Articles on role of inflammation in hypertension and stroke

Articles on Inflammation & Hypertension

Association between blood pressure variability and inflammatory marker in hypertensive patients. Kim KI. Lee JH. Chang HJ. Cho YS. Youn TJ. Chung WY. Chae IH. Choi DJ. Park KU. Kim CH. Circulation Journal. 72(2):293-8, 2008 BACKGROUND: Blood pressure (BP) variability has been reported to be associated with hypertensive target organ damage and cardiovascular events. However, the exact mechanism linking BP variability and organ damage is uncertain. This study was designed to investigate the association between BP variability and inflammatory marker in hypertensive patients. METHODS AND RESULTS: Fifty-two hypertensive patients (28 men, 55.9+/-1.5 years) completed 24-h ambulatory BP monitoring. Inflammatory markers were evaluated by measuring plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha by enzyme-linked immunosorbent assay and high sensitive C-reactive protein (hs-CRP) by particle-enhanced light-scattering immunoassay. BP variability was obtained by calculating within-subject standard deviation (SD) and coefficient of variation of BP. Subjects were grouped into tertiles according to IL-6, TNF-alpha, and hs-CRP levels. A significant association between ambulatory BP and TNF-alpha level was identified (P for trend =0.011). In contrast, no association was observed between BP and IL-6 level; however, BP variability index was linked to IL-6 level (P for trend =0.046). The association between inflammatory marker and pattern of diurnal variation was investigated. The hs-CRP concentration was significantly higher in the riser group compared with the dipper group. However, IL-6 and TNF-alpha levels did not differ among the different diurnal variation groups. Correlation analysis showed varying associations between IL-6 and TNF-alpha. TNF-alpha level correlated with the BP index; however, IL-6 level correlated with the BP variability index. Multiple linear regression models revealed that the SD of daytime systolic BP (beta=0.065, p=0.001) and age (beta=0.024, p=0.016) were all positively and significantly related to IL-6. In contrast, only daytime diastolic BP (beta=0.029, p=0.002) was independently related to TNF-alpha. CONCLUSION: Inflammatory markers are associated with BP variability in hypertensive patients. This finding implies that inflammation may be a mediator for the link between BP variability and target organ damage.

Association of low-grade inflammation and platelet activation in patients with hypertension with microalbuminuria. Ferroni P. Guagnano MT. Falco A. Paoletti V. Manigrasso MR. Michetti N. Santilli F. Guadagni F. Basili S. Davi G. Clinical Science. 114(6):449-55, 2008 Increased levels of sCD40L (soluble CD40 ligand) have been associated with enhanced in vivo platelet activation, and may represent a molecular link between inflammation and a prothrombotic state. The aim of the present study was to analyse the relationship between platelet activation, endothelial dysfunction, low-grade inflammation and sCD40L in patients with hypertension with or without MA (microalbuminuria). A cross-sectional comparison of sCD40L levels was performed in 25 patients with MH (essential hypertension with MA) pair-matched for gender and age with 25 patients with EH (essential hypertension) and 25 HS (healthy subjects with normotension). Circulating levels of CRP (C-reactive protein), a marker of inflammation, sP-selectin (soluble P-selectin), a marker of in vivo platelet activation, and ADMA (asymmetric dimethylarginine) and vWF (von Willebrand factor), markers of endothelial dysfunction, were analysed in each subject. sCD40L levels were increased in patients with MH compared with either patients with EH (P<0.001) or HS (P<0.0001). A highly significant correlation between plasma sCD40L and sP-selectin (P<0.0001), vWF (P<0.001) or CRP levels (P<0.05) was observed in patients with MH. Multivariate regression analysis showed that sP-selectin was the strongest independent predictor of sCD40L levels (P<0.0001) in patients with MH. Patients with hypertension with both vWF and CRP levels above the median had the highest sCD40L levels (P<0.0001). Factorial ANOVA of all of the patients with hypertension confirmed that only patients with MH with low-grade inflammation had elevated levels of sCD40L. In conclusion, sCD40L levels appear to discriminate a subset of patients characterized by MA and low-grade inflammation, suggesting that inhibition of the CD40/CD40L system may represent a potential therapeutic target in subjects with hypertension at a high risk of cardiovascular events.

Endothelial progenitor cells, endothelial dysfunction, inflammation, and oxidative stress in hypertension. [Review] [109 refs] Watson T. Goon PK. Lip GY. Antioxidants & Redox Signaling. 10(6):1079-88, 2008 With a prevalence in excess of 20%, hypertension is a common finding among Western adult populations. Hypertension is directly implicated in the pathophysiology of various cardiovascular disease states and is a significant contributor to ill health, leading to an excess of both morbidity and mortality. The etiology of hypertension has been explored in depth, but the pathophysiology is multifactorial, complex, and poorly understood. Recent interest has been directed toward investigating the purported role of the endothelium, which acts as an important regulator of vascular homeostasis. Endothelial dysfunction is now recognized to occur in hypertension, regardless of whether the etiology is essential or secondary to endocrine or renal processes. Nitric oxide (NO) is a volatile gas produced by endothelial cells that acts to maintain vascular tone. Reduced bioavailability of NO appears to be the key process through which endothelial dysfunction is manifested in hypertension. The result is of an imbalance of counteracting mechanisms, normally designed to maintain vascular homeostasis, leading to vasoconstriction and impaired vascular function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress, possibly as a result of systemic and localized inflammatory responses. This article provides an overview of endothelial dysfunction in hypertension and focuses on the purported role of oxidative stress and inflammation as the catalysts for this process.

Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation. Yamamoto E. Tamamaki N. Nakamura T. Kataoka K. Tokutomi Y. Dong YF. Fukuda M. Matsuba S. Ogawa H. Kim-Mitsuyama S. Stroke. 39(11):3049-56, 2008 BACKGROUND AND PURPOSE: The precise mechanism of salt-induced brain injury is unclear. We examined the detailed causative role of angiotensin II and NADPH oxidase in salt-accelerated brain injury of stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: We examined the effect of salt loading on brain reactive oxygen species (ROS), inflammation, and apoptosis in SHRSP. Salt-loaded SHRSP were given vehicle, valsartan (an angiotensin AT1 receptor blocker), or hydralazine to compare their efficacy on brain injury. We also examined the efficacy of apocynin (a NADPH oxidase inhibitor) on brain injury of salt-loaded SHRSP. RESULTS: Cerebral NADPH oxidase activity and ROS in SHRSP were already increased at 1 week after salt loading followed by the significant increase in ED-1-positive cells and neuronal apoptosis. Thus, cerebral NADPH oxidase activation preceded cerebral inflammation and neuronal apoptosis. Despite comparable hypotensive effects between valsartan and hydralazine in salt-loaded SHRSP, valsartan reduced cerebral NADPH oxidase activity and ROS more than hydralazine being accompanied by more prevention of stroke by valsartan than hydralazine. Valsartan, but not hydralazine, prevented neuronal apoptosis, being associated with the suppression of apoptosis signal-regulating kinase 1 activation by valsartan. Moreover, cerebral inflammation was also prevented by valsartan more than hydralazine, being associated with more suppression of monocyte chemotactic protein-1 and tumor necrosis factor-alpha expressions by valsartan. Thus, angiotensin II was directly involved in salt-induced neuronal NADPH oxidase activation, ROS, apoptosis, and inflammation in SHRSP. Apocynin attenuated the enhancement of ROS, cerebral inflammation, neuronal apoptosis, and apoptosis signal-regulating kinase 1 activation and prevented stroke in salt-loaded SHRSP, indicating the causative role of cerebral NADPH oxidase in salt-induced brain injury. CONCLUSIONS: We obtained the evidence that excess salt, through ROS produced by angiotensin II-activated NADPH oxidase, caused cerebral neuronal apoptosis and inflammation as well as stroke in SHRSP.

Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women. Nasca MM. Zhou JR. Welty FK. American Journal of Cardiology. 102(1):84-6, 2008 Recently, it was shown that substituting soy nuts for nonsoy protein in a therapeutic lifestyle change (TLC) diet lowered systolic and diastolic blood pressure by 9.9% and 6.8%, respectively, in postmenopausal women with hypertension and by 5.2% and 2.9%, respectively, in normotensive postmenopausal women. In this study, to examine mechanisms for these reductions, markers of inflammation were measured, including soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, C-reactive protein, interleukin-6, and matrix metalloproteinase-9. Sixty healthy postmenopausal women (48 normotensive and 12 with hypertension) were randomized in a crossover design to a TLC diet alone or a TLC diet in which 0.5 cups of soy nuts (25 g soy protein and 101 mg aglycone isoflavones) replaced 25 g of nonsoy protein daily. Each diet was followed for 8 weeks. Compared with the TLC diet alone, levels of soluble vascular cell adhesion molecule-1 were significantly lower on the soy diet in women with hypertension (623.6 +/- 153.8 vs 553.8 +/- 114.4 ng/ml, respectively, p = 0.003), whereas no significant differences were observed in normotensive women. Soy nuts were associated with a trend toward reduction in C-reactive protein in normotensive women. No effect on levels of soluble intercellular adhesion molecule-1, interleukin-6, or matrix metalloproteinase-9 was observed. In conclusion, the reduction in soluble vascular cell adhesion molecule-1 with soy nuts in women with hypertension suggests an improvement in endothelial function that may reflect an overall improvement in the underlying inflammatory process underlying atherosclerosis.

Insulin resistance and blood pressure. [Review] [43 refs] Addison S. Stas S. Hayden MR. Sowers JR. Current Hypertension Reports. 10(4):319-25, 2008 Insulin resistance, cardiometabolic syndrome, and hypertension are common health problems with significant consequences for individuals and society. The pathogenesis of these disorders is complex and not fully understood. In this article we review the current knowledge about the effects of lifestyle modification and pharmacologic antihypertensive agents on insulin resistance and hypertension.

