Nahoko Ikeda

Contribution of Fluid Shear Response in Leukocytes to Hemodynamic Resistance in the Spontaneously Hypertensive Rat

The mechanisms for elevation of peripheral vascular resistance in spontaneously hypertensive rats (SHR), a glucocorticoid-dependent form of hypertension, are unresolved. An increase in hemodynamic resistance caused by circulating blood may be a factor. Physiological fluid shear stress induces a variety of responses in circulating leukocytes, including pseudopod retraction. Due to high rigidity, leukocytes with pseudopods have greater difficulty to pass through capillaries. Because SHR have more circulating leukocytes with pseudopods, we hypothesize that inhibition of the leukocyte shear response by glucocorticoids in SHR impairs normal leukocyte passage through capillaries and causes enhanced resistance in capillary channels. Fluid shear leads to retraction of pseudopods in normal leukocytes, whereas shear induces pseudopod projection in SHR and dexamethasone-treated Wistar rats. The high incidence of circulating leukocytes with pseudopods results in slower cell passage through capillaries under normal blood flow and during reduced flow enhanced capillary plugging both in vivo and in vitro. SHR blood requires higher pressure (90.0±8.2 mm Hg) than Wistar Kyoto rat (WKY, 69.6±6.5 mm Hg; P <0.0001) or adrenalectomized SHR (73.5±2.1 mm Hg; P =0.0009) at the same flow rate in the resting hemodynamically isolated skeletal muscle microcirculation. Intravenous injection of blood from SHR, but not WKY, causes blood pressure increase in normal rats, which depends on pseudopod formation. We conclude that in addition to enhanced vascular tone, pseudopod formation with lack of normal fluid shear response may serve as mechanisms for an elevated hemodynamic resistance in SHR.

Peak C-Reactive Protein Level Predicts Long-Term Outcomes in Type B Acute Aortic Dissection

Acute aortic dissection (AAD) is associated with an inflammatory reaction, as evidenced by elevated inflammatory markers, including C-reactive protein (CRP). The association between the peak CRP level and long-term outcomes in type B AAD has not been systematically investigated. The purpose of this study was to investigate whether the peak CRP level during admission predicts long-term outcomes in type B AAD. We conducted a clinical follow-up study of type B AAD. We divided the study population into 4 groups according to the tertiles of peak CRP levels (T1: 0.60 to 9.37 mg/dL; T2: 9.61 to 14.87 mg/dL; T3: 14.90 to 32.60 mg/dL; and unavailable peak CRP group). Multivariate Cox regression analysis was applied to investigate whether the tertiles of peak CRP predict adverse events even after adjusting for other variables. A total of 232 type B AAD patients were included in this analysis. The median follow-up period was 50 months. CRP reached its peak on day 4.5±1.7. Mean peak CRP values in T1, T2, and T3 were 6.4±2.4, 12.0±1.5, and 19.5±4.0 mg/dL, respectively. There were 65 events (39 deaths and 26 aortic events) during the follow-up. T3 and T2 (versus T1) were strong predictors of adverse events (T3: hazard ratio: 6.02 [95% CI: 2.44 to 14.87], P=0.0001; T2: hazard ratio: 3.25 [95% CI: 1.37 to 7.71], P=0.01) after controlling for all of the confounding factors. In conclusion, peak CRP is a strong predictor for adverse long-term events in patients with type B AAD.

Nicorandil and leukocyte activation.

Nicorandil, a hybrid compound of an ATP-sensitive potassium (KATP) channel opener and a nitric oxide donor, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. The aim of the current study was to test the hypothesis that nicorandil suppresses activation of polymorphonuclear leukocytes (PMNLs), resulting in reduction of PMNL migration into tissue upon ischemia/reperfusion. Nicorandil, along with the mitochondrial KATP channel opener diazoxide and the nitric oxide donors nitroglycerin and isosorbide dinitrate, suppressed pseudopod projection in human PMNLs treated with 10−9M N-formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress (5 dyn/cm2) with a cone-and-plate shear device. Suppression by nicorandil and diazoxide was reversed by KATP channel blockers, 5 hydroxydecanoate and glibenclamide. FMLP-induced increase of [Ca2+]in in PMNLs was suppressed by nicorandil and diazoxide, and 5 hydroxy-decanoate and glibenclamide reversed this suppression. Results of reverse transcription polymerase chain reaction with rat PMNL mRNA indicated the presence of mRNAs of Kir6.2 and Kir6.1 but not mRNAs of sulfonylurea receptor 1 or 2. Isosorbide dinitrate, diazoxide, and nicorandil reduced leukocyte migration and microvascular obstruction in reperfused ischemic tissue of rat mesenteric microcirculation. In conclusion, nicorandil attenuates ischemia/reperfusion-induced PMNL activation via donation of nitric oxide and K channel–related cascade.

Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes

BackgroundOsteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes.MethodsThe subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels.ResultsVascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3.ConclusionsThese findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.

Src family kinases and nitric oxide production are required for hepatocyte growth factor-stimulated endothelial cell growth

Hepatocyte growth factor (HGF) is a potent mitogen for vascular endothelial cells (EC); however, signal transduction pathways for HGF-stimulated EC growth remain unclear. In the present study we investigated the role of Src family kinases and nitric oxide (NO) in HGF-stimulated EC growth. Human umbilical vein endothelial cells (HUVEC) were stimulated with HGF and NO was measured by an NOx analyzing HPLC system. Activation of ERK1/2 and p38 MAPK was assessed by Western blot. NO production in HUVEC increased 1.8-fold by HGF. A Src family kinases inhibitor PP1 inhibited HGF-stimulated NO production by 71%. HUVEC growth increased 1.9-fold in cell number by HGF. PP1 and Nitro-L-arginine methylester (L-NAME) inhibited HGF-stimulated HUVEC growth by 51 and by 71%. ERK1/2 and p38 MAPK were phosphorylated by HGF and a MEK inhibitor PD98059 and a p38 MAPK inhibitor SB203580 inhibited HGF-stimulated HUVEC growth by 66% and by 58%; however, HGF-induced phosphorylation of ERK1/2 and p38 MAPK was not inhibited by L-NAME, indicating that NO is not an upstream activator of ERK1/2 and p38 MAPK. These findings demonstrated that Src family kinases regulate HGF-stimulated NO production in HUVEC and that HGF stimulates HUVEC growth through NO-dependent and NO-independent pathways.

Determinants of long-term mortality in patients with type B acute aortic dissection.

BACKGROUND Type B acute aortic dissection (AAD) carries a high short- and midterm mortality rate; however, knowledge related to long-term outcome is largely incomplete. The objective of this study was to identify long-term predictors including antihypertensive medications in type B AAD. METHODS We conducted a clinical follow-up study on 202 type B AAD patients. Univariate and multivariate Cox regression analyses were performed to identify predictors of mortality. RESULTS There were 44 postdischarge deaths in 202 consecutive type B AAD patients with a median follow-up of 55 months. In univariate Cox regression analysis, age (10 year incremental: hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.35-2.46, P < 0.0001), previous myocardial infarction or angina pectoris (HR 3.93, 95% CI 1.72-8.99, P = 0.001), and impaired renal function (HR 4.90, 95% CI 2.48-9.65, P < 0.0001) were predictors of death. Calcium channel blockers (CCBs), beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors as antihypertensive medications at discharge were predictors of increased survival. In multivariate Cox regression analysis, CCBs were a significant predictor of increased survival (vs. no antihypertensive medication at discharge: HR 0.38, 95% CI 0.15-0.97, P = 0.04). Impaired renal function was a significant predictor of death (HR 3.41, 95% CI 1.58-7.33, P = 0.002). No antihypertensive medication at discharge group was significantly associated with increased mortality (vs. 1 class of antihypertensive medication: HR 9.51, 95% CI 1.85-48.79, P = 0.007). CONCLUSIONS Impaired renal function was a predictor for adverse outcome in patients with type B AAD. The use of CCBs as antihypertensive medication at discharge was associated with increased survival.

Idiopathic pulmonary artery aneurysm.

A 45-year-old man was referred to our hospital after a prolonged history of exertional dyspnea. Clinical examination revealed systolic and diastolic heart murmurs without any systolic click in the second right sternal border. Chest x-ray showed pulmonary artery dilation (Figure 1). Multidetector computed tomography showed a huge pulmonary artery aneurysm ≈70 mm in diameter (Figure 2). Transthoracic echocardiography showed a huge aneurysm of the pulmonary artery by 2D echocardiography (Figure 3). There was no significant tricuspid regurgitation in either the 4-chamber view or the short-axis view, and pulmonary regurgitation due to dilatation of pulmonary annulus was …

Pulmonary hypertension due to left heart disease: The prognostic implications of diastolic pulmonary vascular pressure gradient.

