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Objective: To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans.Research Design and Methods: We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels.Results: Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R(2) = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R(2) = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R(2) = 0.32).Conclusions: In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population. [ABSTRACT FROM AUTHOR]

Key Points: •  Central sympatholytic drugs reduce blood pressure mainly by stimulating central α(2) -adrenergic receptors in the brainstem centers, thereby reducing sympathetic nerve activity and neuronal release of norepinephrine to the heart and peripheral circulation. •  This class of drugs, however, is currently used mainly as fourth-line (or beyond) drug therapy for hypertension because of side effects of drowsiness, fatigue, and dry mouth. •  Rebound hypertension is also another major concern in certain drugs with a short half-life, particularly in patients who are nonadherent to the regimen. Therefore, their use on a "PRN" basis for treatment of blood pressure surge in the absence of symptoms or acute target complications should also be avoided. [ABSTRACT FROM AUTHOR]

Following a hypertension symposium in Los Angeles in October 2007, a panel was convened to discuss how to treat hypertension in patients with coronary artery disease or with evidence of multiple major risk factors for coronary heart disease. Marvin Moser, MD, Clinical Professor of Medicine at the Yale University School of Medicine, New Haven, CT, moderated the discussion. Jackson T. Wright Jr, MD, PhD, Professor of Medicine, Program Director of William T. Dahms Clinical Research, and Director of the Clinical Hypertension Program at Case Western Reserve University, Cleveland, OH; Ronald G. Victor, MD, Professor and Division Chief, Hypertension, University of Texas Southwestern Medical Center, Dallas, TX; and Joel Handler, MD, Hypertension Lead, Care Management Institute, Kaiser Permanente, Anaheim, CA, participated in the discussion. [ABSTRACT FROM AUTHOR]

Hookah (waterpipe) smoking is a growing tobacco epidemic. Though perceived as a safer tobacco alternative, hookah smoke contains, in addition to tobacco combustion products, large amounts of charcoal combustion products-implicated in cardiovascular disease-from the burning charcoal used to heat the flavored tobacco. To date, little is known on the vascular effects of hookah smoking. The aim of this study was to characterize the peripheral circulatory response to acute hookah smoking in cutaneous and muscular beds. In 21 healthy young adult habitual hookah smokers who did not smoke cigarettes (age 24 ± 1 years, mean ± SE), we measured plasma nicotine, exhaled carbon monoxide, skin blood flow (laser Doppler velocimetry) and calf muscle blood flow (strain-gauge plethysmography) before and for up to 60 minutes after ad lib hookah smoking. In nine subjects, nonsmoking time-control studies were performed. Hookah smoking, which increased plasma nicotine by 5.8 ng/ml (from 0.6 ± 0.1 to 6.4 ± 1.3, p <0.001) and exhaled carbon monoxide by 27 ppm (from 2.7 ± 0.2 to 29.5 ± 2.2, p <0.001), decreased skin blood flow by 23% (20.1 ± 2.8 to 14.8 ± 1.9 units, p <0.001) and increased skeletal muscle blood flow by 34% (2.3 ± 0.1 to 2.9 ± 0.2 units, p = 0.010). These responses required more than one hour to recover after smoking cessation. All cardiovascular parameters were unchanged in the nonsmoking time-control studies. Although perceived to be innocuous, hookah smoking produces acute cutaneous vasoconstriction with skeletal muscle vasodilation, a dissociated pattern of peripheral blood flow responses that is characteristic of nicotine and carbon monoxide. In conclusion, these findings provide objective evidence to challenge the perception that hookah smoking is a safer tobacco alternative., (Copyright © 2020 Elsevier Inc. All rights reserved.)

neuECG, the simultaneous noninvasive recording of ECG and skin sympathetic nerve activity (SKNA), directly records sympathetic nerve activity over a long period of time. It can be used to measure sympathetic tone in healthy subjects and in subjects with non-cardiovascular diseases. The electrical activity that can be measured on the surface of the skin originates from the heart, the muscle or nerve structures. Because the frequency content of nerve activity falls in a higher frequency range than that of the ECG and myopotential, it is possible to use high-pass or band-pass filtering to specifically isolate the SKNA. neuECG is voltage calibrated and does not require invasive procedures to impale electrodes in nerves and thus has advantages over microneurography. Here, we present a protocol that takes <10 min to set up. The neuECG can be continuously recorded over a 24-h period or longer. We also describe methods to efficiently analyze neuECG from humans using commercially available hardware and software to facilitate adoption of this technology in clinical research.