Role of inflammation in the development of renal damage and dysfunction in angiotensin II-induced hypertension.[see comment]. Liao TD. Yang XP. Liu YH. Shesely EG. Cavasin MA. Kuziel WA. Pagano PJ. Carretero OA. Hypertension. 52(2):256-63, 2008 Angiotensin II (Ang II)-induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II-induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2-/-). The natural ligand of CCR2 is monocyte chemoattractant protein-1, a chemokine important for macrophage recruitment and activation. CCR2-/- and age-matched wild-type (CCR2+/+) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g per minute) or vehicle via osmotic minipumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2-/- mice with Ang II-induced hypertension, oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly decreased, and glomerular filtration rate was significantly higher than in CCR2+/+ mice. We concluded that, in Ang II-induced hypertension, CCR2 activation plays an important role in the development of hypertensive nephropathy via increased oxidative stress and inflammation.

Abdominal obesity and inflammation predicts hypertension among prehypertensive men and women: the ATTICA Study. Pitsavos C. Chrysohoou C. Panagiotakos DB. Lentzas Y. Stefanadis C. Heart & Vessels. 23(2):96-103, 2008 The aim of this work was to assess the 5-year incidence of hypertension and its predictors among prehypertensive adults. Under the context of the ATTICA Study, data from 1188 individuals, free of cardiovascular disease, but with defined high blood pressure levels (prehypertension) at baseline examination (during 2001-2002) were retrieved. In 2006, the 5-year follow-up of the study was performed, and 798 of the prehypertensive participants were allocated. In this work, incidence and determinants of developing hypertension were evaluated. The 5-year ageadjusted incidence of hypertension was 18.7% in men and 24.6% in women (P = 0.05); while almost one half of prehypertensive individuals at the age of 55-65 years developed hypertension, and approximately 6 out of 10 people over 65 years of age developed the disease. Multiple logistic regression analysis revealed that increased age (odds ratio [OR] per 1 year = 1.09, 95% confidence interval [CI] 1.07-1.12), male sex (OR = 0.40, 95% CI 0.21-0.68), high education status (OR per 1 year of school = 0.94, 95% CI 0.88-0.98), waist circumference (OR per 1 cm = 1.04, 95% CI 1.02-1.06) and C-reactive protein (OR per 1 mg/l = 1.12, 95% CI 1.05-1.20), were positively associated with the development of hypertension. Moreover, greater adherence to Mediterranean diet seems to protect only prehypertensive, with abdominal obesity patients prone to develop hypertension (OR = 0.94, 95% CI 0.90-0.98). Annual incidence of hypertension was roughly 4% in men and women. Older people, with low education, abdominal obesity, lower adherence to the Mediterranean diet, and increased inflammation, constitute a model of prehypertensive individuals that are prone to develop hypertension.

The combined effect of calcium channel blocker Lercanidipine and antioxidants on low-grade systemic inflammation parameters in essential hypertension patients. Farah R. Shurtz-Swirski R. Minerva Cardioangiologica. 56(5):467-76, 2008 The influence of oxidative stress (OS) and inflammation on up-regulation of blood pressure (BP) has been well established. Peripheral polymorphonuclear leukocytes (PMNLs) are primed in essential hypertension (EH) patients, releasing uncontrolled superoxide anion contributing to OS in these patients. PMNL priming correlates with PMNL intracellular calcium [Ca2+]i. Previous studies have shown that treatment by calcium channel blockers lowers BP, OS and inflammation. In the same time, there are some trials showing down regulation influence of ''anti-oxidative'' drugs as Vitamin E and C to inflammation and OS. The data of clinical significance of anti-oxidative drugs to BP is controversial. The aim of this paper was to evaluate the benefit of combined treatment by calcium channel blockers (Lercanidipine) and antioxidative drugs (Vitamins C and E) on BP and on parameters of inflammation and OS. METHODS: Sixteen new diagnosed patients with mild to moderate BP were sampled to 2 groups after randomization by age, sex, and mean arterial pressure (MAP), cholesterol and glucose level. The first group was treated by Lercanidip-ine only, the second group by combination of Lercanidipine and antioxidative drugs both for 6 months. PMNL priming was assessed by the rate of superoxide release from separated, phorbol ester-stimulated PMNLs and by PMNL-CD11b level. Inflammation was reflected by plasma C-reactive protein (CRP) and albumin levels, white blood cells (WBC) and PMNL counts and by PMNL apoptosis. RESULTS: In both groups, BP decreased after 6 months of treatment, and in a more pronounced manner following the combined treatment. In both groups PMNL priming parameters remained unchanged after 6 months of treatment, with transient differences between the two groups during the experimental period. In both groups inflammation parameters remained unchanged after 6 months of treatment, without difference between the two groups, except a pronounced decrease in the percentage of apoptotic PMNLs in the combined treatment group. CONCLUSION: Our trial shows a clinical benefit combining calcium channel blockers treatment with antioxidants in BP treatment, although it did not reveal significant influence of complementation of antioxidants to calcium channel blockers on OS and inflammation parameters. Additional clinical and laboratory investigations are needed to clear this issue. Conflicting data are reported on the influence of vitamins E and C on OS and inflammation together with controversy regarding anti-oxidative drugs and their effect on BP.

