Olson, Thomas P.

Introduction Although used as an experimental approach to stimulate group III/IV afferents by causing venous congestion, locomotor subsystolic regional circulatory occlusion (SubRCO) during exercise may lead to accelerated local metabolic acidosis, whilst complicating the interpretation of cardiovascular reflexes using this technique. Moreover, compared to low pedal rate, greater type II fiber recruitment is expected during high pedal rate cycling. Thus, inordinate changes in muscle blood flow and muscle oxygen requirements provoked by augmented energy demands should elicit delayed or absent steady‐state oxygen uptake (VO 2 ), which would not be adequately described using a single‐component exponential on‐transient VO 2 kinetics model. This study aimed to test the hypothesis that increased pedal rate combined with SubRCO during low intensity hyperbolic exercise would shift the exponential fit of on‐transient VO 2 kinetics from a single to a two‐component model. Methods Healthy adults (N = 15, 53% male; age 36 ± 17 years; BMI 24 ± 4 kg/m 2 ) completed 2 study visits of 3 identical sessions of fixed‐load (20W) ergometry at fixed pedal rates of 35 or 100 rpm (randomized). Sessions began with 5 min of rest, followed by 3 min of exercise without SubRCO, and immediately transitioning to a 5 min period of exercise+SubRCO at 90 mm Hg bilateral‐thigh cuff inflation pressure. A metabolic system integrated with gas mass‐spectrometry was used to measure breath‐by‐breath VO 2 . Data were linearly interpolated to 1 sec intervals and ensemble averaged across 3 sessions/day for each participant prior to modeling. All models excluded the cardiodynamic phase. Exponential models were: single‐component, VO 2REST + A [1 − e −(t−TD)/τ ]; two‐component, VO 2REST + A [1 − e −(t−TD)/τ ] + A 2 [1 − e − (t−TD2)/τ2 ]; where τ = time‐constant; A = asymptote; TD = time delay. Results Best‐fit residuals for single vs. two‐component models did not differ within either 35 rpm (0.031 ± 0.009 vs 0.028 ± 0.007, P = 0.15) or 100 rpm (0.052 ± 0.013 vs 0.050 ± 0.013, P = 0.48) sessions, respectively; suggesting SubRCO does not influence on‐transient VO 2 kinetics. Thus, 35 rpm single‐component parameters were: τ = 48 ± 24 sec, A = 0.32 ± 0.04 L/min, and TD = 12 ± 10 sec, which differed significantly vs 100 rpm single‐component parameters: τ = 25 ± 20 sec, A = 0.87 ± 0.12 L/min, and TD = 1 ± 9 sec (all P<0.05), suggesting an independent effect of pedal rate on on‐transient VO 2 kinetics. Conclusions These data do not support our hypothesis, whilst suggesting that the oxygen requirement during hyperbolic exercise for a transition from low‐intensity ergometry without SubRCO to a longer period with SubRCO is not exaggerated to appreciably evoke a phase III on‐transient VO 2 kinetic response in healthy adults. Therefore, if on‐transient VO 2 kinetics mirror muscle oxygen utilization patterns at steady‐state moderate exercise, these data suggest locomotor SubRCO during moderate exercise does not exacerbate local metabolic acidosis in healthy adults. Support or Funding Information NHLBI R01 HL126638; AHA 16POST30260021

Introduction A disproportionate increase in ventilation relative to carbon dioxide output (V E /VCO 2 ) slope is a strong prognostic indicator in heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) patients. Similarly, secondary pulmonary hypertension also poses a profound mortality risk in these patients. Exaggerated ventilation and pulmonary pressures appear to parallel one another during exercise in HF. However, an underlying pathophysiologic mechanism relating these two outcomes remains incompletely understood. Thus, the aim of this study was to determine associations