Targeting Hypertension in Patients with Cardiorenal Metabolic Syndrome
Edward Rojas, Manuel Velasco, Valmore Bermúdez, Zafar Israili & Peter Bolli
Current Hypertension Reports ISSN 1522-6417 Curr Hypertens Rep DOI 10.1007/s11906-012-0292-5
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Author's personal copy Curr Hypertens Rep DOI 10.1007/s11906-012-0292-5 ANTIHYPERTENSIVE THERAPY: PATIENT SELECTION AND SPECIAL PROBLEMS (K KARIO AND H RAKUGI, SECTION EDITORS)
Targeting Hypertension in Patients with Cardiorenal Metabolic Syndrome Edward Rojas & Manuel Velasco & Valmore Bermúdez & Zafar Israili & Peter Bolli
# Springer Science+Business Media, LLC 2012
Abstract Diabetes mellitus coexisting with hypertension is greater than chance alone would predict. Hypertensive patients have been shown to have altered composition of skeletal muscle tissue, decreased blood flow to skeletal muscle and post-receptor signaling alterations in the IRS insulin pathway, all inducing insulin resistance states, which partially explains why blood pressure goals in DM patients are lower than in normoglycemic patients. Although optimal first-step antihypertensive drug therapy in type 2 DM or impaired fasting glucose levels (IFG) should be individualized for each patient, converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been demonstrated in some but not all studies to decrease the rate of development of proteinuria and diabetic renal disease. According to the ACCF/AHA 2011 Expert Consensus, elderly persons with diabetes, hypertension, and nephropathy should be initially treated with ACEIs or ARBs, although the choice of a specific antihypertensive may also depend on other associated comorbidities.
E. Rojas (*) : V. Bermúdez Endocrine and Metabolic Diseases Research Centre “Dr. Felix Gomez”, University of Zulia, 20th Avenue, Maracaibo 4004, Venezuela e-mail:
[email protected] M. Velasco Clinical Pharmacology Unit of José María Vargas School of Medicine, Central University of Venezuela, Caracas, Venezuela Z. Israili Emory University School of Medicine, Atlanta, GA, USA P. Bolli Clinical Professor of Medicine, McMaster University Hamilton, Hamilton, ON, Canada
Keywords Diabetes . Hypertension . Blood pressure . Cardiorenal metabolic syndrome . Kidney disease . Reninangiotensin-aldosterone system . RAAS . Antihypertensive therapy . Pharmacologic therapy
Introduction Hypertension is an increasingly important medical and public health issue affecting developed and developing countries. Worldwide analysis of data shows that 26.4 % (95 % CI 26.0–26.8 %) of the adult population had hypertension by the year 2000 and 29.2 % (28.8–29.7 %) are projected to have hypertension by 2025 [29.0 % of men (28·6–29·4 %) and 29.5 % of women (29.1–29.9 %)]. The number of adults with hypertension is predicted to increase by about 60 % to a total of 1.56 billion (95 % CI 1.54–1.58 billion) by the year 2025 [1]. Hypertension is no longer only a problem of established market economies according to a meta-analysis by Kearney et al. [1], who showed that in the year 2000 developed countries (USA, Canada, Spain, Japan, England, Germany) had a prevalence of 37.4 % (36.6–38.2) in men and 37.2 % (36.6–37.8) in women, and Latin America and the Caribbean (Mexican, Paraguayan and Venezuelan data) had a prevalence of 40.7 % (40.1-41.4) in men and 34.4 % (34.3-35.4) in women by 2000. This might be due to very similar sedentary and dietary lifestyles in spite of the economic disparity. High blood pressure is a powerful, consistent and independent risk factor for cardiovascular disease and renal disease [2], nonetheless, when it associates with another medical condition such as diabetes mellitus (DM), the risk significantly increases. By 2010 the estimated DM prevalence was 285 million, representing 6.4 % of the world’s adult population [3], and its coexistence with hypertension is greater than chance alone would predict [4].
