Erik H. Van Iterson

Physiological dead space and arterial carbon dioxide contributions to exercise ventilatory inefficiency in patients with reduced or preserved ejection fraction heart failure

Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. The physiological correlates of the V̇E/V̇CO2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (VD/VT) and arterial CO2 tension (PaCO2) differentially contribute to the V̇E/V̇CO2 slope in HFrEF vs. HFpEF.

Impaired cardiac and peripheral hemodynamic responses to inhaled β 2 -agonist in cystic fibrosis

BackgroundPulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional β2-adrenergic receptors (β2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, β2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled β-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective β2AR agonist albuterol in individuals with CF.Methods18 CF and 30 control (CTL) subjects participated (ages 22 ± 2 versus 27 ± 2 and BSA = 1.7 ± 0.1 versus 1.8 ± 0.0 m2, both p < 0.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAP = DBP + 1/3(SBP–DBP); systemic vascular resistance (SVR) = (MAP/Q)•80; CP = Q•MAP; stroke work (SW) = SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI).ResultsAt baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (p < 0.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (p < 0.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (p < 0.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (p < 0.05).ConclusionsCardiac and peripheral hemodynamic responsiveness to acute β2AR stimulation via albuterol is attenuated in individuals with CF, suggesting β2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

Comparisons of Noninvasive Methods Used to Assess Exercise Stroke Volume in Heart Failure with Preserved Ejection Fraction

Introduction Cardiopulmonary exercise testing (CPET) plays an important role in properly phenotyping signs and symptoms of heart failure with preserved ejection fraction (HFpEF). The prognostic value of CPET is strengthened when accompanied by cardiac hemodynamic measurements. Although recognized as the “gold” standard, cardiac catheterization is impractical for routine CPET. Thus, advancing the scientific/methodologic understanding of noninvasive techniques for exercise cardiac hemodynamic assessment is clinically impactful in HFpEF. This study tested the concurrent validity of noninvasive acetylene gas (C2H2) uptake, echocardiography (ECHO), and oxygen pulse (O2pulse) for measuring/predicting exercise stroke volume (SV) in HFpEF. Methods Eighteen white HFpEF and 18 age-/sex-matched healthy controls participated in upright CPET (ages, 69 ± 9 yr vs 63 ± 9 yr). At rest, 20 W, and peak exercise, SV was measured at steady-state via C2H2 rebreathe (SVACET) and ECHO (SVECHO), whereas O2pulse was derived (=V˙O2/HR). Results Resting relationships between SVACET and SVECHO, SVECHO and O2pulse, or SVACET and O2pulse were significant in HFpEF (R2 = 0.30, 0.36, 0.67), but not controls (R2 = 0.07, 0.01, 0.09), respectively. Resting relationships persisted to 20 W in HFpEF (R2 = 0.70, 0.53, 0.70) and controls (R2 = 0.05, 0.07, 0.21), respectively. Peak exercise relationships were significant in HFpEF (R2 = 0.62, 0.24, 0.64), but only for SVACET versus O2pulse in controls (R2 = 0.07, 0.04, 0.33), respectively. Standardized standard error of estimate between techniques was strongest in HFpEF at 20 W: SVACET versus SVECHO = 0.57 ± 0.22; SVECHO versus O2pulse = 0.71 ± 0.28; SVACET versus O2pulse = 0.56 ± 0.22. Conclusions Constituting a clinically impactful step towards construct validation testing, these data suggest SVACET, SVECHO, and O2pulse demonstrate moderate-to-strong concurrent validity for measuring/predicting exercise SV in HFpEF.

V̇O2 Kinetics Associated with Moderate Intensity Exercise in Heart Failure: Impact of Intrathecal Fentanyl Inhibition of Group III/IV Locomotor Muscle Afferents

