Interleukin-6 and tumor necrosis factor-alpha levels increase in response to maximal exercise in patients with chronic heart failure

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. Strenuous exercise causes activation of both systems but the effect of acute bouts of exercise on cytokines is not known in patients with CHF. This study determined whether maximal exercise induces activation of cytokines in CHF. Plasma interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, epinephrine, norepinephrine, and atrial and brain natriuretic peptides (ANP and BNP) were determined before and after symptom-limited cardiopulmonary exercise testing in 80 patients with CHF (LVEF=38+/-1%, peak VO(2)=18.8+/-0.5 ml/min/kg) and age-matched 33 controls. Resting IL-6 (Controls vs. CHF: 1.3+/-0.2 vs. 2.5+/-0.3 pg/ml, P<0.001) and TNF-alpha (2.7+/-0.2 vs. 3.8+/-0.2 pg/ml, P<0.01) were elevated in CHF. LogIL-6 and logTNF-alpha were positively correlated (r=0.34 and r=0.35, respectively) with logplasma norepinephrine, and were negatively correlated (r=-0.39 and r=-0.32, respectively) with peak VO(2). Maximal exercise increased IL-6 and TNF-alpha both in controls and CHF (all P<0.01). Changes in IL-6 (DeltaIL-6) correlated with Deltaepinephrine (r=0.63, P<0.0001) and Deltanorepinephrine (r=0.57, P=0.0006) in controls, but not in CHF. DeltaTNF-alpha correlated with DeltaANP (r=0.28, P=0.01) only in CHF. In summary, cytokine activation at rest was associated with high plasma norepinephrine and exercise intolerance. Maximal exercise caused increases in IL-6 and TNF-alpha concentrations. Sympathetic activation seems to be important for the IL-6 increase during exercise in controls. In CHF, changes in ANP during exercise were associated with the exercise-induced increase in TNF-alpha, but still unknown mechanisms are involved for the cytokine activation during exercise.     

Disruption of L-histidine decarboxylase reduces airway eosinophilia but not hyperresponsiveness

Histamine has a variety of airway actions and is considered to be an important mediator in asthma. This study examined the role of endogenous histamine in allergic airway eosinophil recruitment and hyperresponsiveness using L-histidine decarboxylase gene knockout mice. Histamine levels of the airways in L-histidine decarboxylase knockout mice were largely diminished compared with wild-type mice. Inhalation challenge with ovalbumin (OVA) in OVA-sensitized wild-type mice caused eosinophil accumulation in the lung as well as airway hyperresponsiveness to methacholine 3 days after the challenge. The eosinophil recruitment was significantly reduced in the knockout mice. In the bone marrow, the proliferation of eosinophils was enhanced after OVA challenge in the wild-type mice; however, the proliferation was significantly reduced in the knockout mice. The induction of P-selectin in the lung after OVA challenge was also inhibited in the knockout mice. In contrast, airway hyperresponsiveness was not suppressed in the knockout mice. These results suggest that endogenous histamine is involved in the accumulation of eosinophils into the airways after allergic challenge, possibly acting in the bone marrow and producing P-selectin in the airways. Furthermore, allergen-induced airway hyperresponsiveness appeared to occur independently of airway eosinophilia in our present model.     

Effects of losartan and benazepril on abnormal circadian blood pressure rhythm and target organ damage in SHRSP

The effects of chronic treatment with losartan, an angiotensin II type 1 (AT1) receptor antagonist, and benazepril, an angiotensin converting enzyme (ACE) inhibitor, on target-organ damage and abnormal circadian blood pressure (BP) rhythm were compared in stroke-prone spontaneously hypertensive rats (SHRSP). Losartan and benazepril were given by intraperitoneal infusion for 3 weeks after 17 weeks of age to minimize any influence of their different pharmacokinetic properties. BP was continuously monitored by telemetrical method before treatment and at the end of the observation period. The left ventricular (LV) weight, 24-hour urinary albumin excretion (UalbV) and morphological changes in the kidney were observed. Losartan and benazepril (1, 3 and 10 mg/day) reduced BP and LV weight in a dose-dependent manner with good correlation between the effects. Losartan significantly improved UalbV in a dose-dependent manner, whereas benazepril was effective at only 10 mg/day. Renal morphological analysis showed that reduction of glomerulosclerosis and collagen fiber thickness was related to the effect on UalbV, but not to the antihypertensive effects. Losartan improved the shifted circadian BP rhythm towards the active phase in a dose-dependent manner, whereas the improvement caused by 1 and 3 mg/day of benazepril was less effective than the same dosage of losartan. These results suggest that both losartan and benazepril can reduce cardiac hypertrophy showing good correlation with their antihypertensive effects, but losartan, especially at a low dose, alleviates renal damage more effectively than benazepril, with its effect correlating well with improvement of the abnormal circadian BP rhythm in SHRSP. Thus, the protective effect against hypertensive target organ damage of the AT1 receptor antagonist seems to be more effective than that of ACE inhibitor.     

