Ramp Protocol Research Articles

Adiposity, Insulin Resistance, Cardiorespiratory Fitness, and Bone Health in Hispanic Children.

Childhood obesity disproportionately affects Hispanic youth. The skeletal system appears to be a target organ of the adverse effects of obesity. Yet, the relationship between adiposity and bone health in youth and the modulating factors are not well understood. This work aims to examine the relationship between adiposity, insulin resistance (IR), cardiorespiratory fitness (CRF), and bone mass in Hispanic youth. A total of 951 Hispanic youth (50% male), aged 4 to 19 years, participated in this cross-sectional design study from the Viva La Familia Study at Children's Nutrition Research Center. Bone mineral content (BMC) and density (BMD), lean mass (LM), total body fat mass (FM), truncal FM were obtained using dual-energy x-ray absorptiometry. Fasting glucose and insulin were obtained and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. CRF was measured using a treadmill ramp protocol. We applied linear regression models and mediation analyses. Adiposity measures were negatively related to BMC and BMD after accounting for LM and sex. IR negatively contributed whereas CRF positively contributed to the variance in BMC and BMD, more notably in the pubertal age group. In mediation analysis, HOMA-IR partially mediated the negative relationship of adiposity to BMC (standardized indirect effect [IE] = -0.0382; 95% CI, -0.0515 to -0.0264) whereas the sequential IE of HOMA-IR and CRF partially attenuated (IE = -0.0026; 95% CI, -0.0053 to -0.0005) this relationship. Similar findings were seen with BMD as the primary outcome. IR mediates the negative relationship between adiposity and bone mass whereas CRF may partially attenuate it.

Electrophysiological characterization of schizophrenia-associated variants in NaV1.2 sodium channel

IntroductionA major pathophysiological hypothesis of schizophrenia states an increased activity of glutamatergic neurons leading to an imbalance of neural excitation and inhibition (E/I-imbalance). One potential molecular mechanism of E/I-imbalance is a dysfunction of voltage-gated sodium channels, which are crucial for the generation of action potentials, the fundamental event of neuronal excitation. Indeed, patients with schizophrenia exhibit an increased burden of rare exonic variants of sodium channel genes, but the literature describing their electrophysiological effect is scarce.ObjectivesThe aim of this project is to assess the functional impact of three mutations of the Sodium Voltage-Gated Channel Alpha Subunit 2 (SCN2A) gene / NaV1.2 channel which were identified in four patients with schizophrenia, using a heterologous expression system.MethodsThree variants of the human SCN2A gene (R850P, V1282F and S1656P) were created using site-directed mutagenesis. HEK293T cells transfected with either the mutant or wild type constructs are being investigated by voltage-clamp technique, applying activation, steady-state fast inactivation, use dependency and ramp protocols.ResultsAll three mutated constructs were successfully created. Preliminary recordings from the V1282F mutant indicate a shift of both the activation and steady-state fast inactivation to the hyperpolarized direction.ConclusionsIn a subgroup of patients, E/I imbalance may be a consequence of Nav1.2 mutations leading to increased excitability of glutamatergic neurons. By integrating insights from different mutations we aim to identify traits of a potentially shared disease pathway which may provide a basis for the development of novel therapeutics.DisclosureNo significant relationships.

Predictive value of body composition and core symptoms in schizophrenia for cardiorespiratory fitness: CORTEX-SP study

IntroductionCardiorespiratory fitness (CRF) can be directly measured and assessed by the cardiopulmonary exercise test (CPET) or estimated from different field tests as the Modified Shuttle Walking Test (MSWT). The CRF in schizophrenia (SP) population may be altered due to sex, age, body composition and core symptoms variables. However, the extent to which each domain influences CRF in this pathology is still unknown.ObjectivesTo analyze the predictive value of body composition and core symptoms in SP for CRF.MethodsParticipants (N = 144, 41.7 ± 10.3 yr old) with SP were assessed with (1) body mass index and fat percentage; (2) upright bicycle ergometer using an incremental ramp protocol and the MSWT; and (3) positive and negative symptoms of the disease [“Positive and Negative Syndrome Scale” (PANSS) and “The Brief Negative Symptom Scale” (BNSS)]. In the Stepwise Multiple Regression analyses, those variables which correlated (Spearman’s Rho) significantly with each CFR scores were includedResultsLower negative symptoms (P<0.001) and positive PANSS (P=0.035) predicted V̇O2peak (L·min−1) (R2=28.3%). Lower negative symptoms (P<0.001), positive PANSS (P=0.006) and fat body mass (P<0.001) explained V̇O2peak (mL·kg−1·min−1) (R2=46.5%). MSWT was predicted (R2=58.9%) by lower negative symptoms (P=0.001), body mass (P<0.001) and total PANSS (P=0.004).ConclusionsIn patients with SP significantly higher CRF was detected in those with lower negative and positive symptoms, as well as lower body mass. Exercise interventions for improving CRF should be promoting in this population for a better control of core symptoms.DisclosureNo significant relationships.