Proinflammation and hypertension: a population-based study. Mauno V. Hannu K. Esko K. Mediators of Inflammation. 2008:619704, 2008. There is evidence that proinflammation may be linked to the development of hypertension (HT). We examined the association of both the interleukin-1 beta (IL-1beta) and the interleukin 1-receptor antagonist (IL-1ra) with future blood pressure (BP) and HT occurrence (BP >or= 140/90 mmHg, or antihypertensive drug) in a population-based prospective study. Our study consisted of 396 (147 men and 249 women) middle-aged, baseline apparently healthy, normotensive subjects participating in a 6.5-year follow-up study. Subjects with high-sensitivity CRP (hs-CRP) < 10 mg/L were excluded at the initial visit. At follow-up, the occurrence of HT was 32%. The levels of baseline IL-1beta and IL-1ra were significantly higher for subjects who developed HT during the follow-up than for those who did not (IL-1beta; 0.67 +/- 0.62 pg/mL versus 0.56 +/- 0.32 pg/mL, P = .020 and IL-1ra; 184 +/- 132 pg/mL versus 154 +/- 89 pg/mL, P = .007). After adjustments for age, follow-up time, sex, baseline systolic BP, and BMI, our results confirm a statistically significant (P = .036) linear association between the quartiles of IL-1beta and change of systolic BP during the study. After adjustments for age, follow-up time, sex, and BMI, our results also show a linear association between incident HT and the quartiles of IL-1ra. (P = .026). These results provide evidence that proinflammation may precede BP elevation and HT.

Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension. Tatasciore A. Zimarino M. Renda G. Zurro M. Soccio M. Prontera C. Emdin M. Flacco M. Schillaci G. DE Caterina R. Hypertension Research - Clinical & Experimental. 31(12):2137-46, 2008 Increased blood pressure (BP) may stimulate vascular inflammation, which may itself induce pathological arterial changes. BP variability has been associated with target-organ damage and future cardiovascular complications. We hypothesized that BP variability, as derived from ambulatory BP monitoring, is related to inflammatory markers in newly diagnosed hypertension. Systolic (S) and diastolic (D) BP variabilities were assessed as the SD of 24-h pressure recordings in a cohort of 190 recently (<6 months) diagnosed, untreated hypertensive subjects. Target organ damage, assessed by measuring the carotid artery intima-media thickness, left ventricular mass index, and microalbuminuria, was related to plasma high-sensitivity C-reactive protein (hsCRP) and soluble (s) E-selectin, an endothelium-specific molecule. The patients' age (mean+/-SD) was 53.0+/-8.5 years, and 59% were male. Multivariable analysis identified awake SBP variability (95% confidence interval [CI]: 0.002-0.042, p=0.034) as an independent correlate of hsCRP and awake SBP (95% CI: 0.003-0.014, p=0.003), awake SBP variability (95% CI: 0.003-0.035, p=0.018), and microalbuminuria (95% CI: 0.075-0.280, p=0.001) as independent correlates of sE-selectin. When patients were divided into low and high awake SBP variability groups, age (p=0.001), hsCRP (p=0.0001), and sE-selectin (p=0.005) were significantly different in the two groups. After adjusting for age, these differences remained significant (p=0.022 and p=0.001 for hsCRP and sE-selectin, respectively). In recently diagnosed hypertensive subjects, hsCRP and sE-selectin levels are related to awake SBP variability. High SBP variability is likely associated with vascular inflammation in newly diagnosed hypertension, independent of SBP.

Is hypertension an immunologic disease?. [Review] [51 refs] Harrison DG. Guzik TJ. Goronzy J. Weyand C. Current Cardiology Reports. 10(6):464-9, 2008 Several studies published in the past three decades have suggested that the adaptive immune system contributes to hypertension. Recent studies have shown that T cells play a crucial role in the blood pressure elevation caused by angiotensin II and in response to sodium and volume challenge. Hypertensive stimuli cause effector T cells to enter visceral fat, in particular perivascular fat, where they release cytokines that promote vasoconstriction. Similarly, effector T cells accumulate in the kidney in hypertension and contribute to renal dysfunction, promoting sodium and volume retention. These findings provide some insight into the relationship between inflammation and hypertension and suggest that efforts to reduce T-cell activation may be useful in preventing or treating this disease.

The use of high-sensitivity assays for C-reactive protein in clinical practice. [Review] [112 refs] Musunuru K. Kral BG. Blumenthal RS. Fuster V. Campbell CY. Gluckman TJ. Lange RA. Topol EJ. Willerson JT. Desai MY. Davidson MH. Mora S. Nature Clinical Practice Cardiovascular Medicine. 5(10):621-35, 2008 High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD.

