Neurogenic Hypertension, the Blood-Brain Barrier, and the Potential Role of Targeted Nanotherapeutics.

Hypertension is a major health concern globally. Elevated blood pressure, initiated and maintained by the brain, is defined as neurogenic hypertension (NH), which accounts for nearly half of all hypertension cases. A significant increase in angiotensin II-mediated sympathetic nervous system activity within the brain is known to be the key driving force behind NH. Blood pressure control in NH has been demonstrated through intracerebrovascular injection of agents that reduce the sympathetic influence on cardiac functions. However, traditional antihypertensive agents lack effective brain permeation, making NH management extremely challenging. Therefore, developing strategies that allow brain-targeted delivery of antihypertensives at the therapeutic level is crucial. Targeting nanotherapeutics have become popular in delivering therapeutics to hard-to-reach regions of the body, including the brain. Despite the frequent use of nanotherapeutics in other pathological conditions such as cancer, their use in hypertension has received very little attention. This review discusses the underlying pathophysiology and current management strategies for NH, as well as the potential role of targeted therapeutics in improving current treatment strategies.

No Evidence for Long Term Blood Pressure Differences Between Eversion and Conventional Carotid Endarterectomy in Two Independent Study Cohorts.

OBJECTIVE: Blood pressure (BP) management is a vital aspect of stroke prevention and post-stroke care. Different surgical carotid endarterectomy (CEA) techniques may impact on BP control post-operatively. Specifically, the carotid sinus nerve, which innervates the carotid baroreceptors and carotid body, is commonly left intact during conventional CEA but is routinely transected as part of eversion CEA. The aim of this study was to assess long term BP control after eversion and conventional CEA. METHODS: Patients from the International Carotid Stenting Study (ICSS cohort) and a personal series of patients from the Stroke Clinical Trials Unit at University College London (UCL cohort) were separately analysed and divided into eversion and conventional CEA groups. Mixed effect linear models were fitted and adjusted for baseline demographic data and antihypertensive treatment to test for changes in BP from baseline over a three year follow up period after the respective procedures. RESULTS: There were no differences in changes in baseline BP readings and follow up readings between eversion and conventional CEA in the ICSS or UCL cohorts. In the ICSS cohort a mild but significant systolic (-8.6 mmHg; 95% confidence interval [CI] -10.6 - -6.6) and diastolic (-4.9 mmHg; 95% CI -6.0 - -3.8) BP lowering effect was evident at discharge in the conventional group but not in the eversion CEA group. BP monitoring during follow up did not reveal any consistent BP changes with either conventional or eversion CEA vs. baseline levels. CONCLUSION: Neither conventional nor eversion CEA seem to result in clinically significant long term BP changes. Potential concerns related to either short or long term alterations in BP levels with transection of the carotid sinus nerve during eversion CEA could not be substantiated.

Predictive impacts of chronic kidney disease and cardiac sympathetic nervous activity on lethal arrhythmic events in chronic heart failure.

BACKGROUND: The clinical implications of chronic kidney disease (CKD) and cardiac sympathetic nervous activity (CSNA) regarding lethal arrhythmic events have not yet been fully elucidated in patients with chronic heart failure (CHF). We hypothesized that the combination of CKD and abnormal CSNA, assessed by 123 I-metaiodobenzylguanidine (123 I-MIBG) scintigraphy, may provide useful prognostic information for lethal arrhythmic events. METHODS: We studied 165 consecutive hospitalized CHF patients without dialysis. Cardiac 123 I-MIBG scintigraphy was performed in a clinically stable condition, and abnormal CSNA was defined as a late heart-to-mediastinum ratio of <1.6. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m2 . We then investigated the incidence of lethal arrhythmic events (sustained ventricular tachyarrhythmia, appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death). RESULTS: During a median follow-up of 5.3 years, lethal arrhythmic events were observed in 40 patients (24.2%). The patients were divided into four groups according to the presence of CKD and CSNA abnormality: non-CKD/normal CSNA (n = 52), CKD/normal CSNA (n = 39), non-CKD/abnormal CSNA (n = 33), and CKD/abnormal CSNA (n = 41). Kaplan-Meier analysis showed that CKD/abnormal CSNA had the highest event rate (log-rank p = .004). Additionally, the Cox proportional hazard analysis revealed that CKD/abnormal CSNA was a predictor for lethal arrhythmic events compared with non-CKD/normal CSNA (hazard ratio, 5.368, p = .001). However, the other two groups did not show significant differences compared with the non-CKD/normal CSNA group. CONCLUSIONS: The combination of CKD and abnormal CSNA, assessed by 123 I-MIBG scintigraphy, had a high predictive value for lethal arrhythmic events in patients with CHF.

