Citations

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

In young women, tonic autonomic nervous system activity contributes less to resting blood pressure than that in men. It is unknown whether the autonomic support of blood pressure increases in postmenopausal women, therefore we examined the effect of autonomic blockade on blood pressure and how this relates to baseline muscle sympathetic nerve activity (MSNA) in women. Five young (23±4 yr) and 6 older (57±3 yr) women were examined before and during autonomic blockade using trimethaphan camsylate (TM). MSNA burst frequency and burst incidence were higher in older women (24±2 vs. 14±3 bursts/min; 41±3 vs. 23±5 bursts/100hb, respectively; p<0.05). Older women had a greater drop in mean arterial pressure (MAP; −25±2 vs. −8±3 mmHg; p<0.01) and total peripheral resistance (−0.7±0.1 vs. −0.2±0.1 AU; p<0.01) during autonomic blockade. MSNA bursts were abolished by TM within minutes. Baseline burst frequency and burst incidence were associated with the decrease in MAP during autonomic blockade (r=−0.64, r=−0.63; respectively; p<0.05). In conclusion, autonomic blockade reduces MAP to a greater extent in older women, and this decrease in blood pressure is associated with resting levels of MSNA. Our results suggest that autonomic support of blood pressure is greater in older women compared to young women. Elevated sympathetic nerve activity may explain the increased incidence of hypertension after menopause.

Dietary sodium loading decreases β‐adrenergic receptor mediated vasodilation in hypertensive men, and paradoxically increases this dilation in normotensive men; no information exists in women. The purpose of this investigation was to test the hypothesis that dietary sodium loading and restriction influences β‐receptor mediated vasodilation in a sex‐dependent manner. Healthy normotensive subjects consumed a high (400 mmol/day, n=36, mean age±SEM 23±1 yr, 23 women) or low (10 mmol/day, n=30, 30±1 yr, 14 women) sodium diet for 5 days prior to study. Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of isoproterenol (ISO: 1, 3, 6, 12 ng/100 ml tissue/min) were measured before and after endothelial NO synthase inhibition with N G ‐monomethyl‐L‐arginine (L‐NMMA). Consistent with prior reports, the FBF response to ISO was greater in men on high sodium compared to men on low sodium (p=0.03, ISO‐by‐sodium interaction). The highest response to ISO was 16.6±1.7 and 11.0±1.1 ml/100 ml tissue/min (high vs. low, p=0.01). After LNMMA the men's response to ISO did not differ based on sodium. In contrast, in women dietary sodium did not affect the response to ISO before or after LNMMA. We conclude that dietary sodium alters β‐adrenergic receptor mediated vasodilation in men, which appears to be dependent on NO. This is the first study to suggest that these mechanisms of vasodilation are resistant to dietary sodium in women. Support: HL‐089331, CTSA RR‐024150

Dietary sodium influences intermediate physiological traits in healthy young adults independent of changes in blood pressure. The purpose of this study was to test the hypothesis that dietary sodium affects cardiac autonomic function. In prospective, randomized cross‐over design separated by 1 month or more between diets, 69 normotensive healthy young adults (M/F: 26/43, ages 18–38 yr) consumed a 5‐day low (10 mmol/day), normal (150 mmol), and high sodium (400mmol) diet prior to a protocol examining cardiovascular traits including heart rate variability (HRV) by time domain and frequency domain analysis (Nevrokard). All women were studied in the low hormone phase of the menstrual cycle. Diet did not affect blood pressure, but HR (mean ± SE) was 68±1, 65±1, and 64±1 in low, normal, and high sodium conditions, resp. (RM ANOVA p < 0.01). For HRV there was a main effect of sodium on SDNN, RMSSD, HF, LFnu, HFnu, and LF/HF ratio (p < 0.01 for all). The response to low sodium was most marked and consistent with sympathetic activation, with increased LFnu and LF/HF ratio, and decreased SDNN, RMSSD, and HFnu compared to both normal and high sodium conditions (p ≤ 0.05 for all). These findings suggest that autonomic control of HRV is altered through changes in dietary sodium without changes in blood pressure. Support: UL1 TR000135 , HL‐89331

Vascular function in older women versus young women may differ based on the β‐adrenergic receptor‐mediated contribution to basal vascular tone. Thus, we tested the hypothesis that forearm blood flow (FBF) responses to the β‐receptor agonist isoproterenol (ISO) are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure FBF in young (26 ± 3 yr; n = 13) and older (61 ± 6 yr; n = 12) women. FBF and mean arterial pressure (MAP) were measured at baseline and during ISO infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 ml tissue/min. The two groups did not differ in body mass index or MAP. Baseline FBF (3.7 ± 1.7 vs. 2.9 ± 1.3 ml/100 ml/min, respectively) and forearm vascular conductance (FVC) (0.04 ± 0.02 vs. 0.03 ± 0.01 AU, respectively) were similar between young and older women. FBF and FVC remained similar between the groups for all ISO doses, including the 12.0 ng/100 ml tissue/min dose of ISO, for which the greatest difference between the groups would be expected; FBF was 10.7 ± 2.3 vs. 9.4 ± 2.1 ml/100 ml/min (young vs. older, respectively) and FVC was 0.11 ± 0.02 vs. 0.10 ± 0.02 AU (young vs. older, respectively). In conclusion, β‐adrenergic receptor‐mediated forearm responses to stimulation are similar between young and older women, suggesting that β‐adrenergic receptor response and contribution to vascular tone are preserved with aging in women. Funded by NIH