between anatomical and physiologic metrics of ventilatory control and pulmonary pressures during exercise in HFrEF and HFpEF. Methods 32 HFpEF and 33 HFrEF (EF: 62±2 vs 22±1%; male: 17 and 31; age: 70±2 and 55±2 yrs; BMI: 34±1 and 28±1 kg/m 2 ; weight: 98±4 and 86±3 (all P <0.05), respectively, participated in cardiopulmonary exercise testing during right heart catheterization. Measures of pulmonary pressures included: systolic (PASP); diastolic (PADP); mean (mPAP); wedge (PCWP); pulse (PP); transpulmonary gradient (TPG). Partial pressure of arterial oxygen (PaO 2 ) and carbon dioxide (PaCO 2 ) were measured via radial arterial catheterization. Ventilation was measured continuously using a breath by breath metabolic measurement system. We calculated dead space to tidal volume [Vd/Vt=(V E ×PaCO 2 )‐(863×VCO 2 )/(V E ×PaCO 2 )] and Alveolar‐arterial oxygen gradient (A‐a)=PAO 2 ‐PaO 2 ; V E /VCO 2 slope=rest to peak exercise. Results At rest, pulmonary pressures did not differ between groups ( P >0.05); whereas Vd/Vt was lower in HFpEF vs HFrEF (0.42±0.02 vs 0.48±0.01, respectively, P =0.03). At peak exercise, HFpEF had higher PCWP (34.8±1.2 vs 30.2±1.5 mm Hg, P =0.02) and PADP (35.4±1.3 vs 29.8±1.6 mm Hg, P =0.02), but lower Vd/Vt (0.32±0.02 vs 0.38±0.01, P =0.03) and V E /VCO 2 slope (35.3±1.6 vs 43.5±2.0, P <0.01) vs HFrEF. At peak in HFpEF, Vd/Vt was related to PASP (r=0.40, P =0.03), PP (r=0.44, P =0.01), and TPG (r=0.53, P <0.01), and A‐a was related to PASP (r=0.43, P =0.01), PP (r=0.44, P =0.01), and TPG (r=0.46, P <0.01). At peak in HFrEF, Vd/Vt was related to PADP (r=0.41, P =0.02), and A‐a was related to PASP (r=0.43, P <0.01), PADP (r=0.42, P =0.01), and mPAP (r=0.44, P <0.01). There were no significant relationships between measures of pulmonary pressures and PaCO 2 . Remaining correlations between pulmonary pressures and anatomical or physiologic metrics of ventilatory control were negligible in both groups ( P >0.05). Conclusion These data suggest pulmonary pressures play a role in dead space ventilation during exercise in HF. Moreover, as suggested by the A‐a gradient, augmented pulmonary pressures may contribute to an exacerbation of ventilation/perfusion mismatch during exercise in both HFrEF and HFpEF patients. Support or Funding Information None

Background Neurophysiological coupling between ventilation and locomotor muscle group III/IV muscle afferent fibers during exercise is an important relationship that favorably influences ventilation in young healthy adults. In contrast, we have shown that group III/IV locomotor muscle afferents provoke aberrant ventilation in aging heart failure patients, which is suggested to be a primary effect of heart failure. However, there remains a limited understanding of the effect of aging in the absence of cardiovascular disease on the group III/IV muscle afferent pathway. Subsystolic circulatory occlusion to elicit venous distension has been suggested to stimulate locomotor muscle afferent neurologic feedback. The purpose of this study was to compare ventilatory responses in young vs aging healthy adults during submaximal constant‐load exercise with intermittent bilateral subsystolic occlusion of locomotor muscles. