Current Hypertension Reviews (v.11, #2)

Meet Our Editor: by Guido Grassi (79-79).

Hypertension is a major risk factor of cardiovascular diseases and a most important health problem in developed countries. Investigations on pathophysiology of hypertension have been based on gene products from coding region that occupies only about 1% of total genome region. On the other hand, non-coding region that occupies almost 99% of human genome has been regarded as 'junk' for a long time and went unnoticed until these days. But recently, it turned out that noncoding region is extensively transcribed to non-coding RNAs and has various functions. This review highlights recent updates on the significance of non-coding RNAs such as micro RNAs and long non-coding RNAs (lncRNAs) on the pathogenesis of hypertension, also providing an introduction to basic biology of noncoding RNAs. For example, microRNAs are associated with hypertension via neuro-fumoral factor, sympathetic nerve activity, ion transporters in kidneys, endothelial function, vascular smooth muscle phenotype transformation, or communication between cells. Although reports of lncRNAs on pathogenesis of hypertension are scarce at the moment, new lncRNAs in relation to hypertension are being discovered at a rapid pace owing to novel techniques such as microarray or next-generation sequencing. In the clinical settings, clinical use of non-coding RNAs in identifying cardiovascular risks or developing novel tools for treating hypertension such as molecular decoy or mimicks is promising, although improvement in chemical modification or drug delivery system is necessary.

Nutrition and Physical Activity on Hypertension: Implication of Current Evidence and Guidelines by Iran Castro, Gustavo Waclawovsky, Aline Marcadenti (91-99).
Hypertension (HTN) is the leading cause of worldwide mortality and is responsible for approximately 40% of deaths from cardiovascular disease, chronicle kidney disease (CKD) and type 2 diabetes mellitus (T2DM) according to the World Health Organization (WHO). It is known that about 80% of all mortality from cardiovascular disorders could be prevented if a healthy diet and higher levels of physical activity were included among general population's lifestyle. Besides, guidelines for the treatment and control of HTN were recently modified for adequate nutritional and physical activity recommendations highlighted in meta-analysis and strong evidences such as randomized clinical trials. Therefore, to discuss nutrition and physical activity in the context of HTN seems to be crucial.

Ventricular and Vascular Stiffening in Aging and Hypertension by L. Faconti, R. M. Bruno, L. Ghiadoni, S. Taddei, A. Virdis (100-109).
The assessment of arterial stiffness, a common feature of aging, exacerbated by pathological conditions like hypertension, has become an attractive tool for identifying structural and functional changes of the arteries even in an early stage of the atherosclerotic disease. Arterial stiffness has been recognized as an important physio-pathological determinant for the age-related rise in systolic blood pressure, demonstrating also an independent predictive value for cardiovascular events. In the recent decades, many techniques and indices to evaluate vascular stiffness have been developed and extensive data concerning their prognostic value have been collected.
Moreover, it has become clear that vessel and heart must be considered as a unique system, in which combined stiffness of vessel and heart interacts to limit cardiovascular performance.
In this review, main methods and indices used to estimate arterial and ventricular stiffness are presented, focusing on their alteration in physiological aging and arterial hypertension. Furthermore, the concept of ventricular–arterial coupling is explained in order to give an insight to the interplay between arterial and ventricular stiffness in aging and hypertension.

The Involvement of Uric Acid in the Pathogenesis of Preeclampsia by Sophia Masoura, Kali Makedou, Theodoros Theodoridis, Anargyros Kourtis, Leonidas Zepiridis, Apostolos Athanasiadis (110-115).
Preeclampsia is a common disorder of human pregnancy and a major cause of worldwide pregnancy-related maternal and neonatal morbidity and mortality. Oxidative stress, angiogenic imbalance, placental ischemia and an inflammatory response have been proposed to play role in the pathogenesis of the disease. Hyperuricemia is a key biochemical feature in preeclampsia with elevated levels of uric acid being diagnosed as early as the 10th week of gestation. Traditionally, elevated uric acid levels were considered a result of renal dysfunction known to exist in preeclampsia. The contribution of uric acid in the pathogenesis of preeclampsia is being recently further investigated. We, hereby, review the possible mechanisms by which uric acid contributes to the development of the disease and its complications both on mother and fetus.

The Effects of Angiotensin II Signaling Blockade on Platelet Activity in Subjects with Hypertension by Nabeel Ahmed, Anoop Mansoor, Joban Sehmi, Keith Gomez, Amarjit Sethi (116-122).
Background: To investigate the effects of Angiotensin II receptor blockade (ARB) and angiotensin converting enzyme (ACE) inhibition on platelet reactivity in patients with mild to moderate hypertension. PFA-100 evaluates platelet function (expressed in seconds as closure time, CT) in anti-coagulated whole blood in vitro at high shear rates. The test cartridge is impregnated with either collagen and epinephrine (Col/Epi) or collagen and ADP (Col/ADP).
Methods: 33 patients were randomized to perindopril 4mg (n = 9), valsartan 80mg/d (n = 9) and for lifestyle modification (n = 15) for 4 weeks. Platelet reactivity was measured at baseline and after 4 weeks by PFA-100. Normotensive controls (n = 11) were also tested at baseline to standardize PFA-100 CT. Haematocrit, platelet count and plasma vWF antigen levels were measured.
Results: There was no difference in baseline haematocrit, platelet count or vWF antigen level between the groups. The vWF antigen levels measured after 4 weeks showed no significant difference either. Significant blood pressure reduction was seen in the treated group (SBP P = 0.002 and DBP P = 0.005) when compared to the life style modification group (SBP P = 0.06 and DBP P = 0.04) after 4 weeks. There was no significant statistical difference in Col/ADP CT in treated and non-treated groups but increase in CT (P = 0.05) in treated group with Col/Epi seen after 4 weeks.
Conclusion: In patients with mild to moderate hypertension, valsartan and perindopril compared to life style modification demonstrate a significant decrease in platelet reactivity.

