Journal of Human Hypertension (2007) 21, 8–11 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh
COMMENTARY
Antihypertensive treatment, adiponectin and cardiovascular risk VJ Karthikeyan and GYH Lip Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Journal of Human Hypertension (2007) 21, 8–11. doi:10.1038/sj.jhh.1002113; published online 26 October 2006
Hypertension is a well-established risk factor for vascular disease, with wide-ranging implications on morbidity and mortality, and endothelial damage/dysfunction, inflammation, insulin resistance, platelet activation and changes in the coagulation cascade leading to a prothrombotic state being some of the many underlying pathological processes responsible for the progression of atherosclerosis and the increase in cardiovascular risk.1 Current principles of antihypertensive treatment aim, in addition to lowering blood pressure to halt the progression of atherosclerosis and alleviating the risk of cardiovascular events. Focus has therefore been directed on developing and improving antihypertensive treatment strategies with effects beyond mere blood pressure control, apart of strategies to comprehensively address the overall cardiovascular risk in a holistic manner.2 In particular, obesity has been identified as a major contributor to many aspects of overall cardiovascular risk.3 However, some caution is needed in interpreting studies that address this relationship, if body-mass index (BMI) is used as a criterion for obesity. One interesting systematic review of 40 studies with 250 152 patients found that patients with a low BMI (i.e., based on a BMI definition of o20 kg/m2) had an increased relative risk (RR) for total mortality (RR 1.37), and cardiovascular mortality (RR 1.45), whereas obese patients had no increased risk for total mortality or cardiovascular mortality. In contrast, patients with severe obesity (X35 kg/m2) did not have an increase in total mortality (RR 1.10) but they did have an increase in cardiovascular mortality (RR 1.88).3 Adipose tissue is not a benign dormant sedentary tissue, but is metabolically active, being the producer of many important hormones (the so-called adipocytokines4). Adiponectin is one such adipose tissue-specific protein with antiatherogenic and Correspondence: Professor GYH Lip, Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Dudley Road, Birmingham B187 QH, UK. E-mail:
[email protected] Published online 26 October 2006
insulin-sensitizing properties.4 Adiponectin is lower in patients with essential hypertension than in healthy subjects, in obese than in non-obese subjects, in men than in women, as well as in patients with coronary artery disease and diabetes mellitus type II.4,5 Low levels are hypothesized to be involved in the pathogenesis of vascular complications in diabetes.5 Adiponectin has been suggested to inhibit formation of initial atherosclerotic lesions by decreasing expression of adhesion molecules such as vascular endothelial growth factor-1, intracellular adhesion molecule-1, E-selectin in endothelial cells in response to inflammatory stimuli such as tumour necrosis factor-a (TNF-a) and suppressing cytokine (also TNF-a) production in macrophages.6,7 Further, adiponectin suppresses lipid accumulation in human monocyte-derived macrophages and inhibits macrophage-to-foam cell transformation as well as oxidized low-density lipoprotein cholesterol stimulated cell proliferation and suppression of cellular super oxide generation.8,9 Adiponectin overexpression in animal models (ApoE-deficient mice) appears to be protective from atherosclerosis.10,11 Adiponectin has also been shown, at least in experimental studies, to improve insulin sensitivity by stimulation of glucose utilization and fatty acid oxidation in skeletal muscles and liver cells and enhanced suppression of hepatic glucogenesis.12 It would therefore seem logical that a treatment strategy aimed at increasing adiponectin levels may be beneficial in the reduction of cardiovascular complications in patients with essential hypertension and diabetes mellitus type II, with or without obesity. Recent studies have explored the relationship between angiotensin II, the renin–angiotensin system and its blockade and adiponectin.13–17 One study13 in rats measured changes in plasma adiponectin levels following angiotensin II infusion and found that angiotensin II infusion decreased plasma adiponectin levels via the angiotensin II type I receptors, resulting in impaired insulin sensitivity. What about clinical studies? Table 1 summarizes the findings of these studies. Furuhashi et al.14 reported a significant increase in adiponectin levels
