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Previous work demonstrates augmented muscle sympathetic nerve activity (MSNA) responses to the cold pressor test (CPT) in older women. Given its interindividual variability, however, the influence of baseline MSNA on CPT reactivity in older adults remains unknown. Sixty volunteers (60–83 yr; 30 women) completed testing where MSNA (microneurography), blood pressure (BP), and heart rate (HR) were recorded during baseline and a 2-min CPT (∼4°C). Participant data were terciled by baseline MSNA ( n = 10/group); comparisons were made between the high baseline men (HM) and women (HW), and low baseline men (LM) and women (LW). By design, HM and HW, versus LM and LW, had greater baseline MSNA burst frequency (37 ± 5 and 38 ± 3 vs. 9 ± 4 and 15 ± 5 bursts/min) and burst incidence (59 ± 14 and 60 ± 8 vs. 16 ± 10 and 23 ± 7 bursts/100 hbs; both P < 0.001). However, baseline BP and HR were not different between the groups (all P > 0.05). During the CPT, there were no differences in the increase in BP and HR (all P > 0.05). Conversely, ΔMSNA burst frequency was lower in HW versus LW (8 ± 9 vs. 22 ± 12 bursts/min; P = 0.012) yet was similar in HM vs. LM (17 ± 12 vs. 19 ± 10 bursts/min, P = 0.994). Furthermore, ΔMSNA burst incidence was lower in HW versus LW (9 ± 13 vs. 28 ± 16 bursts/100 hbs; P = 0.020), with no differences between HM versus LM (21 ± 17 vs. 31 ± 17 bursts/100 hbs; P = 0.455). Our findings suggest that heightened baseline activity in older women attenuates the typical CPT-mediated increase in MSNA without changing cardiovascular reactivity. Although the underlying mechanisms remain unknown, altered sympathetic recruitment or neurovascular transduction may contribute to these disparate responses.

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered. ispartof: JOURNAL OF HYPERTENSION vol:40 issue:10 pages:1859-1875 ispartof: location:Netherlands status: published

