<p>Lower extremity peripheral artery disease (PAD) is an increasingly prevalent manifestation of atherosclerosis that substantially limits mobility and increases mortality. Few options currently exists for practical conservative treatment of individuals with PAD. We have previously demonstrated that lower limb heat therapy (HT) can improve leg blood flow and reduce systolic blood pressure in patient with lower extremity PAD. Using three unique clinical trials, we sought to test the hypothesis that repeated exposure to HT would improve walking tolerance and vascular function in patients with lower extremity PAD. In these trials, we have sought to examine the clinical efficacy of HT, the physiological mechanisms which may underpin changes in walking endurance in this population, and also the practicality of employing HT in a home-based setting. The primary finding from these trials was that daily application of leg HT improved walking endurance in patients with lower-extremity PAD. Furthermore, the treatment adherence rate was excellent (<96%) and was not associated with severe adverse events. The changes in walking tolerance were consistently not associated with positive changes in vascular function, suggesting an alternative mechanism should be examined in future studies. </p>

The locus coeruleus (LC) is a putative site of action for angiotensin II in the brain. Immunocytochemical studies have identified angiotensin II-like immunoreactive material in nerve terminals innervating the LC, and the LC contains one of the highest densities of angiotensin II receptor binding sites in the rat brain. Recent studies using selective neurotoxins suggest that the binding sites for angiotensin II in the LC are present on noradrenergic perikarya. Angiotensin II receptors are now known to exist as two subtypes that are distinguishable both pharmacologically and biochemically. Radioligand binding studies using agonists and antagonists selective for these angiotensin II receptor subtypes indicate that the rat LC contains a mixture of the two known angiotensin II receptor subtypes, but that the PD123177-sensitive AIIβ receptor subtype is predominant. Comparisons of spontaneously hypertensive rats with normotensive rats indicates that angiotensin II and its receptors in the LC are elevated in the hypertensive rat strain. Studies of the biochemical and physiological actions of angiotensin II in the LC have not yet established an agreed-upon function for angiotensin II in this nucleus.

The effects of stimulation of the A5 cell group of the caudal ventrolateral pons electrically or with L-glutamate on heart rate and blood pressure were determined in rabbits. Electrical stimulation caused blood pressure increases and reflex bradycardia. L-glutamate caused decreases in blood pressure and heart rate which were blocked by the L-glutamate antagonist aminophosphoheptanoic acid. Transection of the brainstem at the level of the midbrain did not alter the effects of either electrical or chemical stimulation. Lesions of the nucleus and tractus solitarius (NTS) attenuated the effects of L-glutamate, but did not change the effectiveness electrical stimulation. Injections of 6-hydroxydopamine three to four weeks before the experiments blocked the effects of electrical stimulation but only reduced the effects of L-glutamate injection. The A5 group may have two functional subdivisions. Some A5 cells may produce blood pressure depressor and bradycardiac effects by means of projections to the NTS and the spinal cord. Other A5 cells may produce blood pressure presser effects by means of projections to the spinal cord.

Substance P (SP) is released from the feline nucleus tractus solitarius (NTS) in response to activation of skeletal muscle afferent input. However, there are differing results about SP release from the rostral NTS in response to baroreceptor afferent input. An anti-sense oligonucleotide to feline SP (SP-asODN) was injected directly into the rostral NTS of chloralose-anesthetized cats to determine whether blood pressure or heart rate responses to ergoreceptor activation (muscle contraction) or baroreceptor unloading (carotid artery occlusion) were sensitive to SP knockdown. Control injections included either buffer alone or a scrambled-sequenced oligonucleotide (SP-sODN). Both muscle contractions and carotid occlusions were performed 3, 6 and 12 h after the completion of the oligonucleotide injections. The cardiovascular responses to contractions were significantly attenuated 3 and 6 h after SP-asODN, but not by the injection of the SP-sODN. The cardiovascular responses to contractions returned to control levels 12 h post anti-sense injection. No detectable release of SP (using antibody-coated microprobes) was measured 3 and 6 h after SP-asODN injections and the expression of SP-immunoreactivity (SP-IR) in the NTS was significantly attenuated, as determined by immunohistochemistry procedures. In contrast, neither the injection of SP-asODN nor the s-ODN attenuated the cardiovascular responses to carotid occlusions, or altered the pattern of release of SP from the brainstem. Injection of the SP-sODN did not affect the expression of SP-IR. These results suggest that the SP involved with mediating the peripheral somatomotor signal input to the rostral NTS comes from SP-containing neurons within the NTS. Our results also suggest that SP in the rostral NTS does not play a direct role in mediating the cardiovascular responses to unloading the carotid baroreceptors. We suggest that the SP released during isometric contractions excites an inhibitory pathway modulating baroreceptor input, thus contributing to the increase in mean blood pressure.