BACKGROUND Compared to transpulmonary pressure gradient (TPPG), diastolic pulmonary vascular pressure gradient (DPG) may be a more sensitive and specific indicator for pulmonary hypertension (PH) due to left heart disease (LHD) with significant pulmonary vascular disease (PVD). The aim of this study was to investigate the incidence and clinical features of PH-LHD with PVD classified by DPG and TPPG. METHODS We analyzed 410 patients admitted for symptomatic heart failure (HF) (New York Heart Association ≥2) and who underwent right heart catheterization (RHC) at compensated stage between 2007 and 2012. Patients with PH-LHD were divided into 3 groups according to the value of DPG and TPPG (Non-PVD group: DPG <7mmHg and TPPG ≤12mmHg; TPPG-PVD group: DPG <7mmHg and TPPG >12mmHg; DPG-PVD group: DPG ≥7mmHg). Multivariate Cox regression analysis was applied to investigate whether each PH-LHD category predicts death or HF readmission after adjusting for other variables. RESULTS PH-LHD was observed in 164 patients (40%) with symptomatic HF. Thirteen patients (3%) were allocated into DPG-PVD group, while 24 patients were allocated into TPPG-PVD group (6%). DPG-PVD group was significantly associated with death or HF readmission compared to non-PVD group (hazard ratio: 3.57; 95% CI: 1.33 to 9.55, p=0.01), while the association between TPPG-PVD group and non-PVD group did not reach statistical significance (hazard ratio: 1.89; 95% CI: 0.77 to 4.64, p=0.17). CONCLUSIONS PH-LHD with PVD classified by DPG was significantly associated with poor long-term clinical outcomes, whereas the association between PH-LHD with PVD classified by TPPG and clinical outcomes did not reach statistical significance. However, further studies are needed, because there was no substantial difference in clinical outcomes between PH-LHD with PVD classified by DPG and PH-LHD with PVD classified by TPPG.

Clinical features of infective endocarditis: Comparison between the 1990s and 2000s

BACKGROUND The circumstances surrounding infective endocarditis (IE) are under constant change due to an increase in drug-resistant organisms, a decrease in rheumatic valve disease, progress in surgical treatment, and aging society. The purpose of this study was to compare clinical features of IE between the 1990s and 2000s and to elucidate the determinants of death or clinical event. METHODS All hospital admission records between January 1990 and December 2009 were retrospectively analyzed. The definition of IE was based on modified Duke criteria. Clinical presentation, blood culture, laboratory results, and echocardiography findings were compared between the 1990s and 2000s. RESULTS There were 112 patients with definite or probable IE according to modified Duke criteria. The most frequent organism causing IE was Streptococcus viridians both in the 1990s and 2000s. The determinants of in-hospital death were hemodialysis and congestive heart failure. The in-hospital mortality of IE was 5.4% in the 1990s and 13.3% in the 2000s. Composite events of in-hospital death and central nervous system disorders were significantly higher in the 2000s compared with the 1990s. CONCLUSION The most frequent causative organism of IE was S. viridians, both in the 1990s and 2000s. Independent predictors of in-hospital mortality in IE were hemodialysis and congestive heart failure.

Long-term follow-up on cardiac function following fulminant myocarditis requiring percutaneous extracorporeal cardiopulmonary support

Fulminant myocarditis is a rapidly progressive, life-threatening disease with severe impairment of systolic left ventricle function in the acute phase. However, the long-term prognosis of patients who survive the acute phase with percutaneous extracorporeal cardiopulmonary support (PCPS) is not established. The purpose of this study was to elucidate the long-term follow-up on chronic cardiac function and long-term outcome. Twenty consecutive patients with fulminant myocarditis in the acute phase supported by PCPS were enrolled between January 1995 and March 2010. Echocardiography was performed at least three times; acute phase (within 3 days from onset), predischarge (days 3–30), and chronic phase (>6 months, 2.67 ± 2.19 years, mean ± SD). The clinical events were queried by their medical record and questionnaires. Eight patients (40%) died in the acute phase. The time course of ejection fraction (%) by echocardiography was 22.7 ± 9.8, 53.1 ± 7.2, and 57.2 ± 9.6 in acute, predischarge, and chronic phase, respectively. Diastolic dimension (mm) was 46.8 ± 7.4, 51.3 ± 2.9, and 50.4 ± 1.8, and systolic dimension (mm) was 41.4 ± 7.7, 36.8 ± 4.0, and 35.2 ± 3.3 in acute, predischarge, and chronic phase, respectively. There was no recurrence or admission related to heart failure during the follow-up period. The cardiac function of patients with fulminant myocarditis recovers rapidly during their stay in hospital. The cardiac function of predischarge patients remains unchanged in the chronic phase. The long-term survival of fulminant myocarditis appears favorable in the chronic phase.