Hypertension as a Metabolic Disorder and the Novel Role of the Gut.

PURPOSE OF REVIEW: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. RECENT FINDINGS: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of "salt-induced obesity"; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

How do we establish cardiac sympathetic nervous system imaging with 123I-mIBG in clinical practice? Perspectives and lessons from Japan and the US.

Cardiac denervation is associated with progressive left ventricular (LV) dysfunction, ventricular arrhythmias, and sudden cardiac death (SCD) in heart failure (HF). In this regard, it is important to evaluate cardiac-specific sympathetic nervous system (SNS) function. The radiotracer Iodine-123 meta-iodobenzylguanidine (123I-mIBG) can noninvasively evaluate pre-synaptic SNS function. Recent multicenter trials have shown 123I-mIBG to have strong predictive value for fatal arrhythmias and cardiac death in HF. 123I-mIBG was initially developed in the USA in the 1970s. In 1992, the Japanese Ministry of Health and Labour approved 123I-mIBG for the assessment of cardiac function. Following approval, the Japanese nuclear cardiology community developed 123I-mIBG imaging services in various medical centers. Japanese groups have been trying to establish the clinical utility of 123I-mIBG and standardize parameters for data acquisition and image analysis. The US Food and Drug Administration (FDA) has approved clinical use of 123I-mIBG for cardiac and non-cardiac imaging. However, clinical use of 123I-mIBG in the US has been very limited. The number of 123I-mIBG studies in Japan has also been limited. There are similarities and differences between the two countries. To establish the clinical utility of 123I-mIBG in both countries, it is important to characterize the situations of 123I-mIBG in each.

Retrograde and oscillatory shear rate in young anabolic androgenic steroid users.

Disturbed shear rate (SR), characterized by increased retrograde and oscillatory SR in the brachial artery, is associated with inflammation, atherosclerosis, endothelial dysfunction, and sympathetic hyperactivity. Young subjects do not have disturbed SR; however, elderly subjects do, which seems to be associated with sympathetic hyperactivity. Anabolic androgenic steroids (AAS) abuse in young is associated with increased muscle sympathetic nerve activity (MSNA). We hypothesized that AAS users might have disturbed SR. We tested the association between retrograde and oscillatory SR with MSNA. In addition, we measured the high-sensitivity C-reactive protein (hs-CRP). We evaluated 10 male AAS users, age 27 ± 4 years, and 10 age-matched AAS nonusers, age 29 ± 5 years. At rest, retrograde and oscillatory SR were evaluated by Doppler ultrasound, MSNA was measured with microneurography, and hs-CRP was measured in blood sample. Flow-mediated dilation (FMD) was also assessed. AAS users had higher retrograde SR (24.42 ± 17.25 vs 9.15 ± 6.62 s- 1 , P = 0.01), oscillatory SR (0.22 ± 0.13 vs 0.09 ± 0.07 au P = 0.01), and MSNA (42 ± 9 vs 32 ± 4 bursts/100 heart beats, P = 0.018) than nonusers. MSNA (bursts/100 heart beats) was correlated with retrograde SR (r = 0.50, P = 0.050) and oscillatory SR (r = 0.51, P = 0.042). AAS users had higher hs-CRP [1.17 (0.44-3.63) vs 0.29 (0.17-0.70) mg/L, P = 0.015] and decreased FMD (6.42 ± 2.07 vs 8.28% ± 1.53%, P = 0.035) than nonusers. In conclusion, AAS abuse is associated with retrograde and oscillatory SR which were associated with augmented sympathetic outflow. In addition, AAS seems to lead to inflammation characterized by increased hs-CRP. These alterations may have the potential of increasing the early risk of atherosclerotic disease in young AAS users.

The effect of α1 -adrenergic blockade on post-exercise brachial artery flow-mediated dilatation at sea level and high altitude.