The prevalence and long-term trends of isolated systolic hypertension (ISH) among untreated adults have not been reported. Data from 24,653 participants aged ≥18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. The prevalence and 95% confidence intervals (CIs) of untreated ISH were estimated by conducting the independent survey t-test. The prevalence of untreated ISH was 9.4% and decreased from 10.3% in 1999-2004 to 8.5% in 2005-2010 (P =.00248). Old persons, females, and non-Hispanic blacks had higher prevalence of untreated ISH. Compared with 1999-2004, the prevalence of untreated ISH in 2005-2010 decreased among older (33.6%; 95% CI, 30.9%-36.3% vs. 25.1%; 95% CI, 22.7%-27.5%) and female individuals (8.3%; 95% CI, 7.5-9.2% vs. 11.4%; 95% CI, 10.4-12.3%). The stratified prevalence of untreated ISH declined in 2005-2010 (vs. 1999-2004) for older non-Hispanic whites (24.6% vs. 32.8%; P <.0001) and blacks (27.7% vs. 40.8%; P =.0013), non-Hispanic white females (7.5% vs. 10.8%; P <.0001), older individuals with higher education (21.0% vs. 30.6%; P =.0024), and females with lower education (10.1% vs. 13.1%; P =.006). Untreated ISH is more prevalent in older adults and females. Significant decreases in untreated ISH prevalence over time among these groups suggest that public health measures and/or treatment patterns are trending in the right direction.

National Kidney Disease Education Program has initiated a serum creatinine standardization program. Glomerular filtration rate (GFR) can be re-estimated from standardized serum creatinine measurements. How the standardized estimated GFR (eGFR) influences hypertension prevalence has not been evaluated. In this study, cross-sectional data from 21 205 participants aged 18 years in the National Health and Nutrition Examination Survey 1999-2006 were analyzed. The differences between standardized and non-standardized eGFRs in the prevalence of hypertension and low eGFR were evaluated. Multiple logistic regression models were conducted to determine the association of standardized eGFR with hypertension prevalence. The prevalence of low eGFR estimated from standardized eGFR was higher than that from non-standardized eGFR (all P0.01), except for the 2005-2006 survey. The prevalence of hypertension under standardized eGFR was not significantly different from that under non-standardized eGFR in both groups of participants with eGFR60 and eGFR60 ml min 1 per 1.73 m 2. Adjusted for age, education, gender, race/ethnicity, smoking, serum cholesterol and diabetes mellitus, the participants with standardized eGFR60 ml min 1 per 1.73 m 2 had 56.1% more chance to be hypertensive patients than those with normal eGFR (P0.0001). The difference in the relationship to hypertension prevalence between standardized and non-standardized eGFR was not found significant.