Impaired exercise-induced vasodilatation in chronic atrial fibrillation--role of endothelium-derived nitric oxide.

Exercise capacity is often reduced in patients with atrial fibrillation (AF), but very few studies have focused on changes in endothelial function as a potential mechanism for the exercise limitation. The present study used using venous occlusion plethysmography to investigate whether nitric oxide (NO)-mediated vasodilatation is attenuated during exercise in patients with AF by measuring forearm blood flow (FBF) in 10 patients at rest and immediately after 2 levels of rhythmic handgrip exercise, before and after inhibition of NO synthesis with N(G)-monomethyl-L-arginine (L-NMMA, 100 micromol). The measurements were repeated 1 day after restoration of sinus rhythm by cardioversion. FBF responses to graded doses of acetylcholine (ACh) were also observed before and after cardioversion. Heart rate decreased after cardioversion, but blood pressure did not change. FBF at rest was not affected by cardioversion, but at the highest level of exercise it increased from 28.4+/-2.3 ml x min(-1) x dl(-1) before to 39.4+/-3.2 ml x min(-1) x dl(-1) after cardioversion (p<0.05). L-NMMA significantly decreased FBF at rest (p<0.01) and depressed the increase in FBF response to exercise after (p<0.01), but not before cardioversion. The FBF response to ACh was also accelerated significantly after cardioversion. The present results provide new evidence that NO bioavailability is depressed at rest and during exercise in patients with AF.     

A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma

The CC chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) attracts eosinophils, basophils, and T cells during inflammation and immune response, indicating a possible role for this chemokine in asthma. Both the -403A and -28G alleles of the RANTES promoter region exhibit significantly enhanced promoter activity in reporter constructs in vitro. We therefore investigated the genetic influence of these alleles on the development of asthma using case-control analysis in a Japanese population (298 patients with asthma and 311 control subjects). Given the evidence for heterogeneity of asthma according to age at onset, we divided patients with asthma into three subgroups: 117 late-onset patients with asthma (onset at more than 40 years of age), 83 middle-onset patients with asthma (onset at 20 to 40 years of age), and 98 early-onset patients with asthma (onset at less than 20 years of age). The -28G allele was significantly associated with late-onset asthma (odds ratio = 2.033; 95% confidence interval, 1.379-2.998; corrected p < 0.0025) but was not associated with the other two asthma subgroups. The -403A allele was not associated with any of the asthma subgroups. Further evidence of the importance of the -28G allele was a significant increase in the production of RANTES in vitro in individuals who carried this allele. Our findings suggest that, among Japanese, the -28G allele of the RANTES promoter region confers susceptibility to late-onset asthma.     

Mitral valve repair for double-orifice mitral valve with flail leaflet: the usefulness of real-time three-dimensional transesophageal echocardiography

We describe a 66-year-old man who required an operation for severe mitral regurgitation associated with a double-orifice mitral valve. Real-time 3-dimensional transesophageal echocardiography clearly demonstrated a double-orifice mitral valve with a central fibrous bridge. A flail posterior leaflet was observed on the anterolateral mitral valve orifice. Mitral valve repair using P1 triangular resection, anterolateral commissure plication, and ring annuloplasty with Duran band (Medtronic, Minneapolis, MN) was successfully performed. Postoperative real-time 3-dimensional transesophageal echocardiography demonstrated a double-orifice mitral valve without regurgitation or stenosis.     

Ascending aortic aneurysm associated with von recklinghausen disease

We report a case of ascending aortic aneurysm complicated with von Recklinghausen disease. A 57-year-old man was referred to our institution for further evaluation of the atrial fibrillation. Computed tomography (CT) revealed an aneurysm of the ascending aorta. The patient underwent resection of aneurysm to prevent rupture. Vascular complications in von Recklinghausen disease and the treatment for the vessels were discussed.     

Severe intestinal ischemia due to chronic aortic dissection; report of a case

We report a rare case with severe intestinal ischemia due to chronic aortic dissection. A 75-year-old man was admitted to our hospital with abdominal and right leg pain. The patient had a history of aortic dissection (Stanford type B) 12 years before admission and had been treated medically. Although a throaco-abdominal aneurysm due to aortic dissection (Crowford type III) had been diagnosed 1 year before admission, he had rejected the operation. Computed tomography (CT) revealed an increased diameter of the aneurysm (6 cm). As abdominal pain was increased, emergent surgery was performed on day 1 after admission. Although perfusion of the superior mesenteric artery and marginal artery was maintained, intestinal ischemia was worsening and general condition was deteriorated during surgery. Bypass surgery and/or resection of colon were not indicated because of peripheral colon artery ischemia, and he expired day 1 after surgery.