Role of the renin-angiotensin system in vascular inflammation. [Review] [74 refs] Marchesi C. Paradis P. Schiffrin EL. Trends in Pharmacological Sciences. 29(7):367-74, 2008 Angiotensin (Ang) II, the main effector of the renin-angiotensin system (RAS), is one of the major mediators of vascular remodeling in hypertension. Besides being a potent vasoactive peptide, Ang II exerts proinflammatory effects on the vasculature by inducing integrins, adhesion molecules, cytokines and growth and profibrotic mediators through activation of redox-sensitive pathways and transcription factors. Clinical findings suggest that inflammation participates in the mechanisms involved in the pathophysiology of hypertension and its complications. Antagonists of the RAS have been shown to exert cardiovascular protection, in part through their vascular anti-inflammatory effects. However, further studies are needed to better understand whether inflammatory biomarkers might be clinically useful for cardiovascular risk stratification and whether targeting inflammation pharmacologically will improve cardiovascular outcomes beyond blood pressure reduction. The present review addresses recent findings regarding the pathophysiology of vascular inflammation in hypertension, focusing specifically on the role of Ang II.

The renin-angiotensin-aldosterone system: a pivotal role in insulin sensitivity and glycemic control. [Review] [42 refs] Perkins JM. Davis SN. Current Opinion in Endocrinology, Diabetes & Obesity. 15(2):147-52, 2008 PURPOSE OF REVIEW: Diabetes mellitus is an exploding epidemic costing billions of dollars yearly. Type 2 diabetes mellitus is characterized by insulin resistance and is closely associated with arterial hypertension. Emerging literature has demonstrated that modulation of the renin-angiotensin-aldosterone system by use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers leads to improved insulin sensitivity, glycemic control and possibly prevention of type 2 diabetes mellitus. RECENT FINDINGS: Several major studies investigating angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use in either hypertensive or heart failure patients have found lower incidence of type 2 diabetes mellitus when compared with placebo, beta-blocker, calcium-channel blocker or diuretic. None of these trials, however, studied prevention of diabetes as a primary endpoint. The Dream Trial and upcoming NAVIGATOR, ONTARGET/TRANSCEND trials specifically look at the prevention of diabetes as a primary endpoint. Several studies have evaluated possible mechanisms of how the renin-angiotensin-aldosterone system can alter insulin sensitivity and glycemic control. SUMMARY: This review will focus on the recent literature that demonstrates renin-angiotensin-aldosterone system modulation and its effects on diabetes prevention, glycemic control and insulin sensitivity, as well as possible mechanisms for achieving this goal.

Therapeutic targets in hypertension: is there a place for antagonists of the most potent vasoconstrictors?. [Review] [112 refs] Giachini FR. Callera GE. Carneiro FS. Tostes RC. Webb RC. Expert Opinion on Therapeutic Targets. 12(3):327-39, 2008 BACKGROUND: Endothelin-1 (ET-1) and urotensin II (U-II) are the most potent and unusually long-lasting constrictors of human vessels known to date. OBJECTIVE: In this review, we focus on the vascular effects of endothelin-1 (ET-1) and urotensin II (U-II) and their role in the pathophysiology of hypertension. RESULTS AND CONCLUSION: Unlike ET-1, which uniformly constricts most blood vessels, the vasoactive effects of U-II depend both on the species, vascular bed and vessel calibre. Both ET-1 and U-II have potent mitogenic, pro-inflammatory and pro-oxidative properties, which have been implicated in the pathogenesis of human cardiovascular and renal diseases. The availability of highly effective peptide and non-peptide antagonists both for ET-1 and U-II receptors has revealed a role for these potent vasoconstrictor peptides in human (patho)physiology.

The renin-angiotensin system, hypertension and cognitive dysfunction in Alzheimer's disease: new therapeutic potential. [Review] [124 refs] Takeda S. Sato N. Ogihara T. Morishita R. Frontiers in Bioscience. 13:2253-65, 2008. Alzheimer's disease, which is the most common cause of dementia, is traditionally thought to be a neurodegenerative disorder and not of vascular origin. However, there is a growing body of evidence suggesting an association between vascular risk factors and Alzheimer's disease. Several epidemiological studies have shown that high mid-life blood pressure is related to the development of Alzheimer's disease in later life. Furthermore, the use of some kinds of antihypertensive medication has been suggested to reduce the incidence of dementia including Alzheimer's disease. Recent findings indicate that the brain has its own renin-angiotensin system, which mediates several physiological and pathological brain functions. The neurobiological links between the renin-angiotensin system and Alzheimer's disease have been investigated and become a source of interest in the pathogenesis of the disease. This review describes the relation between the renin-angiotensin system, hypertension and Alzheimer's disease, and also discusses the potential use of antihypertensive drugs acting via the renin-angiotensin system in the treatment and prevention of the disease.

Reduction of C-reactive protein and the use of anti-hypertensives. [Review] [93 refs] Savoia C. Schiffrin EL. Vascular Health & Risk Management. 3(6):975-83, 2007. Inflammatory processes are increasingly recognized as important participants in the pathophysiology of hypertension and cardiovascular disease. Angiotensin II may be to a large degree responsible for triggering vascular inflammation by inducing oxidative stress, resulting in up-regulation of inflammatory mediators. Inflammatory markers such as C-reactive protein are increased in the blood of patients with hypertension and predict the development of cardiovascular disease. Moreover, C-reactive protein may be a pro-inflammatory molecule under certain circumstances. C-reactive protein and high blood pressure in combination have additional predictive value for cardiovascular outcomes, as they contribute as independent determinants of cardiovascular risk. Therapeutic intervention aimed to reduce vascular inflammation in hypertensive patients has been proposed. Recent lines of evidence suggest that lifestyle modification and pharmacological approaches may reduce blood pressure and inflammation in patients with hypertension. Antagonism of the renin-angiotensin system with the selective angiotensin receptor blockers may improve cardiovascular outcome beyond blood pressure control, by reducing vascular inflammation and remodeling.

