Current Hypertension Reviews - Volume 9, Issue 4, 2013

The increase in the prevalence of obesity, which has been considered as an epidemic by the World Health Organisation, is a serious, worldwide, health problem. Importantly, hypertension and diabetes are frequently associated with obesity, and, together, they constitute a significant burden, in terms of both morbidity and health care costs. The association with increase in the prevalence of obesity, prevalence of hypertension and diabetes have elevated significantly in the last decade. The driving forces linking obesity, hypertension, and diabetes remain to be clarified due in part to the fact that environmental, genetic, life style and behavioural confounders are involved generating the disease state. Additionally, it is recognized that neuroendocrine mechanisms, including insulin resistance, sympathetic nervous activation, and stimulation of the rennin-angiotensinaldosterone system (RAAS), are related to obesity, hypertension, and type 2 diabetes. Importantly, taken in isolation, obesity, hypertension, and diabetes are all associated with increased risk of the development of cardiac and renal complications. However, with coexistence of diabetes and hypertension, the risk is elevated substantially more. I edited “Hypertension and type 2 Diabetes in Obesity” in 2011 as a special issue. After 2011, numerous investigations have been reported to prevent hypertension, diabetes and related cardiovascular risks. This special issue entitled by “Hypertension and Diabetes –Update in 2013” includes several new discoveries /findings such as Nasfatin/Nucleobindid-2 and salt-sensitivity in obesity-hypertension. In addition, this issue is honoured to include a section on dyslipidemia consisting of 3 reviews written by Director and Dr. Morales-Villegas, who was featured as a hot topic in the European Society of Cardiology-2013 regarding lifestyle modification in Mexican young population to prevent cardiovascular risks. This special issue has been edited systematically, from [1] mechanisms and pathophysiology, [2] complications, and [3] treatments for practical usage. Therefore, several parts based on but updated from the previous issue over the last 3 years. [1] The mechanisms and pathophysiology includes the following; (i) the mechanisms of hypertension, especially focused on the sympathetic nervous activity, and renal denervation in patients with resistant hypertension by Masuo; (ii) Reninangiotensin- aldosterone system (RAAS) including recent clinical trials findings with blocking agents of the RAAS by Kamide; (iii) The relations between adrenoceptor polymorphisms, hypertension and diabetes (metabolic syndrome) was updated over the last 3 years by Masuo; (iv) Blood pressure variability (dipper versus non-dipper) in hypertension and diabetes by Eguchi, (v) Sympathetic nervous activity in salt sensitivity by Ando. This author, himself, is one of the first investigators to show increased salt sensitivity in obese hypertension. And (vi) recently discovered anorexigenic protein, nesfatin-1 and glucose metabolism by Shimizu and Osaki, who was one of the investigators for discovering the protein. This protein may be a candidate of treatments for obesity and diabetes. [2] “Complications” includes (i) Cardiac complications in hypertension and diabetes, especially focused on the role of the sympathetic nervous activity, by Kishi and Hirooka; (ii) Atherosclerosis and lipids metabolism by Morales-Villegas. Patients with diabetes and hypertension frequently have atherogenic diseases and dyslipidemia. Atherosclerosis and abnormal lipids metabolism are a serious risk factor for cardiovascular mortality and morbidity. First, he reviewed the relationship between dyslipidemia, hypertension and diabetes covering a wide range of information such as epidemiology, mechanism, cardiovascular risk factors. And then he moved to “Coronary atherosclerosis in women”, which is different from “male” pattern of coronary atherosclerosis. And he discussed the molecular biology on PCSK9-LDLR, which regulates the entry of cholesterol into the cell to stabilize the intracellular cholesterol concentration. In the previous special issue in 2011 entitled “Hypertension and Diabetes in Obesity”, he wrote a very helpful review to understand why statins can reduce cardiovascular risks. Taken together, I think most of new knowledge on lipids metabolisms in hypertension and diabetes have been covered. [3] The first step to treat for diabetes and hypertension in obesity is weight loss with lifestyle modifications, however, many patients fail to achieve the blood pressure goal with only lifestyle modification. “Treatments for hypertension in obesity: Nonpharmacological and pharmacological measurements-update in 2013” was updated on “Treatments on obesity-related hypertension” in Current Hypertension Reviews (2011, vol 7:pp184-200)” by Masuo. Most important thing to treat hypertension in type 2 diabetes is the target of blood pressure reduction is lower (<130/85 mmHg) than non-diabetic patients due to higher prevalence of cardiac and renal complications in diabetic patients. Furthermore, weight loss can help the efficacy of antihypertensive medications. This special issue covered a wide range of “Hypertension and Diabetes” including pathophysiology, complications and treatment, but all articles are very unique. The editor would thank the authors for their contributions and the reviewers for their 226 Current Hypertension Reviews, 2013, Vol. 9, No. 4 Editorial help. I enjoyed to edit a variety of articles, and learned systematically from the editing. I hope that this special issue is useful for your clinical medicine, research and preventing cardiovascular risks from hypertension and diabetes worldwide.

