Nonlinear progression across the occult transition establishes cancer lethality.

Cancer screening is based upon a linear model of growth and invasion. Yet, early dissemination during the lengthy pre-diagnostic phase suggests that nonlinearity in growth can also occur. Therefore, we quantitatively traced the invisible and visible phases of tumorigenesis in the mammary gland for more than two-thousand tumors. Dynamic mathematical models of the invisible phase revealed an occult checkpoint resulting in nonlinear progression of transformed field cells. We found that expansile fields have increased dwell time at the occult checkpoint resulting in a large reservoir of image detectable precursors prior to invasion. In contrast, slowly proliferating lesions disseminate early and then transition rapidly through an occult checkpoint in a process we term nascent lethality. Our data illustrate how nonlinear growth across an occult checkpoint can account for a paradoxical increase in early-stage cancer detection without a dramatic reduction in metastatic burden. Highlights: Growth during the invisible phase of tumorigenesis is a nonlinear processField size and field growth rate are uncoupled from metastatic potentialOccult transition rates vary by genotypeNascent lethal lesions are currently undetectable.

Heart Rate Variability Thresholds: Agreement with Established Approaches and Reproducibility in Trained Females and Males.

PURPOSE: To determine in trained females and males: i) the agreement between the gas exchange threshold (GET), lactate threshold 1 (LT1) and heart rate variability threshold 1 (HRVT1), as well as between the respiratory compensation point (RCP), lactate threshold 2 (LT2) and heart rate variability threshold 2 (HRVT2) and ii) the reproducibility of HRVT1 and HRVT2 during two-min incremental step protocols. METHODS: Fifty-seven trained participants (24 females) completed a 2 min step incremental test to task failure. Nineteen participants (8 females) completed a second test to evaluate reproducibility. Gas exchange and ventilatory responses, blood lactate concentration, and RR time series were recorded to assess the oxygen consumption (V̇O2) and heart rate (HR) associated with the GET, RCP, LT1, LT2, HRVT1 and HRVT2. RESULTS: V̇O2-GET vs V̇O2-HRVT1 and HR-GET vs HR-HRVT1 were statistically different for females (29.5 ± 4.0 vs 34.6 ± 6.1 mL·kg-1·min-1; 154 ± 11 vs 166 ± 12 bpm) and for males (33.9 ± 4.2 vs 42.7 ± 4.6 mL·kg-1·min-1; 145 ± 11 vs 165 ± 9 bpm) (p < 0.001). V̇O2 and HR at HRVT1 were greater than at LT1 (p < 0.05). V̇O2-RCP vs V̇O2-HRVT2 and HR-RCP vs HR-HRVT2 were not statistically different for females (40.1 ± 4.7 vs 39.5 ± 6.7 mL·kg-1·min-1; 177 ± 9 vs 176 ± 9 bpm) and males (48.4 ± 5.4 vs 47.8 ± 4.8 mL·kg-1·min-1; 176 ± 8 vs 175 ± 9 bpm) (p > 0.05). V̇O2 and HR responses at LT2 were similar to HRVT2 (p > 0.05). Intraclass correlation (ICC) for V̇O2-HRVT1, HR-HRVT1, V̇O2-HRVT2, and HR-HRVT2 indicated good reproducibility when comparing the two different timepoints to standard methods. CONCLUSIONS: Whereas HRVT2 is a valid and reproducible estimate of the RCP/LT2, current approaches for HRVT1 estimation did not show good agreement with outcomes at GET and LT1.

Combining Near-Infrared Spectroscopy and Heart Rate Variability Derived Thresholds to Estimate the Critical Intensity of Exercise.

