Takashi Sugamori

Contribution of Endogenous Nitric Oxide to Basal Vasomotor Tone of Peripheral Vessels and Plasma B-Type Natriuretic Peptide Levels in Patients With Congestive Heart Failure

OBJECTIVES We examined whether a relationship exists between the vasoconstrictive response to endogenous nitric oxide (NO) synthesis inhibition and the severity of heart failure in patients with congestive heart failure (CHF). BACKGROUND Controversy exists as to whether the vasoconstrictive response to NO synthesis inhibition in patients with CHF is comparable to that in normal subjects or is enhanced. METHODS Forearm blood flow (FBF) and calculated forearm vascular conductance (FVC) were obtained using plethysmography before and after administration of the NO synthesis inhibitor L-NMMA (NG-monomethyl-L-arginine) in 40 patients with CHF due to dilated cardiomyopathy and in 16 normal control subjects. Basal plasma B-type natriuretic peptide (BNP) and nitric oxide concentrations were measured in all subjects. RESULTS Plasma BNP and nitrite/nitrate (NOx) levels in the patients group were significantly greater and baseline FBF was significantly less. Administration of L-NMMA significantly decreased FBF and FVC in both groups. The percent changes in FBF (%FBF) and FVC (%FVC) from the baseline after L-NMMA correlated significantly with plasma BNP level (%FBF: r = 0.72; %FVC: r = 0.76; both p < 0.001). Percent changes in both FBF and FVC were greater in patients with BNP > or = 100 pg/ml than in normal subjects; however, in patients with BNP < 100 pg/ml they were comparable to those in normal subjects. CONCLUSIONS Vasoconstrictive response to L-NMMA in patients with CHF was preserved or enhanced in proportion to the basal plasma BNP level, indicating a close relationship between the contribution of endogenous NO to basal vasomotor tone and the severity of heart failure.

Effects of long-term nicorandil administration on endothelial function, inflammation, and oxidative stress in patients without coronary artery disease.

Long-term administration of nicorandil has been shown to improve outcomes through cardioprotective effects in patients with coronary artery disease. To identify the mechanisms responsible for these effects, this study examined the impact of long-term nicorandil administration on endothelial function, systemic inflammatory markers, and oxidative stress in patients with cardiovascular risk factors. Fifty-three patients were assigned to receive either nicorandil therapy (15 mg/day; n = 26) (nicorandil group) or usual care (n = 27) (nonnicorandil group). All study participants underwent flow-mediated vasodilatation (FMD) of the brachial artery 1 month before treatment, just before treatment, and at 3, 6, and 12 months following treatment. At identical time points, serum levels of malondialdehyde-modified low-density lipoprotein (MDA-LDL) and high-sensitivity C-reactive protein (hs-CRP) were collected. Compared with the nonnicorandil group, the nicorandil group demonstrated significantly increased FMD at 12 months, a finding not replicated for endothelium-independent vasodilatation with nitroglycerine. Analysis of biochemical markers revealed significantly reduced MAD-LDL levels in the nicorandil group at 12 months, as compared to slightly increased MAD-LDL levels in the nonnicorandil group. Significant reductions in hs-CRP levels were also noted at 6 and 12 months in the nicorandil group, while no change was found in the nonnicorandil group. Results demonstrated that long-term nicorandil therapy is associated with gradual improvements in endothelial function. Our findings also suggest that nicorandil treatment may result in cardiovascular protection through pleiotropic effects including reductions in oxidative injury and systemic inflammation.

An inhibitor of inducible nitric oxide synthase decreases forearm blood flow in patients with congestive heart failure

OBJECTIVES The functional activation of inducible nitric oxide synthase (iNOS) was evaluated as a source of nitric oxide (NO) in the forearm of patients with heart failure. BACKGROUND Although endogenous NO is normally produced by constitutive NO synthase (cNOS) in patients with congestive heart failure (CHF), expression of iNOS provides an additional source of NO. However, there are no in vivo studies showing functional activation of iNOS in humans. METHODS A nonselective NOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and a selective inhibitor of iNOS, aminoguanidine, were administered intra-arterially in graded doses into the brachial arteries of 13 patients with CHF and 10 normal control subjects. Forearm blood flow (FBF) was measured simultaneously in the infused and noninfused arms by plethysmography. Arterial and venous plasma concentrations of nitrite/nitrate (NOx) were measured at baseline and at the highest dose of each drug. RESULTS L-NMMA significantly reduced the FBF ratio between the infused and noninfused arms in both the control and patient groups (35 +/- 12% and 34 +/- 10%, respectively; both p < 0.001). Aminoguanidine at the same concentration significantly reduced the ratio in the patient group (15 +/- 9%, p < 0.01), with no change in the control group. The arterial NOx concentration was not affected by either drug; however, venous NOx concentrations were significantly decreased in both the control and patient groups by L-NMMA (18 +/- 5% and 18 +/- 17%, respectively; both p < 0.05) and in the patient group only by aminoguanidine (7 +/- 6%, p < 0.05). CONCLUSIONS These findings suggest that NO production in the forearms of patients with CHF is induced partly by iNOS activation, whereas in normal subjects, it can be ascribed to cNOS activation.

HLA-B*58:01 strongly associates with allopurinol-induced adverse drug reactions in a Japanese sample population.