Racial disparities in cardiovascular disease (CVD) have become a matter of national concern. We investigated racial disparities and trends in glycosylated hemoglobin, high-density lipoprotein (HDL), C-reactive protein, plasma homocysteine, albuminuria, and other risk factors among 4758 diagnosed hypertensive subjects age 18 years or older from the National Health and Nutrition Examination Survey, 1999-2006. Compared with non-Hispanic whites, Hispanics, and non-Hispanic blacks were more likely to have uncontrolled blood pressure (BP) (Hispanics odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.21-2.07; blacks OR: 1.42, 95% CI: 0.21-1.67), elevated glycosylated hemoglobin (Hispanics OR: 2.70, 95% CI: 1.89-3.87; blacks OR: 2.17, 95% CI: 1.70-2.77), albuminuria (Hispanics OR: 2.36, 95% CI: 1.71-3.27; blacks OR: 1.80, 95% CI: 1.47-2.20), and less likely to have central obesity (Hispanics OR: 0.68, 95% CI: 0.51-0.91; blacks OR: 0.70, 95% CI: 0.58-0.84). Blacks had lower risks of elevated serum cholesterol (OR: 0.81, 95% CI: 0.67-0.98) and low HDL (OR: 0.76, 95% CI: 0.61-0.94) than whites. The risk of high serum homocysteine was lower in Hispanics and higher in blacks compared with whites (Hispanics OR: 0.64, 95% CI: 0.46-0.90; blacks OR: 1.36, 95% CI: 1.14-1.63). These results highlight the need for targeted interventions to aggressively treat uncontrolled BP, elevated glycosylated hemoglobin in Hispanic and black hypertensive subjects, and high serum homocysteine in blacks, to reduce disparities in CVD risk factors and CVD-associated morbidity and mortality.

Background: Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the RYR which functions to release stored endoplasmic reticulum calcium ions (Ca2+) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affect cardiac contraction, insulin secretion, and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes. Methods: Family data sets were used to explore association of RYR3 polymorphisms with risk and age at onset (AAO) of hypertension, diabetes, and AD. Results: Family-based association tests using generalized estimating equations (FBAT-GEE) showed several unique or shared disease-1 associated variants in the RYR3 gene. Three single nuclear polymorphisms (SNPs; rs2033610, rs2596164, and rs2278317) are significantly associated with risk for hypertension, diabetes, and AD. Two SNPs (rs4780174 and rs7498093) are significantly associated with AAO of the 3 diseases. Conclusions: RYR3 variants are associated with hypertension, diabetes, and AD. Replication of these results of this gene in these 3 complex traits may help to better understand the genetic basis of calcium-signaling gene, RYR3 in association with risk and AAO of these diseases.

Background Obesity and hypertension are two risk factors of left ventricular hypertrophy (LVH) in adults. We aimed to examine the impacts of body weight and blood pressure (BP) from childhood on adult LV geometric remodeling. Methods The study cohort consisted of 1256 adults aged 27–42 years who had 2–10 measurements of body mass index (BMI) and BP from childhood in 1987 to adulthood in 2010. We calculated the cumulative and incremental values of BMI and BP from childhood to adulthood. In adulthood, four LV geometric patterns were defined based on the values of left ventricular mass index (g/m2.7) and relative wall thickness: normal geometry, concentric remodeling (CR), eccentric hypertrophy (EH) and concentric hypertrophy (CH). Results The prevalence of abnormal LV geometric patterns in adults was 26.4% for CR, 2.0% for EH and 2.5% for CH. For childhood values, systolic BP (Odds Ratio [OR] = 1.26, 95% confidence interval [CI] = 1.08–1.47) but not BMI (OR = 1.06, 95%CI = 0.93-1.18) was associated with adult CR, whereas BMI (OR = 3.53, 95%CI = 2.09–5.98) but not systolic BP (OR = 1.04, 95%CI = 0.65–1.66) was associated with adult EH. Both childhood BMI (OR = 2.69, 95%CI = 1.77–4.09) and systolic BP (OR = 1.64, 95%CI = 1.07–2.51) were independently associated with adult CH. For adulthood, cumulative and incremental values, BMI and systolic BP were independently associated with adult CR, EH and CH. Conclusion Excessive body weight and elevated BP from childhood have independent influences on the development of adult LV geometric remodeling.

Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insen-sitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. NEW & NOTEWORTHY Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.