ABSTRACT: Fleitas-Paniagua, PR, de Almeida Azevedo, R, Trpcic, M, Murias, JM, and Rogers, B. Combining near-infrared spectroscopy and heart rate variability derived thresholds to estimate the critical intensity of exercise. J Strength Cond Res 38(1): e16-e24, 2024-Critical intensity determination often requires costly tools and several testing sessions. Alternative approaches display relatively large individual variation. Therefore, simpler estimations with improved precision are needed. This study evaluated whether averaging the heart rate (HR) and oxygen uptake (V̇O 2 ) responses associated with the muscle deoxyhemoglobin concentration breakpoint ([HHb] BP ) and the heart rate variability (HRV) given by the detrended fluctuation analysis second threshold (HRVT2) during ramp incremental (RI) test improved the accuracy of identifying the HR and V̇O 2 at the respiratory compensation point (RCP). Ten female and 11 male recreationally trained subjects performed a 15 W·minute -1 RI test. Gas exchange, near-infrared spectroscopy (NIRS), and RR interval were recorded to assess the RCP, [HHb] BP , and HRVT2. Heart rate (mean ± SD : 158 ± 14, 156 ± 13, 160 ± 14 and, 158 ± 12 bpm) and V̇O 2 (3.08 ± 0.69, 2.98 ± 0.58, 3.06 ± 0.65, and 3.02 ± 0.60 L·minute -1 ) at the RCP, [HHb] BP , HRVT2, and HRVT2&[HHb] BP average (H&H Av ), respectively, were not significantly different ( p > 0.05). The linear relationship between H&H Av and RCP was higher compared with the relationship between [HHb] BP vs RCP and HRVT2 vs RCP for both HR ( r = 0.85; r = 0.73; r = 0.79, p > 0.05) and V̇O 2 ( r = 0.94; r = 0.93; r = 0.91, p > 0.05). Intraclass correlation between RCP, [HHb] BP , HRVT2, and H&H AV was 0.93 for V̇O 2 and 0.79 for HR. The [HHb] BP and the HRVT2 independently provided V̇O 2 and HR responses that strongly agreed with those at the RCP. Combining [HHb] BP and the HRVT2 resulted in estimations of the V̇O 2 and HR at the RCP that displayed smaller variability compared with each modality alone.

Correlation properties of heart rate variability to assess the first ventilatory threshold and fatigue in runners.

PURPOSE: The short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA-a1) of heart rate variability (HRV) has shown potential to delineate the first ventilatory threshold (VT1). The aims of this study were to investigate the accuracy of this method for VT1 determination in runners using a consumer grade chest belt and to explore the effects of acute fatigue. METHODS: We compared oxygen uptake (V̇O2) and heart rate (HR) at gas exchange VT1 to V̇O2 and HR at a DFA-a1 value of 0.75. Gas exchange and HRV data were obtained from 14 individuals during a treadmill run involving two incremental ramps. Agreement was assessed using Bland-Altman analysis and linear regression. RESULTS: Bland-Altman analysis between gas exchange and HRV V̇O2 and HR at VT1 during the first ramp showed a mean (95% limits of agreement) bias of -0.5 (-6.8 to 5.8) ml∙kg-1∙min-1, and -0.9 (-12.2 to 10.5) beats∙min-1, with R2 of 0.83 and 0.56, respectively. During the second ramp, the differences were -7.3 (-18.1 to 3.5) ml∙kg-1∙min-1 and -12.3 (-30.4 to 5.9) beats∙min-1, with R2 of 0.62 and 0.43, respectively. CONCLUSION: A chest-belt derived DFA-a1 of 0.75 is closely related to gas exchange VT1, with the variability in accuracy at an individual level being similar to gas exchange methods. This suggests this to be a useful method for exercise intensity demarcation. The altered relationship during the second ramp indicates that DFA-a1 is only able to accurately demarcate exercise intensity thresholds in a non-fatigued state, but also opens opportunities for fatigue-based training prescription.

The first ventilatory threshold determined with a nonlinear method (DFA-a1) to analyse heart rate variability derived from a chest-belt shows close agreement to the gas exchange first ventilatory threshold, with the variability in accuracy at an individual level being similar to gas exchange methods. This suggests this to be a useful method for exercise intensity demarcation.The altered relationship during fatigue indicates that DFA-a1 is only able to accurately demarcate exercise intensity thresholds in a non-fatigued state, but this also opens opportunities for fatigue-based training prescription.

Effect of ramp slope on intensity thresholds based on correlation properties of heart rate variability during cycling.