[1] Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361:496–509. [2] Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat ImmuHidehisa Saeki*, Tomomitsu Hirota, Hidemi Nakagawa, Yuichiro Tsunemi, Toyoaki Kato, Sayaka Shibata, Makoto Sugaya, Shinichi Sato, Satoru Doi, Akihiko Miyatake, Kouji Ebe, Emiko Noguchi, Tamotsu Ebihara, Masayuki Amagai, Hitokazu Esaki, Satoshi Takeuchi, Masutaka Furue, Yusuke Nakamura, Mayumi Tamari

Association between Takayasu arteritis and ulcerative colitis – case report and review of serological HLA analysis

Summary Background Takayasu arteritis and ulcerative colitis are immune-mediated inflammatory diseases; genetic factors are assumed to play an important role in the pathogenesis of these 2 diseases. However, the coexistence of these 2 diseases has rarely been reported. Case Report In this report, we present a rare case of a 29-year-old man with a 4 years history of ulcerative colitis who developed Takayasu arteritis. He was found to carry the following human leukocyte antigens (HLA): A11, A24, B52, B62, DR4, and DR9. Conclusions We present a case report and review of the pertinent literature on serological analysis of HLA haplotype of the patients who exhibit both these diseases. In patients with both Takayasu arteritis and ulcerative colitis, high frequency of HLA-A24, B52, and DR 2 is observed. The pathological relevance of HLA-A24, B52, and DR2 to concomitant Takayasu arteritis and ulcerative colitis requires further investigation.

Activation of Inducible NOS in Peripheral Vessels and Outcomes in Heart Failure Patients

BACKGROUND Activation of inducible nitric oxide synthase (iNOS) has been reported in congestive heart failure (CHF) conditions. However, it is unknown whether activation of iNOS affects prognosis of CHF patients. We prospectively studied the influence of activation of iNOS in the forearm on the outcome of CHF patients. METHODS AND RESULTS Forearm blood flow (FBF) responses to 3 doses of acetylcholine (ACh) and nitroglycerin (NTG), and 4 doses of a selective iNOS inhibitor (aminoguanidine: Amn) and a nonselective NOS inhibitor (L-NMMA) were examined using plethysmography in 68 patients with CHF from idiopathic dilated cardiomyopathy. Plasma brain natriuretic peptide (BNP) and tumor necrosis factor-alpha (TNF-alpha) were also measured in all patients. During the mean follow-up period of 3.8 years, 25 patients were hospitalized for worsening heart failure and 9 of these patients died. Patients with adverse events had a diminished vasodilator response to ACh (P < .001) compared to patients without adverse events. Amn significantly decreased FBF (P < .001) in patients with adverse events, but not in patients without adverse events. FBF responses to NTG and L-NMMA were not significantly different between the 2 groups. When grouped by maximum FBF responses to each drug above and below the median value, multivariate Cox proportional hazards model analyses for cardiac event showed a significance in the FBF response to Amn (adjusted hazard ratio 5.89, P < .001). FBF responses to maximum dose of Amn significantly correlated with BNP and TNF-alpha levels (both P < .001). CONCLUSIONS CHF patients with vascular iNOS activation, as demonstrated by a greater vasoconstrictor response to Amn, had poor outcomes. Activation of iNOS in peripheral vessels, associated with proinflammatory cytokines in accordance to the severity of heart failure, is a marker for, or contributes to, adverse events in patients with CHF.

Cardiac involvement in Kugelberg-Welander disease: a case report and review.

There are few reports of cardiac involvement in patients with Kugelberg-Welander disease. We report a case of a 51-year-old man with Kugelberg-Welander disease who presented with syncope. His electrocardiogram showed complete right bundle branch block and transient complete atrioventricular block without escape rhythm. He was successfully treated with emergency temporary pacing followed by permanent pacemaker implantation. In this report, we review the relevant literature and argue that patients with Kugelberg-Welander disease should be evaluated regularly for cardiac disease.

EFFECTS OF ORAL BERAPROST SODIUM, A PROSTAGLANDIN I2 ANALOGUE, ON ENDOTHELIUM DEPENDENT VASODILATATION IN THE FOREARM OF PATIENTS WITH CORONARY ARTERY DISEASE

1 Previous clinical studies with prostaglandin I2 (PGI2) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2 Beraprost sodium (120 mg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium‐dependent vasodilatation was assessed by plethysmography, and urinary 8‐iso‐prostaglandin F2a (8‐iso‐PGF2a) was measured at baseline, 4 weeks and 8 weeks. 3 Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8‐iso‐PGF2a remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8‐iso‐PGF2a decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8‐iso‐PGF2a (P < 0.001). 4 Beraprost sodium decreased oxidative stress and improved forearm endothelium‐dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.

Nitric oxide-mediated vasodilatory effect of atrial natriuretic peptide in forearm vessels of healthy humans.

1. The aim of the present study was to determine whether the vasorelaxant effect of atrial natriuretic peptide (ANP) is, in part, endothelium dependent in humans.

The pitfall of coagulase-negative staphylococci: A case of Staphylococcus lugdunensis endocarditis

We report a case of a 60-year-old woman. She was transferred from a local hospital to our cardiovascular medicine department with a diagnosis of infectious endocarditis due to Staphylococcus lugdunensis. Transthoracic echocardiograph confirmed the presence of large vegetations on the native aortic and mitral valve, and subsequent severe regurgitation due to the aortic and mitral valve destruction. Emergent operation was performed and patients life was barely rescued. However, S. lugdunensis belongs to coagulase-negative staphylococci, which are generally regarded as relatively avirulent bacterium, the endocarditis caused by S. lugdunensis can be invasive and often resembles endocarditis due to Staphylococcus aureus. Therefore, whenever this organism is found in patients with endocarditis, early surgical treatment of the infected valve should be considered.