Neuromuscular Training, Exercise Physiology Clinic, Real-time Exercise, and Cardiac Rehabilitation

Neuromuscular Training, Exercise Physiology Clinic, Real-time Exercise, and Cardiac Rehabilitation

C73 PICK YOUR THRESHOLD! HOW TO CALCULATE THE ANAEROBIC THRESHOLD TO STRATIFY HEART FAILURE PROGNOSIS: A COMPARISON BETWEEN ABSOLUTE VALUE, PERCENTAGE OF PEAK VO2 OR PERCENTAGE OF PREDICTED MAXIMUM VO2 IN A LARGE MULTICENTER COHORT OF HFREF PATIENTS WHO UNDER

Abstract Background The anaerobic threshold (AT), identifies the moment during a maximal exercise when hyperventilation occurs in response to the introduction of an anaerobic metabolism. Its value is indicative of the subject‘s training and/or health, it can be used to guide training, rehabilitation or to define appropriateness to undergo major thoracic or abdominal surgery, and it is related to heart failure (HF) prognosis. AT can be expressed as absolute value or as the percentage of predicted maximum VO2 (VO2AT%pred). However, it is not uncommon to find papers that refer AT to the peak VO2 value achieved (VO2AT%peak), rather than its predicted value, but a direct comparison of the prognostic power of these different variables is missing. In this work, we aim to compare the risk–identifying ability of the AT value when expressed in these three different ways in a large population of HF patients. This will help identify which is more correct to use in assessing patient prognosis, especially when peakVO2 is not reached appropriately. Methods The population analyzed counts 7746 patients with HF with history of reduced EF (<40%), recruited between 1998 and 2020 within the MECKI score project. All patients underwent a maximal cardiopulmonary exercise test (CPET), executed in using a ramp protocol on an electronically braked cycle ergometer. Results The present study considered 6157 HF patients with identified AT during the CPET, with a median follow up of 1528 days (689–1826). The main characteristics are reported in Figure 1. Figure 2 shows stratification of patients according to these 3 variables divided in tertiles, considering cardiovascular death (combination of cardiovascular death, urgent transplant or LVAD implantation) as an end point. Comparing the AUC of the three variables considered, we found similar values between VO2AT and VO2AT%pred, while the peak VO2AT% value was significantly lower (p < 0.001), as shown in Figure 3A. Moreover VO2AT%pred is the only variable to maintain a comparable ROC to the peakVO2 one, with the others being significantly lower (Figure 3B). Conclusions VO2 at AT should always be expressed as % of predicted maximal VO2 to be reliable in predicting prognosis in HF patients. Moreover, evaluating a sub–maximal exercise, VO2AT%pred is the only variable to maintain a comparable prognostic power to the peakVO2 one.

P408 CERTIFICATION FOR COMPETITIVE SPORTS ACTIVITY IN A TEENAGER WITH WPW BY VIA INTRAHYSSIAN ACCESSORY PATHWAY

Abstract The case of a 12–year–old male, height 160 cm, weight 46 kg, who practices water polo at a competitive level is reported. Negative family history of cardiovascular pathologies, general and cardiovascular physical examination within the limits of normality. On the electrocardiographic trace (ECG) presence of delta wave from ventricular pre–excitation from intrahyssian accessory pathway (Fig. 1). Echocardiography + color Doppler was normal. The subject underwent a cardiopulmonary stress test with an incremental ramp protocol and steps of 20 watts / min. Shutdown at 190 watts for muscle exhaustion with peak oxygen consumption (VO2) = 43.9 mL / Kg / min, Heart rate = 197 beats / minute, BP = 210/70 mmHg, VE / VCO2 slope = 27.6. Normal course of the cronotropic and pressure curve. The ventricular pre–excitation delta wave persisted for the entire duration of the test and in recovery (Fig. 2, Fig. 3). Secondary disturbances of ventricular repolarization characterized by ST segment sub–leveling and negative T wave appeared at high load and persisted in the first minutes of recovery, delta VO2 / delta WR = 12. Given the non–disappearance of the delta wave from ventricular pre–excitation during the maximal stress test, the subject was sent to an electrophysiological study and subsequent ablation of the accessory pathway. The electrophysiological study was negative for inducibility of atrial fibrillation (AF) and ventricular arrhythmias. Safe ablation was impossible given the intrahyssian position of the accessory pathway. Considering the negativity of the electrophysiological study due to non inducibility of supraventricular and ventricular arrhythmias, eligibility for competitive sports was granted.

