successive RR interval differences; SDNN, standard deviation of the normal RR intervals; pNN50, percentage of successive RR intervals that differ by more than 50 ms.
      low asterisk P < .05 vs men.
      p < .05 vs rest within group.
      Resting systolic and mean BP was lower in women compared to men. As expected, systolic, diastolic and mean BP increased during isometric exercise with men achieving a higher value than women. HR significantly increased and RR interval decreased during isometric handgrip exercise in a similar magnitude in men and women. HRV indices similarly decreased during exercise in men and women.
      Fig. 1 displays the recovery of HR and mean BP at the cessation of exercise. The HR recovery was slower in women (10s: ∆-14 ± 8 beats.min−1; 20s: ∆-20 ± 9 beats.min−1; and 30s: ∆-22 ± 10 beats.min−1) compared to men (10s: ∆-18 ± 6 beats.min−1; 20s: ∆-25 ± 8 beats.min−1; and 30s: ∆-27 ± 9 beats.min−1) regardless of time point (P = .027 Fig. 1A). Notably, the fall in mean BP was similar between men (10s: Δ-7 ± 7 mmHg; 20s: Δ-16 ± 9 mmHg; and 30s: Δ-13 ± 9 mmHg) and women (10s: Δ-5 ± 5 mmHg; 20s: Δ-14 ± 7 mmHg; and 30s: Δ-13 ± 6 mmHg; P = .386) at the cessation of exercise (Fig. 1B).
      Fig. 1
      Fig. 1Change in heart rate (A) and mean blood pressure (B) at the cessation of isometric handgrip exercise and onset of muscle metaboreflex activation. BP, blood pressure; PEI, post-exercise ischemia.
      Fig. 2 shows the recovery of RR interval and the cardiac vagal reactivation represented by pNN50, RMSSD and SDNN at the cessation of exercise. The RR interval rise was slower in women (10s: ∆114 ± 69 ms; 20s: ∆179 ± 76 ms; and 30s: ∆194 ± 73 ms) compared to men (10s: ∆ 147 ± 54 ms; 20s: ∆232 ± 80 ms; and 30s: ∆261 ± 108 ms) regardless of time point (P = .015; Fig. 2A). The increase in RMSSD (Fig. 2C) and SDNN (Fig. 2D) was lower in women compared to men at the cessation of exercise (P = .016 and P = .019, respectively).
      Fig. 2
      Fig. 2Change in RR interval (A) and heart rate variability indexes (B to D) at the cessation of isometric exercise and the onset of muscle metaboreflex activation. PEI, post-exercise ischemia; pNN50, percentage of successive RR intervals that differ by more than 50 ms; RMSSD, root mean square of successive RR interval differences; SDNN, standard deviation of the normal RR intervals.