An index of heart rate variability (HRV), detrended fluctuation analysis (DFA a1) has gathered interest as a surrogate marker of exercise intensity boundaries. The aim of this report was to examine heart rate variability threshold (HRVT) behavior across different ramp incremental (RI) slopes. Seventeen participants completed a series of three RI (15, 30, and 45 W · min-1 slopes) with monitoring of gas exchange parameters, heart rate (HR) and HRV. HRVT1 was defined as the V̇O2 or HR at which DFA a1 reached 0.75 and the HRVT2 at which these values reached 0.5. HRVTs were compared by Pearson's r, Bland-Altman analysis, ICC3,1 , ANOVA, and paired t-testing. An excellent degree of reliability was seen across all three ramps, with an ICC3,1 of 0.93 and 0.88 for the HRVT1 V̇O2 and HR, respectively, and 0.90 and 0.92 for the HRVT2 V̇O2 and HR, respectively. Correlations between HRVT1/2 of the individual ramps were high with r values 0.84-0.95 for both HR and V̇O2 . Bland-Altman differences ranged between -1.4 and 1.2 mL · kg-1 · min-1 and -2 and +2 bpm. Paired t-testing showed no mean differences between any HRVT1/2 ramp comparisons. Cycling ramp slope does not appear to affect either HRVT1 or HRVT2 in terms of HR or V̇O2 .

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596.

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor.

The Between-Day Reliability of Correlation Properties of Heart Rate Variability During Running.

The short-term scaling exponent of detrended fluctuation analysis (DFA-a1) of heart rate variability may be a helpful tool to assess autonomic balance as a prelude to daily, individualized training. For this concept to be useful, between-session reliability should be acceptable. The aim of this study was to explore the reliability of DFA-a1 during a low-intensity exercise session in both a non-fatigued and a fatigued condition in healthy males and females. Ten participants completed two sessions with each containing an exhaustive treadmill ramp protocol. Before and after the fatiguing ramp, a standardized submaximal low-intensity exercise bout was performed during which DFA-a1, heart rate, and oxygen consumption (VO2) were measured. We compared between-session reliability of all metrics prior to the ramps (i.e., non-fatigued status) and after the first ramp (i.e., fatigued status). Intraclass correlation coefficients (ICC) with 95% confidence intervals (CI), the standard error of measurement, and the smallest worthwhile change (SWC) were determined. The ICC and SWC pre fatiguing ramp were 0.85 (95% CI 0.39-0.96) and 5.5% for DFA-a1, 0.85 (0.38-0.96) and 2.2% for heart rate, and 0.84 (0.31-0.96) and 3.1% for VO2. Post fatiguing ramp, the ICC and SWC were 0.55 (0.00-0.89) and 7.9% for DFA-a1, 0.91 (0.62-0.98) and 1.6% for heart rate, and 0.80 (0.17-0.95) and 3.0% for VO2. DFA-a1 shows generally acceptable to good between-session reliability with a SWC of 0.06 and 0.07 (5.5-7.9%) during non-fatigued and fatigued conditions. This suggests that this metric may be useful to inform on training readiness.

Improved Estimation of Exercise Intensity Thresholds by Combining Dual Non-Invasive Biomarker Concepts: Correlation Properties of Heart Rate Variability and Respiratory Frequency.