P251 PERIODIC BREATHING (EOV) ON CARDIORESPIRATORY STRESS TESTING: ARE THERE PROGNOSTIC DIFFERENCES BETWEEN PATIENTS WITH PERIODIC BREATHING THAT PERSISTS THROUGHOUT THE TEST AND PATIENTS TO WHOM IT DISAPPEARS?

Abstract Introduction Oscillatory exercise ventilation (EOV) is frequently seen in patients with severe heart failure (HF) and has a ne:gative prognostic value in both patients with reduced HF and those with average ejection fraction. Two types of EOV have been described one that lasts throughout exercise and one that disappears before the end of exercise, Figure 1 Aim of the Study It is currently unknown whether there are differences in prognosis and functional capacity between HF patients with EOV that persists or disappears during exercise. Population Male and female patients, aged≥18 years, diagnosed with HF and LVEF<45% were enrolled. Methods The retrospective study enrolled patients who performed a cardiopulmonary exercise test (CPET) and presented with EOV during exercise (Monzino Heart Center Laboratory and patients included in the MECKI score registry, identified a total of 255 patients). A subset of 100 patients underwent measurement of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) before and after exercise (Table 2). All patients were treated at the top of therapy for HF. CPETs were performed and analyzed with a standard approach using a customized ramp protocol. The main parameters obtained are reported and compared in Table 1. EOV was defined according to as a cyclic fluctuation in ventilation as proposed by Corrà et al. Statistical analysis:Data are reported as mean ± standard deviation or median and interquartile range as appropriate. The two groups of patients were compared by t test for unpaired data in the case of data with normal distribution. Mortality was analyzed by Kaplan Meier curves and Log Rank test. Survival was considered using the composite end–point of cardiovascular death, urgent cardiac transplantation, or implantation of a left ventricular assist device. The median MECKI score of the total population was 5.5% (2.5–13.7) with no significant differences between the 2 groups. Figure 1 shows the Kaplan Meyer describing the 5–year survival analysis in both groups. Conclusions Patients with disappearing EOV demonstrated better exercise performance but no significant difference in survival and major prognostic parameters.

Acute effects of high intensity training on cardiac function: a pilot study comparing subjects with type 2 diabetes to healthy controls

This study evaluated acute cardiac stress after a high-intensity interval training session in patients with type 2 diabetes (T2D) versus healthy controls. High intensity aerobic exercise was performed by 4 × 4-min intervals (90–95% of maximal heart rate), followed by a ramp protocol to peak oxygen uptake. Echocardiography was performed before and 30 min after exercise. Holter electrocardiography monitored heart rhythms 24 h before, during, and 24 h after the exercise. Left atrial end-systolic volume, peak early diastolic mitral annular velocity, and the ratio of peak early to late diastolic mitral inflow velocity were reduced by approximately 18%, 15%, and 31%, respectively, after exercise across groups. Left ventricular end-diastolic wall thickness was the only echo parameter that significantly differed between groups in response to exercise. The T2D group had a rate of supraventricular extrasystoles per hour that was 265% greater than that of the controls before exercise, which remained higher after exercise. A single exhaustive exercise session impaired left ventricular diastolic function in both groups. The findings also indicated impaired right ventricular function in patients with T2D after exercise.ClinicalTrials.gov Identifier: NCT02998008.

The effect of high intensity combined training on functional capacity, muscle strength, body composition, agility and dynamic balance in patients with coronary artery disease