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By 2005 there were about 1.6 billion overweight adults aged 15 years and above and at least 400 million obese adults. It is widely known that obesity increases the risk of chronic diseases such as diabetes mellitus, cardiovascular disease, stroke and some cancers, representing a serious public health problem that is growing in countries with low or middle incomes [5]. According to the International Diabetes Federation (IDF) Atlas, more than 80 % of the 246 million people with diabetes (by 2003) lived in low and middle income countries, which demonstrates that DM is no longer only a problem of industrialized countries, but a worldwide issue with a larger burden in developing countries [6]. Impaired glucose tolerance (IGT) is even more common than DM, affecting 344 million people by 2010 (7.9 % of the worldwide population) and with a 2030 prevalence projection of 472 million (8.4 %) [6]. Also, relatively isolated populations with recently evolving economies, such as Kiribati, the Marshall Islands and Kuwait, are known to have the first places in worldwide diabetes prevalence [7]. On the other hand, trends in the prevalence of diabetic kidney disease (DKD) have demonstrated an ascending pattern in the US since 1988 to nowadays according to de Boer et al. [8]. The prevalence of DKD in the US population was 2.2 % in NHANES III 1988-1998, and 3.3 % in NHANES 2005-2008, showing an increase directly proportional to the prevalence of diabetes, and without a change in the prevalence of DKD among those with diabetes. Metabolic syndrome (MS) has been classically defined as the concurrence in the same patient of several cardiovascular disease (CVD) risk factors, including obesity, hypertension, diabetes and dyslipidemia, significantly increasing the risk of acute coronary syndrome and stroke [9, 10]. Lakka et al. [11] carried out a prospective cohort study following Finnish men for an average of 11.4 years, and assessed the association of metabolic syndrome with cardiovascular and all-cause mortality. The authors found that cardiovascular and all-cause mortality are increased in men with the metabolic syndrome even in the absence of baseline CVD and diabetes.
Hypertension and Metabolic Syndrome: Pathophysiology According to the IDF, the main feature of metabolic syndrome is central (visceral) obesity [10]. Visceral obesity has been linked to many of the known atherosclerotic risk factors, including dyslipidemia, hypertension, insulin resistance and proinflammatory states. Hence, adipose tissue plays a determining role in cardiovascular disease pathogenesis because of its functions as an endocrine organ producing several substances able to modulate inflammation (TNF-
α, IL-6 and IL-1), intermediary metabolism (adiponectin, leptin, resistin, ghrelin), endothelial function, thrombosis/ fibrinolysis (PAI-1) and, our main concern in this review of the literature, blood pressure (renin, angiotensinogen) [12, 13]. Almost all of the renin-angiotensin-adosterone system (RAAS) genes (e.g., AGT, REN, ACE, AT1R, AT2R) are expressed in human adipocytes [14], taking place in adipose tissue RAS or local adipose tissue RAS [15, 16]. The genes encoding for both ACE and AT1 receptor expression are significantly upregulated in obese and hypertensive patients as compared to either lean or obese normotensives, which suggests that the formation of AngII and its effects transmitted by the AT1 receptor may be increased in obese hypertensive patients [17]. Engeli et al. in 2005 indirectly demonstrated a relationship between obesity and the expression of RAAS components. The authors compared circulating and adipose tissue RAAS in 19 obese (visceral obesity) and 19 lean postmenopausal women, observing that obese women had higher circulating renin, angiotensinogen, aldosterone and angiotensin converting enzymes, suggesting that RAAS was significantly induced in obese compared to lean subjects [18]. In the same study and after 5 % weight reduction in obese women, circulating levels of renin, angiotensinogen, aldosterone and angiotensin converting enzymes were all diminished. Nonetheless, under experimental conditions angiotensin II (AngII) via the AT1 receptor inhibited the adipogenic differentiation of human pre-adipocytes. When the effect of AngII is blocked by blocking the AT1 receptor, the preadipocyte differentiation is augmented [19]. A possible clinical implication could be that by blocking the renin angiotensin system, the number of small newly differentiated adipocytes is increased, and it is known that these small adipocytes are more insulin sensitive than the older, large adipocytes [19, 20]. Additionally, large insulin-resistant adipocytes act as a source for AngII production. This increased production of AngII results in inhibition of both preadipocyte recruitment and differentiation, at some point involving extracellular signal-regulated kinase 1,2 (ERK1,2) activation and PPAR gamma phosphorylation, as demonstrated in Fuentes et al.’s recent work [21]. As a result of the reduced fat storage capacity due to the reduced number of preadipocytes, excess lipids in the form of triglycerides are stored in ectopic tissues, such as the liver or muscle cells, and results in reduced insulin sensitivity in skeletal muscle cell. Skeletal muscle tissue of patients with hypertension shows phenotypic features that predispose to insulin resistance. These are: (1) altered composition of skeletal muscle tissue (fewer slow-twitch insulin-sensitive muscle fibers and increased fat interspersed between skeletal muscle fibers);
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(2) decreased blood flow and delivery of insulin and glucose to skeletal muscle tissue because of vascular hypertrophy and vasoconstriction; (3) postreceptor abnormalities in metabolic signaling responses to insulin in skeletal muscle tissue (Fig. 1) [22, 23]. By blocking the effect of AngII with either angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, preadipocyte recruitment is promoted, resulting in the production of more small insulin-sensitive adipocytes. This can then result in the redistribution of excess lipids out of ectopic tissue such as the liver and skeletal muscle cells into adipose cells for storage. Reduction in fat storage by skeletal muscle cells results in improved insulin sensitivity.
Hypertension and Metabolic Syndrome: Antihypertensive Therapy The Seventh Report of the Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure (JNC-7) set a blood pressure target of