The role of nitric oxide in the maintenance of vasoactive balance. [Review] [70 refs] Pechanova O. Simko F. Physiological Research. 56 Suppl 2:S7-S16, 2007. Endothelial dysfunction may be considered as the interstage between risk factors and cardiovascular pathology. An imbalance between the production of vasorelaxing and vasoconstricting factors plays a decisive role in the development of hypertension, atherosclerosis and target organ damage. Except vasorelaxing and antiproliferative properties per se, nitric oxide participates in antagonizing vasoconstrictive and growth promoting effects of angiotensin II, endothelins and reactive oxygen species. Angiotensin II is a potent activator of NAD(P)H oxidase contributing to the production of reactive oxygen species. Numerous signaling pathways activated in response to angiotensin II and endothelin-1 are mediated through the increased level of oxidative stress, which seems to be in casual relation to a number of cardiovascular disturbances including hypertension. With respect to the oxidative stress, the NO molecule seems to be of ambivalent nature. On the one hand, NO is able to reduce generation of reactive oxygen species by inhibiting association of NAD(P)H oxidase subunits. On the other hand, when excessively produced, NO reacts with superoxides resulting in the formation of peroxynitrite, which is a free radical deteriorating endothelial function. The balance between vasorelaxing and vasoconstricting substances appears to be the principal issue for the physiological functioning of the vascular bed.

Common pathways of hypercholesterolemia and hypertension leading to atherothrombosis: the need for a global approach in the management of cardiovascular risk factors. [Review] [67 refs] Tunon J. Martin-Ventura JL. Blanco-Colio LM. Tarin N. Egido J. Vascular Health & Risk Management. 3(4):521-6, 2007. In the last years there has been increasing evidence suggesting that the treatment of cardiovascular risk factors must be done on a global rather than on a separate approach, because they have additive effects and share common pathways leading to atherothrombosis. Of special interest is the relationship between hypertension and dyslipidemia. An excessive activity of the renin-angiotensin system (RAS), that plays an important role in hypertension, contributes to endothelial dysfunction, vascular inflammation and thrombosis. Dyslipidemia induces the same effects through similar mechanisms. In fact, combined therapy with statins and RAS modulators shows synergic beneficial effects in the treatment of atherosclerosis. Then, in the future, the traditional hypertension and dyslipidemia units should probably evolve into global cardiovascular risk management Units. Also, polypills combining antihypertensive and lipid-lowering drugs will make easier the treatment of these conditions. These changes would provide us the necessary tools to treat our patients in accordance with the current strategies of cardiovascular therapy and prevention.

From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. [Review] [57 refs] McDermott MF. Tschopp J. Trends in Molecular Medicine. 13(9):381-8, 2007 Pattern-recognition receptors, such as Toll-like receptors and NOD-like receptors (NLRs), are able through the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns to sense microbe-dependent and microbe-independent danger and thereby initiate innate immune responses. In some autoinflammatory conditions, abnormalities in NLR signaling pathways are involved in pathogenesis, as exemplified by NOD2 mutations associated with Crohn's disease. Some other NLRs are components of the inflammasome, a caspase-1- and prointerleukin-1beta-activating complex. Clinical and experimental studies are beginning to reveal the central role of the inflammasome in innate immunity. Here, we focus on monogenic hereditary inflammatory diseases, such as Muckle-Wells syndrome, which are associated with mutations in proteins that modulate the activity of the inflammasome, and on some multifactorial disorders, such as Type 2 diabetes and hypertension.

Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. [Review] [205 refs] Vasdev S. Gill V. Singal P. Cell Biochemistry & Biophysics. 49(1):48-63, 2007. The vascular diseases, hypertension and atherosclerosis, affect millions of individuals worldwide, and account for a large number of deaths globally. A better understanding of the mechanism of these conditions will lead to more specific and effective therapies. Hypertension and atherosclerosis are both characterized by insulin resistance, and we suggest that this plays a major role in their etiology. The cause of insulin resistance is not known, but may be a result of a combination of genetic and lifestyle factors. In insulin resistance, alterations in glucose and lipid metabolism lead to the production of excess aldehydes including glyoxal and methylglyoxal. These aldehydes react non-enzymatically with free amino and sulfhydryl groups of amino acids of proteins to form stable conjugates called advanced glycation end products (AGEs). AGEs act directly, as well as via receptors to alter the function of many intra- and extracellular proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation and oxidative stress. All these changes are characteristic of hypertension and atherosclerosis. Human and animal studies have demonstrated that increased AGEs are also associated with these conditions. A pathological role for AGEs is substantiated by studies showing that therapies that attenuate insulin resistance and/or lower AGEs, are effective in decreasing oxidative stress, lowering blood pressure, and attenuating atherosclerotic vascular changes. These interventions include lipoic acid and other antioxidants, AGE breakers or soluble receptors of AGEs, and aldehyde-binding agents like cysteine. Such therapies may offer alternative specific means to treat hypertension and atherosclerosis. An adjunct therapy may be to implement lifestyle changes such as weight reduction, regular exercise, smoking cessation, and increasing dietary intake of fruits and vegetables that also decrease insulin resistance as well as oxidative stress.

