Validity of Ultrasound Lung Comets for Assessment of the Severity of Interstitial Pneumonia.

OBJECTIVES: Ultrasound (US) lung comets are often observed in patients with interstitial lung disease or congestive heart failure, but few studies have explored the clinical importance of US lung comets in patients with the former condition. We explored whether the US lung comet number could be used to assess the severity of interstitial pneumonia. METHODS: Forty stable patients with interstitial pneumonia were examined. Lung comets evident on transthoracic US imaging in 12 selected regions of the posterior chest wall were analyzed. We defined lung comets accompanied by thickened and irregular pleural lines as interstitial US lung comets; these predominated in patients with interstitial pneumonia. The total number of interstitial US lung comets was correlated with the data from chest high-resolution computed tomography, pulmonary function tests, serologic tests, and the 6-minute walk test. RESULTS: The 40 patients included 16 with idiopathic pulmonary fibrosis and 24 with nonspecific interstitial pneumonia. Thirty-four patients had interstitial US lung comets, which were more common in the lower than the upper lung area. Good correlations were evident between the lung comet number and the extent of the reticular pattern on chest high-resolution computed tomography (r = 0.710; P < .01), predicted forced vital capacity (r = -0.614; P < .01), and lung diffusion capacity for carbon monoxide (r = -0.577; P < .01). Notably, the lung comet number had a strong negative correlation with the percutaneous oxygen saturation level after the 6-minute walk test (r = -0.751; P < .01). CONCLUSIONS: The number of interstitial US lung comets evident on transthoracic US imaging may be a valuable marker of disease severity in patients with interstitial pneumonia.

Reduction of ST elevation in repeated coronary occlusion model depends on both altered metabolic response and conduction property.

The aim of this study was to elucidate the mechanisms of altered electrical response to ischemia in repeated coronary occlusion model. To test its dependence on metabolic response, extracellular K+ concentration (eKC), myocardial pH and PCO2 were simultaneously measured with epicardial ECG during three consecutive 4 min of left anterior descending coronary artery (LAD) occlusion separated by 15 min of reperfusion in canine hearts. ECG changes induced by infusion of high K+-buffer (10 mM) into the coronary arterial bed via carotid artery-LAD bypass (referred to as high K+-challenges: HKC) were also tested prior to (the first HKC), and during each reperfusion period (the second to the fourth HKC). ST elevation was significantly reduced in subsequent occlusions (3.14 +/- 0.48 and 2.98 +/- 0.47 mV in the second and third occlusion, both P<0.05, compared to 4.91 +/- 0.78 mV in the first). This was accompanied by significant attenuation of the changes in eKC, tissue pH and PCO2. ST elevation induced by HKC also significantly reduced after repeated occlusion (4.09 +/- 0.79 mV in the fourth HKC vs. 5.64 +/- 0.68 mV in the first, P<0.05) in spite of the identical changes in eKC during HKC. This progressive decrease in ST changes by HKC was rather consistent with augmented conduction delay (86.4 +/- 7.1% increase in activation time in the fourth vs. 54.3 +/- 3.4% in the first, P<0.01). These findings indicate that repeated ischemia induces altered electrical response to subsequent ischemia based on both attenuated metabolic response and altered conduction property.

[Cardiomyopathy showing progression from diffuse left ventricular hypertrophy to dilated phase associated with mitochondrial DNA point mutation A3243G: A case report].

A 44-year-old man was admitted to our hospital because of congestive heart failure. He had various symptoms caused by insulin-dependent diabetes mellitus, sensorineural deafness, Wolff-Parkinson-White syndrome and cardiomyopathy associated with mitochondrial DNA point mutation A3243G. Echocardiography had showed symmetrical hypertrophy of the left ventricular wall and normal cardiac function (ejection fraction 55%) at age 32 years. However, echocardiography showed cardiac transformation, consisting of posterior wall thinning and significantly reduced cardiac function (ejection fraction 11%), at age 44 years. Electrocardiography showed lowered R-wave in the chest leads and QRS widening. Both lactic acid and pyruvate serum levels were increased. Mitochondrial respiratory enzyme analysis in gastrocnemius muscle tissue indicated a partial deficiency of rotenone-sensitive NADH cytochrome C reductase. He was discharged from our hospital, and medically treated with coenzyme Q10(30 mg/day). He had no progression of cardiomyopathy or congestive heart failure. However, he suddenly died of lactic acidosis at age 47 years.

Role of augmented expression of intermediate-conductance Ca2+-activated K+ channels in postischaemic heart.

1. The rat intermediate conductance calcium-activated potassium channel (ImK) was cloned from a cDNA library of vascular smooth muscle cells (VSM) in rat pulmonary artery. The ImK distributes in a variety of tissue, including VSM, endothelial cells, leucocytes and fibroblasts. The ImK has a tyrosine phosphorylation consensus site in the proximal portion of the C-terminus and motifs exist for the DNA-binding protein AP-1 in the promoter, suggesting this channel is upregulated and active in cell cycle functions. The aim of the present study was to examine the role of ImK in postischaemic cardiovascular remodelling in relation to the angiotensin AT1 receptor-mediated AP-1 signalling pathway. 2. Rats underwent left coronary artery ligation for periods between 1 day and 3 weeks. The temporal profile of expression of ImK mRNA was analysed by RNase protection assay. To test the effect of AT1 receptor blockade, candesartan (3 mg/kg per day) was administered via an osmotic mini-pump implanted in the intraperitoneal space 3 days prior to coronary occlusion. 3. ImK expression in postischaemic hearts showed a significant increase with two distinct peaks; the first peak at day 3 (2.7-fold compared with control levels; P < 0.001) and the second after 2 weeks (1.5-fold; P < 0.01). Reperfusion following 30 min of ischaemia markedly accelerated and augmented the first peak at days 1-3 (4.8-fold), but completely abolished the second peak after 1-2 weeks (0.8-fold). In situ hybridization of ImK mRNA and immunostaining of ImK protein with specific antibody revealed that this was not only the result of the increase in ImK expression in vascular cells, but also related to infiltration of mononuclear leucocytes and fibroblasts into the ischaemic region. Candesartan inhibited cardiac hypertrophy and perivascular fibrosis of coronary arterioles in the non-ischaemic region. Candesartan also abrogated both peaks in ImK expression. 4. These findings indicate that both the inflammatory reaction and the postischaemic cardiovascular remodelling promote increased expression of ImK in postischaemic hearts via the AT1 receptor-mediated AP-1 signalling pathway.