Identifying exercise intensity boundaries has been shown to be important during endurance training for performance enhancement and rehabilitation. Unfortunately, even though surrogate markers show promise when assessed on a group level, substantial deviation from gold standards can be present in each individual. The aim of this study was to evaluate whether combining two surrogate intensity markers improved this agreement. Electrocardiogram (ECG) and gas exchange data were obtained from 21 participants who performed an incremental cycling ramp to exhaustion and evaluated for first (VT1) and second (VT2) ventilatory thresholds, heart rate (HR) variability (HRV), and ECG derived respiratory frequency (EDR). HRV thresholds (HRVT) were based on the non-linear index a1 of a Detrended Fluctuation Analysis (DFA a1) and EDR thresholds (EDRT) upon the second derivative of the sixth-order polynomial of EDR over time. The average of HRVT and EDRT HR was set as the combined threshold (Combo). Mean VT1 was reached at a HR of 141 ± 15, HRVT1 at 152 ± 14 (p < 0.001), EDRT1 at 133 ± 12 (p < 0.001), and Combo1 at 140 ± 13 (p = 0.36) bpm with Pearson's r of 0.83, 0.78, and 0.84, respectively, for comparisons to VT1. A Bland-Altman analysis showed mean biases of 8.3 ± 7.9, -8.3 ± 9.5, and -1.7 ± 8.3 bpm, respectively. A mean VT2 was reached at a HR of 165 ± 13, HRVT2 at 167 ± 10 (p = 0.89), EDRT2 at 164 ± 14 (p = 0.36), and Combo2 at 164 ± 13 (p = 0.59) bpm with Pearson's r of 0.58, 0.95, and 0.94, respectively, for comparisons to VT2. A Bland-Altman analysis showed mean biases of -0.3 ± 8.9, -1.0 ± 4.6, and -0.6 ± 4.6 bpm, respectively. Both the DFA a1 and EDR intensity thresholds based on HR taken individually had moderate agreement to targets derived through gas exchange measurements. By combining both non-invasive approaches, there was improved correlation, reduced bias, and limits of agreement to the respective corresponding HRs at VT1 and VT2.

Validation of a non-linear index of heart rate variability to determine aerobic and anaerobic thresholds during incremental cycling exercise in women.

Studies highlight the usage of non-linear time series analysis of heart rate variability (HRV) using the short-term scaling exponent alpha1 of Detrended Fluctuation Analysis (DFA-alpha1) during exercise to determine aerobic and anaerobic thresholds. The present study aims to further verify this approach in women. Gas exchange and HRV data were collected from 26 female participants with different activity levels. Oxygen uptake (VO2) and heart rate (HR) at first (VT1) and second ventilatory thresholds (VT2) were compared with DFA-alpha1-based thresholds 0.75 (HRVT1) and 0.50 (HRVT2). Results: VO2 at VT1 and VT2 were 25.2 ml/kg/min (± 2.8) and 31.5 ml/kg/min (± 3.6) compared with 26.5 ml/kg/min (± 4.0) and 31.9 ml/kg/min (± 4.5) for HRVT1 and HRVT2, respectively (ICC3,1 = 0.77, 0.84; r = 0.81, 0.86, p < 0.001). The mean HR at VT1 was 147 bpm (± 15.6) and 167 bpm (± 12.7) for VT2, compared with 152 bpm (± 15.5) and 166 bpm (± 13.2) for HRVT1 and HRVT2, respectively (ICC3,1 = 0.87, 0.90; r = 0.87, 0.90, p < 0.001). Bland-Altman analysis for VT1 vs. HRVT1 showed a mean difference of - 1.3 ml/kg/min (± 2.4; LoA: 3.3, - 6.0 ml/kg/min) for VO2 and of - 4.7 bpm (± 7.8; LoA: 10.6, - 20.0 bpm) for HR. VT2 vs. HRVT2 showed a mean difference of - 0.4 ml/kg/min (± 2.3; LoA: 4.1, - 4.9 ml/kg/min) for VO2 and 0.5 bpm (± 5.7; LoA: 11.8, - 10.8 bpm) for HR. DFA-alpha1-based thresholds showed good agreement with traditionally used thresholds and could be used as an alternative approach for marking organismic transition zones for intensity distribution in women.

Fractal correlation properties of HRV as a noninvasive biomarker to assess the physiological status of triathletes during simulated warm-up sessions at low exercise intensity: a pilot study.