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise ergometry test. Visit 2: constant‐load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg) and intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between occlusions thereafter. Minute ventilation (V E ), respiratory rate (RR), tidal volume (V T ), oxygen uptake (VO 2 ) indexed to weight, carbon dioxide output (VCO 2 ), respiratory exchange ratio (RER), V E /VCO 2 , and end tidal partial pressure CO 2 (P ET CO 2 ) were measured continuously via breath by breath system. Results At rest, V E , RR, V T , or RER did not differ in YNG vs OLD ( P >0.05); whereas VO 2 (6.3±0.3 vs 3.9±0.2 mL/kg/min) and VCO 2 (0.3±0.0 vs 0.2± 0.0 L/min) were higher in YNG vs OLD (respectively, P <0.05). During all exercise occlusions, V E was higher in YNG vs OLD, with the largest difference at 100 mm Hg (36.7±1.7 vs 30.2±1.6 L/min, respectively, P <0.05). However, the % change from rest to 0 mm Hg or each cuff occlusion resulted in no differences in YNG vs OLD for V E ( P >0.05). In contrast, in YNG vs OLD, the largest % change from 0 mm Hg to the cuff occlusion resulting in between group differences included V E (3.3±3.0 vs 17.3±3.6 at 80 mm Hg, P <0.05), VCO 2 (2.3±2.3 vs 20.8±3.4 at 100 mm Hg, P <0.05) and V E /VCO 2 (7.0±2.6 vs 0.5±1.8 at 100 mm Hg, P <0.05). In addition, there was a trend for significant differences between YNG and OLD for V T (−1.2±4.4 vs 5.9±4.1 % at 80 mm Hg, P =0.15), VO 2 (−2.1±1.5 vs 3.3±1.8 %, at 100 mm Hg, P =0.09) and P ET CO 2 (−6.4±1.9 vs −2.3±1.4 % at 100 mm Hg, P =0.11). Conclusions These data suggest that aging is associated with altered ventilatory responses to venous occlusion of locomotor muscles during constant load submaximal exercise. These changes may be a result of an increased contribution of locomotor muscle afferents on ventilatory control with aging. Support or Funding Information none

Activation of group III/IV skeletal muscle afferents (ergoreflex) and hypoxia (chemoreflex) are two potent stimuli of the sympathetic nervous system during exercise. Venous distention by graded sub‐systolic occlusion contributes to the ergoreflex during exercise. Although the ergoreflex causes greater increases in blood pressure (BP) compared with the chemoreflex, the interaction of the ergoreflex and hypoxia during lower extremity dynamic exercise is unknown. Objective To determine the effect of hypoxia and graded cuff occlusion on hemodynamic responses during low‐intensity cycling exercise. Methods 19 healthy adults (9 men, 25±5 yr) completed two sessions. Session 1 included a maximal cycle ergometry exercise test. Session 2 included two randomized bouts (hypoxia: 12.5% FiO 2 and normoxia: 21% FiO 2 ) of constant‐load cycling at 30% peak workload for 3 min (control, CTL) followed by randomized inflation of bilateral thigh pressure tourniquets to 20, 40, 60, 80, 100 mmHg for 2 min with 2 min of deflation between occlusions. The bouts were separated by 30 minutes of rest. Blood pressure, heart rate and cardiac output (CO) were measured continuously. Results During hypoxia, the average SPO 2 was 80%. Venous occlusion and hypoxia had differential effects on mean arterial pressure (MAP, occlusion × hypoxia, p=0.02). Significant increases of MAP from CTL occurred at 60 (Δ9 ± 6mmHg), 80 (Δ15 ± 8mmHg), and 100mmHg (Δ17 ± 9mmHg) under normoxia (p<0.05). MAP only increased at 100mmHg (Δ14 ± 9mmHg) under hypoxia (p<0.05). Under hypoxia, MAP was much greater at CTL and 20mmHg as compared to normoxia (p<0.05). SBP exhibited responses similar to MAP under hypoxia (100mmHg increase, p<0.001, occlusion × hypoxia interaction, p=0.02). CO was greater with venous occlusion as mediated by increases in HR (p<0.001). In addition, CO increased under hypoxia (p=0.007) but had no interaction with venous occlusion. Conclusion During low pressure venous occlusion, hypoxia had a greater effect on BP, but as pressure increased (60–100mmHg), there were no significant differences in BP between normoxia and hypoxia. Therefore, sympathetically mediated increases of BP during exercise attributed to hypoxia may negate any responses mediated by the ergoreflex when elicited by venous occlusion at low pressures.