      4. Discussion

      Previous studies have elucidated, via pharmacological approaches, that a parasympathetic mechanism plays a predominant role in mediating the rapid fall in HR at the onset of muscle metaboreflex isolation (i.e., PEI) in humans. Herein, we posit that this HR recovery at the cessation of isometric handgrip exercise might be dependent on whether the subject is male or female, given a plethora of previous studies in the literature indicating sex differences in autonomic function (
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.
      • Joyner M.J.
      Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors.
      ;
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.H.
      • Joyner M.J.
      Sex differences in sympathetic neural-hemodynamic balance: implications for human blood pressure regulation.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Galdino I.
      • Nobrega A.C.
      • Vianna L.C.
      Sex differences in the contribution of blood pressure to acute changes in aortic augmentation index.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Nóbrega A.C.
      • Vianna L.C.
      Cardiovascular response to trigeminal nerve stimulation at rest and during exercise in humans: does sex matter?.
      ;
      • Samora M.
      • Incognito A.V.
      • Vianna L.C.
      Sex differences in blood pressure regulation during ischemic isometric exercise: the role of the beta-adrenergic receptors.
      ;
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ). The main finding of the present study is that women demonstrated a slower recovery in HR at the cessation of isometric handgrip exercise compared to men, while the fall in mean BP was similar between sexes. In addition, increases in both RMSSD and SDNN at the cessation of exercise were lower in women compared to men. Overall, these findings suggest for the first time a sex-related difference in cardiac vagal reactivation immediately upon the cessation of isometric exercise and onset of PEI.
      HR increases during exercise in an intensity-dependent manner and it is partially mediated by a withdrawal of parasympathetic tone primarily due to activation of central command (
      • Mitchell J.H.
      • Reeves Jr., D.R.
      • Rogers H.B.
      • Secher N.H.
      • Victor R.G.
      Autonomic blockade and cardiovascular responses to static exercise in partially curarized man.
      ) and skeletal muscle mechanoreceptors (
      • Gladwell V.F.
      • Fletcher J.
      • Patel N.
      • Elvidge L.J.
      • Lloyd D.
      • Chowdhary S.
      • Coote J.H.
      The influence of small fibre muscle mechanoreceptors on the cardiac vagus in humans.
      ;
      • Teixeira A.L.
      • Ramos P.S.
      • Samora M.
      • Sabino-Carvalho J.L.
      • Ricardo D.R.
      • Colombari E.
      • Vianna L.C.
      GABAergic contribution to the muscle mechanoreflex-mediated heart rate responses at the onset of exercise in humans.
      ). On the other hand, the muscle metaboreflex contributes to an increase in BP via augmented peripheral vasoconstriction instead of playing a substantial role in cardiac regulation (
      • Rowell L.B.
      • O’Leary D.S.
      Reflex control of the circulation during exercise: chemoreflexes and mechanoreflexes.
      ;
      • Teixeira A.L.
      • Daher M.
      • Souza M.C.
      • Ramos P.S.
      • Fisher J.P.
      • Vianna L.C.
      Sympathetically mediated cardiac responses to isolated muscle metaboreflex activation following exercise are modulated by body position in humans.
      ;
      • Teixeira A.L.
      • Fernandes I.A.
      • Vianna L.C.
      Cardiovascular control during exercise: the connectivity of skeletal muscle afferents to the brain.
      ). Isolated activation of the muscle metaboreflex via PEI support this observation in which there is a maintenance of the exercise-induced increases in sympathetic nerve activity, vascular resistance and BP, while HR returns towards baseline (
      • Alam M.
      • Smirk F.H.
      Observations in man upon a blood pressure raising reflex arising from the voluntary muscles.
      ;
      • Teixeira A.L.
      • Fernandes I.A.
      • Vianna L.C.
      GABA(A) receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans.
      ;
      • Teixeira A.L.
      • Fernandes I.A.
      • Vianna L.C.
      Cardiovascular control during exercise: the connectivity of skeletal muscle afferents to the brain.
      ). Elegantly, Fisher and collaborators (
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      ) used a challenging pharmacological approach eliminating cardiac parasympathetic or sympathetic tone to examine the autonomic control of HR during metaboreflex activation in humans. It was suggested that the muscle metaboreflex provides sympathetic drive to the heart in humans, but that is generally masked during PEI by an increase in cardiac parasympathetic tone, probably explained by the loss of neural inputs from central command and muscle mechanoreceptors upon the cessation of the exercise and/or baroreflex mechanism (
      • Iellamo F.
      • Pizzinelli P.
      • Massaro M.
      • Raimondi G.
      • Peruzzi G.
      • Legramante J.M.
      Muscle metaboreflex contribution to sinus node regulation during static exercise: insights from spectral analysis of heart rate variability.
      ;
      • O’Leary D.S.
      Autonomic mechanisms of muscle metaboreflex control of heart rate.
      ). In this regard, indexes from HR variability in which estimate parasympathetic nerve activity (i.e. RMSSD and HF component) also are augmented during PEI (
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      ;
      • Teixeira A.L.
      • Daher M.
      • Souza M.C.
      • Ramos P.S.
      • Fisher J.P.
      • Vianna L.C.
      Sympathetically mediated cardiac responses to isolated muscle metaboreflex activation following exercise are modulated by body position in humans.