BACKGROUND: The non-linear index alpha 1 of Detrended Fluctuation Analysis (DFA a1) of heart rate variability, has been shown to be a marker of fatigue during endurance exercise. This report aims to explore its ability to assess the physiological status as a surrogate metric for "readiness to train" while performing simulated warm-up sessions the day after two different exercise sessions. METHODS: 11 triathletes were recruited to determine the first ventilatory threshold (VT1) during a baseline assessment and to perform 10-min of cycling at 90% of VT1 (simulating a warm-up bout) before (PRE) and within 36 h after (POST) light and heavy running exercise. RR intervals were recorded for DFA a1 analysis along with neuromuscular testing to verify the effects of the performed exercise sessions. In addition to common statistical methods, magnitude-based inferences (MBI) were applied to assess the changes in true score and thus also the practical relevance of the magnitude. RESULTS: Rating of perceived exertion for the heavy exercise session showed a significant higher rating as opposed to the light exercise session (p < 0.001, d = 0.89). In regard of MBIs, PRE versus POST comparisons revealed a significant reduced DFA a1 with large effect size after the heavy exercise session (p = 0.001, d = - 1.44) and a 99% chance that this negative change was clinically relevant. CONCLUSIONS: Despite inter-individual differences, DFA a1 offers potential to assess physiological status and guide athletes in their training as an easy-to-apply monitoring procedure during a standardized warm-up. A regular assessment including individual data history and statistical references for identification of response is recommended. Further data are necessary to confirm the results in a larger and more homogeneous population.

Estimation of Respiratory Frequency in Women and Men by Kubios HRV Software Using the Polar H10 or Movesense Medical ECG Sensor during an Exercise Ramp.

Monitoring of the physiologic metric, respiratory frequency (RF), has been shown to be of value in health, disease, and exercise science. Both heart rate (HR) and variability (HRV), as represented by variation in RR interval timing, as well as analysis of ECG waveform variability, have shown potential in its measurement. Validation of RF accuracy using newer consumer hardware and software applications have been sparse. The intent of this report is to assess the precision of the RF derived using Kubios HRV Premium software version 3.5 with the Movesense Medical sensor single-channel ECG (MS ECG) and the Polar H10 (H10) HR monitor. Gas exchange data (GE), RR intervals (H10), and continuous ECG (MS ECG) were recorded from 21 participants performing an incremental cycling ramp to failure. Results showed high correlations between the reference GE and both the H10 (r = 0.85, SEE = 4.2) and MS ECG (r = 0.95, SEE = 2.6). Although median values were statistically different via Wilcoxon testing, adjusted median differences were clinically small for the H10 (RF about 1 breaths/min) and trivial for the MS ECG (RF about 0.1 breaths/min). ECG based measurement with the MS ECG showed reduced bias, limits of agreement (maximal bias, -2.0 breaths/min, maximal LoA, 6.1 to -10.0 breaths/min) compared to the H10 (maximal bias, -3.9 breaths/min, maximal LoA, 8.2 to -16.0 breaths/min). In conclusion, RF derived from the combination of the MS ECG sensor with Kubios HRV Premium software, tracked closely to the reference device through an exercise ramp, illustrates the potential for this system to be of practical usage during endurance exercise.

Validity of the Polar H10 Sensor for Heart Rate Variability Analysis during Resting State and Incremental Exercise in Recreational Men and Women.

Heart rate variability (HRV) is frequently applied in sport-specific settings. The rising use of freely accessible applications for its recording requires validation processes to ensure accurate data. It is the aim of this study to compare the HRV data obtained by the Polar H10 sensor chest strap device and an electrocardiogram (ECG) with the focus on RR intervals and short-term scaling exponent alpha 1 of Detrended Fluctuation Analysis (DFA a1) as non-linear metric of HRV analysis. A group of 25 participants performed an exhaustive cycling ramp with measurements of HRV with both recording systems. Average time between heartbeats (RR), heart rate (HR) and DFA a1 were recorded before (PRE), during, and after (POST) the exercise test. High correlations were found for the resting conditions (PRE: r = 0.95, rc = 0.95, ICC3,1 = 0.95, POST: r = 0.86, rc = 0.84, ICC3,1 = 0.85) and for the incremental exercise (r > 0.93, rc > 0.93, ICC3,1 > 0.93). While PRE and POST comparisons revealed no differences, significant bias could be found during the exercise test for all variables (p < 0.001). For RR and HR, bias and limits of agreement (LoA) in the Bland−Altman analysis were minimal (RR: bias of 0.7 to 0.4 ms with LoA of 4.3 to −2.8 ms during low intensity and 1.3 to −0.5 ms during high intensity, HR: bias of −0.1 to −0.2 ms with LoA of 0.3 to −0.5 ms during low intensity and 0.4 to −0.7 ms during high intensity). DFA a1 showed wider bias and LoAs (bias of 0.9 to 8.6% with LoA of 11.6 to −9.9% during low intensity and 58.1 to −40.9% during high intensity). Linear HRV measurements derived from the Polar H10 chest strap device show strong agreement and small bias compared with ECG recordings and can be recommended for practitioners. However, with respect to DFA a1, values in the uncorrelated range and during higher exercise intensities tend to elicit higher bias and wider LoA.