Background: Uncontrolled hypertension contributes to disparities in cardiovascular outcomes. Patient intervention strategies informed by behavioral economics and social psychology could improve blood pressure (BP) control in disadvantaged minority populations., Objective: To assess the impact on BP control of an intervention combining short-term financial incentives with promotion of intrinsic motivation among highly disadvantaged patients., Design: Randomized controlled trial., Participants: Two hundred seven adults (98% African American or Latino) aged 18 or older with uncontrolled hypertension attending Federally Qualified Health Centers., Intervention: Six-month intervention, combining financial incentives for measuring home BP, recording medication use, BP improvement, and achieving target BP values with counseling linking hypertension control efforts to participants' personal reasons to stay healthy., Main Measures: Primary outcomes: percentage achieving systolic BP (SBP) < 140 mmHg, percentage achieving diastolic BP (DBP) < 90 mmHg, and changes in SBP and DBP, all after 6 months. Priority secondary outcomes were SBP < 140 mmHg, DBP < 90 mmHg, and BP change at 12 months, 6 months after the intervention ended., Key Results: After 6 months, rates of achieving target BP values for intervention and control subjects respectively was 57.1% vs. 40.2% for SBP < 140 mmHg (adjusted odds ratio (AOR) 2.53 (1.13-5.70)), 79.8% vs 70.1% for DBP < 90 mmHg (AOR 2.50 (0.84-7.44)), and 53.6% vs 40.2% for achieving both targets (AOR 2.04 (0.92-4.52)). However, at 12 months, the groups did not differ significantly in these 3 measures: 39.5% vs 35.0% for SBP (AOR 1.20 (0.51-2.83)), 68.4% vs 75.0% for DBP (AOR 0.70 (0.24-2.09)), and 35.5% vs 33.8% for both (AOR 1.03 (0.44-2.42)). Change in absolute SBP and DBP did not differ significantly between the groups at 6 or 12 months. Exploratory post hoc analysis revealed intervention benefit only occurred among individuals whose providers intensified their regimens, but not among those with intensification but no intervention., Conclusions: The intervention achieved short-term improvement in SBP control in a highly disadvantaged population. Despite attempts to enhance intrinsic motivation, the effect was not sustained after incentives were withdrawn. Future research should evaluate combined patient/provider strategies to enhance such interventions and sustain their benefit., Trial Registration: NCT01402453; http://clinicaltrials.gov/show/NCT01402453.

Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34-1.64 for out-of-office systolic BP and 1.15 [1.04-1.28] for clinic systolic BP; 1.71 [1.43-2.05] for out-of-office diastolic BP, and 1.03 [0.86-1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00344903.

Background: Hookah smoking is marketed to youth as a harmless alternative to cigarettes. Although cigarette smoking acutely impairs endothelial function, the effect of smoking fruit-flavored hookah tobacco is unknown. Because charcoal traditionally is used to heat the hookah tobacco in the waterpipe, hookah smoke delivers tobacco toxicants and nicotine plus charcoal combustion products: not only carbon-rich nanoparticles, oxidants that may destroy nitric oxide and impair endothelial function, but also large amounts of carbon monoxide (CO), a putative vasodilator molecule., Methods: To test the acute effect of hookah smoking on endothelial function, in young adult hookah smokers (n=30, age 26±1 years, mean±SE), we measured plasma nicotine, exhaled CO, and brachial artery flow-mediated dilation (FMD) before and after charcoal-heated hookah smoking. To remove the effect of charcoal combustion, the same measurements were performed when the same flavored hookah tobacco product was heated electrically (n=20). As a positive internal control, we studied age-matched cigarette smokers (n=15) who smoked 1 cigarette. To isolate the effect of the CO boost on FMD, hookah smokers (n=8) inhaled a 0.1% CO gas mixture to approximate their CO boost achieved with charcoal-heated hookah smoking., Results: Nicotine levels increased similarly with all types of smoking, whereas exhaled CO increased 9- to 10-fold more after charcoal-heated hookah than after either electrically heated hookah or cigarette smoking. FMD did not decrease after smoking charcoal-heated hookah but instead increased by +43±7% ( P<0.001). In contrast, FMD decreased by -27±4% ( P<0.001) after smoking electrically heated hookah, comparable to the decrease after cigarette smoking. FMD increased markedly by 138±71% ( P<0.001) after breathing CO gas, 2.8 times more than the increase induced in the same subjects after smoking charcoal-heated hookah ( P<0.001), despite comparable increases in exhaled CO (24±1 versus 28±3 ppm, hookah versus CO)., Conclusions: Smoking hookah tobacco, similar to cigarette tobacco, acutely impairs endothelial function. With traditional charcoal-heated hookah smoking, the acute endothelial dysfunction is masked by high levels of carbon monoxide, a potent vasodilator molecule generated by charcoal combustion. With respect to large-artery endothelial function, smoking hookah is not harmless., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT03616002 and NCT03067701.

