Eisenach, John H.

Heart failure (HF) patients have reduced cardiac reserve and increased work of breathing (WOB)., Increased demand for locomotor muscle blood flow (i.e. activities of daily living) may result in competition between respiratory and locomotor vascular beds. We hypothesized that HF patients would demonstrate improved locomotor blood flow with respiratory muscle unloading during moderate activity. We studied 10 HF patients (EF=30±8%) and 10 controls during two 10 min. cycling sessions at 60% VO 2 max. Session 1 (S1): 5 min of normal breathing (NB) and 5 min respiratory muscle unloading with a ventilator. Session 2 (S2): 5 min NB and 5 min of respiratory muscle loading with inspiratory resistance. Measurements included: leg blood flow (LBF), cardiac output (CO), and inspiratory pleural pressure time integral as an index of the WOB. During S1, WOB was reduced similarly in both groups (HF: 50±60%; CTL: 50±56%, p<0.05 for both). In HF, CO was reduced (9.6±1.4 vs 8.2±2.1 L/min, p<0.05) and LBF increased (4.9±2.6 vs 6.2±2.9 L/min, p<0.01). In CTL, there was no change in CO (14.7±3.1 vs 14.8±5.0 L/min) or LBF (10.9±5.6 vs 10.3±5.2 L/min). During S2, WOB was increased similarly in both groups (HF: 111±75%, CTL: 110±85%, p<0.01 for both). In HF, there was no change in CO (10.0±1.3 vs 10.3±2.5 L/min) or LBF (5.0±1.8 vs 4.9±1.4 L/min). In CTL, CO increased (15.4±4.3 vs 16.9±4.7 L/min, p<0.01) with no change in LBF (10.7±5.3 vs 10.3±5.6 L/min). These data suggest that the respiratory muscles of HF patients preferentially recruit blood flow away from the locomotor muscles during moderate intensity, whole body exercise.

The complex forearm vasodilator response during mental stress (MS) is mediated in part by unchanged or decreased forearm muscle sympathetic nerve activity. However, immediately after MS, nerve activity is increased. To determine the effect of chronic sympathetic denervation on forearm blood flow (FBF, [ml/100ml forearm volume/min]) response to MS, we studied patients pre and post sympathotomy (ETS) for palmar hyperhidrosis. 15 healthy subjects (11 F; 19‐32 yr) with a mean BMI of 23 ± 5 kg/m2 were studied 1 day‐6 mo before ETS and 1‐6 mo after ETS. FBF (plethysmography) was recorded during baseline, 3 min Stroop test, and 2 min post‐MS recovery. ETS did not affect resting HR, BP or FBF. However, resting forearm vascular resistance (FVR, [MAP/FBF]) was reduced after ETS (50 ± 20 vs 33 ± 14, p < 0.01) and forearm vascular conductance (FVC, [(FBF/MAP)*100]) was increased (3 ± 2 vs 4 ± 2, p < 0.05). MS caused significant increases in FBF and FVC, and a decrease in FVR, and these responses were unaffected by ETS. However during post‐MS recovery, ETS caused a significant increase in FBF (2 ± 1 vs 3 ± 1), FVC (3 ± 1 vs 4 ± 2), and a decrease in FVR (52 ± 22 vs 32 ± 16) (p < 0.01). Chronic sympathetic denervation influences post‐MS forearm vasoconstriction, which likely has minor hemodynamic consequences but confirms a greater role for sympathetic control of FBF in the post‐MS period as opposed to during MS. NIH HL‐089331, NS‐32352