Introduction Healthy aging in adults is associated with attenuated cardiac output (Q) for a given exercise workload compared to younger healthy adults. This is important because skeletal muscle perfusion pressure during exercise is dependent on coordinated adjustments between cardiac and vascular hemodynamics. Cardiac power (CP) quantifies the flow and peripheral pressure generating capacity of the heart, and may be the strongest measure of cardiac function during exercise. Group III/IV muscle afferents are suggested to favorably influence Q and arterial pressure during exercise in young healthy adults. However, the influence of group III/IV afferents on cardiac hemodynamic and arterial pressure coupling during exercise remains unclear across the aging spectrum. Venous distension via subsystolic circulatory occlusion of locomotor muscles is suggested to increase group III/IV afferent outflow. The aim of this study was to assess the influence of subsystolic circulatory occlusion of locomotor muscles on CP in young vs aging healthy adults. Methods Healthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m 2 ; % predicted peak VO 2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P <0.05). Visit 1: peak exercise test. Visit 2: constant load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P <0.05) with the first 3 min without cuffing (0 mm Hg), but thereafter included intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between inflations. Non‐invasive Q and mean arterial (MAP) pressure were measured using continuous hemodynamic photoplethysmography. We calculated CP=Q*MAP. Q and CP were indexed to BSA. Results At rest, MAP did not differ in YNG vs OLD, but Q and CP were higher in YNG vs OLD (P<0.05), which persisted throughout each exercise cuff occlusion. In YNG, the greatest increase in CP from 0 mm Hg occurred at 100 mm Hg (754±48 vs 899±48 L/min/m 2 · mm Hg, P <0.05) due to increased MAP (19±4%, P <0.05) but not Q (1±2%, P >0.05). In OLD, Q, MAP, and CP did not differ between 0 mm Hg and any occlusion ( P >0.05). The % increase in Q from rest to 0, 20, 60, 80, and 100 mm Hg was higher in YNG vs OLD ( P <0.05). The % increase in MAP from rest to any occlusion did not differ in YNG vs OLD ( P >0.05). The % increase in CP from rest to occlusions of 60 (130±9 vs 98±11%), 80 (142±9 vs 108±20%), and 100 (158±11 vs 114±14%) were higher in YNG vs OLD (all P <0.05). Within YNG, the % increase in CP from rest to 100 mm Hg was higher than the % increase from rest to 0, 20, 40, or 60 mm Hg ( P <0.05), driven by increased MAP ( P <0.05). Within OLD, these differences for % increase in CP did not occur despite MAP that was similar to YNG ( P >0.05). Conclusions These data suggest that CP is attenuated in OLD vs YNG healthy adults during subsystolic circulatory occlusion of locomotor muscles during submaximal constant load exercise. The reduced CP generation in older adults is related to a blunted increase in Q mediated by attenuated influence of group III/IV muscle afferents on cardiac function during exercise.