Fractal Correlation Properties of Heart Rate Variability as a Biomarker for Intensity Distribution and Training Prescription in Endurance Exercise: An Update.

While established methods for determining physiologic exercise thresholds and intensity distribution such as gas exchange or lactate testing are appropriate for the laboratory setting, they are not easily obtainable for most participants. Data over the past two years has indicated that the short-term scaling exponent alpha1 of Detrended Fluctuation Analysis (DFA a1), a heart rate variability (HRV) index representing the degree of fractal correlation properties of the cardiac beat sequence, shows promise as an alternative for exercise load assessment. Unlike conventional HRV indexes, it possesses a dynamic range throughout all intensity zones and does not require prior calibration with an incremental exercise test. A DFA a1 value of 0.75, reflecting values midway between well correlated fractal patterns and uncorrelated behavior, has been shown to be associated with the aerobic threshold in elite, recreational and cardiac disease populations and termed the heart rate variability threshold (HRVT). Further loss of fractal correlation properties indicative of random beat patterns, signifying an autonomic state of unsustainability (DFA a1 of 0.5), may be associated with that of the anaerobic threshold. There is minimal bias in DFA a1 induced by common artifact correction methods at levels below 3% and negligible change in HRVT even at levels of 6%. DFA a1 has also shown value for exercise load management in situations where standard intensity targets can be skewed such as eccentric cycling. Currently, several web sites and smartphone apps have been developed to track DFA a1 in retrospect or in real-time, making field assessment of physiologic exercise thresholds and internal load assessment practical. Although of value when viewed in isolation, DFA a1 tracking in combination with non-autonomic markers such as power/pace, open intriguing possibilities regarding athlete durability, identification of endurance exercise fatigue and optimization of daily training guidance.

The Movesense Medical Sensor Chest Belt Device as Single Channel ECG for RR Interval Detection and HRV Analysis during Resting State and Incremental Exercise: A Cross-Sectional Validation Study.

The value of heart rate variability (HRV) in the fields of health, disease, and exercise science has been established through numerous investigations. The typical mobile-based HRV device simply records interbeat intervals, without differentiation between noise or arrythmia as can be done with an electrocardiogram (ECG). The intent of this report is to validate a new single channel ECG device, the Movesense Medical sensor, against a conventional 12 channel ECG. A heterogeneous group of 21 participants performed an incremental cycling ramp to failure with measurements of HRV, before (PRE), during (EX), and after (POST). Results showed excellent correlations between devices for linear indexes with Pearson's r between 0.98 to 1.0 for meanRR, SDNN, RMSSD, and 0.95 to 0.97 for the non-linear index DFA a1 during PRE, EX, and POST. There was no significant difference in device specific meanRR during PRE and POST. Bland-Altman analysis showed high agreement between devices (PRE and POST: meanRR bias of 0.0 and 0.4 ms, LOA of 1.9 to -1.8 ms and 2.3 to -1.5; EX: meanRR bias of 11.2 to 6.0 ms; LOA of 29.8 to -7.4 ms during low intensity exercise and 8.5 to 3.5 ms during high intensity exercise). The Movesense Medical device can be used in lieu of a reference ECG for the calculation of HRV with the potential to differentiate noise from atrial fibrillation and represents a significant advance in both a HR and HRV recording device in a chest belt form factor for lab-based or remote field-application.