Designing and Evaluating Health Systems Level Hypertension Control Interventions for African-Americans: Lessons from a Pooled Analysis of Three Cluster Randomized Trials by Valory N. Pavlik, Wenyaw Chan, David J. Hyman, Penny Feldman, Gbenga Ogedegbe, Joseph E. Schwartz, Margaret McDonald, Paula Einhorn, Jonathan N. Tobin (123-131).
Objectives: African-Americans (AAs) have a high prevalence of hypertension and their blood pressure (BP) control on treatment still lags behind other groups. In 2004, NHLBI funded five projects that aimed to evaluate clinically feasible interventions to effect changes in medical care delivery leading to an increased proportion of AA patients with controlled BP. Three of the groups performed a pooled analysis of trial results to determine: 1) the magnitude of the combined intervention effect; and 2) how the pooled results could inform the methodology for future health-system level BP interventions.
Methods: Using a cluster randomized design, the trials enrolled AAs with uncontrolled hypertension to test interventions targeting a combination of patient and clinician behaviors. The 12-month Systolic BP (SBP) and Diastolic BP (DBP) effects of intervention or control cluster assignment were assessed using mixed effects longitudinal regression modeling.
Results: 2,015 patients representing 352 clusters participated across the three trials. Pooled BP slopes followed a quadratic pattern, with an initial decline, followed by a rise toward baseline, and did not differ significantly between intervention and control clusters: SBP linear coefficient = -2.60A±0.21 mmHg per month, p<0.001; quadratic coefficient = 0.167A± 0.02 mmHg/month, p<0.001; group by time interaction group by time group x linear time coefficient=0.145 A± 0.293, p=0.622; group x quadratic time coefficient= -0.017 A± 0.026, p=0.525). Results were similar for DBP. The individual sites did not have significant intervention effects when analyzed separately.
Conclusion: Investigators planning behavioral trials to improve BP control in health systems serving AAs should plan for small effect sizes and employ a 'run-in' period in which BP can be expected to improve in both experimental and control clusters.

Oxidative Stress and Antioxidants in Hypertension–A Current Review by Nakshi Sinha, Pradeep Kumar Dabla (132-142).
Free radicals or reactive oxygen species (ROS) are generated by oxygen metabolism which is balanced by the rate of oxidant formation and the rate of oxidant elimination. Oxidative stress is a result of imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defence systems. Hypertension is one of the major risk factors for cardiovascular diseases and is considered as a leading cause of mortality and morbidity. These diseases affect more than 600 million people and it has been estimated that 29% of the world population will be suffering from hypertension by 2025. It has been indicated by experimental evidence that reactive oxygen species (ROS) play an important role in the pathophysiology of hypertension. The vasculature is a rich source of NADPH oxidase which produces most of the reactive oxygen species and plays an important role in renal dysfunction and vascular damage. Recent studies indicate that increased oxidative stress is the important mediator of endothelial injury in the pathology of hypertension associated to increased production of pro oxidants such as superoxideanion hydrogen peroxide, reduced nitric oxide synthesis and decreased bioavailability of antioxidants. Oxidative stress is found to be associated with endothelial dysfunction, inflammation, hypertrophy, apoptosis, cell migration, fibrosis, and angiogenesis in relation to vascular remodelling of hypertension. Results in humans are still less conclusive inspite of data available that involve oxidative stress as a causative factor of essential hypertension. The aim of this review is to present a novel focus on the role of oxidative stress in the pathophysiology of hypertension and recent biomarkers which are found to be associated with reactive oxygen species and the role of antioxidants as therapy of hypertension.

In vivo and in silico Investigation of Antidiabetic Activity of Fruit of Withania coagulans Dunal by Sudhanshu Kumar Bharti, Supriya Krishnan, Neeraj Kumar Sharma, Amit Kumar, Om Prakash, Ashok Kumar Gupta, Awanish Kumar (143-158).
This study evaluates the antidiabetic activities of methanolic extract of Withania coagulans Dunal (Ashutosh booti) fruit (WCFE) in poloxamer-407 induced type 2 diabetic Wistar rats. The electrochemical behaviour of WCFE with anodic peak of 1.19A± 0.01V was found similar to standards used indicating that extract is antioxidant in nature. Unlike diabetic control rats, the WCFE treated diabetic rats presented significant amelioration of glycaemia, insulinamia and lipid dysmetabolism, remarkable reduction of oxidative markers and improved cecal and pancreatic characteristics. HYBRID and FRED docking were performed for 25 documented WCFE botanicals for putative action mechanism concerning three diabetic therapeutic proteins namely PTP-1B, PPAR-γ and DPP-IV fully support the in vivo findings. Botanicals like nicandrenone10 and Acnistin F have shown considerable interaction potential with aforesaid proteins. Results provide pharmacological evidence of WCFE as antihyperglyceamic mediated by interaction of various botanicals with various targets operating in diabetes mellitus.