A mechanical stimulus to skeletal muscle during exercise activates the sympathetic nervous system via the skeletal muscle mechanoreflex. However, to date, the receptor mechanisms responsible for mechanotransduction in skeletal muscle afferents have not been fully identified. Transient receptor potential vanilloid 4 (TRPV4), a multimodally activated, nonselective cation channel, is sensitive to mechanical stimuli such as shear stress, osmotic pressure and stretch in various organs. Therefore, it is hypothesized that TRPV4 contributes to mechanotransduction in thin-fiber primary afferents innervating skeletal muscle. Purpose: The aim of this investigation was to determine 1) the extent to which TRPV4 and the afferent marker peripherin are co-localized in dorsal root ganglion (DRG) neurons subserving thin-fiber skeletal muscle afferents using a retrograde tracing technique, and 2) the impact of a selective TRPV4 antagonist, HC067047 on mechanotransduction in small DRG neurons. Methods: To label muscle afferent DRG neurons, dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate, (Dil, 60 mg/mL, 3 μL total) was injected into the white portion of the gastrocnemius muscle. Five days after the injection, L4-L6 DRGs were harvested from rats (Sprague-Dawley (SD), n = 3, body weight: 318.0 ± 8.7 g). The number of positively stained small-diameter DRG neurons (i.e. less than 30 μm in diameter) were counted and the percentage of peripherin- or DiI-positive neurons in TRPV4-positive neurons was calculated. In vitro whole-cell patch clamp recordings from cultured rat DRG neurons (SD, n = 10, body weight: 352.1 ± 52.4 g), mechanically-activated (MA) current amplitude and mechanical threshold were measured before and 5 min after the application of either HEPES-buffered solution as a control or 1 μM HC067047 solution. Results: Fluorescence immunostaining demonstrated that 20.1 ± 10.1% of TRPV4 positive neurons were expressed with Dil-labeled small DRG neurons. Of these, 9.5 ± 6.1% and 10.6 ± 7.2% were peripherin-positive and -negative neurons, respectively. In in vitro whole-cell patch clamp recordings, MA current amplitude was significantly decreased 5 min after the application of HC067047 ( P < 0.01), while mechanical threshold did not change. Conclusion: The data demonstrates that 1) TRPV4 is expressed in DRGs innervating group IV muscle afferent C-fibers, and 2) HC067047 suppresses the response to mechanical stimulation in DRG neurons. These findings suggest that TRPV4 channels play an important role as mechanoreceptors contributing to mechanotransduction in thin muscle afferents. Supported by NIH HL-151632, JSPS 21J20070 & 22KK0154, and UMF 202131013 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Type 2 diabetes mellitus (T2D) leads to alterations in insulin signaling and autonomic function, including abnormal cardiovascular response to exercise. Cardiovascular control during exercise is in part mediated by the exercise pressor reflex (EPR). The EPR transmits information from primary sensory neurons in working skeletal muscle to cardiovascular control centers in the brain, resulting in reflexively increased blood pressure (BP). Insulin receptors are expressed on neurons in these cardiovascular control centers. Thus, it is logical to suggest that insulin signaling could be disrupted in these neurons in T2D. We hypothesized that the augmented cardiovascular and sympathetic responses to exercise in T2D may be attenuated by administration of insulin into the brain. Purpose: This study was conducted to demonstrate that insulin administration into the central nervous system of rats acutely attenuates the augmented BP and sympathetic responses to muscle contraction in rats with T2D. Methods: T2D and control rats were generated by feeding Sprague-Dawley rats either a high fat diet (T2D, n=10) or normal diet (control, n=7) for 12-16 wks. Before beginning the diet, either two low doses of i.p. streptozotocin (T2D, 35mg/kg week 1, 25mg/kg week 2) or two i.p. saline injections (control) were administered. A precollicular decerebration was performed, and the left L4 and L5 ventral roots were electrically stimulated to evoke hindlimb skeletal muscle contractions. Renal sympathetic nerve activity (RSNA) and BP responses to activation of the EPR were assessed before, and post 1 and 2hr intracerebroventricular (ICV) insulin injection (500mU, 50nL). Fasting blood glucose was measured before experiments. Data were evaluated by Two-way Repeated Measures ANOVA or Student’s t-test. Results: Fasting blood glucose was significantly higher in T2D as compared to control rats (T2D 150±55 mg/dL vs 100±16 mg/dL, P=0.0353). In the T2D group, the BP and RSNA responses to contraction were significantly attenuated at 1hr post-ICV insulin (ΔMAP Pre [36±14 mmHg] vs 1hr post [21±14 mmHg], P=0.0002; ΔRSNA Pre [107.5±40%], vs 1hr post [75.4±46%], P=0.0043), and then further attenuated at 2hr post (ΔMAP 1hr [21±14 mmHg] vs 2hr [11±6 mmHg], P= 0.0155; ΔRSNA 1hr [75.4±46%] vs 2hr [51±35%], P=0.0363). There were no differences in pressor or sympathetic responses observed in the control group post-ICV insulin. Conclusion: The data demonstrate that brain insulin normalizes the potentiated BP and RSNA responses to muscle contraction in T2D rats. Thus, impaired insulin signaling within cardiovascular control centers of the brain may underlie the augmented EPR in T2D rats. Central insulin treatment may potentially restore normal autonomic function in part by decreasing neuronal excitability in T2D. Supported by NIH-NHLBI, Lawson & Rogers Lacy Research Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Skeletal muscle reflexes play a crucial role in determining the magnitude of the cardiovascular response to exercise. However, evidence supporting an association between the magnitude of the pressor response and velocity of muscle deformation has remained to be elucidated. Thus, we investigated the impact of different muscle deformation rates on the neural discharge of muscle afferents as well as pressor and sympathetic responses in Sprague-Dawley rats. In an ex vivo muscle-nerve preparation, action potentials elicited by sinusoidal mechanical stimuli (137 mN) at different frequencies (0.01, 0.05, 0.1, 0.2, and 0.25 Hz) were recorded in mechanosensitive group III and IV fibers. The afferent response magnitude to sine-wave stimulation significantly varied at different frequencies (ANOVA, P=0.025). Specifically, as compared to 0.01 Hz (0.83±0.96 spikes/s), the response magnitudes were significantly greater at 0.20 Hz (4.07±5.04 spikes/s, P=0.031) and 0.25 Hz (4.91±5.30 spikes/s, P=0.014). In an in vivo decerebrated rat preparation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch (1kg) of hindlimb skeletal muscle at different velocities of loading (slow, medium, fast) was measured. Pressor responses to passive stretch were significantly associated with velocity of muscle deformation (ANOVA, P