Increased locomotor muscle afferent feedback may be linked to the reduced exercise capacity (peak VO 2 ) and poor ventilatory efficiency (high V E /VCO 2 slope) observed in heart failure (HF). We examined the relationship between peak VO 2 and change in V E /VCO 2 with afferent inhibition during exercise in HF. 9 HF (60±6 yr) and 9 controls (CTL) (63±7 yr) completed 3 visits. Visit 1: cycle exercise to volitional exhaustion. Visits 2‐ 3: 5 min constant‐load cycling (65% of peak work) randomized to lumbar intrathecal fentanyl injection (afferent block) or placebo. VO 2 , ventilation (V E ), carbon dioxide production (VCO 2 ), and end‐tidal CO 2 (P ET CO 2 ) were measured. In HF, peak work (120±34 vs 176±54 W, p <0.05) and VO 2 (18.4±2.7 vs 27.2±4.7 ml/kg/min, p <0.05) were reduced, whereas V E /VCO 2 slope was elevated (39.7±1.8 vs 35.3±0.8, p<0.05) compared with CTL. With afferent inhibition, HF patients had a greater reduction in V E /VCO 2 (‐18.8±8.1 vs ‐5.4±13.3%, p <0.05) and increase in P ET CO 2 (20.3±10.5 vs 6.1±9.5%, p <0.01) during constant‐load cycling. Lower VO 2peak was related to a greater decline in V E /VCO 2 and rise in P ET CO 2 after afferent inhibition in HF (r=0.82, p <0.01 and r=‐0.69, p <0.05, respectively) but not CTL ( p >0.05). Our data demonstrate that patients with the lowest VO 2peak have the greatest improvement in V E /VCO 2 , suggesting a close link between afferent feedback, ventilatory efficiency and exercise capacity in HF. Grant Funding Source : Supported by AHA 12GRNT11630027 and National Center for Advancing Translational Science KL2TR000136.

β 2 ‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β 2 ‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3–7 mg/min), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR ( P = 0.06). For SNP position 16, the highest dose of TERB produced lower SVR in Gly16 vs Arg16 ( P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 ( P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16. Supported from NIH and DFG.

Young men display a positive association between breathing rate and muscle sympathetic nerve activity (MSNA). We compared breathing rate, peroneal MSNA and cardiovascular variables at rest in 17 men (age 27 ± 2 yrs) and 15 women (age 25 ± 1 yrs). Breathing rates and MSNA were similar in men and women but women had significantly lower systolic and mean blood pressures, cardiac output and stroke volume. In men breathing rate correlated positively to MSNA (r = 0.58, p<0.05) but not in women (r = 0.12, p> 0.05).. In men respiratory rate correlated positively to total peripheral resistance (r = 0.65, p<0.05) and inversely to cardiac output (r = − 0.84, p<0.05) and heart rate (r = − 0.60, p<0.05) but there were no such relationships in women (p> 0.05 for all). In another group of subjects, linear regression was performed on respiratory rate and brachial arterial plasma norepinephrine. There was no relationship in men (r=0.0847, n=38) or women (r=0.0367, n=74). Importantly, MSNA does not always predict plasma NE levels at rest. The positive relationship between breathing and MSNA in men, and the inverse coupling of breathing to cardiac output and heart rate suggest that influences of respiration may be important, not only for dynamic, but also for “tonic” cardiovascular function. The lack of relationships among these variables in women shows that there are fundamental differences in basic blood pressure regulation between the sexes.

We tested the hypothesis that dietary Na + intake alters the hemodynamic response to mental stress (MS) in normotensive subjects, which could be mediated by β‐adrenergic receptors (ADRB). As part of an ongoing ADRB2 phenotyping protocol, 12 subjects (age 23±5 year) completed 5 days of low (10 mmol day −1 ), normal (150) and high (400) dietary Na + intake. We measured heart rate (ECG), mean arterial pressure (MAP, Finometer), and calculated stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) responses to arithmetic MS, before and after administration of propranolol. The high Na + diet decreased CO (6.3±0.3 vs. 5.7±0.3 l min −1 , p<0.01) and increased SVR (1187±47 vs. 1311±68 dynes s −1 cm −1 , p<0.01) at rest, but MAP was unchanged (92±2 vs. 93±3 mmHg, p=0.37). During MS, the increase in HR, CO, and MAP was not affected by diet, nor was the decrease in SVR. However, on the high Na + diet β‐blockade increased resting MAP (93±3 vs. 97±2 mmHg, p<0.01), while the absolute MAP response to MS was unchanged, the ΔMAP was blunted (7.3 vs. 4.3 %, p=0.03) and ΔSV was decreased (1.7±3.5 vs. −5.3±2.0 %, p=0.03). In conclusion, reactivity to MS was not influenced by dietary Na + , but systemic β‐blockade after high Na + blunted the SV response during MS. This may be suggestive of augmented ADRB function or blunted non‐ADRB mechanisms of ventricular function during MS after high Na + . Support: R‐01 HL‐089331 and CTSA RR‐024150.