KEY POINTS: Our objective was to quantify endothelial function (via brachial artery flow-mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate-intensity cycling exercise with and without administration of an α1 -adrenergic blockade. Brachial endothelial function did not differ between sea level and high altitude at rest, nor following maximal exercise. At sea level, endothelial function decreased following 30 min of moderate-intensity exercise, and this decrease was abolished with α1 -adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate-intensity exercise, and administration of α1 -adrenergic blockade resulted in an increase in flow-mediated dilatation. Our data indicate that post-exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high-altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function. ABSTRACT: We examined the hypotheses that (1) at rest, endothelial function would be impaired at high altitude compared to sea level, (2) endothelial function would be reduced to a greater extent at sea level compared to high altitude after maximal exercise, and (3) reductions in endothelial function following moderate-intensity exercise at both sea level and high altitude are mediated via an α1 -adrenergic pathway. In a double-blinded, counterbalanced, randomized and placebo-controlled design, nine healthy participants performed a maximal-exercise test, and two 30 min sessions of semi-recumbent cycling exercise at 50% peak output following either placebo or α1 -adrenergic blockade (prazosin; 0.05 mg kg -1 ). These experiments were completed at both sea-level (344 m) and high altitude (3800 m). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (ultrasound) were recorded before, during and following exercise. Endothelial function assessed by brachial artery flow-mediated dilatation (FMD) was measured before, immediately following and 60 min after exercise. Our findings were: (1) at rest, FMD remained unchanged between sea level and high altitude (placebo P = 0.287; prazosin: P = 0.110); (2) FMD remained unchanged after maximal exercise at sea level and high altitude (P = 0.244); and (3) the 2.9 ± 0.8% (P = 0.043) reduction in FMD immediately after moderate-intensity exercise at sea level was abolished via α1 -adrenergic blockade. Conversely, at high altitude, FMD was unaltered following moderate-intensity exercise, and administration of α1 -adrenergic blockade elevated FMD (P = 0.032). Our results suggest endothelial function is differentially affected by exercise when exposed to hypobaric hypoxia. These findings have implications for understanding the chronic impacts of hypoxaemia on exercise, and the interactions between the α1 -adrenergic pathway and endothelial function.

Effects of doxazosin as the third agent on morning hypertension and position-related blood pressure changes in diabetic patients with chronic kidney disease.

We conducted a prospective study to assess the effects of doxazosin, as the third agent, on morning and position-related blood pressure (BP) in 77 diabetic patients with chronic kidney disease, who were allocated randomly to doxazosin and diuretics groups. Doxazosin decreased morning BP but diuretics could not decrease pre-awakening diastolic BP. Only doxazosin improved sympathovagal balance. Doxazosin and diuretics decreased standing and sitting BP but only doxazosin improved sympathovagal balance regardless of body positions. Doxazosin did not decrease absolute BP changes shortly after standing. In diabetic patients, doxazosin decreased morning BP through improving sympathovagal balance without causing significant orthostatic hypotension (ClinicalTrials.gov number, NCT00295555).

Heterogeneity of Ventricular Sympathetic Nervous Activity is Associated with Clinically Relevant Ventricular Arrhythmia in Postoperative Patients with Tetralogy of Fallot.

This study aimed to clarify whether there is an association between ventricular sympathetic nervous activity (SNA) and clinically relevant ventricular arrhythmia (a run of ≥ 3 consecutive ventricular beats, RVA) in postoperative patients with tetralogy of Fallot (TOF). We performed a retrospective study in a national referral center of pediatric cardiology in Japan. Twenty-four postoperative TOF patients (13 males, median age 17 years) undergoing myocardial (123)I metaiodobenzylguanidine (MIBG) scintigraphy were included. We measured the heart-to-mediastinum ratio (HMR) and washout ratio (WR) from planar MIBG myocardial scintigraphy. Tomographic images and polar maps were generated with 20 segments. The standard deviation of percentage uptake of 20 segments (SD-uptake) as an index of heterogeneous MIBG uptake to the ventricular myocardium was calculated. We compared these MIBG-derived variables with the patients' clinical profiles, including ECG findings and hemodynamics. Eight of 24 patients had RVA (RVA group), and the other 16 did not have RVA (non-RVA group). There were no significant differences in the HMR (1.9 ± 0.5 vs. 2.2 ± 0.4) and WR (50 ± 5 vs. 42 ± 10) between the two groups. SD-uptake was significantly higher in the RVA group than in the non-RVA group (15 ± 3 vs. 12 ± 3, p = 0.03). QT dispersion (ms) was also higher in the RVA group than in the non-RVA group (53 ± 23 vs. 44 ± 18, p = 0.04). Multivariate logistic regression showed that SD-uptake and QT dispersion were independent predictors in the RVA group (p = 0.02, p = 0.03). In addition to greater QT dispersion, heterogeneous SNA is associated with RVA in TOF patients postoperatively.