      ). These data suggest that even though there is an increase in cardiac sympathetic nervous activity mediated by isolated muscle metaboreflex activation via PEI, the tachycardia is masked by augmented cardiac parasympathetic tone due to vagal reactivation. Importantly, for the first time,
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      demonstrated that the rapid HR fall in the first 30 s of PEI is primarily dependent on cardiac vagal reactivation, which overcomes the sympathetic outflow to the heart. However, to date, it is unknown whether there are sex differences in this cardiac vagal reactivation at the onset of PEI following isometric exercise.
      In the present study, there are no sex differences in HR response to exercise (Table 2). However, HR recovery upon the cessation of the isometric exercise was slower in women compared to men regardless of the time point (Fig. 1A). Since the fall in mean BP was similar between sexes at the cessation of exercise (Fig. 1B), our data clearly suggest an attenuated cardiac vagal reactivation rather than a counteraction of the arterial baroreflex per se mediating the HR responses. This attenuated cardiac vagal reactivation in women was also confirmed by the lower HRV indexes (i.e. RMSSD and SDNN; Fig. 2) compared to men at the cessation of exercise. Furthermore, we previously demonstrated an increase in cardiac baroreflex sensitivity in men but not in women during PEI followed by isometric exercise (
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ). The arterial baroreflex determined by spontaneous cardiac baroreflex sensitivity reflects the gain at the operating point of the full cardiac baroreflex and the sensitivity at this locus is heavily dependent on cardiac parasympathetic activity (
      • Fisher J.P.
      • Ogoh S.
      • Junor C.
      • Khaja A.
      • Northrup M.
      • Fadel P.J.
      Spontaneous baroreflex measures are unable to detect age-related impairments in cardiac baroreflex function during dynamic exercise in humans.
      ;
      • Teixeira A.L.
      • Daher M.
      • Souza M.C.
      • Ramos P.S.
      • Fisher J.P.
      • Vianna L.C.
      Sympathetically mediated cardiac responses to isolated muscle metaboreflex activation following exercise are modulated by body position in humans.
      ). Therefore, the lack of increase in cardiac baroreflex sensitivity in women during PEI supports the contention that women have an attenuated cardiac vagal reactivation and this is clearly observed immediately upon cessation of exercise (i.e., during the transition between exercise and PEI) in the present investigation.
      Notably, HR recovery has clinical applications and previous studies have suggested that delayed HR recovery is an independent predictor of mortality (
      • Cole C.R.
      • Blackstone E.H.
      • Pashkow F.J.
      • Snader C.E.
      • Lauer M.S.
      Heart-rate recovery immediately after exercise as a predictor of mortality.
      ;
      • Imai K.
      • Sato H.
      • Hori M.
      • Kusuoka H.
      • Ozaki H.
      • Yokoyama H.
      • Takeda H.
      • Inoue M.
      • Kamada T.
      Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure.
      ;
      • Jouven X.
      • Empana J.P.
      • Schwartz P.J.
      • Desnos M.
      • Courbon D.
      • Ducimetiere P.
      Heart-rate profile during exercise as a predictor of sudden death.
      ). Nevertheless, it is still controversial whether sex affects HR recovery after dynamic exercise (
      • Antelmi I.
      • Chuang E.Y.
      • Grupi C.J.
      • Latorre Mdo R.
      • Mansur A.J.
      Heart rate recovery after treadmill electrocardiographic exercise stress test and 24-hour heart rate variability in healthy individuals.
      ;
      • Arena R.
      • Arrowood J.A.
      • Fei D.
      • Shelar S.
      • Helm S.
      • Kraft K.A.
      The influence of sex on the relationship between heart rate recovery and other cardiovascular risk factors in apparently healthy subjects.
      ;
      • Nunes R.A.
      • Barroso L.P.
      • Pereira Ada C.
      • Krieger J.E.
      • Mansur A.J.
      Gender-related associations of genetic polymorphisms of alpha-adrenergic receptors, endothelial nitric oxide synthase and bradykinin B2 receptor with treadmill exercise test responses.
      ). For example,
      • de Mendonca G.V.
      • Teodosio C.
      • Bruno P.M.
      Sexual dimorphism in heart rate recovery from peak exercise.
      demonstrated that there is no sex difference in HR at the 1st minute of recovery after cycling exercise. Interestingly, after performing multiple regression analyses, these authors found an interaction between sex and maximal oxygen uptake that can potentially predict HR at the 2nd minute of recovery. Despite the aforementioned discrepancies, a sex-depended effect on HR recovery has been posited. Although our present data partially support these previous findings, we would like to highlight a few aspects. It may be that these conflicting findings are partially attributable to differences in autonomic dynamics during recovery from exercise. In general, HR deceleration following a standard exercise test (i.e., treadmill and cycle ergometer) reflects a combination of vagal reactivation and sympathetic withdrawal (
      • Imai K.
      • Sato H.
      • Hori M.
      • Kusuoka H.
      • Ozaki H.
      • Yokoyama H.
      • Takeda H.
      • Inoue M.
      • Kamada T.
      Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure.
      ;
      • Pierpont G.L.
      • Voth E.J.
      Assessing autonomic function by analysis of heart rate recovery from exercise in healthy subjects.
      ). However, in our approach, the sympathetic outflow is steadily elevated via metaboreflex activation (i.e., PEI) (
      • Fisher J.P.
      • Adlan A.M.
      • Shantsila A.
      • Secher J.F.
      • Sorensen H.
      • Secher N.H.
      Muscle metaboreflex and autonomic regulation of heart rate in humans.
      ;
      • Teixeira A.L.
      • Fernandes I.A.
      • Vianna L.C.
      GABA(A) receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans.