Many reviews focused on the role of sympathetic nervous activity in hypertension have been published. Recently a new treatment, radiofrequency renal denervation for the treatment of resistant hypertension has been developed and examined in several clinical trials such as the Symplicity HTN and EnligHTN studies. In the Symplicity HTN-1 study the efficacy for lowering blood pressure remained satisfactory at 3 years follow up and many ancillary ameliorative effects have been reported including cardiovascular, psychosocial, and metabolic effects. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and hypertension, especially focus on the importance of renal sympathetic nervous activity for the onset and development of hypertension. In addition, the methods to assess sympathetic nervous activity are reviewed. The renal denervastion was developed for the treatment-resistant hypertensive patients, and excessive confidence of the efficacy and safety existed by the end of 2013, although several issues on the efficacy and safety were reported in 2014. Furthermore, long-term efficacy and impact on renal function have been unclear. Those issues have to be clear for clinical usage. This review will also address the recent data from the renal denervation.

Several recent clinical trials show that blocking agents of the renin-angiotensin-aldosterone system (RAAS) reduce cardiovascular events in patients with metabolic syndrome based on insulin resistance and obesity, especially accumulated visceral fat. Our laboratory has focused on the relationship between the vascular RAAS and the action of insulin on the vasculature. We first revealed that the addition of insulin to cultured vascular smooth muscle cells (VSMC) markedly increases angiotensinogen and angiotensin II (Ang II) expression and production. Insulin addition also induces VSMC growth that is inhibited by the blockade of the RAAS by either ACEI or ARB which suggests a role for the RAAS in insulin-mediated growth. Insulin has a quite different effect on cultured vascular endothelial cells (EC) as it reduces angiotensinogen and renin expression. However, insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration. Ang II induces the progression of atherosclerosis through the production of oxidative stress that blocks insulin signaling and accelerates atherosclerosis. In this paper, we attempt to clarify the relationship between insulin resistance, the RAAS, and oxidative stress in vascular tissues to mimic in vivo conditions found in patients with metabolic syndrome and obesity-related hypertension as previously I reviewed in “Current Hypertension Reviews” in 2010 [1]. In addition, I update the relationships between vascular RAAS and insulin resistance for the last 4 years. JSH-2014 [2] states that the target goals of blood pressure (BP) for diabetes patients is lower than 130/80 mmHg, whereas updated JNC 8 [3] and ESH-ESC 2013 [4] recommends the target BP was changed to <140/90 mmHg for hypertensive patients with diabetes. Patients with diabetes and hypertension have reduced mortality as well as improved cardiovascular and cerebrovascular outcomes with treatment to a goal SBP < 150 mm Hg, but no randomized controlled trials support a goal <140/90 mm Hg. Despite this, the panel opted for a conservative recommendation in patients with diabetes and hypertension, opting for a goal level of <140/90 mm Hg in adult patients with diabetes and hypertension rather than the evidence based goal of <150/90 mm Hg [3, 5]. JSH-2014 recommends that the first choice of antihypertensive medication should be RAAS blockers such as ACE inhibitor or ARB. For the last several years, several large cohort clinical studies using ACEI and ARB have shown more favorable effects, but aldosterone receptor inhibitor (mineral corticoid receptor inhibitors; MR inhibitors) and Renin Inhibitors have been withdrawn. Some studies showed the strong support to use these medications for diabetic patients. This review will discuss the relationships between vascular RAAS and insulin resistance in patients with hypertension and diabetes as previously reviewed with new updated findings for the last 4 years, and clinical implications based on updated JNC-8, ESH-ESC2013 and JSH-2014.