Postmenopausal women (PMW) display exaggerated increases in blood pressure (BP) during exercise, yet the mechanism(s) involved remain unclear. Moreover, research on the impact of menopausal changes in estradiol on cardiovascular control during exercise are limited. Herein, we tested the hypothesis that sympathetic responses during exercise are augmented in PMWcompared with young women (YW), and estradiol administration attenuates these responses.Muscle sympathetic nerve activity (MSNA) and mean arterial pressure (MAP) were measured in 13 PMW (58 ± 1 yr) and 17 YW (22 ± 1 yr) during 2 min of isometric handgrip. Separately, MSNA and BP responses were measured during isometric handgrip in six PMW (53 ± 1 yr) before and after 1 month of transdermal estradiol (100 μg·d-1). A period of postexercise ischemia (PEI) to isolate muscle metaboreflex activation followed all handgrip bouts.Resting MAP was similar between PMW and YW, whereas MSNA was greater in PMW (23 ± 3 vs 8 ± 1 bursts per minute; P0.05). During handgrip, the increases in MSNA (PMW Δ16 ± 2 vs YW Δ6 ± 1 bursts per minute; P0.05) and MAP (PMW Δ18 ± 2 vs YW Δ12 ± 2 mm Hg; P0.05) were greater in PMW and remained augmented during PEI. Estradiol administration decreased resting MAP but not MSNA in PMW. Moreover, MSNA (PMW (-E2) Δ27 ± 8 bursts per minute versus PMW (+E2) Δ12 ± 5 bursts per minute; P0.05) and MAP (Δ31 ± 8 mm Hg vs Δ20 ± 6 mm Hg; P0.05) responses during handgrip were attenuated in PMW after estradiol administration. Likewise, MAP responses during PEI were lower after estradiol.These data suggest that PMW exhibit an exaggerated MSNA and BP response to isometric exercise, due in part to heightened metaboreflex activation. Furthermore, estradiol administration attenuated BP and MSNA responses to exercise in PMW.

Current guidelines recommend blood pressure (BP) target based on office BP taken in a seated position for hypertensive patients. However, the accuracy of standing BP measurements for determining blood pressure control in patients with autonomic (ATF) is unknown.We measured BP in seated and standing positions in 47 hypertensive and normotensive adults with ATF. Office BP was measured in the seated position 3 times and after standing for 3 minutes. Adequate BP control was defined by 24-hour ambulatory SBP/DBP of < 125/75 mmHg. Area under receiver operator characteristic curve (AUROC) was calculated to determine accuracy of seated and standing BP in assessing BP control. Bayes factor (BF) was used to assess the significance of the difference between AUROC of seated and standing BP. Sensitivity and specificity of standing BP in determining blood pressure control was derived using cut-off points derived from Youden’s Index.Prevalence of HTN was 72% (34/47) and the mean age was 71 ± 11 years. Sensitivity and specificity of seated SBP was 65% and 73%, respectively. Optimal cutoffs selected by Youden’s index for standing SBP/DBP was 104/83 mmHg. Sensitivity and specificity of standing SBP was 96% and 64%, respectively. The AUROC of standing SBP was significantly higher when compared to seated SBP alone, when controlled SBP was defined as 24-Hr SBP < 125 mmHg (BF > 3). Similarly, when controlled SBP was defined as daytime SBP < 130 mmHg, the AUROC of 3 rd standing was significantly higher when compared to seated SBP alone or in combination (BF > 3).In conclusion, standing SBP is more useful than seated SBP in assessing BP control in patients with ATF.