Heart failure (HF) patients demonstrate impaired pulmonary, circulatory, and nervous system responses to exercise. While HF demonstrates prolonged [time constant (τ)] pulmonary O2 uptake (V̇o2) on-kinetics, contributing to exercise intolerance, it is unknown whether abnormal V̇o2 kinetics couple with ventilatory and circulatory dysfunction secondary to impaired group III/IV afferents in HF. Because lower lumbar intrathecal fentanyl inhibits locomotor muscle afferents, resulting in improved exercise ventilation and hemodynamics, we tested these hypotheses: HF will demonstrate 1) rapid V̇o2 on-kinetics and 2) attenuated steady-state V̇o2 amplitude and O2 deficit (O2def) during exercise with fentanyl versus placebo. On separate visits (randomized), breath-by-breath V̇o2 was measured in HF (ejection fraction: 27 ± 6%, New York Heart Association class I-III) and age- and sex-matched controls (both n = 9, ages: 60 ± 6 vs. 63 ± 8 yr, P = 0.37) during cycling transitions at 65% peak workload (78 ± 24 vs. 115 ± 39 W, P < 0.01) with intrathecal fentanyl or placebo. Regardless of group or condition, optimal phase II (primary component) curve fits reflected a phase I period equal to 35 s (limb-to-lung timing) via single-exponential functions. Condition did not affect steady-state V̇o2, the phase II τ of V̇o2, or O2def within controls (P > 0.05). Without differences in steady-state V̇o2, reduced O2def in fentanyl versus placebo within HF (13 ± 4 vs. 22 ± 15 ml/W, P = 0.04) was accounted for by a rapid phase II τ of V̇o2 in fentanyl versus placebo within HF (45 ± 11 vs. 57 ± 14 s, P = 0.04), respectively. In an integrative manner, these data demonstrate important effects of abnormal locomotor muscle afferents coupled to pulmonary and circulatory dysfunction in determining impaired exercise V̇o2 in HF. Effects of abnormal muscle afferents on impaired exercise V̇o2 and hence exercise intolerance may not be discernable by independently assessing steady-state V̇o2 in HF.NEW & NOTEWORTHY Inhibition of locomotor muscle afferents results in rapid primary-component O2 uptake (V̇o2) on-kinetics accounting for the decreased O2 deficit in heart failure (HF). This study revealed that abnormal musculoskeletal-neural afferents couple with pulmonary and circulatory dysfunction to provoke impaired exercise V̇o2 in HF. Steady-state V̇o2 cannot properly phenotype abnormal muscle afferent contributions to impaired exercise V̇o2 in HF.

Reliability of Triaxial Accelerometry for Measuring Load in Men's Collegiate Ice-Hockey.

Abstract Van Iterson, EH, Fitzgerald, JS, Dietz, CC, Snyder, EM, and Peterson, BJ. Reliability of triaxial accelerometry for measuring load in mens collegiate ice hockey. J Strength Cond Res 31(5): 1305–1312, 2017—Wearable microsensor technology incorporating triaxial accelerometry is used to quantify an index of mechanical stress associated with sport-specific movements termed PlayerLoad. The test-retest reliability of PlayerLoad in the environmental setting of ice hockey is unknown. The primary aim of this study was to quantify the test-retest reliability of PlayerLoad in ice hockey players during performance of tasks simulating game conditions. Division I collegiate male ice hockey players (N = 8) wore Catapult Optimeye S5 monitors during repeat performance of 9 ice hockey tasks simulating game conditions. Ordered ice hockey tasks during repeated bouts included acceleration (forward or backward), 60% top-speed, top-speed (forward or backward), repeated shift circuit, ice coasting, slap shot, and bench sitting. Coefficient of variation (CV), intraclass correlation coefficient (ICC), and minimum difference (MD) were used to assess PlayerLoad reliability. Test-retest CVs and ICCs of PlayerLoad were as follows: 8.6% and 0.54 for forward acceleration, 13.8% and 0.78 for backward acceleration, 2.2% and 0.96 for 60% top-speed, 7.5% and 0.79 for forward top-speed, 2.8% and 0.96 for backward top-speed, 26.6% and 0.95 for repeated shift test, 3.9% and 0.68 for slap shot, 3.7% and 0.98 for coasting, and 4.1% and 0.98 for bench sitting, respectively. Raw differences between bouts were not significant for ice hockey tasks (p > 0.05). For each task, between-bout raw differences were lower vs. MD: 0.06 vs. 0.35 (forward acceleration), 0.07 vs. 0.36 (backward acceleration), 0.00 vs. 0.06 (60% top-speed), 0.03 vs. 0.20 (forward top-speed), 0.02 vs. 0.09 (backward top-speed), 0.18 vs. 0.64 (repeated shift test), 0.02 vs. 0.10 (slap shot), 0.00 vs. 0.10 (coasting), and 0.01 vs. 0.11 (bench sitting), respectively. These data suggest that PlayerLoad demonstrates moderate-to-large test-retest reliability in the environmental setting of male Division I collegiate ice hockey. Without previously testing reliability, these data are important as PlayerLoad is routinely quantified in male collegiate ice hockey to assess on ice physical activity.

