Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.

CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-delta plays a pivotal role in transactivation of PPAR-gamma gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-delta expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-delta through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-delta is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.

Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation.

BACKGROUND: In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling. METHODS AND RESULTS: Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. CONCLUSIONS: Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.

Soluble Fas ligand and atherosclerosis in hypertensive patients.

BACKGROUND: The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis. OBJECTIVE: To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients. PATIENTS AND MAIN OUTCOME MEASURES: Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay. RESULTS: Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030). CONCLUSIONS: These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.

Occurrence of transient U-wave inversion during vasospastic anginal attack is not related to the direction of concurrent ST-segment shift.

STUDY OBJECTIVES: We sought to assess the incidence of transient U-wave inversion during vasospasm of the left anterior descending coronary artery (LAD) with ST-segment depression as opposed to that with ST-segment elevation. DESIGN: Retrospective study. SETTING: Cardiology division of acute-care hospitals. PATIENTS: We studied 49 patients with vasospastic angina whose vasospasm was induced in the LAD, not in the left circumflex coronary artery, by intracoronary injection of acetylcholine. MEASUREMENTS AND RESULTS: The ECG traces obtained during acetylcholine-induced vasospasm of the LAD were examined. Based on the direction of ST-segment shift, the patients were categorized into two groups: the ST-segment elevation group (n = 27) and the depression group (n = 22). There were no differences in age, gender, or cardiovascular risk factors between the two groups. The distribution of the spastic site in the LAD was also similar. A total reduction in luminal diameter during a provoked attack was more often observed in the ST-segment elevation group than in the ST-segment depression group (37% vs 9%, p = 0.02). Collateral circulation to the LAD was found in only one patient in each group. There were no differences between the two groups in heart rate, systolic BP, and double product of heart rate and systolic BP during the attack. The incidence of acetylcholine-induced anginal attack with U-wave inversion in the ST-segment depression group was nearly as high as that in the ST-segment elevation group (77% vs 78%, p > 0.99). CONCLUSIONS: The development of transient U-wave inversion during vasospasm of the LAD induced by intracoronary injection of acetylcholine does not depend on the magnitude of myocardial ischemia as judged by the direction of ST-segment shift.

Carotid hemodynamic alterations in hypertensive patients with insulin resistance.

BACKGROUND: Insulin resistance (IR) is implicated in the pathogenesis of atherosclerosis. One mechanism is thought to be the impaired vasodilation, which can lead to a reduction in peripheral blood flow. Hypertensive patients with IR have greater intima-media thickness (IMT) in the common carotid artery (CCA) than those without IR. However, the relationship between IR and hemodynamic alterations of the CCA has not been clarified. METHODS: Seventy patients with essential hypertension (EHT) and 11 normotensive controls (NT) participated in this study. The IMT, number of plaques, and internal dimensions of the CCA were evaluated by ultrasound imaging. Mean diastolic (Vd) and systolic (Vs) velocity were determined by the Doppler flow method, and other parameters such as Vd/Vs and the cross-sectional distensibility coefficient (CSDC) were further calculated. When the homeostasis model assessment (HOMA) index exceeded 2.0, the subject was considered to have IR. RESULTS: The IMT was positively correlated with the HOMA index in all subjects. The Vd/Vs and CSDC were significantly decreased in EHT patients with IR compared to NT and EHT patients without IR. The Vd/Vs and CSDC were negatively correlated with the HOMA index. A stepwise regression analysis revealed that age, HDL-cholesterol, and the HOMA index were independently associated with IMT in patients with EHT. Age, the HOMA index, and mean blood pressure (MBP) were independently associated with CSDC, and the first two factors were independently associated with Vd/Vs. CONCLUSIONS: Decreased distensibility of the arterial wall and ensuing low diastolic perfusion are possible mechanisms of atherosclerotic changes in the CCA in EHT patients with IR.

Brain natriuretic peptide as a risk marker for incident hypertensive cardiovascular events.