Background Hypertension is assumed to be asymptomatic. Yet, clinically significant nocturia (≥2 nightly voids) constitutes a putative symptom of uncontrolled hypertension. Black men with hypertension may be prone to nocturia because of blunted nocturnal blood pressure ( BP ) dipping, diuretic drug use for hypertension, and comorbidity that predisposes to nocturia. Here, we test the hypothesis that nocturia is a common and potentially reversible symptom of uncontrolled hypertension in black men. Methods and Results We determined the strength of association between nocturia (≥2 nightly voids) and high BP (≥135/85 mm Hg) by conducting in-person health interviews and measuring BP with an automated monitor in a large community-based sample of black men in their barbershops. Because nocturia is prevalent and steeply age-dependent after age 50 years, we studied men aged 35 to 49 years. Among 1673 black men (mean age, 43±4 years [ SD ]), those with hypertension were 56% more likely than men with normotension to have nocturia after adjustment for diabetes mellitus and sleep apnea (adjusted odds ratio, 1.56; 95% CI , 1.25-1.94 [ P<0.0001]). Nocturia prevalence varied by hypertension status, ranging from 24% in men with normotension to 49% in men whose hypertension was medically treated but uncontrolled. Men with untreated hypertension were 39% more likely than men with normotension to report nocturia ( P=0.02), whereas men whose hypertension was treated and controlled were no more likely than men with normotension to report nocturia ( P=0.69). Conclusions Uncontrolled hypertension was an independent determinant of clinically important nocturia in a large cross-sectional community-based study of non-Hispanic black men aged 35 to 49 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unqiue identifier: NCT 02321618.

Objective: To assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD)., Methods: The Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL)., Results: Twenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls ( p = 0.007)., Conclusions: Intracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted., Classification of Evidence: This phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: We developed a new model of hypertension care for non-Hispanic black men that links health promotion by barbers to medication management by American Society of Hypertension-certified pharmacists and demonstrated efficacy in a 6-month cluster-randomized trial. The marked reduction in systolic blood pressure (BP) seen at 6 months warranted continuing the trial through 12 months to test sustainability, a necessary precondition for implementation research., Methods: We enrolled a cohort of 319 black male patrons with systolic BP ≥140 mm Hg at baseline. Fifty-two Los Angeles County barbershops were assigned to either a pharmacist-led intervention or an active control group. In the intervention group, barbers promoted follow-up with pharmacists who prescribed BP medication under a collaborative practice agreement with patrons' primary care providers. In the control group, barbers promoted follow-up with primary care providers and lifestyle modification. After BP assessment at 6 months, the intervention continued with fewer in-person pharmacist visits to test whether the intervention effect could be sustained safely for 1 year while reducing pharmacist travel time. Final BP and safety outcomes were assessed in both groups at 12 months., Results: At baseline, mean systolic BP was 152.4 mm Hg in the intervention group and 154.6 mm Hg in the control group. At 12 months, mean systolic BP fell by 28.6 mm Hg (to 123.8 mm Hg) in the intervention group and by 7.2 mm Hg (to 147.4 mm Hg) in the control group. The mean reduction was 20.8 mm Hg greater in the intervention (95% CI, 13.9-27.7; P<0.0001). A BP <130/80 mm Hg was achieved by 68.0% of the intervention group versus 11.0% of the control group ( P<0.02). These new 12-month efficacy data are statistically indistinguishable from our previously reported 6-month data. No treatment-related serious adverse events occurred in either group over 12 months. Cohort retention at 12 months was 90% in both groups., Conclusions: Among black male barbershop patrons with uncontrolled hypertension, health promotion by barbers resulted in large and sustained BP reduction over 12 months when coupled with medication management by American Society of Hypertension-certified pharmacists. Broad-scale implementation research is both justified and warranted., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02321618.

