Comparison of arterial functional evaluations as a predictor of cardiovascular events in hypertensive patients: the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study.

Increased arterial stiffness and impaired vasodilator response have been associated with cardiovascular events in high-risk patients. However, whether arterial changes predict the occurrence of hypertensive complications is still unclear. Therefore, we designed a hospital-based cohort study to examine the prognostic impact of arterial functional changes on stroke and cardiovascular diseases in hypertensive patients. The study employed 676 patients with essential hypertension. At baseline, we evaluated second-derived photoplethysmography, carotid-femoral pulse wave velocity (PWV), and forearm reactive hyperemia. We classified subjects into quartile groups according to the baseline measurements of these evaluations and assessed the ability of each measure to predict stroke and cardiovascular diseases (CVD). During a mean follow-up period of 57 months, 52 strokes, 40 CVD, and 22 deaths were recorded. Kaplan-Meier analysis revealed that patients in the highest quartile of PWV showed a higher frequency of stroke and CVD (p<0.0001) and total mortality (p=0.0016), and those in the highest quartile of reactive hyperemia showed a lower frequency of stroke and CVD (p=0.0415). A Cox hazard model identified that classification in the highest quartile of PWV (relative risk=2.717) and reactive hyperemia (0.416) were predictive of stroke and CVD after adjustment for other risk factors. In subjects who did not experience stroke or CVD before the study period (n=558), only PWV was related with the occurrence of stroke and CVD based on the Cox hazard model. In conclusion, increased aortic stiffness evaluated by PWV is more prognostic of cardiovascular events in hypertensive patients than several non-invasive atherosclerotic evaluations.

Evaluation of morning blood pressure elevation and autonomic nervous activity in hypertensive patients using wavelet transform of heart rate variability.

To evaluate morning autonomic nervous activity and blood pressure profiles in hypertensive patients by analyzing heart rate variability and ambulatory blood pressure. Data from 82 patients with untreated essential hypertension were analyzed. We evaluated the 24-h profile of blood pressure and that of indices of autonomic nervous activity, i.e., the high frequency component (HF) and low frequency component/HF (LF/HF), which were obtained by wavelet transform of heart rate variability. Patients were classified by dipping status (nondippers, n=28; dippers, n=32; extreme-dippers, n=8; and risers, n=14) and morning blood pressure profile (large, n=9; small, n=60; and inverted, n=13). Nocturnal systolic blood pressure in extreme-dippers was significantly lower than that in the other groups; that in the risers was significantly higher (p<0.05). There were no significant group differences in daytime systolic blood pressure. Daytime and 24-h HF levels were significantly higher in the dipper vs. the riser group (p<0.05). Morning blood pressure elevation negatively correlated to preawake (p<0.01) and nocturnal blood pressure (p<0.05), but not to daytime and post-awake blood pressure. The preawake/postawake ratio of systolic blood pressure positively correlated to that of LF/HF (p<0.01) and negatively correlated to preawake HF levels (p<0.05). Multivariate regression analysis revealed that preawake HF levels (p=0.037) and preawake/postawake ratio of LF/HF (p=0.033) were independently correlated with morning blood pressure elevation ratio. Our results suggest that activation of HF before waking and LF/HF during waking might play an important role in the development of morning blood pressure elevation.

Serum interleukin-15 concentration in patients with essential hypertension.

BACKGROUND: Interleukin (IL)-15 is one of the cytokines produced by neutrophils and monocytes/macrophages, and its expression is found immunohistochemically in inflammatory cells adjacent to vulnerable atherosclerotic plaques. However, the influence of systemic IL-15 on cardiovascular disease is still unclear. Therefore, we designed clinical investigations to clarify the relationship between cardiovascular complications and serum IL-15 levels. METHODS AND RESULTS: Three hundred ninety-nine patients with essential hypertension were analyzed. We divided the study subjects into the following three groups according to the modified World Health Organization-International Society of Hypertension classification of 1999: patients with no organ damage (n = 213), patients with mild organ damage (n = 128), and patients with severe organ damage (n = 58). We measured serum IL-15, highly sensitive C reactive protein, IL-6, soluble intercellular adhesion molecule, and soluble vascular cell adhesion molecule levels. Serum IL-15 concentration in patients with severe organ damage was significantly higher than that in those with no organ damage (P < .01) and those with mild organ damage (P < .01). Serum IL-15 concentration in patients with coronary artery disease or peripheral artery disease was significantly higher than that in those without coronary artery disease or peripheral artery disease. Moreover, serum IL-15 concentration in patients with lacunar infarction was significantly higher than that in those without lacunar infarction (P < .005). By multiple linear logistic regression analysis, serum IL-15 concentration was independently correlated with cardiovascular disease. CONCLUSIONS: These data suggest that a systemic inflammatory response involving IL-15 might be involved in the occurrence of cardiovascular disease in patients with essential hypertension.

Serum hepatocyte growth factor concentration is correlated with the forearm vasodilator response in hypertensive patients.

To evaluate the clinical importance of serum hepatocyte growth factor (HGF) concentration, we designed two clinical investigations. The first study analyzed the correlation between serum HGF concentration and clinical arterial stiffness or the vasodilator response to reactive hyperemia in hypertensive patients. The second study investigated the correlation between changes in serum HGF concentration and clinical arterial stiffness or reactive hyperemia during treatment with cilazapril or atenolol. A total of 210 hypertensive patients were analyzed in the first study, and 25 patients with essential hypertension were evaluated in the second study. Pulse wave velocity (PWV), strain gauge plethysmography, and serum HGF concentration were measured in the first study. We also evaluated these factors before and after treatment with either cilazapril (2.0 mg/day) or atenolol (25 mg/day) for 6 months in the second study. Serum HGF concentration was negatively correlated to reactive hyperemia in overall (r = 0.434, P < .0001) and nontreatment (r = 0.452, P < .0001) hypertensive patients. Arterial stiffness was weakly related to serum HGF concentration (P < .05) after adjusting for age and mean blood pressure (BP). By multiple regression analysis, only serum HGF concentration showed a strong independent correlation with reactive hyperemia, age and mean BP with PWV. Moreover, a relationship between endothelium-dependent vasodilation and serum HGF concentration was observed during treatment with cilazapril or atenolol (r = 0.406, P < .005). These results suggest that in evaluation of serum HGF concentration, the forearm vasodilator response to reactive hyperemia and PWV might be useful for managing hypertension in patients who are receiving antihypertensive therapy.

Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II.

Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.

Association of hypoadiponectinemia with impaired vasoreactivity.

Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total (r=0.257, P<0.001) and no-medication (r=0.296, P=0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout (KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.