Previous studies have shown standard deviation (SD) of daytime ambulatory systolic BP (DaySBP) as a screening tool for detecting autonomic failure. While ambulatory arterial stiffness index (AASI) has shown to be a predictor of cardiovascular morbidity and mortality, the usefulness of AASI in detecting the presence of autonomic failure has not been investigated. We assessed AASI in 336 hypertensive and normotensive adults with and without autonomic failure (ATF). Area under receiver operator characteristic curve (AUROC) was calculated to determine accuracy of AASI in detecting ATF. Bayes factor (BF) was used to assess the significance of the difference between AUROC of AASI compared to SD daytime SBP and AASI combined with SD daytime SBP compared to SD daytime SBP alone. Sensitivity and specificity of AASI in detecting autonomic failure was derived using cut-off points from Youden’s Index. Prevalence of ATF in our cohort was 14 % (47/336). The prevalence of HTN was 55 % (184/336). The mean age of the ATF group was higher than the control group (71 ± 11 vs. 61 ± 14 years, respectively, p < 0.05). The mean AASI of ATF patients was higher than control group (0.58 ± 0.11 vs. 0.51 ± 0.15, respectively, p < 0.05). The AUROC of AASI in ATF detection was not significantly higher than SD daytime SBP (BF =0.12). Sensitivity and specificity of AASI was 87 % and 43 %, respectively. The optimal cutoff for AASI selected by Youden’s index was 0.48. The addition of AASI to SD daytime SBP significantly improved ATF detection compared to AASI alone (BF > 3, Fig 1). In conclusion, AASI in combination with SD DaySBP significantly outperformed AASI alone in detecting autonomic failure in patients with or without HTN.

Clinical guidelines recommend office blood pressures (BP) to be taken in a seated position. However, the accuracy of standing BP measurements for diagnosing hypertension (HTN) has not been investigated. We assessed BP in both seated and standing positions in 125 healthy adults not on anti-HTN medications. HTN was defined by 24-hour ambulatory SBP/DBP of ≥ 125/75 mmHg. Area under receiver operator characteristic curve (AUROC) was calculated to determine accuracy of seated and standing BP in diagnosing HTN. Bayes factor (BF) was used to assess the significance of the difference between AUROC of seated and standing BP. Sensitivity and specificity of standing BP in diagnosing HTN was derived using cut-off points derived from Youden’s Index. Our cohort’s mean age was 49 ± 17 years, with 62% female (77 of 125), and 24% Black (30 of 125). Prevalence of HTN was 33.6% (42 of 125). Sensitivity and specificity of seated SBP was 43% and 92%, respectively. Optimal cutoffs selected by Youden’s index for standing SBP/DBP was 124/81 mmHg. Sensitivity and specificity of standing SBP was 74% and 65%, respectively. The AUROC of standing SBP was significantly higher than seated SBP (BF =11.8), when HTN was defined as 24-Hr SBP ≥ 125 mmHg (Fig 1). Similarly, when HTN was defined as 24-Hr DBP ≥ 75 mmHg or daytime DBP ≥ 80 mmHg, the AUROC of standing DBP was higher than seated DBP (all BF >3). The addition of standing to seated BP improved HTN detection than seated BP alone based on 24-Hr SBP/DBP ≥ 125/75 mmHg or daytime SBP/DBP ≥ 130/80 mmHg (all BF >3). In conclusion, standing office BPs both alone and in combination with seated BPs, outperformed seated BPs in diagnosing hypertension in untreated adults.