Most guidelines have recommended lower home blood pressure (BP) threshold when clinic BP threshold of 140/90 mm Hg is used for diagnosis of hypertension. However, home BP thresholds to define hypertension have never been determined in the general population in the United States. We identified home BP thresholds for stage 1 (BP ≥130/80 mm Hg) hypertension using a regression-based approach in the DHS (Dallas Heart Study; n=5768) and the NCMH study (North Carolina Masked Hypertension; n=420). Home BP thresholds were also assessed using outcome-derived approach based on the composite of all-cause mortality or cardiovascular events in the DHS cohort. For this approach, BP thresholds were identified only for systolic BP because diastolic BP was not associated with the outcome. Among untreated participants, the regression-derived thresholds for home BP corresponding to clinic BP for stage 1 hypertension were 129/80 mm Hg in blacks, 130/80 mm Hg in whites, and 126/78 mm Hg in Hispanics, respectively. The results are similar in the North Carolina cohort. The 11-year composite cardiovascular and mortality events corresponding to clinic systolic BP >130 mm Hg were higher in blacks than in whites and Hispanics (13.3% versus 5.98% versus 5.52%, respectively). Using a race/ethnicity-specific composite outcome in the untreated DHS participants, the outcome-derived home systolic BP thresholds corresponding to stage 1 hypertension were 130 mm Hg in blacks, 129 mm Hg in whites, and 131 mm Hg in Hispanics, respectively. Our data based on both regression-derived and outcome approach support home BP threshold of 130/80 mm Hg for diagnosis of hypertension in blacks, whites, and Hispanics.

Hookah (waterpipe) smoking is rapidly increasing in popularity worldwide. Despite being heavily advertised in the media as a healthier alternative to cigarettes, the toxicology of hookah smoke suggest otherwise. Cigarette smoking unequivocally causes an acute increase in arterial stiffness, but whether hookah does the same is unknown. In 48 young healthy habitual hookah but not cigarette smokers, we measured heart rate, peripheral and central blood pressure, carotid-femoral pulse wave velocity (measure of arterial stiffness), aortic augmentation index (measure of wave reflection), plasma nicotine, and exhaled carbon monoxide before and after ad lib hookah smoking. Hookah smoking increased heart rate by +16 ± 1 beats/min and mean brachial arterial pressure by +6 ± 1 mm Hg (both p <0.05, mean ± SE). Most importantly, it increased carotid-femoral pulse wave velocity and aortic augmentation index by +0.66 ± 0.09 m/s -1 and +8.76 ± 3.99%, respectively (p <0.05, mean ± SE), denoting increased acute arterial stiffness. These vascular effects were accompanied by increases in plasma nicotine concentration (+5.8 ± 1.2 ng/ml, p <0.05) and expired carbon monoxide (+25.44 ± 1.68 ppm, p <0.05). All these parameters were unchanged during time-control studies (n = 14). Thus, in contrast to effective media marketing of hookah as a safer alternative to cigarettes, the present study shows for the first time that in young adult hookah smokers, a single hookah smoking session causes an acute increase in arterial stiffness of comparable magnitude to what has been previously reported for cigarettes. Further research is warranted to determine whether habitual hookah smoking accelerates the age-dependent development of hypertension and its cardiovascular complications., (Copyright © 2018. Published by Elsevier Inc.)