An Index of Non-Linear HRV as a Proxy of the Aerobic Threshold Based on Blood Lactate Concentration in Elite Triathletes.

A non-linear index of heart rate (HR) variability (HRV) known as alpha1 of Detrended Fluctuation Analysis (DFA a1) has been shown to change with increasing exercise intensity, crossing a value of 0.75 at the aerobic threshold (AT) in recreational runners defining a HRV threshold (HRVT). Since large volumes of low-intensity training below the AT is recommended for many elite endurance athletes, confirmation of this relationship in this specific group would be advantageous for the purposes of training intensity distribution monitoring. Nine elite triathletes (7 male, 2 female) attended a training camp for diagnostic purposes. Lactate testing was performed with an incremental cycling ramp test to exhaustion for the determination of the first lactate threshold based on the log-log calculation method (LT1). Concurrent measurements of cardiac beta-to-beat intervals were performed to determine the HRVT. Mean LT1 HR of all 9 participants was 155.8 bpm (±7.0) vs. HRVT HR of 153.7 bpm (±10.1) (p = 0.52). Mean LT1 cycling power was 252.3 W (±48.1) vs. HRVT power of 247.0 W (±53.6) (p = 0.17). Bland-Altman analysis showed mean differences of -1.7 bpm and -5.3 W with limits of agreement (LOA) 13.3 to -16.7 bpm and 15.1 to -25.6 W for HR and cycling power, respectively. The DFA a1-based HRVT closely agreed with the LT1 in a group of elite triathletes. Since large volumes of low-intensity exercise are recommended for successful endurance performance, the fractal correlation properties of HRV show promise as a low-cost, non-invasive option to that of lactate testing for identification of AT-related training boundaries.

Effects of Troponoids on Mitochondrial Function and Cytotoxicity.

The α-hydroxytropolones (αHTs) are troponoid inhibitors of hepatitis B virus (HBV) replication that can target HBV RNase H with submicromolar efficacies. αHTs and related troponoids (tropones and tropolones) can be cytotoxic in cell lines as measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays that assess mitochondrial function. Previous studies suggest that tropolones induce cytotoxicity through inhibition of mitochondrial respiration. Therefore, we screened 35 diverse troponoids for effects on mitochondrial function, mitochondrial/nuclear genome ratios, cytotoxicity, and reactive oxygen species (ROS) production. Troponoids as a class did not inhibit respiration or glycolysis, although the α-ketotropolone subclass interfered with these processes. The troponoids had no impact on the mitochondrial DNA/nuclear DNA ratio after 3 days of compound exposure. The patterns of troponoid-induced cytotoxicity among three hepatic cell lines were similar for all compounds, but three potent HBV RNase H inhibitors were not cytotoxic in primary human hepatocytes. Tropolones and αHTs increased ROS production in cells at cytotoxic concentrations but had no effect at lower concentrations that efficiently inhibit HBV replication. Troponoid-mediated cytotoxicity was significantly decreased upon the addition of the ROS scavenger N-acetylcysteine. These studies show that troponoids can increase ROS production at high concentrations within cell lines, leading to cytotoxicity, but are not cytotoxic in primary hepatocytes. Future development of αHTs as potential therapeutics against HBV may need to mitigate ROS production by altering compound design and/or by coadministering ROS antagonists to ameliorate increased ROS levels.

Analysis of Fractal Correlation Properties of Heart Rate Variability during an Initial Session of Eccentric Cycling.