      ). Further, we have analyzed only the first 30-s of PEI based on previous studies indicating a major role of cardiac vagal reactivation in mediating the rapid fall in HR (
      • Fisher J.P.
      • Adlan A.M.
      • Shantsila A.
      • Secher J.F.
      • Sorensen H.
      • Secher N.H.
      Muscle metaboreflex and autonomic regulation of heart rate in humans.
      ;
      • Fisher J.P.
      • Seifert T.
      • Hartwich D.
      • Young C.N.
      • Secher N.H.
      • Fadel P.J.
      Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.
      ). As such, our data demonstrated, for the first time, sex differences in cardiac vagal reactivation after cessation of isometric exercise during the onset of PEI. Importantly, our data support that autonomic control of circulation at rest and during exercise is affected by sex (
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.
      • Joyner M.J.
      Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors.
      ;
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.H.
      • Joyner M.J.
      Sex differences in sympathetic neural-hemodynamic balance: implications for human blood pressure regulation.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Galdino I.
      • Nobrega A.C.
      • Vianna L.C.
      Sex differences in the contribution of blood pressure to acute changes in aortic augmentation index.
      ;
      • Prodel E.
      • Barbosa T.C.
      • Nóbrega A.C.
      • Vianna L.C.
      Cardiovascular response to trigeminal nerve stimulation at rest and during exercise in humans: does sex matter?.
      ;
      • Samora M.
      • Incognito A.V.
      • Vianna L.C.
      Sex differences in blood pressure regulation during ischemic isometric exercise: the role of the beta-adrenergic receptors.
      ;
      • Samora M.
      • Teixeira A.L.
      • Sabino-Carvalho J.L.
      • Vianna L.C.
      Spontaneous cardiac baroreflex sensitivity is enhanced during post-exercise ischemia in men but not in women.
      ). Nevertheless, we believe that further research is warranted to explore the sex differences in HR recovery after whole-body exercise and the potential role of PEI as a laboratory technique to further our understanding on the relationship between autonomic tone and clinical outcomes.
      The present study was not without limitations. First, we studied only young, healthy and physically active participants, which does not allow extrapolation of our results to other populations such as older, sedentary, and/or diseased individuals. Second, we did not screen and report race/ethnicity in this study, although the majority of the participants are Latin-Americans and Caucasians. Thus, our findings cannot be extrapolated to all racial/ethnic groups, as significant racial differences have been observed in cardiovascular parameters (
      • Drew R.C.
      • Charkoudian N.
      • Park J.
      Neural control of cardiovascular function in black adults: implications for racial differences in autonomic regulation.
      ;
      • Young B.E.
      • Kaur J.
      • Vranish J.R.
      • Stephens B.Y.
      • Barbosa T.C.
      • Cloud J.N.
      • Wang J.
      • Keller D.M.
      • Fadel P.J.
      Augmented resting beat-to-beat blood pressure variability in young, healthy, non-Hispanic black men.
      ). Third, we have employed ultra-short-term HRV measures and hence one could argue that this could be a limitation. However, previous studies have demonstrated excellent validity/reliability indices between ultra-short-term HRV measures (i.e., 10-s windows) and wider window measures (e.g., 5-min) in healthy subjects (
      • Dekker J.M.
      • Schouten E.G.
      • Klootwijk P.
      • Pool J.
      • Swenne C.A.
      • Kromhout D.
      Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen study.
      ;
      • Hamilton R.M.
      • McKechnie P.S.
      • Macfarlane P.W.
      Can cardiac vagal tone be estimated from the 10-second ECG?.
      ;
      • Nussinovitch U.
      • Elishkevitz K.P.
      • Katz K.
      • Nussinovitch M.
      • Segev S.
      • Volovitz B.
      • Nussinovitch N.
      Reliability of ultra-short ECG indices for heart rate variability.
      ), athletes (
      • Esco M.R.
      • Flatt A.A.
      Ultra-short-term heart rate variability indexes at rest and post-exercise in athletes: evaluating the agreement with accepted recommendations.
      ), elderly population (
      • de Bruyne M.C.
      • Kors J.A.
      • Hoes A.W.
      • Klootwijk P.
      • Dekker J.M.
      • Hofman A.
      • van Bemmel J.H.
      • Grobbee D.E.
      Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: the Rotterdam study.
      ) and patients during and after myocardial infarction (
      • Karp E.
      • Shiyovich A.
      • Zahger D.
      • Gilutz H.
      • Grosbard A.
      • Katz A.
      Ultra-short-term heart rate variability for early risk stratification following acute ST-elevation myocardial infarction.
      ).
      In summary, our study demonstrates that women have a slower HR recovery at the cessation of isometric handgrip exercise and onset of PEI compared to men, suggesting a sex-related difference in cardiac vagal reactivation in healthy young humans.

      Funding

      The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: M.S. and J.L.S-C receive scholarship support from Coordination for the Improvement of Higher Education Personnel (CAPES; Finance Code 001). L.C.V. receives research support from the National Council for Scientific and Technological Development (CNPq; grant: 307293/2019-0 and 431740/2018-6). The present work was partially funded by a Beverly Petterson Bishop Award for Excellence in Neuroscience from The American Physiological Society awarded to L.C.V.

      Declaration of competing interest

      None of the authors declares a conflict of interest.

      Acknowledgments

      The time and effort expended by all the volunteer subjects are greatly appreciated.

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