Background: Uncontrolled hypertension is a major problem among non-Hispanic black men, who are underrepresented in pharmacist intervention trials in traditional health care settings., Methods: We enrolled a cohort of 319 black male patrons with systolic blood pressure of 140 mm Hg or more from 52 black-owned barbershops (nontraditional health care setting) in a cluster-randomized trial in which barbershops were assigned to a pharmacist-led intervention (in which barbers encouraged meetings in barbershops with specialty-trained pharmacists who prescribed drug therapy under a collaborative practice agreement with the participants’ doctors) or to an active control approach (in which barbers encouraged lifestyle modification and doctor appointments). The primary outcome was reduction in systolic blood pressure at 6 months., Results: At baseline, the mean systolic blood pressure was 152.8 mm Hg in the intervention group and 154.6 mm Hg in the control group. At 6 months, the mean systolic blood pressure fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group and by 9.3 mm Hg (to 145.4 mm Hg) in the control group; the mean reduction was 21.6 mm Hg greater with the intervention (95% confidence interval, 14.7 to 28.4; P<0.001). A blood-pressure level of less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% of the participants in the control group (P<0.001). In the intervention group, the rate of cohort retention was 95%, and there were few adverse events (three cases of acute kidney injury)., Conclusions: Among black male barbershop patrons with uncontrolled hypertension, health promotion by barbers resulted in larger blood-pressure reduction when coupled with medication management in barbershops by specialty-trained pharmacists. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT02321618 .).

Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD)., Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg -1 ·d -1 , tadalafil 0.6 mg·kg -1 ·d -1 , or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome., Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil ( p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil ( p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state., Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age., Clinicaltrialsgov Identifier: NCT01865084., Classification of Evidence: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (S I ) in a nonhypertensive obese canine model. S I was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 ± 0.6 vs. 0.7 ± 0.6 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L - 1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L -1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic S I in HFD-fed animals (1.8 ± 0.3 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L -1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor α through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic S I in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a new therapeutic target to counteract insulin resistance., (© 2016 by the American Diabetes Association.)

Hookah (water pipe) smoking is a major new understudied epidemic affecting youth. Because burning charcoal is used to heat the tobacco product, hookah smoke delivers not only nicotine but also large amounts of charcoal combustion products, including carbon-rich nanoparticles that constitute putative coronary vasoconstrictor stimuli and carbon monoxide, a known coronary vasodilator. We used myocardial contrast echocardiography perfusion imaging with intravenous lipid shelled microbubbles in young adult hookah smokers to determine the net effect of smoking hookah on myocardial blood flow. In 9 hookah smokers (age 27 ± 5 years, mean ± SD), we measured myocardial blood flow velocity (β), myocardial blood volume (A), myocardial blood flow (A × β) as well as myocardial oxygen consumption (MVO2) before and immediately after 30 minutes of ad lib hookah smoking. Myocardial blood flow did not decrease with hookah smoking but rather increased acutely (88 ± 10 to 120 ± 19 a.u./s, mean ± SE, p = 0.02), matching a mild increase in MVO2 (6.5 ± 0.3 to 7.6 ± 0.4 ml·minute(-1), p <0.001). This was manifested primarily by increased myocardial blood flow velocity (0.7 ± 0.1 to 0.9 ± 0.1 second(-1), p = 0.01) with unchanged myocardial blood volume (133 ± 7 to 137 ± 7 a.u., p = ns), the same pattern of coronary microvascular response seen with a low-dose β-adrenergic agonist. Indeed, with hookah, the increased MVO2 was accompanied by decreased heart rate variability, an indirect index of adrenergic overactivity, and eliminated by β-adrenergic blockade (i.v. propranolol). In conclusion, nanoparticle-enriched hookah smoke either is not an acute coronary vasoconstrictor stimulus or its vasoconstrictor effect is too weak to overcome the physiologic dilation of coronary microvessels matching mild cardiac β-adrenergic stimulation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Noninvasive blood pressure (BP) measurement often triggers a transient rise in BP, known as an alerting reaction. However, the prevalence and prognostic significance of the alerting reaction has never been assessed in the general population., Methods: We evaluated the association between the alerting reaction and left ventricular mass by MRI and urinary albumin-to-creatinine ratio in the Dallas Heart Study, a large population sample of 3069 individuals. Participants were categorized into four groups based on levels of consecutive BP: first, normal first BP and average third to fifth (avg3-5) BP of less than 140/90 mmHg (control group); second, high first BP of at least 140/90 mmHg and normal (avg3-5) BP (alerting reaction group); third, normal first BP and high (avg3-5) BP; and fourth, high first to fifth BP. Then, associations between BP categories with incident cardiovascular outcomes (coronary heart disease, stroke, atrial fibrillation, heart failure, and cardiovascular death) over a median follow-up period of 9.4 years were assessed., Results: The sample-weighted prevalence of isolated hypertension during the first BP measurement was 9.6%. Presence of an alerting reaction was independently associated with increased left ventricular mass, urinary albumin-to-creatinine ratio, cardiovascular events after adjustment for traditional cardiovascular risk factors, and baseline BP (adjusted hazard ratio 1.24, 95% confidence interval 1.07-1.43)., Conclusion: Our study indicated that the alerting reaction is independently associated with increased cardiovascular and renal complications., Competing Interests: None