We examined the effects of aging and hypertensive left ventricular hypertrophy on the plasma level of brain natriuretic peptide (BNP), and assessed BNP as a risk marker for incident hypertensive cardiovascular events. One hundred and eighty-five hypertensive patients were echocardiographically divided into a hypertensive group with normal left ventricular mass (n=96; age range, 37-86 years; left ventricular mass, 97+/-14 g/m2) and a hypertensive group with left ventricular hypertrophy (n=89; 37-90 years; 140+/-20 g/m2). Forty-four normotensive subjects served as the normotensive group (32-84 years; 91+/-15 g/m2). We examined the association of age with BNP in the three groups and also evaluated BNP as a risk marker for incident cardiovascular events by following up all patients for 40 months. All three groups demonstrated a significant positive relationship between age and BNP. The slope of the relation between age and BNP was steepest in the hypertensive group with left ventricular hypertrophy (p<0.0001 vs. the other two groups). Multiple regression analysis revealed that age, pulse pressure and left ventricular mass index were significantly associated with the increase in BNP. Multivariate Cox proportional hazards regression analysis, which was used to assess the potential association of age, pulse pressure, left ventricular mass index and BNP with the cardiovascular events during follow-up, revealed the highest correlation between BNP and incident cardiovascular events (risk ratio=1.011; p=0.0011). BNP, which is synergistically increased with aging and left ventricular hypertrophy, may be an important risk marker for hypertensive cardiovascular events.

Serum cystatin C level is a marker of end-organ damage in patients with essential hypertension.

High urinary albumin excretion rate (AER) has been associated with the presence of atherosclerotic vascular damages and is an independent risk factor for all causes of death and cardiovascular morbidity and mortality in essential hypertensive patients. Serum cystatin C (s-CC) is a recently identified nonglycosylated 13-kD basic protein that has been suggested to be a useful marker of glomerular filtration rate. In the present study, we investigated the relationship between s-CC level and end-organ damages in the kidney, heart, and vessels of patients with essential hypertension. Sixty patients with essential hypertension participated in the present study. Patients with renal failure were excluded. Serum-CC level was measured by a particle-enhanced turbidimetric assay. Left ventricular mass index (LVMI) and intima media thickness (IMT) in the common carotid arteries were evaluated by ultrasound images. Twenty-four-hour blood pressure was measured by a cuff-oscillometric method. Serum-CC level was negatively correlated with creatinine clearance (r=-0.617, p<0.0001). It was also correlated with mean 24-h systolic blood pressure (24h-SBP) (r=0.308, p= 0.0167), LVMI (r=0.528, p<0.0001), and IMT (r=0.539, p<0.0001). Both AER and s-CC level were independently associated with mean 24h-SBP. AER but not s-CC level was associated with HDL-cholesterol. The present study was the first to demonstrate that s-CC level is a useful and convenient parameter of renal function, and may also prove to be an early marker of the severity of end-organ damage in patients with essential hypertension.

A case of metastatic extra-adrenal pheochromocytoma 12 years after surgery.

At the age of 53, a 65-year-old man had been diagnosed with extra-adrenal pheochromocytoma in the retroperitoneum and underwent total tumorectomy. Afterward, he had his serum catecholamine periodically measured in an outpatient clinic. In February 1999, 12 years after surgery, he complained of lower left abdominal pain. Computed tomography and magnetic resonance imaging revealed an osteolytic lesion in thoracic vertebrae 11Th (Th 11). Although his basal serum and urine catecholamines were at normal levels, glucagon injection increased blood pressure and plasma catecholamine levels. 131I-metaiodobenzylguanidine (MIBG) scintigraphy was specifically taken up to Th 11. By bone biopsy, the osteolytic lesion in Th 11 was finally diagnosed with metastasis of pheochromocytoma. For post-operative pheochromocytoma, long-term follow-up involving biochemical tests, including serum catecholamines, and MIBG is needed.

Questionnaire survey on the Japanese guidelines for treatment of hypertension in the elderly: 1999 revised version.

A questionnaire survey was administered to Japanese clinical specialists in hypertension in order to gauge their opinions on the 1999 revised version of the Guidelines for Hypertension in the Elderly prepared by the Comprehensive Research Project on Aging and Health of the Ministry of Health and Welfare. Out of 162 council members of the Japanese Society of Hypertension, 122 (75%) replied. The majority (93%) of respondents approved of the guidelines in general, and 72% of them approved of the age-related setting of a therapeutic goal for blood pressure. Sixty-five percent of respondents selected long-acting Ca antagonists, ACE inhibitors and low-dose diuretics as first-line agents for hypertension without complications in the elderly. The results of the questionnaire survey should be reflected in the next version of the guidelines.