Nitric oxide and superoxide interactions in the kidney and their implication in the development of salt-sensitive hypertension. [Review] [79 refs] Majid DS. Kopkan L. Clinical & Experimental Pharmacology & Physiology. 34(9):946-52, 2007 Enhanced superoxide (O2(-)) activity as a result of the inhibition of the superoxide dismutase (SOD) enzyme results in vasoconstrictor and antinatriuretic responses in the canine kidney; these responses were shown to be greatly enhanced during inhibition of nitric oxide synthase (NOS). Glomerular filtration rate remained mostly unchanged during SOD inhibition in the intact nitric oxide (NO) condition, but was markedly reduced during NOS inhibition. These findings indicate that endogenous NO has a major renoprotective effect against O2(-) by acting as an anti-oxidant. Nitric oxide synthase inhibition was also shown to enhance endogenous O2(-) activity. 2. Experiments in our laboratory using dogs, rats and gene knockout mice have shown that renal vasoconstrictor and antinatriuretic responses to acute or chronic angiotensin (Ang) II administration are mediated, in part, by O2(-) generation. In the absence of NO, enhanced O2(-) activity largely contributes to AngII-induced renal tubular sodium reabsorption. Acute or chronic treatment with the O2(-) scavenger tempol in experimental models of hypertension (induced by chronic low-dose treatment with AngII and NO inhibitors) causes an improvement in renal haemodynamics and in excretory function, abolishes salt sensitivity and reduces blood pressure. 3. The present mini review also discusses related studies from many other laboratories implicating a role for O2(-) and its interaction with NO in the development of salt-sensitive hypertension. 4. Overall, the collective data support the hypothesis that an imbalance between the production of NO and O2(-) in the kidney primarily determines the condition of oxidative stress that alters renal haemodynamics and excretory function leading to sodium retention and, thus, contributes to the development of salt-sensitive hypertension.

The potential anti-inflammatory benefits of improving physical fitness in hypertension. [Review] [142 refs] Edwards KM. Ziegler MG. Mills PJ. Journal of Hypertension. 25(8):1533-42, 2007 Hypertension is associated with an increased risk of stroke and atherosclerosis. In addition to elevated blood pressure, hypertension is characterized by neuroendocrine and immune activation, including elevated levels of C-reactive protein, inflammatory cytokines, and soluble adhesion molecules, which are predictive of morbidity and mortality outcomes. Pharmacological treatment for hypertension reduces blood pressure, but has limited effectiveness in reducing the accompanying inflammation and its associated morbidity and mortality. Exercise and diet interventions regularly show reductions in blood pressure in hypertensive individuals. Similar interventions in other populations show reductions in many inflammatory markers, but these effects have not been routinely examined in hypertensive individuals. The mechanisms through which exercise might exert an anti-inflammatory action include the sympathetic nervous system, the hypothalamic-pituitary-adrenal axis, as well as direct effects of blood pressure. Here, exercise is promoted as a potentially effective treatment for both the elevated blood pressure and chronic inflammation found in hypertension.

Chronic kidney disease: effects on the cardiovascular system. [Review] [124 refs] Schiffrin EL. Lipman ML. Mann JF. Circulation. 116(1):85-97, 2007 Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.

Gestational diabetes, pregnancy hypertension, and late vascular disease.[erratum appears in Diabetes Care. 2007 Dec;30(12):3154]. [Review] [24 refs] Carpenter MW. Diabetes Care. 30 Suppl 2:S246-50, 2007 The complexity of the several pathogenic pathways that cause hypertension and vascular disease and the prolonged interval that appears to predate clinical morbidity have hindered inquiry into the association between GDM and vascular disorders. As a forme fruste of later type 2 diabetes, GDM-affected gravidas are identified as at risk of diabetes-related atherosclerosis, glomerular disruption, and pathogenic retinal angio-genesis. That GDM is evidence for underlying chronic conditions such as dysregulation of innate immune response that, independent of the diabetic state, produces vascular disease is difficult state, produces vascular disease is difficult to assert with the present published literature. Cross-sectional studies of patients with established gestational hypertension or preeclampsia are ambiguous as to the possible pathogenic effect of insulin resistance. Cohort studies initiated in early and mid-pregnancy show evidence that both gestational hypertension and preeclampsia may be more prevalent in gravidas with greater insulin resistance. The association of gestational glucose intolerance with gestational hypertension appears to be independent of obesity and ambient glycemia but explained in part by insulin resistance. Late pregnancy preeclampsia is associated with elevated mid-pregnancy BMI, blood pressure, fasting glucose and insulin, urate, and C-reactive protein, suggestive of metabolic and immune dysregulation. GDM appears to be associated with overexpressed innate immune response, which, in turn, is associated with vascular dysfunction and vascular disease. Among women with GDM, markers of insulin resistance do not appear to correlate with hypertension in short-term cohort studies. However, when non-GDM subjects are compared with subjects with GDM, postpregnancy studies do show an associated with vascular dysfunction and vascular disease. Among women with GDM, markers of insulin resistance do not appear to correlate with hypertension in short-term cohort studies. However, when non-GDM subjects are compared with subjects with GDM, postpregnancy studies do show an association of insulin resistance with both inflammatory dysregulation and vascular dysfunction. Cohort studies that have used population-based pregnancy databases consistently identify a clinically significant association of both gestational hypertension and preeclampsia with later hypertensive disorders. Associations with coronary artery disease or stroke are less consistent, requiring further investigation. Preventing the evolution of diabetes and lipid and immune dysregulation of the metabolic syndrome has become a silent public health issue because of the epidemic of childhood and early adulthood obesity and the opportunity at hand to treat insulin resistance by behavioral and pharmacological interventions. However, limited available literature highlights the need for long-term cohort studies of women with well-characterized metabolic and vascular profiles during pregnancy and decades later. Our present knowledge suggests that screening for GDM provides an opportunity of pregnancy outcome improvement. Limited studies of diabetes prevention in at-risk patient groups suggest that we may have the opportunity to reduce the risk of later diabetes. Additional investigation is required to determine if interventions that prevent or postpone diabetes also delay the onset of vascular disease.