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSμ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSμ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Background: Only half of hypertensive adults achieve blood pressure (BP) control in the United States, and it is unclear how BP control rates may be improved most effectively and efficiently at the population level., Objective: We sought to compare the potential effects of system-wide isolated improvements in medication adherence, visit frequency, and higher physician prescription rate on achieving BP control at 52 weeks., Design: We developed a Markov microsimulation model of patient-level, physician-level, and system-level processes involved in controlling hypertension with medications. The model is informed by data from national surveys, cohort studies and trials, and was validated against two multicenter clinical trials (ALLHAT and VALUE)., Subjects: We studied a simulated, nationally representative cohort of patients with diagnosed but uncontrolled hypertension with a usual source of care., Interventions: We simulated a base case and improvements of 10 and 50%, and an ideal scenario for three modifiable parameters: visit frequency, treatment intensification, and medication adherence. Ideal scenarios were defined as 100% for treatment intensification and adherence, and return visits occurring within 4 weeks of an elevated office systolic BP., Main Outcome: BP control at 52 weeks of follow-up was examined., Results: Among 25,000 hypothetical adult patients with uncontrolled hypertension (systolic BP ≥ 140 mmHg), only 18% achieved BP control after 52 weeks using base-case assumptions. With 10/50%/idealized enhancements in each isolated parameter, enhanced treatment intensification achieved the greatest BP control (19/23/71%), compared with enhanced visit frequency (19/21/35%) and medication adherence (19/23/26%). When all three processes were idealized, the model predicted a BP control rate of 95% at 52 weeks., Conclusion: Substantial improvements in BP control can only be achieved through major improvements in processes of care. Healthcare systems may achieve greater success by increasing the frequency of clinical encounters and improving physicians' prescribing behavior than by attempting to improve patient adherence to medications.

Arterial baroreceptors are mechanosensitive sensory nerve endings in the walls of the carotid sinuses and aortic arch that buffer the increases and decreases in arterial blood pressure. Electrical field stimulation of the carotid sinus, known as carotid baroreflex activation therapy, holds promise as a novel device-based intervention to supplement, but not replace, drug therapy for patients with resistant hypertension. Acute electrical field stimulation of even one carotid sinus can cause a sufficiently large reflex decrease in blood pressure to overcome offsetting reflexes from the contralateral carotid baroreceptors and aortic baroreceptors that are not paced. However, the initial phase III Rheos Pivotal Trial on continuous carotid baroreceptor pacing for resistant hypertension with the first-generation baroreceptor pacemaker yielded equivocal data on efficacy and adverse effects due to facial nerve injury during surgical implantation. A miniaturized second-generation pacing electrode has seemingly overcome the safety issue, and early results with the new device suggest efficacy of unilateral carotid sinus stimulation in heart failure. A phase III trial of this new device for resistant hypertension has been registered.

Objective: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD)., Methods: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil., Results: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD., Conclusions: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD., Classification of Evidence: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis., (© 2014 American Academy of Neurology.)