Table 1 Studies investigating the influence of antihypertensive agents on adiponectin levels Study
Number (n)
Drug(s)
Findings
Comments
Furuhashi et al.14
50 (30 hypertensives, 20 normotensives)
Temocapril/candesartan
Decrease in blood pressure in 16/30
Temocapril–candesartan in a crossover trial
Lower adiponectin levels in insulin-resistant hypertensives than normotensives and non-insulinresistant hypertensives Increase in adiponectin levels as well as insulin sensitivity with treatment Endothelial function, bradykinin and nitric oxide higher after ACE-I treatment
Hypoadiponectinaemia and insulin resistance are related in essential hypertension RAS blockade increases adiponectin levels with improvement in insulin sensitivity
Tomiyama et al.15
23 hypertensives
Insulin sensitivity and adiponectin levels similar after both treatments 53 hypertensives (7diabetes mellitus) vs 20 normotensives
Valsartan
Nowak et al.17
20 hypertensives
Rilmenidine
Nomura et al.18
103 (73 hypertensives & 30 normotensives); 40/73 with type 2 diabetes
Nifedipine
Rilmenidine therapy correlated with an increase in adiponectin levels without any significant changes of insulin sensitivity and body fat content Nifedipine therapy improved platelet activation markers, micro particles and adiponectin levels in hypertensive patients with type II diabetes Nifedipine has possible beneficial antiatherosclerotic effects in addition to its antihypertensive action
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; RAS, renin–angiotensin system.
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Journal of Human Hypertension
Adiponectin levels significantly low in hypertensives with type II diabetes (Po0.01), but increased with valsartan treatment (before vs after: 5.272.5 vs 7.672.7 Ag/ml, Po0.001) Monocyte activation markers, monocyte cheomotactic peptide, monocyte-derived micro particles, endothelial cell activation markers and soluble vascular cell adhesion molecule-1 significantly raised in the above group (Po0.01), but found to fall with valsartan treatment Six-month treatment with rilmenidine resulted in a significant decrease in systolic (P ¼ 0.007), diastolic and mean arterial blood pressure (P ¼ 0.002) Plasma adiponectin levels increased significantly with treatment (12.576.1 to 16.9711.1; P ¼ 0.0002) Hypertensives with type II diabetes found to have significantly low levels of adiponectin compared to normotensive controls (Po0.01) Six-month nifedipine therapy reduced blood pressure, with a significant rise in adiponectin levels in subjects with type II diabetes (Po0.01) Significant fall in the baseline high levels of procoagulant markers (platelet- and monocytederived microparticles) in hypertensives with diabetes with nifedipine therapy
Antihypertensive treatment, adiponectin and cardiovascular risk VJ Karthikeyan and GYH Lip
Nomura et al.16
ACE-I and ARB have similar effects on insulin sensitivity, despite the more pronounced effects of ACE-I on endothelial function Endothelial function, perhaps, is not a major determinant of insulin resistance under physiologic conditions Angiotensin II receptor blockade may be beneficial as an antiatherosclerotic therapy in patients with type II diabetes, in addition to its antihypertensive action
Antihypertensive treatment, adiponectin and cardiovascular risk VJ Karthikeyan and GYH Lip 10
(15 and 30%, respectively) and decrease in blood pressure in 16 out of 30 essential hypertensive patients treated with an angiotensin-converting enzyme inhibitor (ACE-inhibitor, Temocapril 4 mg/ day) or an angiotensin receptor blocker (ARB, Candesartan 8 mg/day). These insulin-resistant essential hypertensives had lower adiponectin concentrations than the normotensives and non-insulin-resistant hypertensives. Further, the degree of insulin sensitivity in the whole body increased with treatment and significantly correlated with the increase in adiponectin concentrations (r ¼ 0.59, Po0.05). A further study by Tomiyama et al.15 compared the effects of these same two drugs on endothelial function and insulin sensitivity, and found similar effects of both on insulin sensitivity. In addition, plasma levels of bradykinin, nitric oxide, TNF-a and adiponectin were measured. The adiponectin levels were found to be similar after both treatments, although endothelial function, bradykinin, TNF-a and nitric oxide levels were higher after the ACE-inhibitor treatment compared to ARB treatment. More recently, Nomura et al.16 investigated the effects of the ARB, valsartan, on monocyte and endothelial cell adhesion markers, as well as on adiponectin levels in