Beneficial Effect of a Long-Term Antihypertensive Therapy on Blood Pressure Response to Isometric Handgrip Exercise in Patients with Essential Hypertension.

To elucidate the effect of a long-term antihypertensive therapy on blood pressure (BP) response to isometric handgrip exercise (IHG) in patients with essential hypertension (EHT, n = 16), IHG was carried out at 30% maximal voluntary contraction of right hand for 3 min before therapy and after a long-term antihypertensive therapy. BP responsiveness to IHG was estimated by the difference between values obtained at rest and at 3 min during IHG (change of systolic BP = DeltaSBP, change of diastolic BP = DeltaDBP. Both DeltaSBP and DeltaDBP before therapy were markedly greater in EHT (DeltaSBP = 64 plus minus 18 mm Hg, DeltaDBP = 33 plus minus 9 mm Hg) than in age-mathced normotensive controls (NT, n = 8, 29 plus minus 4 mm Hg, 18 plus minus 4 mm Hg). By antihypertensive therapy, SBP and DBP in EHT were decreased from 152 plus minus 22 mm Hg to 136 plus minus 14 mm Hg and from 90 plus minus 18 mm Hg to 83 plus minus 10 mm Hg, respectively, but both SBP and DBP in EHT after antihypertensive therapy were still greater than those in NT. Both DeltaSBP and DeltaDBP in EHT after a long-term antihypertensive therapy were significantly smaller than those in EHT before therapy but were still significantly larger than those in NT. These results demonstrate that a long-term antihypertensive therapy reduces the exaggerated BP response to IHG in EHT.

Efficacy and safety of the selective aldosterone blocker eplerenone in Japanese patients with hypertension: a randomized, double-blind, placebo-controlled, dose-ranging study.

Approximately 40% of Japanese patients with essential hypertension, including low-renin hypertension, are inadequately managed. Low-renin hypertension generally responds poorly to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, but may respond more optimally to diuretics, calcium channel blockers, and aldosterone blockers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluated the efficacy and safety of the selective aldosterone blocker eplerenone in 193 Japanese patients with essential hypertension. Although not a study inclusion criterion, baseline active plasma renin levels were consistently low (5.7-10.1 mU/L); most patients met the criteria for low-renin hypertension (< or =42.5 mU/L; normal range, 7-76 mU/L). Patients received placebo or eplerenone 50, 100, or 200 mg once daily for 8 weeks. Systolic blood pressure decreased significantly (-6.8 to -10.6 mm Hg vs. -2.1 mm Hg; p< or =0.0022 vs. placebo). Eplerenone offers significant blood pressure reduction with good tolerability in Japanese patients with hypertension, including those with low-renin hypertension.

[A case of central diabetes insipidus caused by metastatic small cell lung cancer].

A 58-year-old man was admitted to our hospital because of cough, polydipsia and polyuria. Chest CT films showed mediastinal lymphadenopathy, nodules in the lung fields, and pleural effusion. Histopathologic examination of transbronchial biopsy specimens showed oat cell carcinoma. MRI films revealed tumorous swelling of the pituitary stalk. Central diabetes insipidus caused by pituitary metastasis of small cell lung cancer was diagnosed. After treatment with whole-brain irradiation and chemotherapy, the size of the swollen pituitary stalk was reduced and his urine volume decreased. He died of respiratory insufficiency 15 months after the initial diagnosis. No recurrence of pituitary metastasis was apparent. This was a rare case of central diabetes insipidus caused by pituitary metastasis of small cell lung cancer successfully treated with radiotherapy and chemotherapy.

[Successful treatment of bronchiolitis obliterans organizing pneumonia with cyclosporin and steroids].

A 71-year-old woman with fever and dry cough was admitted to our hospital. Chest computed tomography, bronchoalveolar lavage and transbronchial lung biopsy were performed, and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed. The patient was treated with corticosteroid, and marked improvement was noted. However, when the dosage was tapered, the BOOP recurred. We increased the dosage of corticosteroid and also put the patient on a daily regimen of cyclosporin. The cyclosporin was administered orally, and was effective, so that we could gradually decrease the dosage of corticosteroid. We concluded that cyclosporin may be useful in the treatment of refractory BOOP.