Black men have less physician contact than other groups and thus lower rates of hypertension treatment and control. In the Barber-Assisted Reduction in Blood Pressure among Ethnic Residents trial, hypertension control in 8 active-intervention barbershops where barbers offered blood pressure (BP) checks with haircuts and motivated black male patrons with high BP to seek provider follow-up showed a small improvement over that in 7 comparison shops where patrons received hypertension pamphlets but not barber-BP checks. Undertreatment of hypertension, which is common in primary care, may have impacted the outcomes. Thus, in patrons with a baseline systolic BP of ≥140 mm Hg and 10-month follow-up including BP and medication data, we performed post hoc comparison of systolic BP reduction between comparison-arm patrons (n = 68) treated by primary care providers (PCPs) with (1) intervention-arm patrons (n = 37) treated by PCPs or (2) intervention-arm patrons (n = 33) who lacked access to PCPs and were treated by hypertension specialist physicians serving as safety net providers. The latter group had higher baseline systolic BP than the others (162 ± 3 vs 155 ± 2 and 154 ± 2 mm Hg, respectively, p <0.01). After adjustment for baseline systolic BP and other covariates, systolic BP reduction was 21 ± 4 mm Hg greater than in the comparison group (p <0.0001), when barbers referred patrons to hypertension specialists but was no different when they referred to PCPs (4 ± 4 mm Hg, p = 0.31). Specialist-treated patrons received more BP medication and different classes of medication than PCP-treated patrons. In conclusion, the barber-based intervention-if connected directly to specialty-level medical care-could have a large public health impact on hypertensive disease in black men., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Generalized lipodystrophy is a rare disorder characterized by marked loss of adipose tissue with reduced triglyceride storage capacity, leading to a severe form of metabolic syndrome including hypertriglyceridemia, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. Recent echocardiographic studies suggest that concentric left ventricular (LV) hypertrophy is another characteristic feature of this syndrome, but the mechanism remains unknown. It has recently been hypothesized that the LV hypertrophy could be an extreme clinical example of "lipotoxic cardiomyopathy": excessive myocyte accumulation of triglyceride leading to adverse hypertrophic signaling. To test this hypothesis, the first cardiac magnetic resonance study of patients with generalized lipodystrophy was performed, using magnetic resonance imaging and localized proton spectroscopy to detect excessive triglyceride content in the hypertrophied myocytes. Six patients with generalized lipodystrophy and 6 healthy controls matched for age, gender, and body mass index were studied. As hypothesized, myocardial triglyceride content was threefold higher in patients than controls: 0.6 ± 0.2% versus 0.2 ± 0.1% (p = 0.004). The presence of pericardial fat was also found, representing a previously undescribed adipose depot in generalized lipodystrophy. Patients with generalized lipodystrophy, compared with controls, also had a striking degree of concentric LV hypertrophy, independent of blood pressure: LV mass index 101.0 ± 18.3 versus 69.0 ± 17.7 g/m(2), respectively (p = 0.02), and LV concentricity 1.3 ± 0.3 versus 0.99 ± 0.1 g/ml, respectively (p = 0.04). In conclusion, these findings advance the lipotoxicity hypothesis as a putative underlying mechanism for the dramatic concentric LV hypertrophy found in generalized lipodystrophy., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cocaine is a major cause of acute coronary syndrome, especially in young adults; however, the mechanistic underpinning of cocaine-induced acute coronary syndrome remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking., Methods and Results: We used myocardial contrast echocardiography to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low, nonintoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naïve young men (median age, 32 years). Postdestruction time-intensity myocardial contrast echocardiography kinetic data were fit to the equation y=A(1-e(-βt)) to quantify functional capillary blood volume (A), microvascular flow velocity (β), and myocardial perfusion (A×β). Heart rate, mean arterial pressure, and left ventricular work (2-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased mean arterial pressure (by 14±2 mm Hg [mean±SE]), heart rate (by 8±3 bpm), and left ventricular work (by 50±18 mm Hg·mL(-1)·bpm(-1)). Despite the increases in these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 arbitrary units [AU]/s; P<0.01) mainly as a result of decreased capillary blood volume (133.9±5.1 to 111.7±7.7 AU; P<0.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 AU)., Conclusions: In healthy cocaine-naïve young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries.

Background: The landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes., Methods: This proof of concept, longitudinal, randomized, double-blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments., Results: Hepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms., Conclusions: Our findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient's metabolic profile.

In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II-dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5-20 mg/d) or metoprolol (100-300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure-induced decreases in oxygenation and forearm blood flow in resting forearm (from -29±5% to -30±5% and from -29±3% to -29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure-induced reduction in oxygenation and forearm blood flow in exercising forearm (from -14±4% to -1±5% and from -15±2% to -6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

Despite a revolution in therapeutics, the ability to control chronic diseases remains elusive. We present here a conceptual model of the potential role of behavioral tools in chronic disease control. Clinicians implicitly accept the assumption that patients will act rationally to maximize their self-interest. However, patients may not always be the rational actors that we imagine. Major behavioral barriers to optimal health behavior include patients' fear of threats to health, unwillingness to think about problems when risks are known or data are ambiguous, the discounting of risks that are far in the future, failure to act due to lack of motivation, insufficient confidence in the ability to overcome a health problem, and inattention due to pressures of everyday life. Financial incentives can stimulate initiation of health-promoting behaviors by reducing or eliminating financial barriers, but may not produce long-term behavior change without additional interventions. Strategies have been developed by behavioral economists and social psychologists to address each of these barriers to better decision-making. These include: labeling positive behaviors in ways consistent with patient life goals and priorities; greater focus on more immediate risks of chronic diseases; intermediate subgoals as steps to a large health goal; and implementation of specific plans as to when, where, and how an action will be taken. Such strategies hold promise for improving health behaviors and disease control, but most have not been studied in medical settings. The effectiveness of these approaches should be evaluated for their potential as tools for the clinician.