Abstract Funding Acknowledgements Type of funding sources: None. Introduction There is still controversy regarding the exercise characteristics that are more effective for improving peak oxygen uptake (VO2 peak), cardiac and metabolic function. High- intensity interval exercise training (HIIT) has been shown to elicit comparable and/or superior performance on endurance capacity (EC), ventricular function (VF) and quality of life. By other side, there is robust evidence that combined endurance and strength training is significantly more effective than endurance training only for improving EC, muscle mass and muscle strength. There is no enough information if the combination of HIIT with high strength training (HST) could enhance the physical conditions of these patients. Purpose The purpose of our study was to analyze the combination of HIIT + HST and its effect on physical performance compared to different types of combined training: HIIT and MCT with low load resistance training (RT) and HIIT or MCT only. Methods We evaluated 140 male patients (p) with CAD documented by angiographic studies, clinically stables with medical treatment and sinus rhythm. All of them performed a stress testing in treadmill without handrail support using a ramp protocol until maximal effort. VO2 peak (ml/kg/min) was measured indirectly through ACSM formula. We used YMCA´s method of estimating body fat with measurement of skinfolds in four sites (BF %), 30-second chair stand test (CST), 8-foot up and go test (FUGT), six-minute walk test (T6min) and one maximum repetition for quadriceps extension (1RMq) .Training intervention: p were randomly allocated to HIIT + RT (n=30), MCT + RT (n=30), HIIT (n=30), MCT (n=30) and HIIT + HST (n=20) during 3 month period of training. HIIT: 4 x 4 (85-95% peak heart rate) and 60-70% during active breaks. (36 min) MCT: 70-75% peak heart rate.(36 min) RT: 40-50% 1RM for lower body with 12-15 repetitions in 2 sets HST: ≥ 70% 1RM for lower body with low number of repetitions. Statistical analysis: all data were analyzed using IBM SPSS V.24. Comparisons were performed by following one-way ANOVA(parametric distribution) with post-hoc Tuckey or Kruskal-Wallis(non parametric distribution). The level of statistical significance was P< 0.05. Results Analyzing values pretraining (PRE) vs. postraining (POST), VO2 peak increased significantly by 27,52% for HIIT + HST P< 0,03 vs. HIIT + RT- MCT + RT and MCT. A positive effect in HIIT + HST with FUGT P< 0,001 and CST P< 0,005 between group changes and favourable observations in relation to 1RMq (PRE 60,00 ± 9,07 vs. POST 73,00 ± 9,86) and %BF(PRE 26,60 ± 3,21 vs. POST 24,80 ± 3,72) compared to MCT and HIIT P < 0,05. We didn´t find statistical significant differences with both modalities of combined training (low workloads) and HIIT for T6min. Conclusions High intensity combined training (HIIT + HST) had an additional effect related to others aerobic and resistance exercises attributed to neuromuscular adaptations, increased power and muscle strength.

Dissipation-Engineered Family of Nearly Dark States in Many-Body Cavity-Atom Systems.

Three-level atomic systems coupled to light have the capacity to host dark states. We study a system of V-shaped three-level atoms coherently coupled to the two quadratures of a dissipative cavity. The interplay between the atomic level structure and dissipation makes the phase diagram of the open system drastically different from the closed one. In particular, it leads to the stabilization of a continuous family of dark and nearly dark excited many-body states with inverted atomic populations as the steady states. The multistability of these states can be probed via their distinct fluctuations and excitation spectra, as well as the system's Liouvillian dynamics which are highly sensitive to ramp protocols. Our model can be implemented experimentally by encoding the two higher-energy modes in orthogonal density-modulated states in a bosonic quantum gas. This implementation offers prospects for potential applications like the realization of quantum optical random walks and microscopy with subwavelength spatial resolution.

Metabolic and Hemodynamic Determinants of Exercise with the HeartMate 3 LVAD

<h3>Purpose</h3> Several studies have reported that peak oxygen consumption (pVO2) is diminished after continuous flow (CF) LVAD support and recent data shows that pVO2 post LVAD predicts outcomes. It has been suggested that augmentation of native cardiac output (NCO) and not LVAD flow supports exercise. Using simultaneous metabolic and hemodynamic measures, we further studied the determinants of maximal exercise with the Heartmate 3 (HM3) LVAD. <h3>Methods</h3> Subjects underwent maximal upright bicycle exercise testing utilizing a 10-15 W ramp protocol with hemodynamic measurements from a right heart and radial arterial catheter, and CPET testing with a metabolic cart (Metalyzer 3B, Cortex, Germany). Mid-point hemodynamics were acquired to plot pressure/flow relationships. NCO was calculated by subtracting LVAD flow from Fick cardiac output (FCO). Arterial lactate and regional tissue oxygenation (rSO2) with the NIRS SenSmart™ were also measured. <h3>Results</h3> Six HM3 subjects (43-76 yrs) were studied at least 12 weeks post implant, all were on at least 2 neurohormonal agents. All patients performed maximal exercise (RER 1.10-1.34). Most did not demonstrate chronotropic incompetence; achieving median 80.8 (63.5- 90.9) % of predicted heart rate. We saw robust oxygen extraction, with median peak A-VO2 difference 14.2 (10.5-15.8) mL/100mL with no change in rSO2 and median peak lactate 6.5 (3.5-9.9) mmol/L. However, 5/6 subjects achieved pVO2 ≤14 ml/kg/min. During exercise, there was minimal augmentation of LVAD flow (0.4-1.6 L/min) while NCO increased by 2.0-7.1 L/min. Mean pulmonary artery (mPA)/FCO relationships were available for 5 subjects (Fig.1), demonstrating abnormal rate of rise of mPA in all patients (slope 3.7-7.0, normal < 3). <h3>Conclusion</h3> Neither chronotropic response nor peripheral extraction appeared to limit exercise. Steep rise in mPA suggests either impaired pulmonary vasoreactivity and or cardiac reserve may be the key determinants of exercise capacity during HM3 support. Further study will clarify these factors.