Circulating levels of insulin-like growth factor-1 and its binding proteins in patients with hypertrophic cardiomyopathy.

Insulin-like growth factor-1 (IGF-1) is important in the hypertrophic response of the myocardium, so the present study was designed to elucidate whether the circulating levels of IGF-1 and its binding proteins (IGFBPs) are related to the disease condition of patients with hypertrophic cardiomyopathy (HCM), in particular the occurrence of congestive heart failure (CHF). The study group comprised 124 patients with HCM and 15 healthy control subjects. The HCM patients were subdivided into 3 groups: 39 with hypertrophic obstructive cardiomyopathy (HOCM), 67 with hypertrophic non-obstructive cardiomyopathy (HNCM), and 18 with HCM and a history of CHF (HF-HCM, n=18). Serum levels of IGF-1 and IGFBPs (IGFBP-1 and -3) were compared between groups. IGF-1 levels were significantly higher in patients with HOCM and HNCM, and lower in patients with HF-HCM than in control subjects (p<0.0001, p<0.005, and p<0.05, respectively). IGFBP-1 levels were significantly higher in patients with HF-HCM than in the other 3 groups (p<0.0001 for all). The findings suggest that circulating levels of IGF-1 and IGFBP-1 are related to the extent of myocardial injury in patients with HCM.

Postprandial elevation of remnant lipoprotein leads to endothelial dysfunction.

Recent studies have demonstrated that elevated levels of cholesterol in the form of remnant-like particles (RLP-C) induce deterioration of endothelial function during the fasting state, but it is not known whether postprandial RLP-C elevation has the same effect. The objective of this study was to assess the effect of postprandial RLP-C elevation on endothelial function in 24 fasting normolipidemic subjects. Flow-mediated dilatation (FMD) during reactive hyperemia in the brachial artery was investigated. Serum lipids and lipoproteins during fasting and 4h after regular fat-loading were measured. Subjects were divided into 2 groups: the high responders (postprandial RLP-C level >7.5mg/dl, n=8) and the normal responders (postprandial RLP-C level < or =7.5mg/dl, n=16). Significant increases in the level of both triglycerides and RLP-C were observed in the high responders. Basal FMD in the high responders (4.3+/-3.0%) was significantly lower than that in the normal responders (8.3+/-2.4%) (p<0.01), but FMD after the fat-loading in both groups did not change significantly. The change in RLP-C levels during the fat-loading test correlated significantly with basal FMD (r=-0.588, p<0.01). Multiple regression analysis showed a significant correlation between basal FMD and the change in RLP-C levels (r=-0.488, p<0.02). The results of this study suggest that postprandial RLP-C elevation could be associated with atherosclerotic progression even in normolipidemic subjects.

Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy.

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/ deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3-7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

Production of eosinophilic chemokines by normal pleural mesothelial cells.

Eosinophilic pleural effusion occurs in many diseases. The mechanisms of eosinophil accumulation are not well understood. We showed previously that eotaxin was readily detectable in most pleural effusions, and its concentration significantly correlated with eosinophil number. To test the hypothesis that pleural eotaxin is produced by resident mesothelial cells, we examined its production by normal pleural mesothelial cells (NPMC). Eotaxin was induced by tumor necrosis factor (TNF)-alpha or interleukin (IL)-4 and was drastically increased by their combination. In contrast, interferon (IFN)-gamma inhibited eotaxin production. Regulated on activation, normal T cells expressed and secreted (RANTES) was also induced by TNF-alpha and was drastically increased by the addition of IFN-gamma. These effects were observed at both protein and mRNA levels. Stabilization of RANTES mRNA was observed with IFN-gamma but not IL-4; neither cytokine stabilized eotaxin mRNA. Eosinophil chemoattractant activity in culture supernatants of NPMC stimulated with TNF-alpha plus IL-4 was diminished by an anti-eotaxin antibody; that induced by TNF-alpha plus IFN-gamma was attenuated by an anti-RANTES antibody. Thus, NPMC can produce eotaxin, and different cytokines act on NPMC to induce different chemokines by different mechanisms. IFN-gamma, a Th1 cytokine, acts at least at the posttranscriptional level to induce RANTES production, but it inhibits eotaxin production. In contrast, IL-4, a Th2 cytokine, acts at the transcriptional level to induce eotaxin.