Cocaine-induced acute hypertension is mediated largely by increased central sympathetic nerve activity. We hypothesized that dexmedetomidine, a central sympatholytic, reverses cocaine-induced increases in sympathetic nerve activity, mean arterial pressure (MAP), and heart rate (HR) in cocaine-addicted subjects. First, we conducted a dose-finding study in 15 nontreatment-seeking cocaine-addicted subjects and 12 cocaine-naive healthy controls to find doses of intravenous dexmedetomidine that lower MAP and HR in the absence of acute-cocaine challenge. We then conducted a placebo-controlled treatment trial in 26 cocaine-addicted subjects to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). Skin sympathetic nerve activity (measured in the second protocol) and skin vascular resistance (measured in both protocols) served as indices of cocaine-sensitive central sympathoexcitation. In doses up to 0.6 µg/kg IV, dexmedetomidine alone caused comparable dose-dependent decreases in blood pressure in cases and controls but a 1.0 µg/kg dose was required to lower HR. In cocaine-addicted subjects, low-dose dexmedetomidine (0.4 µg/kg; n=14) abolished cocaine-induced increases in skin sympathetic nerve activity (156 ± 26 versus -15 ± 22%, cocaine/placebo versus cocaine/dexmedetomidine; P<0.05), skin vascular resistance (+10 ± 2 versus -2 ± 3 U; P<0.05), and MAP (+6 ± 1 versus -5 ± 2 mm Hg; P<0.01) without affecting HR (+13 ± 2 versus +9 ± 2 bpm; P=ns). When dexmedetomidine was increased to 1 µg/kg (high dose; n=12) to reverse cocaine-induced increases in HR, MAP did not fall further and increased paradoxically in 4 of 12 subjects. Thus, in a low nonsedating dose, dexmedetomidine constitutes a putative new treatment for cocaine-induced acute hypertension but higher sedating doses can increase blood pressure unpredictably during acute-cocaine challenge and should be avoided.

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/ΔFVC rest=0.88 ± 0.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio=0.92 ± 0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio=0.22 ± 0.03; P<0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.

In healthy individuals, sympathetic vasoconstriction is markedly blunted in exercising muscles to optimize blood flow to the metabolically active muscle fibres. This protective mechanism, termed functional sympatholysis, is impaired in rat models of angiotensin-dependent hypertension. However, the relevance of these findings to human hypertension is unknown. Therefore, in 13 hypertensive and 17 normotensive subjects we measured muscle oxygenation and forearm blood flow (FBF) responses to reflex increases in sympathetic nerve activity (SNA) evoked by lower body negative pressure (LBNP) at rest and during moderate-intensity rhythmic handgrip exercise. In the normotensives, LBNP caused decreases in oxygenation and FBF (−16 ± 2% and −23 ± 4%, respectively) in resting forearm but not in exercising forearm (−1 ± 2% and −1 ± 3%, respectively; P < 0.05 vs. rest). In the hypertensives, LBNP evoked decreases in oxygenation and FBF that were similar in the resting and exercising forearm (−14 ± 2% vs. −12 ± 2% and −20 ± 3% vs. −13 ± 2%, respectively; P > 0.05), indicating impaired functional sympatholysis. In the hypertensives, SNA was unexpectedly increased by 54 ± 11% during handgrip alone. However, when SNA was experimentally increased during exercise in the normotensives, sympatholysis was unaffected. Treatment for 4 weeks with the angiotensin receptor blocker irbesartan, but not with the thiazide-type diuretic chlorthalidone, restored sympatholysis in the hypertensives. These data provide the first evidence that functional sympatholysis is impaired in hypertensive humans by a mechanism that appears to involve an angiotensin-dependent increase in sympathetic vasoconstriction in the exercising muscles.