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2- adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in “Journal of Obesity” [1], and another of my own reviews on the relationships with hypertension in 2010 in “International journal of Hypertension” [2], with 37 articles provided by the “PubMed” with the keywords of “adrenoceptor polymorphisms, obesity, hypertension and diabetes” searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be related to the ethnicity, gender, severeity of obesity, duration of hypertension or obesity, etc (refer the “Possible confounding variable affecting the relationships” section and Table 4). Therefore, this review may not be so much different from the previous ones, but, of importance, currently most investigations have shown that the β-adrenoceptor polymorphisms accompanying sympathetic nervous activity contribute to the onset and maintenance of hypertension, diabetes and obesity.

It has been well recognized that hypertension in diabetes is a potent risk of micro- and macrovascular complications. BP levels are most important component of BP management. Next to BP levels, other component such as BP variability is also important. BP variability consists of several concepts [1]: 1. Very Short term BP variability (beat-to-beat) 2. Short term BP variability (over the 24h) 3. Diurnal BP variation in diabetes 4. Long term BP variability (day-by-day) 5. Visit-to-Visit Variability (months ~ years) Among these, abnormal circadian rhythm of BP belongs to short-term BP variability. There have been a number of papers about BP variability in recent years. In this chapter, the significance of BP variability in patients with diabetes will be reviewed.

Salt sensitivity of blood pressure (BP) is increased in hypertension associated with obesity and/or metabolic disorders. Reversely, patients with salt-sensitive hypertension often reveal metabolic disorders. Thus, salt excess and overeating, which are major bad dietary habits in civilized men and women, strengthen the effect to increase BP each other. Actually, there are similar pathophysiological characteristics between hypertension induced by high salt intake and obesity: the sympathetic excitation has been suggested to contribute to increase in BP of the two types of hypertension. Also, several investigators indicated that reactive oxygen species (ROS) production is increased in important organs of salt-sensitive and/or obese hypertension. Recently, we demonstrated that, in salt- and obesity-induced hypertension, hypothalamic ROS levels was elevated and intracerebroventricular antioxidants suppress BP and renal sympathetic nerve activity more profoundly, compared to their control. Thus, it is suggested that brain ROS overproduction increases BP through central symapthoexcitation in salt- and obesity-induced hypertension, which are often associated.

Anorexigenic protein, nesfatin/nucleobindin-2 (NUCB2) is ubiquitously expressed in peripheral tissues including white adipose tissue. Nesfatin/NUCB2 is selectively expressed in pancreatic β-cell, but not α-cells, δ-cells, PPcells. Starvation significantly increased circulating nesfatin-1 concentrations, and refeeding restores the increase by starvation. There is an obvious dissociation in changes between nesfatin-1 releases from pancreatic β-cells and circulating nesfatin-1, and an increase of nesfatin-1 from pancreatic islets may not be reflected to circulating concentrations of nesfatin-1.Nesfatin-1 may be a novel insulinotropic peptide, since endogenous pancreatic islet NUCB2/nesfatin is altered in diabetes and diet-induced obesity. Nesfatin-1 may also contribute to the improvement of insulin sensitivity in hyperglycemic state. An increase of circulating nesfatin-1may shift glucose uptake to peripheral organs from skeletal muscles to adipocytes. Nesfatin-1 may involve the feedback system from adipocytes to the hypothalamus via general circulation, and from the hypothalamus to adipocytes via sympathetic nervous system. The details of those molecular mechanisms should be clarified by future studies including the analysis of gene targeted animals.

Hypertension and diabetes mellitus are closely associated, Cardiovascular complications and organ damages are augmented in hypertensive patients with diabetes mellitus compared to those without diabetes mellitus. The important common worsening factors in diabetes mellitus and essential hypertension are insulin resistance associated with sympathoexcitation. We should consider that sympathoinhibition is a reasonable therapy for the hypertensive patients with diabetes mellitus to prevent cardiovascular complications and organ damages, and that sympathoinhibition could be contributes to improve the survival of the hypertensive patients with diabetes mellitus.