Aging humans exhibit lower exercise blood flow (exercise hyperemia), but the vascular mechanisms mediating this remain unknown. In aging humans, agonist infusions suggest endothelial dysfunction, due in part to less nitric oxide (NO) and prostaglandin (PG) mediated vasodilation. Notably, in young adults inhibition of NO or PGs decreases exercise hyperemia by 20% and 12%, respectively. We tested the hypothesis that aging humans would exhibit an attenuated reduction in exercise hyperemia following inhibition of NO or PGs, due to less vasodilation from these signals. Eleven older males and females (55–76 years) performed dynamic forearm exercise for 20 minutes. Forearm blood flow (FBF) was measured beat‐to‐beat with Doppler ultrasound while saline or drugs were infused sequentially via brachial artery catheter in the exercising forearm. After achieving steady state exercise (min 5), L‐NAME (25 mg) was infused for 5 minutes to inhibit NO synthase. After 2 more minutes of exercise (saline), ketorolac (6 mg) was infused for 5 minutes to inhibit PGs, followed by 3 more minutes of exercise with saline. L‐NAME reduced exercise hyperemia by 13–18% in older subjects, whereas ketorolac had no net effect on blood flow. In the reverse drug order (n=6), ketorolac did not effect FBF, but L‐NAME reduced FBF by 10–13%. Our results suggest that in aging humans, the contribution of NO to exercise hyperemia may be modestly reduced, but the role of PGs mediating vasodilation is completely lost. Loss of vasodilating PGs along with diminished NO may contribute to lower blood flow in aging humans. Grant support: HL‐69692, HL‐46493, and GCRC RR‐00585.

The Gly allele of the Arg16/Gly β 2 ‐adrenergic receptor polymorphism has been associated with hypertension in a linkage analysis in Rochester, MN. Gly homozygotes have greater forearm β 2 ‐receptor mediated vasodilation than Arg after a normal Na + diet (150 mmol/day), and the difference is mediated by endothelial NO. To test the hypothesis that dietary Na + restriction affects β 2 ‐mediated dilation in these groups, we measured forearm blood flow (FBF, plethysmography) during brachial arterial infusion of isoproterenol (ISO) after 5 days of low dietary Na + (10 mmol/day), in healthy subjects homozygous for Arg (n=15, 8 women, 29 ± 8 yrs, mean ± SD) vs. Gly (n=17, 7 women, 31 ± 7 yrs). Baseline FBF did not differ between groups. ISO caused a significant increase in FBF that was not different based on genotype (P = 0.51, main effect of genotype; P = 0.72, genotype‐by‐ISO‐interaction). For example, the highest response to ISO was 10.3 ± 5.5 in Arg and 12.0 ± 4.4 ml/100 ml forearm vol/min in Gly (P t‐test = 0.33). NO inhibition with L‐NMMA decreased baseline FBF, and significantly blunted the response to ISO, but there was no evidence to suggest the responses were influenced by genotype (P = 0.89, genotype‐by‐ISO‐by‐L‐NMMA interaction). We conclude that greater NO‐mediated β 2 ‐receptor vasodilation in Gly homozygotes is no longer apparent following dietary Na + restriction, suggesting that greater dilator function in Gly homozygotes during normal Na + intake may be a protective vascular mechanism in a population where the Gly allele is associated with hypertension. Support: HL‐63328, GCRC RR‐00585, NCRR K23‐17520.

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.

The forearm blood flow response to mental stress (MS) is due to circulating epinephrine (Epi), release of nitric oxide, and forearm sympathetic withdrawal. We recently demonstrated that forearm venous Epi predicts the vascular conductance (FVC) and HR response to MS. In a large, ongoing phenotyping study of sympathoexcitation and adrenergic receptor gene variation, we hypothesized that arterial Epi would predict the forearm vasodilator response to MS, while norepinephrine (NE) would predict the pressor response. In 54 healthy, normotensive young adults, FVC (plethysmography), HR (ECG), and blood pressure (brachial artery) were measured in a recumbent chair at rest and during 3 min of a computerized Stroop colored‐word test. During the final 30 sec of stress, arterial Epi and NE were assayed (HPLC). MS increased HR, BP, FVC, Epi, and NE (p < 0.05 for all). Unexpectedly, during MS the arterial Epi levels did not correlate with HR or FVC. However, a robust correlation existed for HR and FVC (r = 0.73, p < 0.001). Further, systolic pressure correlated with FVC (r = 0.36, p < 0.01) and NE (r = 0.46, p < 0.001). We conclude that the HR response to MS is a major contributor to FVC, independent of arterial Epi, suggestive of mechanical effects and potentially flow‐mediated dilation. This also confirms previous work that catecholamine spillover assays are more indicative of sympathoadrenal activation and hemodynamic responses. Support: K23 RR17520, HL 46493.