The Influence of 17 Hours of Normobaric Hypoxia on Parallel Adjustments in Exhaled Nitric Oxide and Airway Function in Lowland Healthy Adults

Van Iterson, Erik H., Eric M. Snyder, and Bruce D. Johnson. The influence of 17 hours of normobaric hypoxia on parallel adjustments in exhaled nitric oxide and airway function in lowland healthy adults. High Alt Med Biol. 18:1-10, 2017.-Currently, there is a disparate understanding of the role that normobaric hypoxia plays in affecting nitric oxide (NO) measured in exhaled air (eNO) and airway function in lowland healthy adults. Compared to normobaric normoxia, this study aimed to test the effect of 17 hours of normobaric hypoxia on relationships between eNO and airway function in healthy adults. In a crossover study including 2 separate visits, 26 lowland healthy Caucasian adults performed eNO and pulmonary function tests on visit 1 in normobaric normoxia, while repeating all tests on visit 2 following 17 hours of normobaric hypoxia (12.5% O2). Compared to normobaric normoxia, eNO (29 ± 24 vs. 36 ± 28 ppb), forced expiratory volume in one second (FEV1) (4.1 ± 0.7 vs. 4.3 ± 0.8 L), mean forced expiratory flow between 25% and 75% FVC (FEF25-75) (3.9 ± 1.0 vs. 4.2 ± 1.2 L/s), and forced expiratory flow at 75% FVC (FEF75) (2.0 ± 0.7 vs. 2.3 ± 0.8 L/s) increased in normobaric hypoxia, respectively (all p < 0.05). Correlations at normoxia between eNO and FEV1 (r = 0.39 vs. 0.44), FEF25-75 (r = 0.51 vs. 0.51), and FEF75 (r = 0.53 vs. 0.55) persisted as both parameters increased in hypoxia, respectively. For the first time, these data suggest that 17 hours of hypoxic breathing in the absence of low ambient pressure contribute to increased eNO and airway function in lowland healthy adults.

Therapeutic Targets for the Multi-system Pathophysiology of Heart Failure: Exercise Training

Opinion statementAdult chronic heart failure (HF) is a terminal syndrome. While the HF phenotype is inhomogeneous across the ejection fraction spectrum, exercise intolerance remains a cardinal feature of all HF patients. Impairment of a single organ system cannot independently account for exercise intolerance in HF. Thus, the multi-system integrative pathophysiology of HF leads to challenges in identifying an effective medical therapy aimed at targeting a single mechanism to improve exercise tolerance. This unresolved medical care approach raises a number of points for discussion in this field as it is well-recognized that exercise intolerance is accompanied by increased hospitalizations and mortality across the HF spectrum. Practitioner-guided individualized exercise training represents an intrinsic multi-level therapeutic approach that inclusively “targets” integrated physiological systems. A rapidly evolving body of evidence provides firm support that structured exercise therapy is safe while leading to improved exercise tolerance (peak oxygen uptake [V̇O2]) followed by reduced hospitalizations and cardiovascular mortality across the HF spectrum. The benefits of guided exercise therapy in HF have been directly attributed to integrative improvements in peak V̇O2, skeletal muscle strength, cardiac function, micro- to macro-vascular function, circulation/organ perfusion, and nervous system function, among others. Despite the sound clinical evidence in support of exercise-based medical care, there remains an appreciable gap in translation of current scientific evidence and implementation of this therapeutic paradigm into routine clinical practice as well as universal insurance coverage for HF patients. In the following review, the theme of discussion is framed in a manner that carries a sense of urgency for the need to increase awareness of the up-to-date evidence-based support for the clinical implementation of structured exercise therapy as a necessary routine component of primary medical care practices for reducing hospitalizations, morbidity, and mortality in all HF patients.

Influence of the Metaboreflex on Pulmonary Vascular Capacitance in Heart Failure

PURPOSE An impaired metaboreflex is associated with abnormal ventilatory and peripheral vascular function in heart failure (HF), whereas its influence on cardiac function or pulmonary vascular pressure remains unclear. We aimed to assess whether metabolite-sensitive neural feedback (metaboreflex) from locomotor muscles via postexercise regional circulatory occlusion (RCO) attenuates pulmonary vascular capacitance (GXCAP) and/or circulatory power (CircP) in patients with HF. METHODS Eleven patients with HF (NYHA class, I/II; ages, 51 ± 15 yr; ejection fraction, 32% ± 9%) and 11 age- and gender-matched controls (ages, 43 ± 9 yr) completed three cycling sessions (4 min, 60% peak oxygen uptake (V˙O2)). Session 1 was a control trial including normal recovery (NR). Session 2 or 3 included bilateral upper thigh pressure tourniquets inflated suprasystolic at end of exercise (RCO) for 2-min recovery with or without inspired CO2 (RCO + CO2) (randomized). Mean arterial pressure, HR, and V˙O2 were continuously measured. Estimates of central hemodynamics; CircP = (V˙O2 × mean arterial pressure)/weight; oxygen pulse index (O2pulseI = (V˙O2/HR)/body surface area); and GXCAP = O2pulseI × end-tidal partial pressure CO2 were calculated. RESULTS At rest and end of exercise, CircP and GXCAP were lower in HF versus those in controls (P < 0.05), with no differences between transients (P > 0.05). At 2-min recovery, GXCAP was lower during RCO versus that during NR in both groups (72 ± 23 vs 98 ± 20 and 73 ± 34 vs 114 ± 35 mL·beat·mm Hg·m, respectively; P < 0.05), whereas CircP did not differ between transients (P > 0.05). Differences (% and Δ) between baseline and 2-min recovery among transients suggest that metaboreflex attenuates GXCAP in HF. Differences (% and Δ) between baseline and 2-min recovery among transients suggest that metaboreflex may attenuate CircP in controls. CONCLUSIONS The present observations suggest that locomotor muscle metaboreflex activation may influence CircP in controls but not in HF. However, metaboreflex activation may evoke decreases in GXCAP (increased pulmonary vascular pressures) in HF and controls.