Pulsatile Pressure Delivery of Continuous Flow LVAD is Speed Dependent and Markedly Reduced Relative to Heart Failure Patients

<h3>Purpose</h3> Although continuous flow left ventricular assist devices (CF-LVADs) provide an augmentation in systemic perfusion, there is a scarcity of in-vivo data regarding systemic pulsatility on support. <h3>Methods</h3> A retrospective cohort study was performed in patients supported on CF-LVAD therapy (n=67) who underwent a combined left and right heart catheterization ramp protocol. Aortic pulsatility was defined by the pulsatile power index (PPI), a quantity derived from the amplitudes of the harmonics of the pressure waveform. PPI was calculated in a cohort of high-output heart failure (HOHF, n=66) and standard HF cohort (n=44) and invasive hemodynamics and pulsatility were compared. <h3>Results</h3> Systemic, pulmonary artery, and pulmonary capillary wedge pressures were lower in the LVAD cohort (<i>P</i>≤.04 for each) compared with HOHF or HF. PPI was drastically lower in CF-LVAD supported patients with median PPI .006 (IQR .002-.012) vs PPI .09 (IQR .06-.17) in HF and PPI .25 (IQR .13-.37) in HOHF (<i>P</i><.0001 among groups). PPI more significantly differed between groups than aortic pulse width. With speed augmentation during ramp, PPI values fell more quickly in centrifugal flow pumps than axial flow (slopes -3.3 × 10⁻⁵ and -1.1 × 10⁻⁵ vs -6.9 × 10⁻⁶ for HW, HM3, and HMII respectively). PPI correlated poorly with LV ejection fraction (LVEF) in CF-LVAD patients and HOHF (<i>P</i>>.05) and modestly (r=.38, <i>P</i>=.01) in HF but in CF-LVAD patients, there was a stronger correlation with LV dP/dt (r=.41, <i>P</i>=.002) than LVEF (r=.21, <i>P</i>=.09, <i>P_int</i> <.001). <h3>Conclusion</h3> CF-LVAD support is associated with a dramatic reduction in arterial pulsatility as measured by PPI relative to HOHF and HF cohorts and decreases with increasing speed. Further work is needed to determine the applicability to the next generation of device therapy.

Surface Electromyography Thresholds as a Measure for Performance Fatigability During Incremental Cycling in Patients With Neuromuscular Disorders.

In healthy persons, there is an excellent relation between the timing of the (two) surface electromyography (sEMG) thresholds and the (two) ventilatory thresholds during exercise. The primary aim of this study was to determine the relative timing of both sEMG and ventilatory thresholds in patients with neuromuscular disorders compared with healthy subjects during a maximal ergospirometry cycling test. We hypothesized that in patients with neuromuscular disorders, the sEMG thresholds would occur relatively earlier in time than the ventilatory thresholds, compared to healthy subjects, because performance fatigability occurs more rapidly. In total, 24 healthy controls and 32 patients with a neuromuscular disorder performed a cardiopulmonary exercise test on a bicycle using a 10-min ramp protocol, during which we collected ergospirometry data: power at both ventilatory and sEMG thresholds, and sEMG data of lower leg muscles. In line with our hypothesis, normalized values for all thresholds were lower for patients than healthy subjects. These differences were significant for the first ventilatory (p = 0.008) and sEMG threshold (p < 0.001) but not for the second sEMG (p = 0.053) and ventilatory threshold (p = 0.238). Most parameters for test–retest reliability of all thresholds did not show any fixed bias, except for the second ventilatory threshold. The feasibility of the sEMG thresholds was lower than the ventilatory thresholds, particularly of the first sEMG threshold. As expected, the sEMG thresholds, particularly the first threshold, occurred relatively earlier in time than the ventilatory thresholds in patients compared with healthy subjects. A possible explanation could be (a combination of) a difference in fiber type composition, disuse, and limited muscle-specific force in patients with neuromuscular disorders. sEMG measurements during submaximal dynamic exercises are needed to generalize the measurements to daily life activities for future use in prescribing and evaluating rehabilitation interventions.

Exercise Physiology Impairments of Patients With Amyotrophic Lateral Sclerosis: Cardiopulmonary Exercise Testing Findings.