The main current threat to the human race is the correlation and synergy between two determining triumvirates of atherosclerosis, cardiovascular disease and death. The first triumvirate is constituted by obesity, metaflammation and insulin resistance; the second triumvirate is constituted by atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus. The etiopathogenic driving force for both triumvirates is the global epidemic of obesity. Metaflammation and insulin resistance are associated with obesity; in turn, insulin resistance determines a high risk for the development of atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus, the three of them being factors responsible for vascular endothelial injury and substrates involved in the genesis of atherosclerosis, cardiovascular disease and death. The present chapter will address both triumvirates. Firstly, the current concepts of obesity, metaflammation and insulin resistance will be reviewed; emphasizing the second (metaflammation) for being a concept that has revolutionized and integrated our understanding of the harmful effects of obesity. Secondly, the impact of insulin resistance in the regulation of intermediary metabolism and endothelial function will be addressed; this will facilitate the understanding of the inextricable link between atherogenic dyslipidemia, hypertension and type 2 diabetes mellitus. Thus, this chapter aims to present to the clinician the best knowledge to link epidemics of obesity and cardiovascular death, through the sequence of metaflammation, insulin Atherogenic-dyslipidemia, atherosclerosis, cardiovascular-disease, diabetes-mellitus, hypertension, insulinresistance, metaflammation, obesity.resistance and cardiovascular risk factors (mixed dyslipidemia, hypertension and type 2 diabetes mellitus).

The profile of ischemic heart disease by coronary atherosclerosis has been developed based on clinical, paraclinical and angiographic grounds inherent to the male gender. A man in his 40s - 50s with "classical” cardiovascular risk factors, angina pectoris and hemodynamically significant myocardial ischemia associated with angiographic stenosis (≥ 50% endovascular diameter reduction equivalent to ≥ 75% endovascular area reduction and determining a transstenotic pressure gradient) is the prototype over which guidelines for prevention, diagnosis and treatment of this disease are structured. However, this "male" pattern of coronary atherosclerosis is not the rule in female gender. Therefore, in women, the frequent lack of a clinical, paraclinical and angiographic profile, classically masculine, results in a suboptimal medical approach, characterized by low implementation of the guidelines for prevention, diagnosis and treatment of ischemic heart disease. The final consequence of this cycle, favored by other gender, social and environmental circumstances, is a high morbidity and mortality caused by this pathology in the female gender. In this chapter, which concludes with a review of the state-of-the-art knowledge of atheroma in females, the current concepts on the physiological level of c-LDL, oxidized c-LDL "a mimicked pathogen" and atherogenesis will be reviewed in sequence for didactic purposes.

The intracellular concentration of cholesterol is a vital constant influenced by the uptake, metabolism and excretion of cholesterol. The synthesis and expression of the PCSK9-LDLR duo is one of the most important mechanisms to regulate this constant; in a physiological state, the yin-yang balance between PCSK9 and LDLR regulates the entry of cholesterol into the cell to keep the intracellular cholesterol concentration stable. The mapping of the human gene encoding the serine protease PCSK9, located at 1p32-3, has allowed the identification of mutations with "gain" and "loss" of protease functions. Gain of function mutations causes decreased LDLR resulting in increased LDL-C and increased incidence of cardiovascular events. Loss of function mutations have opposite effect, increased LDLR, decreased LDL-C and decreased incidence of cardiovascular events. The identification of human mutations with PCSK9 “loss” of function demostrated the benefit of decreased PCSK9 and opened the door to developing new anti-PCSK9 therapies. The goal of this research area is to reduce the incidence of cardiovascular events beyond statins; the strategy is to mimic the state of PCSK9 “loss” of function by tactics as oligonucleotide therapies targeting PCSK9 mRNA and/or biological therapies with human monoclonal antibodies targeting PCSK9. This chapter reviews, the characteristics of the PCSK9, the physiological significance of the PCSK9-LDLR duo, and the therapeutic implications of the human genetic models of PCSK9 “loss” of function. The phase I-II clinical trial data of two promising monoclonal antibodies to PCSK9, Alirocumab formerly SAR236553/REGN727and AMG145 will be presented.