Alveolar air and oxidative metabolic demand during exercise in healthy adults: the role of single‐nucleotide polymorphisms of the β2AR gene

The predominating β‐adrenergic receptor subtype expressed on human alveolar tissue is the β2AR. The homozygous arginine (Arg16Arg) single‐nucleotide polymorphism (SNP) at codon 16 of the β2AR gene has been associated with abnormal β2AR function accompanied by decreased resting alveolar‐capillary membrane gas‐transfer in certain healthy adults. Although not previously studied in the context of the β2AR gene, pulmonary gas‐transfer is also influenced by alveolar volume (VA) and with it the availability of alveolar surface area, particularly during exercise. Small VA implies less alveolar surface area available for O2 transport. We tested the following hypothesis in healthy adults during exercise: compared with Gly16Gly and Arg16Gly β2AR genotypes, Arg16Arg will demonstrate reduced VA and ventilation (V̇A) relative to V̇E and oxidative metabolic demand. Age‐ BMI‐ and gender‐matched groups of Arg16Arg (N = 16), Gly16Gly (N = 31), and Arg16Gly (N = 17) performed consecutive low (9‐min, 40%‐peak workload) and moderate (9‐min, 75%‐peak workload) intensity exercise. We derived VA and V̇A using “ideal” alveolar equations via arterialized gases combined with breath‐by‐breath ventilation and gas‐exchange measurements; whereas steady‐state V̇O2 was used in metabolic equations to derive exercise economy (EC = workload÷V̇O2). Variables at rest did not differ across β2AR genotype. Strongest β2AR genotype effects occurred during moderate exercise. Accordingly, while V̇E did not differ across genotype (P > 0.05), decreased in Arg16Arg versus Arg16Gly and Gly16Gly were V̇O2 (1110 ± 263, 1269 ± 221, 1300 ± 319 mL/(min·m2), respectively, both P < 0.05), V̇A (59 ± 21, 70 ± 16, 70 ± 21 L/min, respectively, both P < 0.05), and VA (1.43 ± 0.37, 1.95 ± 0.61, 1.93 ± 0.65 L, respectively, both P < 0.05). Also reduced was EC in Arg16Arg versus Arg16Gly (P < 0.05) and Gly16Gly (P > 0.05) (1.81 ± 0.23, 1.99 ± 0.30, and 1.94 ± 0.26 kcal/(L·m2), respectively). Compared with Gly16Gly and Arg16Gly genotypes, these data suggest the Arg16Arg β2AR genotype plays a role in the loss of oxidative metabolic efficiency coupled with an inadaptive VA and, hence, smaller alveolar surface area available for O2 transport during submaximal exercise in healthy adults.

Streamlining cardiopulmonary exercise testing for use as a screening and tracking tool in primary care

Cardiopulmonary exercise testing (CPET) using a spectrum of different approaches demonstrates usefulness for objectively assessing patient disease severity in clinical and research settings. Still, an absence of trained specialists and/or improper data interpretation techniques can pose major limitations to the effective use of CPET for the clinical classification of patients. This study aimed to test an automated disease likelihood scoring algorithm system based on cardiopulmonary responses during a simplified step-test protocol. For patients with heart failure (HF), pulmonary hypertension (PAH), obstructive lung disease (OLD), or restrictive lung disease (RLD), we compared patient scores stratified into one of four “silos” generated from our novel algorithm system against patient evaluations provided by expert clinicians. Patients with HF (n = 12), PAH (n = 9), OLD (n = 16), or RLD (n = 10) performed baseline pulmonary function testing followed by submaximal step-testing. Breath-by-breath measures of ventilation and gas exchange, in addition to oxygen saturation and heart rate were collected continuously throughout testing. The algorithm demonstrated close alignment with patient assessments provided by clinical specialists: HF (r = 0.89, P < 0.01); PAH (r = 0.88, P < 0.01); OLD (r = 0.70, P < 0.01); and RLD (r = 0.88, P < 0.01). Furthermore, the algorithm was capable of differentiating major disease from other disease pathologies. Thus, in a clinically relevant manner, these data suggest this simplified automated disease algorithm scoring system used during step-testing to identify the likelihood that patients have HF, PAH, OLD, or RLD closely correlates with patient assessments conducted by trained clinicians.