Background and ObjectiveIn amyotrophic lateral sclerosis (ALS), progressive weakness significantly limits the ability to exercise. However, measurements of the impaired exercise function and their practical value to assess disease progression in ALS are scarce. Cardiopulmonary exercise testing (CPET) is a non-invasive accurate method used to comprehensively quantify exercise physiology in a variety of diseases. This study aimed to evaluate the clinical value of CPET and to explore its association with disease severity and prognosis prediction in ALS.MethodsA total of 319 participants were enrolled in this 3-year prospective study. After strict quality control, 109 patients with ALS and 150 age- and sex-matched healthy controls were included with comprehensive clinical assessment and follow-ups. The incremental ramp protocol for symptom-limited CPET was applied in both groups. The exercise physiology during peak effort exercise was systematically measured, including the overall aerobic capacity of exercise (VO2 peak) and the respective capacity of the exercise-involved organs [cardiac response (heart rate peak—HR peak), ventilatory efficiency (VE/VCO2 slope), breathing economy (VE/VO2 peak), and other relevant parameters]. Disease severity and progression were evaluated using recognized scales. Survival was monitored with regular follow-ups every 6 months.ResultsDecreased exercise capacity (VO2 peak < 16 ml/kg/min) occurred more frequently in patients with ALS than in controls (44.95% vs. 9.33%, p < 0.01). In patients with ALS, the average VO2 peak (16.16 ± 5.43 ml/kg/min) and HR peak [135 (112–153) bpm] were significantly lower (p < 0.01) than in controls [22.26 ± 7.09 ml/kg/min; 148 (135–164) bpm], but the VE/VCO2 slope was significantly higher [28.05 (25.03–32.16) vs. 26.72 (24.37–29.58); p = 0.03]. In patients with ALS, the VO2 peak and HR peak were significantly correlated with disease severity and progression scores (p < 0.05). Survival analyses revealed the VO2 peak and HR peak as protective indicators while the VE/VO2 peak as a detrimental indicator for the prognostic prediction in ALS (HR = 0.839, p = 0.001; HR = 0.967, p < 0.001; HR = 1.137, p = 0.028, respectively).ConclusionOur prospective study quantified the significantly decreased exercise capacity in ALS through non-invasive CPET. The impaired VO2 peak and HR peak closely correlated with disease severity and independently predicted a worse prognosis. Our findings identified the clinical value of CPET as an objective indicator of disease progression in ALS.

Left Ventricular Hemodynamics and Relationship With Myocardial Recovery and Optimization in Patients Supported on CF-LVAD Therapy

BackgroundDespite interest in left ventricular (LV) recovery, there is an absence of data on the relationship between intrinsic LV hemodynamics and both reverse remodeling on a continuous flow LV assist device (CF-LVAD) therapy. We hypothesized that the markers of intrinsic LV function would be associated with remodeling, optimization, and outcomes. Methods and ResultsPatients with continuous flow LVADs between 2015 and 2019 who underwent combined left and right heart catheterization ramp protocol at a single institution were enrolled. Patients were stratified by response to continuous flow LV assist device therapy: full responders, partial responders, or nonresponders per the Utah–Inova criteria. Hemodynamic data, including LV hemodynamics of peak LV dP/dt and tau (τ) were obtained at each phase. The 1-year heart failure hospitalization-free survival was the primary end point. Among 61 patients included in the current study 38 (62%) were classified as nonresponders, 14 as partial responders (23%), and 9 as full responders (15%). The baseline LV dP/dt and τ varied by response status (P ≤ .02) and generally correlated with reverse remodeling on linear regression. Biventricular filling pressures varied with τ and there was an interaction effect of speed on the relationship between τ and pulmonary capillary wedge pressure (P = .04). Last, τ was a prognostic marker and associated with 1-year HF hospital-free survival (odds ratio 1.04, 95% confidence interval 1.00–1.07, P = .02 per millisecond increase). ConclusionsSignificant correlations between τ and LV dP/dt and reverse remodeling were noted, with τ serving as a prognostic marker. A higher LVAD speed was associated with a greater reliance on LVAD for unloading. Future work should focus on defining the optimal level of LVAD support in relation to LV recovery.

Real-Time Monitoring of Metabolism during Exercise by Exhaled Breath.