Introduction Several common and functional genes are known to contribute to renal, blood vessel, and cardiac functional characteristics associated with sodium (Na + ) handling, vascular reactivity, and cardiac output, respectively. Many of these same genes are suggested to contribute to differential responsiveness to blood pressure (BP) therapy. Few studies have explored the simultaneous phenotypic consequence of multiple genes critical for BP control. Despite a significant impulse of the medical community towards personalized medicine, BP therapy is typically guided by algorithms that do not include a patient's genetic information. Purpose The purpose of this study was to determine the impact of 14 genes on time to BP control in response to common BP therapy, with a specific focus on genes associated with drug metabolism and protein function in the kidney, the blood vessels, and the heart. Methods Eighty‐six patients completed one study visit consisting of a buccal swab for DNA extraction and genotyping, measurement of ambulatory BP, and a medical chart review for objective BP history. Genes in the analysis included those that encode for one drug metabolizing enzyme (CYP2D6), renal Na + handling (SCNN1A, WNK1, SLC12A3, and Alpha Adducin), vascular function (angiotensin, ACE, angiotensin‐II receptor type‐I, and renin), and cardiac function (the β 1 and β 2 adrenergic receptors ADRB1 and ADRB2, respectively). Results Genetic variation of WNK1 (rs1159744) demonstrated differential responses to diuretic therapy (determined as those with blood pressure under 140/90 vs. those above 140/90 according to genotype)(WNK1=GG>CG/CC, P<0.05). Genes that encode ADRB1 (rs1801252), ADRB2 (rs1042713), and CYP2D6 (rs3892097) demonstrated differential response to β‐blocker therapy (ADRB1=Ser/Ser>SerThr/ThrThr, ADRB2=GG>AG/AA, CYP2D6=CC>CT/TT, P<0.05). Genes that encode angiotensin (rs699), ACE (rs1799752), and renin (rs12750834) demonstrated differential response to ACE‐inhibition and angiotensin receptor blockade (angiotensin=CT/TT>CC, ACE=Ins/Ins>InsDel/DelDel, renin=AG/AA>GG, p<0.05). Conclusion These results demonstrate that genetic variants encoding proteins involved in renal Na + handling, vascular function, and cardiac output influence response to BP therapy for their respective drug classes. Support or Funding Information Funded by Geneticure

Introduction Hypertension is one of the most important preventable contributors to disease and death worldwide and represents the most common condition seen in the primary care setting. Approximately one in three adults living in the US has hypertension. Despite the prevalence and impact of hypertension, little data exists on the average time to blood pressure (BP) control in US patients and time to control according to common BP medication classes. Purpose Therefore, the purpose of this study was to assess the average time to BP control in adults with controlled hypertension, according to drug class. Methods For this study we assessed how long (in months) and how many clinic visits were needed in order to control BP according to common medication classes in patients with existing hypertension. The study was performed at two clinical sites where patients came in for one visit for an in‐clinic assessment of BP and for completion of a patient survey regarding their history of BP. The primary care physician performed a chart review for a detailed objective BP history. Results Ninety‐nine patients completed all aspects of the study (age=58±0.8yrs., %female=46, height=169±1.0cm, weight=86±1.4kg, BMI=29.9±0.4m/kg 2 ). The average initial BP was 151±2mmHg systolic (SBP), 91±1mmHg diastolic, and 111±1mmHg mean arterial (MAP). Patients demonstrated a significant drop in BP with therapy (SBP=16mmHg, DBP=10mmHg, MAP=12mmHg). Patients were prescribed an average of 1.8 BP medications (62% on ACE‐inhibitor, 42% on diuretic, 33% on β‐blocker, 27% on angiotensin receptor blocker, and 16% on Ca + channel blocker). The average time to BP control was 14.9 months or 3.6 clinic visits. Patients on a diuretic had the longest time to BP control, while patients on a Ca + channel blocker had the shortest time to control (diuretic=19.5±10.4, angiotensin receptor blocker=22.8±13.1, ACE‐inhibitor=22.2±11.4, β‐blocker=24.5±16.9, Ca + channel blocker=9.9±4.5 months, pANOVA<0.05). In contrast, patients on a Ca + channel blocker had significantly more clinic visits to attain BP control (diuretic=4.5±0.6, ACE‐inhibitor=3.1±0.4, angiotensin receptor blocker=3.9±0.6, β‐blocker=4.9±0.7, Ca + channel blocker=5.1±0.7 visits). Conclusion These results suggest important differences in the time to BP control, and the number of office visits necessary for BP control according to common classes of hypertension therapies. Funding was provided by Geneticure, LLC Support or Funding Information Funded by Geneticure