The blood pressure response to exercise is exaggerated in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2DM is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2DM rats. Additionally, TRPV1 and protein kinase C (PKC) protein levels in dorsal root ganglia (DRG) subserving skeletal muscle were assessed. For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or high fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2DM). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic neve activity in decerebrated T2DM than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2DM was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high glucose environment. T2DM showed significantly increased phospholyrated-TRPV1 and −PKCα levels in DRG neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early-stage T2DM with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

BACKGROUND Renal denervation (RDN) is effective at lowering blood pressure. However, it is unknown if ablative procedures elicit sympathetic denervation of the kidneys in humans. The aim of this investigation was to assess sympathetic innervation of the renal cortex following perivascular chemical RDN, which may be particularly effective at ablating perivascular efferent and afferent nerves. METHODS Seven hypertensive patients (4F:3M; 50–65 years) completed PET–CT sympathetic neuroimaging of the renal cortex using 11C-methylreboxetine (11C-MRB, norepinephrine transporter ligand) and 6-[18F]-fluorodopamine (18F-FDA; substrate for the cell membrane norepinephrine transporter) before and 8 weeks after chemical RDN (Peregrine System Infusion Catheter, Ablative Solutions; n = 4; 2F:2M) or control renal angiography (n = 3; 2F:1M). Patients completed physiological phenotyping including 24-hour ambulatory blood pressure, hemodynamics, muscle sympathetic nerve activity, and 24-hour urine collection. RESULTS RDN decreased 11C-MRB-derived radioactivity by ~30% (Δ 11C-MRB/chamber: −0.95 a.u. confidence interval (CI): −1.36 to −0.54, P = 0.0002), indicative of efferent RDN. In contrast, 18F-FDA-derived radioactivity increased (Δ 18F-FDA/chamber: 2.72 a.u. CI: 0.73–4.71, P = 0.009), consistent with reduced vesicular turnover. Controls showed no change in either marker. Ambulatory systolic pressure decreased in 3 of 4 patients (−9 mm Hg CI: −27 to 9, P = 0.058), and central systolic pressure decreased in all patients (−23 mm Hg CI: −51 to 5, P = 0.095). CONCLUSIONS These results are the first to show efferent sympathetic denervation of the renal cortex following RDN in humans. Further studies of mechanisms underlying variable blood pressure lowering in the setting of documented RDN may provide insights into inconsistencies in clinical trial outcomes. CLINICAL TRIALS REGISTRATION Trial Number NCT03465917.

Background: SGLT2i (sodium-glucose cotransporter 2 inhibitor), a class of anti-diabetic medications, is shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes. Mechanisms underlying this action are unknown but SGLT2i-induced sympathoinhibition is thought to play a role. Whether SGLT2i reduces BP and sympathetic nerve activity (SNA) in a nondiabetic prehypertension model is unknown. Methods: Accordingly, we assessed changes in conscious BP using radiotelemetry and alterations in mean arterial pressure and renal SNA during simulated exercise in nondiabetic spontaneously hypertensive rats during chronic administration of a diet containing dapagliflozin (0.5 mg/kg per day) versus a control diet. Results: We found that dapagliflozin had no effect on fasting blood glucose, insulin, or hemoglobin A 1C levels. However, dapagliflozin reduced BP in young (8-week old) spontaneously hypertensive rats as well as attenuated the age-related rise in BP in adult spontaneously hypertensive rat up to 17-weeks of age. The rises in mean arterial pressure and renal SNA during simulated exercise (exercise pressor reflex activation by hindlimb muscle contraction) were significantly reduced after 4 weeks of dapagliflozin (Δmean arterial pressure: 10±7 versus 25±14 mm Hg, Δrenal SNA: 31±17% versus 68±39%, P Conclusions: These data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of glycemic control. Our study may have important clinical implications for preventing hypertension and hypertensive heart disease in young prehypertensive individuals.

Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n = 407). Sites differed in their prevalence of polypharmacy, χ2(3) = 56.0, p

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

The updated scientific statement by the American Heart Association has defined resistant hypertension (HTN;RH) as uncontrolled blood pressure (BP) ≥ 130/80 mmHg, despite concurrent use of 3 anti-HTN drug classes comprising a calcium channel blocker, a blocker of renin-angiotensin system, and a thiazide diuretic, preferably chlorthalidone. Using the updated BP criteria, the prevalence of RH in the United States is found to be modestly increased by approximately 3–4% among treated population. Meta-analysis of observational studies have demonstrated that pseudo-RH from white coat HTN or medication nonadherence is as much common as the truly RH. Thus, screening for pseudo-resistance in the evaluation of all apparent RH is of utmost importance as diagnosis of white-coat HTN requires no treatment, while medication nonadherence would benefit from identifying and targeting barriers to adherence.

Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. KEY POINTS: Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.

The widespread treatment of hypertension and resultant improvement in blood pressure have been major contributors to the dramatic age-specific decline in heart disease and stroke. Despite this progress, a persistent gap remains between stated public health targets and achieved blood pressure control rates. Many factors may be important contributors to the gap between population hypertension control goals and currently observed control levels. Among them is the extent to which patients adhere to prescribed treatment. The goal of this scientific statement is to summarize the current state of knowledge of the contribution of medication nonadherence to the national prevalence of poor blood pressure control, methods for measuring medication adherence and their associated challenges, risk factors for antihypertensive medication nonadherence, and strategies for improving adherence to antihypertensive medications at both the individual and health system levels.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia. The relationship of sFlt-1 with markers of subclinical atherosclerosis and future atherosclerotic cardiovascular disease (ASCVD) events in a generally healthy population is unknown.Participants in the Dallas Heart Study with sFlt-1 measured were included (n = 3292). Abdominal aortic atherosclerosis was measured by MRI and coronary artery calcium (CAC) by CT. The cohort was also followed for subsequent ASCVD events (CV death, MI, stroke, unstable angina, revascularization). Multivariable linear and logistic regression analyses and Cox regression analyses were performed adjusting for demographics and traditional cardiac risk factors.sFlt-1 levels were higher in older individuals, males, and African Americans, and tracked with most traditional risk factors. sFlt-1 was significantly associated with higher prevalence of aortic plaque [OR 1.33 (95% CI 1.02-1.73)], greater abdominal aortic wall thickness (p0.01) and aortic plaque area (p0.02) but no difference in coronary artery calcification. There were 322 ASCVD events over 12 years of follow-up. Higher sFlt-1 levels associated with increased ASCVD events in unadjusted (16.1% vs. 8.9%, p0.001, quartile 4 vs. quartile 1) and adjusted analyses (HR 1.58 [1.14-2.18], p0.01, quartile 4 vs. quartile 1). Findings were unchanged when analyzing sFlt-1 as a continuous variable or when excluding those with a history of ASCVD.In a population-based cohort, sFlt-1 is associated with measures of subclinical aortic atherosclerosis and clinical ASCVD events. Future studies are warranted on the therapeutic potential of targeting sFlt-1 for atherosclerotic disease.