Salt sensitivity is a major cardiovascular focus, but extremes of sodium (Na + ) intake can affect subject dropout rates. We analyzed dietary compliance and baseline cardiovascular indices in an ongoing genotype‐phenotype protocol in healthy young adults. Study visits followed 5 day consumption of 3 daily Na + levels: normal (150) low (10) and high (400 mmol/day). Compliance was determined by 24‐hour Na + excretion. Vital signs were obtained on each visit. Of the first 30 subjects to date, one was unable to tolerate the low Na + diet due to palatability. Mean ± SE urine Na + excretion was 113 ± 27, 25 ± 18 and 328 ±110 mmol for normal, low, and high Na + , respectively. Low Na + caused a significant weight change of −1.6 ± 2.2 kg from screen. High Na + diet decreased resting HR (−2.7 bpm) and increased 24hr urine volume 25% from the normal Na + diet. No correlation was found between urine indices and weight change in the subjects. This dietary sodium crossover study is generally well‐tolerated with high compliance. Low Na + diet appears to cause weight loss; high Na + causes an increase in urine volume and decrease in HR, but no effects on weight or blood pressure. HL 089331

Background Heart failure (HF) causes abnormal ventilatory responses to exercise which are inked to poor prognosis. We examined the impact of blocking fine afferents from locomotor muscles on exercise ventilatory efficiency in HF. Methods 9 HF patients (60±6yrs, LVEF 27±6%) and 9 healthy controls (63±7yrs) underwent two 5 min cycling sessions at 65% peak workload with and without intrathecal fentanyl. VO 2 , VCO 2 , V E , breathing frequency (fb), tidal volume (V T ), and chemoreceptor sensitivity (CO 2 rebreathe) were measured. Results Fentanyl did not influence exercise VO 2 in either group (HF=1.5±0.3 vs 1.5±0.3 L/min, control=1.7±0.4 vs 1.7±0.5 L/min). V E was lower with fentanyl in HF but not control (−12.3±7.1 vs 0.8±6.2%, p<0.001) due to lower fb (−10.5±4.6 vs 0.5±7.1%, p<0.01) with no change in V T (−1.2±9.4 vs 0.4±5.7%, p=0.67). V E /VCO 2 improved during exercise with fentanyl in HF but not in controls (−14.8±7.1 vs ‐ 0.5±7.0, p<0.01). Fentanyl did not influence chemoreceptor sensitivity in either group. Conclusion Blocking group III and IV afferent feedback from the locomotor muscles during exercise improves ventilatory efficiency in HF. NIH/NCRR grant KL2‐RR024151.

Normotensive individuals who show a robust pressor response to sympathoexcitatory stimuli are at increased risk for developing hypertension. In healthy young adults, we defined a cumulative pressor score (CPS) as the mean increase in systolic arterial pressure across 3 stressors: mental stress, cold pressor test (CPT), and isometric handgrip to fatigue (HG). We hypothesized that individuals with high CPS would possess other physiologic traits associated with cardiovascular reactivity. In 143 subjects (M/F: 57/86, ages 18–40 yr) quartiles were formed with hyper‐responders (CPS ≥ 27.0 mmHg) in the top and hypo‐responders (≤ 16.6 mmHg) in the bottom quartile. Comparisons across quartiles included age, sex, BMI, arterial catecholamines at rest and during stress, HR variability, baroreflex sensitivity by modified Oxford, pulse wave velocity, and 24‐hr ambulatory BP measures. Age was associated with CPS, as hyper‐responders (mean age±SE: 29±1 yr) were approximately 4 yrs older than each quartile (p<0.01). Hypo‐responders had decreased norepinephrine during CPT (p<0.01) and HG (p<0.01), and epinephrine during HG (p<0.01) when compared to each quartile. No other physiologic variable was associated with CPS or quartile. These findings imply that while hyper‐responders may be at greatest cardiovascular risk, it appears to be a consequence of normal aging, as few other intermediate physiologic markers of BP reactivity were associated with pressor scores. Support: HL‐089331, CTSA RR‐024150