hypertensive patients with type II diabetes. The levels of these markers were significantly increased in these patients compared to normotensive controls, with a significant fall after valsartan treatment. However, adiponectin levels were significantly decreased in patients with type II diabetes. Valsartan was found to alleviate this hypoadiponectinaemia in hypertensives with diabetes mellitus (Po0.001), with no effect in the nondiabetic hypertensive group, with a near normal average baseline adiponectin levels. Hence, angiotensin II receptor blockade may have antiatherosclerotic effects in patients with type II diabetes, in addition to its antihypertensive action. Another class of drugs with effects diverse from that of the renin–angiotensin–aldosterone system blockade has also being found to increase plasma adiponectin levels in patients with essential hypertension.17 Rilmenidine is a clonidine-like antihypertensive agent that blocks sympathetic nervous system activity by reducing the firing rate of sympathetic neurons with main action in the brainstem, as an agonist of both a2-adrenergic and proposed imidazoline receptors. Six months of treatment with rilmenidine caused a significant drop in systolic, diastolic and mean arterial blood pressures. A marked increase in plasma adiponectin concentration was observed (P ¼ 0.002), and significant positive correlations between plasma adiponectin concentrations and markers of insulin sensitivity both before and after 6 months of treatment with rilmenidine were observed. In this issue of the Journal of Human Hypertension, Nomura et al.18 extend these observations Journal of Human Hypertension
further by examining the effect of a calcium channel blocker (CCB), nifedipine on adiponectin concentrations in hypertensive patients with type II diabetes mellitus. Their study involved 103 subjects (73 hypertensives and 30 normotensive controls). Of the 73 hypertensives, 40 had type II diabetes mellitus. The hypertensives were treated with a long-acting CCB, Nifedipine CR for 6 months, with monitoring of their adiponectin levels and platelet-derived microparticles (PDMP) before and after nifedipine therapy. Their hypertensive subjects, particularly those with diabetes, were found to have significantly lower levels of adiponectin compared to the normotensive controls. Treatment with nifedipine resulted in a fall in the blood pressures in the hypertensive group as a whole, associated with an increase in the adiponectin levels in the hypertensive group with diabetes (Po0.01). Interestingly, there was no change in adiponectin levels in the hypertensiononly group. Nomura et al.19 also studied the effects of nifedipine on platelet/monocyte activation and found raised levels of soluble markers soluble CD40 ligand, soluble P-selectin, soluble E-selectin (sE-selectin), PDMP, monocyte-derived microparticles and endothelial cell-derived microparticles (EDMP) in the hypertensive group with diabetes compared with the normotensive group, although sE-selectin and EDMP levels were similar in the hypertension-only and the normotensive groups. Nifedipine was found to have a significant effect on these markers in the hypertensive diabetic group following 3 months’ treatment but the effect was less marked in the hypertension-only patient group. The findings of Nomura et al.18 suggest a cardioprotective role (at least from the adiponectin perspective) of the CCB nifedipine, although it remains to be determined whether this is a nifedipine-specific effect or whether it is a class effect of all dihydropyridine calcium antagonists. The implication here is that CCBs, particularly nifedipine, may have beneficial effects on the cardiovascular system, with antiatherosclerotic effects beyond blood pressure lowering. This appears most marked in hypertensive patients with diabetes. The precise pathophysiological mechanisms underlying this putative benefit on adiponectin are unclear. However, suppression of monocyte activation, with consequent inhibition of microparticle generation is one of the proposed mechanisms.19 Another mechanism proposed is the inhibition of platelet activation by its effects on endothelial function and increased nitric oxide activity.20,21 The translation of these pathophysiological changes to the benefits seen in clinical outcome trials will give added insight into the value of antihypertensive agents in particular patient subgroups, especially those with diabetes and impaired insulin sensitivity.22
Antihypertensive treatment, adiponectin and cardiovascular risk VJ Karthikeyan and GYH Lip 11
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