Continuous monitoring of metabolites in exhaled breath has recently been introduced as an advanced method to allow non-invasive real-time monitoring of metabolite shifts during rest and acute exercise bouts. The purpose of this study was to continuously measure metabolites in exhaled breath samples during a graded cycle ergometry cardiopulmonary exercise test (CPET), using secondary electrospray high resolution mass spectrometry (SESI-HRMS). We also sought to advance the research area of exercise metabolomics by comparing metabolite shifts in exhaled breath samples with recently published data on plasma metabolite shifts during CPET. We measured exhaled metabolites using SESI-HRMS during spiroergometry (ramp protocol) on a bicycle ergometer. Real-time monitoring through gas analysis enabled us to collect high-resolution data on metabolite shifts from rest to voluntary exhaustion. Thirteen subjects participated in this study (7 female). Median age was 30 years and median peak oxygen uptake (VO2max) was 50 mL·/min/kg. Significant changes in metabolites (n = 33) from several metabolic pathways occurred during the incremental exercise bout. Decreases in exhaled breath metabolites were measured in glyoxylate and dicarboxylate, tricarboxylic acid cycle (TCA), and tryptophan metabolic pathways during graded exercise. This exploratory study showed that selected metabolite shifts could be monitored continuously and non-invasively through exhaled breath, using SESI-HRMS. Future studies should focus on the best types of metabolites to monitor from exhaled breath during exercise and related sources and underlying mechanisms.

Arthroscopic single anchor repair techniques for upper third subscapularis tears provide sufficient biomechanical stability.

Upper third tears of the subscapularis tendon can be repaired successfully with a single anchor according to previous literature. The aim of the present study was to compare three single anchor repair techniques regarding fixation strength, footprint coverage and contact pressure in a biomechanical test set-up on human cadaveric shoulders. Eighteen human cadaveric shoulders were randomized in three groups with respect to the repair technique; group 1: knotted lasso-loop mattress, group 2: knotted mattress and group 3: knotless tape repair. Upper third tears of the subscapularis tendon (Lafosse type 2) were created and repairs were performed with additional contact pressure and area measurement using a pressure mapping system. Cyclic testing was performed by loading the subscapularis from 10 to 100N for 300 cycles. A position-controlled ramp protocol up to 30 and 50N was used to allow for pressure measurements. Finally, specimens were loaded to failure and failure modes were recorded. The three groups were not significantly different regarding age, gender, bone mineral density at the lesser tuberosity, subscapularis footprint size and defect area created at the upper subscapularis insertion. A significant difference was detected between group 1 (48.6 ± 13.8%) and group 2 (25.9 ± 5.7%) regarding pressurized footprint coverage (p = 0.028). Ultimate load to failure was 630.8 ± 145.3N in group 1, 586.9 ± 220.7N in group 2 and 678.2 ± 236.5N in group 3, respectively. Cyclic displacement was similar in all three groups with an average displacement of 1.2 ± 0.6mm. The highest stiffness was found in group 1 with 88 ± 30.3, which was not statistically significantly different to group 2 (65 ± 27N/mm) and group 3 (83.9 ± 32.9N/mm). The most common mode of failure was suture cut-through at the suture-tendon interface (44%). Failures in group 3 were less common associated with suture cut-through (33% vs. 50% in group 1 and 2), but no significant differences were found. All three tested single anchor repair techniques of upper third subscapularis tears were able to provide sufficient biomechanical stability. Knotted lasso-loop mattress and knotless tape repair were superior regarding pressurized footprint coverage compared to a knotted horizontal mattress technique and are, therefore, preferable techniques for upper subscapularis repair.

Comparison of the Ramp and Step Incremental Exercise Test Protocols in Assessing the Maximal Fat Oxidation Rate in Youth Cyclists.

The incremental exercise test is the most common method in assessing the maximal fat oxidation (MFO) rate. The main aim of the study was to determine whether the progressive linear RAMP test can be used to assess the maximal fat oxidation rate along with the intensities that trigger its maximal (FATmax) and its minimal (FATmin) values. Our study comprised 57 young road cyclists who were tested in random order. Each of them was submitted to two incremental exercise tests on an electro-magnetically braked cycle-ergometer - STEP (50 W·3 min-1) and RAMP (~0.278 W·s-1) at a 7-day interval. A stoichiometric equation was used to calculate the fat oxidation rate, while the metabolic thresholds were defined by analyzing ventilation gases. The Student’s T-test, Bland-Altman plots and Pearson’s linear correlations were resorted to in the process of statistical analysis. No statistically significant MFO variances occurred between the tests (p = 0.12) and its rate amounted to 0.57 ± 0.15 g·min-1 and 0.53 ± 0.17 g·min-1 in the STEP and RAMP, respectively. No statistically significant variances in the absolute and relative (to maximal) values of oxygen uptake and heart rate were discerned at the FATmax and FATmin intensities. The RAMP test displayed very strong oxygen uptake correlations between the aerobic threshold and FATmax (r = 0.93, R2 = 0.87, p < 0.001) as well as the anaerobic threshold and FATmin (r = 0.88, R2 = 0.78, p < 0.001). Our results corroborate our hypothesis that the incremental RAMP test as well as the STEP test are reliable tools in assessing MFO, FATmax and FATmin intensities.