Introduction: Obesity and hypertension (HTN) are highly prevalent comorbid risk factors for heart failure with preserved ejection fraction (HFpEF). Obesity and HTN independently increase sympathetic nervous activity and impair muscle blood flow during exercise. Previous work has reported attenuated limb blood flow in patients with HFpEF; however, these findings were compared to controls with dissimilar comorbidities and during small muscle mass exercise. It is unclear if HFpEF alters muscle blood flow responses independent of the obesity- and HTN-mediated alterations. Hypothesis: We hypothesized the muscle blood flow response during cycling would be lower in HFpEF patients than age, sex, BMI, and HTN matched controls (CTL). Methods: HFpEF patients (n=14, 9M/5W, 71±7yrs, 32±4 kg/m 2 ) and CTL (n=12, 8M/4W, 69±7yrs, 31±4 kg/m 2 ) performed an incremental cycling test. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) by open-circuit acetylene wash-in technique, and systemic vascular resistance (SVR) was calculated. Vastus lateralis blood flow index (BFI) was measured by near-infrared spectroscopy and indocyanine green dye injections and venous norepinephrine concentration was measured. Changes from rest to 40 W of the incremental test are reported. Results: Resting Q, mean arterial pressure, SVR, and venous norepinephrine concentration were not statistically different between groups (p>0.18). From rest to 40 W, the increases in Q (CTL: 3.9±0.8 vs. HFpEF: 3.6±0.7 L/min), mean arterial pressure (CTL: 5.7±2.7 vs. HFpEF: 6.6±6.1 mmHg), and SVR (CTL: -7.3±2.1 vs. HFpEF: -6.0±2.0 mmHg/L/min) were not statistically different between groups (all, p>0.13). The HFpEF group had smaller increases in vastus lateralis BFI at 40 W compared to CTL (CTL: 7.2±3.6 vs. HFpEF: 4.2±2.6 fold-increase from rest) (p=0.02). The HFpEF group had greater increases in venous norepinephrine concentration from rest to 40 W than CTL (CTL: 164±216 vs. HFpEF: 377±247 pg/mL) (p=0.05). Conclusions: Our findings suggest that, compared to age, sex, BMI, and HTN matched controls, patients with HFpEF have an impaired locomotor muscle blood flow response during submaximal cycling exercise likely due to higher locomotor muscle vascular resistance.

Introduction: Cardiac rehabilitation (CR) is a comprehensive secondary cardiovascular disease (CVD) program which integrates structured lifestyle interventions to reduce morbidity and mortality. The Life’s Simple 7 (LS7) is an objective measure of cardiovascular health (CVH) which incorporates health-promoting behaviors and clinical factors however, it has not been rigorously evaluated in the CR setting. Methods: Retrospective cohort study of 937 patients who attended center-based CR at Mayo Clinic from Jan 2018 -Sept 2020. Patient characteristics and LS7 component metrics at baseline (pre-CR) and completion (post-CR) were collected: 3 clinical factors (blood pressure [BP], cholesterol, and hemoglobin A1c [HbA1c]), and 4 health behaviors (smoking, body mass index [BMI], physical activity [PA] and diet). LS7 score was computed as a composite of each LS7 component by assigning 2-points for ideal, 1-point for intermediate, or 0-points for poor CVH ranging from 0-14 points. LS7 score was further categorized as poor 0-6, intermediate 7-8 and ideal 9 -14. Results: Patients were 64±13 years old, 34% were female, and attended a mean of 11±12 CR sessions, Table 1. At baseline, the LS7 components with the highest proportion within the poor category were HbA1c (201/495, 41%) and BMI (465/936, 50%), Table 2. From pre to post-CR, there was a reduction in proportion of patients classified within the poor category for each LS7 component except HbA1c ( Figure 1 ), and the proportion of patients with LS7 scores in the ideal range increased from 6.4% to 19% (P<0.001). There was a statistically significant improvement in LS7 score from 5.5±1.8 to 6.7± 2.4 (+Δ1.6±2.4, P<.0001), Table 2 . Conclusions: Patients attending CR demonstrated an improvement in LS7 score and almost all LS7 components suggesting an overall positive impact of CR on CVH. Further research is needed to better understand the impact of the individual LS7 components on CV outcomes in diverse populations participating in CR.