Importance National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, setting, and participants The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main outcomes and measures In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and relevance The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Background: Medication nonadherence presents one of the greatest challenges to hypertension management. Previous studies from our group have shown therapeutic drug monitoring (TDM), biochemical monitoring of drug levels, is more accurate than self-report, detailed questionnaires, or prescription fill rate in detecting nonadherence. Prior studies have also shown a prevalence of nonadherence from 45% to 80% among insured patients with uncontrolled hypertension despite having been prescribed a multi-drug regimen. Previous studies have not assessed adherence to antihypertensive drugs in a safety net population by TDM. Methods: We performed a cross-sectional study in patients with uncontrolled hypertension in the primary care Internal Medicine and Cardiology Clinics at Parkland Health& Hospital System (PHHS). Patients with BP of 130/80 mmHg, prescribed ≥2 antihypertensive medications, and self-reporting medication adherence were enrolled after informed consent. Plasma samples were obtained for measurement of 44 cardiovascular drugs using liquid chromatography mass spectrometry. Results: Among 77 patients with uncontrolled hypertension (57% female, 65% Black, 12% Hispanic), 13 (17%) were nonadherent to at least one anti-hypertensive drug by TDM. There was no difference in baseline characteristics between the two groups. The adherent and nonadherent groups had similar systolic (146±13 vs 148±18, p=0.67) and diastolic (83±9 vs 88±10 mmHg, p=0.13) BP. All patients had either medical insurance or some form of prescription financial assistance. 15 patients had prescription financial assistance, while 62 patients had medical insurance. Nonadherence rates for patients on financial assistance programs did not significantly differ from patients with medical insurance (13% vs 18%, p>0.999). Conclusions: We found a surprisingly low prevalence of anti-hypertensive medication nonadherence in this uncontrolled hypertension population despite many barriers to treatment. Our study suggests a lesser role of medication nonadherence in uncontrolled hypertension in the safety net population.

Hypertension affects nearly half of the US population but only 43% achieved blood pressure control with medication alone. Medical devices for hypertension include implantable lead electrodes that stimulate the carotid baroreceptors with promising results, albeit with significant adverse complications. To address these limitations, we have proposed the use of deep peroneal nerve stimulation (DPNS), which elicited a depressor response in anesthetized, breathing supported, spontaneously hypertensive rats (SHR). In this study, we further define the electrical stimulation parameters that optimize the DPNS depressor response, and demonstrated that increasing the pulse duration from 0.15 ms to 1ms, of 1.0 mA pulses at 2 Hz for 10 sec, significantly reduced the mean arterial pressure (MAP) by 8±4 mmHg (p

Patients with diabetes display heightened blood pressure response to exercise but the underlying mechanism are remains to be elucidated. There is no direct evidence that insulin resistance (hyperinsulinemia or hyperglycemia) impact neural cardiovascular control during exercise. We propose a novel paradigm in which hyperinsulinemia or hyperglycemia significantly influence neural regulatory pathways controlling the circulation during exercise in diabetes.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

KEY POINTS Insulin is known to activate the sympathetic nervous system centrally. A mechanical stimulus to tissues activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, we report the novel finding that insulin augments the mechanical responsiveness of thin fibre afferents not only at dorsal root ganglion, but also at muscle tissue levels. Our data suggest that sympathoexcitation is mediated via the insulin-induced mechanical sensitization peripherally. The present study proposes a novel physiological role of insulin in the regulation of mechanical sensitivity in somatosensory thin fibre afferents. ABSTRACT Insulin activates the sympathetic nervous system, although the mechanism underlying insulin-induced sympathoexcitation remains to be determined. A mechanical stimulus to tissues such as skin and/or skeletal muscle, no matter whether the stimulation is noxious or not, activates the sympathetic nervous system via thin fibre afferents. Evidence suggests that insulin modulates putative mechanosensitive channels in the dorsal root ganglion (DRG) neurons of these afferents. Accordingly, we investigated whether insulin augments whole-cell current responses to mechanical stimuli in small DRG neurons of normal healthy mice. We performed whole-cell patch clamp recordings using cultured DRG neurons and observed mechanically-activated (MA) currents induced by mechanical stimuli applied to the cell surface. Local application of vehicle solution did not change MA currents or mechanical threshold in cultured DRG neurons. Insulin (500 mU mL-1 ) significantly augmented the amplitude of MA currents (P

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14–16 wk) in combination with two low doses (35 mg/kg week 1, 25 mg/kg week 2) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664

Background: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. Methods: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. Results: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P =0.01) and increased sedentary time ( P =0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4 , Hsl , Fasn , and Pparγ , in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. Conclusions: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.