Fast-slow analysis as a technique for understanding the neuronal response to current ramps.

The standard protocol for studying the spiking properties of single neurons is the application of current steps while monitoring the voltage response. Although this is informative, the jump in applied current is artificial. A more physiological input is where the applied current is ramped up, reflecting chemosensory input. Unsurprisingly, neurons can respond differently to the two protocols, since ion channel activation and inactivation are affected differently. Understanding the effects of current ramps, and changes in their slopes, is facilitated by mathematical models. However, techniques for analyzing current ramps are under-developed. In this article, we demonstrate how current ramps can be analyzed in single neuron models. The primary issue is the presence of gating variables that activate on slow time scales and are therefore far from equilibrium throughout the ramp. The use of an appropriate fast-slow analysis technique allows one to fully understand the neural response to ramps of different slopes. This study is motivated by data from olfactory bulb dopamine neurons, where both fast ramp (tens of milliseconds) and slow ramp (tens of seconds) protocols are used to understand the spiking profiles of the cells. The slow ramps generate experimental bifurcation diagrams with the applied current as a bifurcation parameter, thereby establishing asymptotic spiking activity patterns. The faster ramps elicit purely transient behavior that is of relevance to most physiological inputs, which are short in duration. The two protocols together provide a broader understanding of the neuron's spiking profile and the role that slowly activating ion channels can play.

Functional capacity and gender-related differences in Fabry disease

Abstract Background Fabry disease (FD) is a rare x-linked lysosomal storage disease characterized by accumulation of glicosphingolipids in several organs, including the heart. Cardiac involvement manifests as left ventricular (LV) hypertrophy, often complicated by myocardial fibrosis. The impact of disease on functional capacity is not well defined, as well as the potential gender-related differences. Aim To evaluate the functional capacity in a cohort of FD patients with different degree of cardiac involvement. Methods Seventy-two patients were prospectively enrolled from March 2015 to December 2019. Patients underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) with cycle ergometer. In addition to standard CPET parameters, Chronotropic Index (CI) was calculated as (HR max − HR rest) / (HR max predicted − HR rest), adjusting with HR max predicted calculated as 119 + (HR rest/2) − (age/2) in case of beta-blockers treatment. Results CMR showed left ventricle (LV) hypertrophy (LV mass greater than normal reference value) in 36.1% of patients, LGE and reduced T1 values were detected in 30.6% and 59.7% of subjects respectively. Twenty-eight patients were males (39%), the median age was 40 (28–54) [median (25th–75th)] years and only 11 (15%) subjects were on beta-blockers. All subjects performed a maximal test [RQ max = 1.21 (1.14–1.26)] using a ramp protocol of 15 (15–20) Watt. The absolute peakVO2 was 18.2 (15.75–24.08) mL/min/kg, whilst the percentage of predicted peakVO2 was 67.7 (57.3–76.6)%. The chronotropic response of the overall population was characterized by reduced peak heart rate (HRmax) [80.3 (73.8–87.6)% of predicted], and diminished chronotropic index (CI) [0.67 (0.55–0.77) normal value: 0.80], but preserved heart rate reserve (HRR) [21 (12–28) bpm]. Ventilatory efficiency was preserved [VE/VCO2 = 25.70 (23.18–28.00)]. At gender analysis, men showed higher absolute peakVO2 [men vs females: 19.95 (17.20–28.28) vs 17.80 (15.50–21.28) mL/min/kg, p=0.02] but lower percentage of predicted [64.24 (52.58–70.61) vs 70.75 (59.05–78.02)%, p&amp;lt;0.001] than females. No differences between genders were observed in chronotropic response [HRmax = 138 (108–154) vs 142 (135–153) bpm, p=0.38; HRR = 22 (13–36) vs 20 (11–26), p=0.097; CI: 0.67 (0.51–0.76) vs 0.67 (0.58–0.79), p=0.33], whilst females showed a lower peak O2 pulse (VO2/HR) than males [men vs females: 12.08 (10.04–13.64) vs 7.76 (6.88–9.22), p&amp;lt;0.001], possibly related to gender differences in LV dimensions and stroke volume. Conclusions This large cohort of FD patients with different degree of cardiac involvement showed a significantly impaired functional capacity, mainly characterized by relevant chronotropic incompetence (independent from the use of beta-blockers), consistent with systemic autonomic dysfunction. The degree of chronotropic incompetence was similar between the genders, but females showed higher predicted peakVO2 despite a lower peak O2 pulse. Funding Acknowledgement Type of funding sources: None.