C-reactive protein and hypertension: is there a causal relationship?. [Review] [57 refs] Virdis A. Ghiadoni L. Plantinga Y. Taddei S. Salvetti A. Current Pharmaceutical Design. 13(16):1693-8, 2007. There is a large body of evidence indicating that inflammation plays a crucial role in all steps characterizing the atherosclerotic process. C-Reactive Protein is a circulating marker of inflammation which recently emerged as a powerful independent determinant of cardiovascular events. Hypertension is closely linked to inflammation. Experimental data and results from cross-sectional studies in humans indicate a relationship between CRP levels and blood pressure. In particular, CRP seems to be related with markers of arterial stiffness, thus suggesting a specific interaction between CRP and systolic blood pressure. However, such observational studies cannot provide any direct evidence for a cause-effect relation. Prospective studies are likely candidates to better define the putative causal relationship on this association. Available results from longitudinal studies are scanty, and do not allow to draw definitive conclusions. Moreover, prospective, placebo-controlled intervention trials documenting that reduction of CRP levels by pharmacological treatment might lead to a reduced risk to develop hypertension are not yet available. Without such crucial information, at the present time the causal connection between inflammation and blood pressure, although regarded as an intriguing possibility, remains undiscovered.

Angiotensin II and oxidative stress. [Review] [42 refs] Hitomi H. Kiyomoto H. Nishiyama A. Current Opinion in Cardiology. 22(4):311-5, 2007 PURPOSE OF REVIEW: Angiotensin II regulates vasoconstriction, homeostasis of salt and water, and cardiovascular hypertrophy and remodeling. Angiotensin II is a potent activator of NAD(P)H oxidase in the cardiovascular system, and augments production of reactive oxygen species. Numerous signaling pathways in response to angiotensin II are mediated by reactive oxygen species and oxidative stress is deeply associated with the progression of cardiovascular disease. The purpose of this review is to discuss the mechanism of reactive oxygen species formation and the pathophysiological effects of angiotensin II in the cardiovascular system. RECENT FINDINGS: Recent studies have demonstrated novel molecular mechanisms of reactive oxygen species generation by angiotensin II and signaling pathways including cell proliferation, hypertrophy and apoptosis. In spite of these findings that strongly suggest the benefits of angiotensin II inhibition for cardiovascular disease, the clinical effects of angiotensin II-induced reactive oxygen species on the cardiovascular system are still controversial. SUMMARY: We focus on the effects of angiotensin II-induced oxidative stress on cardiovascular function and remodeling after discussing the source of reactive oxygen species and novel signaling pathways in response to reactive oxygen species.

Hypertension: endothelial dysfunction, the prothrombotic state and antithrombotic therapy. [Review] [87 refs] Kakar P. Lip GY. Expert Review of Cardiovascular Therapy. 5(3):441-50, 2007 The pathophysiology of essential hypertension and its complications has been a focus of much research and clinical interest. More recent attention has been directed towards inflammation and endothelial dysfunction, especially since inflammation can promote endothelial dysfunction and the latter has been intimately related to thrombogenesis and atherogenesis. Hypertension is also associated with a prothrombotic or hypercoagulable state, and this may contribute to the observation that despite the blood vessels being exposed to high pressures in hypertension the common complications of the latter are paradoxically thrombotic rather than hemorrhagic--the so-called 'thrombotic paradox of hypertension' (or 'Birmingham paradox'). Despite these thrombotic complications, the role of antithrombotic therapy for primary prevention in hypertension is less defined, unless the patient is at significant risk of cardiovascular events or has renal impairment. Antithrombotic therapy for secondary prevention in hypertension is recommended, but unanswered questions regarding the interactions between aspirin and angiotensin-converting enzyme inhibitors remain.

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