Eccentric cycling (ECC) has attracted attention as a method to improve muscle strength and aerobic fitness in populations unable to tolerate conventional methods. However, agreement on exercise prescription targets have been problematic. The current report is an initial exploration of a potentially useful tool, a nonlinear heart rate (HR) variability (HRV) index based on the short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA a1), which has been previously shown to correspond to exercise intensity. Eleven male volunteers performed 45 min of concentric (CON) cycling and ECC separated by 1 month. Work rates were matched for HR (~50% of the maximal HR) during the first 5 min and remained stable thereafter. HRV, HR, oxygen consumption (VO2), and cycling power were monitored and evaluated at elapsed times of 10 (T10) and 45 (T45) minutes duration. HR significantly increased between ECC T10 and ECC T45 (p = 0.003, d = 1.485), while DFA a1 significantly decreased (p = 0.004, d = 1.087). During CON, HR significantly increased (p < 0.001 d = 1.570) without significant DFA a1 change (p = 0.48, d = 0.22). Significantly higher HR was observed at T45 in ECC than in CON (p = 0.047, d = 1.059). A session of unaccustomed ECC lead to decreased values of DFA a1 at T45 in comparison to that seen with CON at similar VO2. ECC lead to altered autonomic nervous system balance as reflected by the loss of correlation properties compared to CON.

Aerobic Threshold Identification in a Cardiac Disease Population Based on Correlation Properties of Heart Rate Variability.

An index of heart rate (HR) variability correlation properties, the short-term scaling exponent alpha1 of detrended fluctuation analysis (DFA a1) has shown potential to delineate the first ventilatory threshold (VT1). This study aims to extend this concept to a group of participants with cardiac disease. Sixteen volunteers with stable coronary disease or heart failure performed an incremental cycling ramp to exhaustion PRE and POST a 3-week training intervention. Oxygen uptake (VO2) and HR at VT1 were obtained from a metabolic cart. An ECG was processed for DFA a1 and HR. The HR variability threshold (HRVT) was defined as the VO2, HR or power where DFA a1 reached a value of 0.75. Mean VT1 was reached at 16.82 ± 5.72 mL/kg/min, HR of 91.3 ± 11.9 bpm and power of 67.8 ± 17.9 watts compared to HRVT at 18.02 ± 7.74 mL/kg/min, HR of 94.7 ± 14.2 bpm and power of 73.2 ± 25.0 watts. Linear relationships were seen between modalities, with Pearson's r of 0.95 (VO2), 0.86 (HR) and 0.87 (power). Bland-Altman assessment showed mean differences of 1.20 mL/kg/min, 3.4 bpm and 5.4 watts. Mean peak VO2 and VT1 did not change after training intervention. However, the correlation between PRE to POST change in VO2 at VT1 with the change in VO2 at HRVT was significant (r = 0.84, p < 0.001). Reaching a DFA a1 of 0.75 was associated with the VT1 in a population with cardiac disease. VT1 change after training intervention followed that of the HRVT, confirming the relationship between these parameters.

Fractal correlation properties of heart rate variability as a biomarker of endurance exercise fatigue in ultramarathon runners.

Although heart rate variability (HRV) indexes have been helpful for monitoring the fatigued state while resting, little data indicate that there is comparable potential during exercise. Since an index of HRV based on fractal correlation properties, alpha 1 of detrended fluctuation analysis (DFA a1) displays overall organismic demands, alteration during exertion may provide insight into physiologic changes accompanying fatigue. Two weeks after collecting baseline demographic and gas exchange data, 11 experienced ultramarathon runners were divided into two groups. Seven runners performed a simulated ultramarathon for 6 h (Fatigue group, FG) and four runners performed daily activity over a similar period (Control group, CG). Before (Pre) and after (Post) the ultramarathon or daily activity, DFA a1, heart rate (HR), running economy (RE) and countermovement jumps (CMJ) were measured while running on a treadmill at 3 m/s. In Pre versus Post comparisons, data showed a decline with large effect size in DFA a1 post intervention only for FG (Pre: 0.71, Post: 0.32; d = 1.34), with minor differences and small effect sizes in HR (d = 0.02) and RE (d = 0.21). CG showed only minor differences with small effect sizes in DFA a1 (d = 0.19), HR (d = 0.15), and RE (d = 0.31). CMJ vertical peak force showed fatigue-induced decreases with large effect size in FG (d = 0.82) compared to CG (d = 0.02). At the completion of an ultramarathon, DFA a1 decreased with large effect size while running at low intensity compared to pre-race values. DFA a1 may offer an opportunity for real-time tracking of physiologic status in terms of monitoring for fatigue and possibly as an early warning signal of systemic perturbation.