TNF-alpha rapidly antagonizes the beta-adrenergic responses of the chloride current in guinea-pig ventricular myocytes.

The purpose of this study was to test the hypothesis that tumor necrosis factor-alpha (TNF-alpha) rapidly antagonizes the beta-adrenergic responses of the chloride current and to clarify the intracellular mechanisms responsible for the anti-adrenergic action. The whole-cell patch-clamp technique was used to monitor the anti-adrenergic effects of TNF-alpha on the cAMP-dependent chloride current (I(Cl)) recorded from isolated guinea-pig ventricular myocytes. Ramp pulses (+/-120 mV; dv/dt = +/-0.4 V/s) were applied from the holding potential of -40 mV. TNF-alpha rapidly (<15 min) inhibited the isoproterenol (Iso, 0.1 micromol/L)-induced I(Cl) in a concentration-dependent manner (30-1,000 U/ml, IC (50) = 144 U/ml, n=30). The inhibitory action of TNF-alpha was also observed when I(Cl) had been previously stimulated by 1 micromol/L forskolin (n=5). Prior exposure of myocytes to 5 microg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). However, when I(Cl) was induced by both 8-bromo-cAMP (100 micromol/L) and isobutylmethylxanthine (0.1 mmol/L), TNF-alpha (1,000 U/ml) failed to decrease I(Cl) amplitude (n=5). Prior exposure of myocytes to 5 mg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). Furthermore, despite of the presence of nitro-L-arginine methyl ester (0.1 mmol/L), a nitric oxide synthase (NOS) inhibitor, TNF-alpha reversed the Iso-induced increase in I(Cl) (n=5). These results suggest that TNF-alpha rapidly antagonizes the beta-adrenergic responses of I(Cl) by reducing cAMP concentration. This anti-adrenergic action is mediated by neither the PTX-sensitive G proteins regulatory pathway nor constitutive NOS activation.

Beneficial effect of dual-chamber pacing for a left mid-ventricular obstruction with apical aneurysm.

Sustained ventricular tachycardia (VT) developed in a 63-year-old woman. The 2-dimensional echocardiogram revealed left mid-ventricular obstructive hypertrophy and a discrete apical chamber. A continuous wave Doppler signal across the mid-ventricular narrowing exhibited early systolic ejection flow and diastolic paradoxical jet flow from the apex to the basal chamber, implying a significant systolic and diastolic intraventricular gradient with a high apical pressure. The left ventriculogram confirmed a mid-ventricular obstruction with an apical aneurysm. Invasive assessment of intraventricular pressure showed a peak-to-peak gradient greater than 100 mmHg. Treatment with antiarrhythmic agents could not prevent the VT, but dual-chamber pacing reduced the intraventricular pressure gradient and suppressed the VT completely. Continuous wave Doppler showed that the early systolic ejection flow from the apex had disappeared, that there was isovolumetric relaxation flow toward the apex and that there was attenuation of the diastolic paradoxical jet flow toward the basal chamber. Such findings by continuous wave Doppler can be useful in pacing therapy for evaluating changes in the severity of mid-ventricular obstruction.

L-nitro-arginine inhibits increase in endothelin binding sites induced by ischemia and reperfusion.

We have demonstrated that ischemia and reperfusion promoted augmented contractile response to endothelin-1 (ET) in coronary arteries in the presence of polymorphonuclear leukocytes (PMN). It has been also reported that ischemia and reperfusion increase ET binding sites in cardiac membrane in isolated rat heart perfused by blood cell-free system. To determine the role of PMN and L-arginine to nitric oxide (NO) pathway in these phenomena, isolated perfused rabbit hearts were subjected to 30 min of global ischemia followed by 30 min of reflow in the absence or presence of PMN and 10(-5)M of L-nitro-arginine (LNA). PMN was prepared with Percoll density gradients from peritoneal exudate elicited by glycogen. PMN activated with 10(-6)M of phorbol myristate acetate or their supernatant were infused into the coronary perfusion circuit after 5 min of reflow. LNA was added to perfusate also after reflow. The effect of superoxide dismutase (SOD: 50 IU/ml) was also determined. After the end of protocols, membrane fraction was isolated from the hearts for (125)I-ET-1 binding assay. ET-1 binding (Bmax) showed a significant increase by ischemia and reperfusion (P<0.01 vs control). That was markedly augmented with addition of activated PMN or their supernatant (both P<0.01), but abolished either by LNA or SOD (P<0.01 and P<0.05, respectively). These results indicate that increase in ET-receptor by ischemia and reperfusion is mediated by free radicals generated via L-arginine to NO pathway.

Pitavastatin inhibits upregulation of intermediate conductance calcium-activated potassium channels and coronary arteriolar remodeling induced by long-term blockade of nitric oxide synthesis.

UNLABELLED: We have reported that intermediate conductance Ca(2+)-activated K(+) channels (ImK) showed augmented expression in angiotensin II (AII) type 1 receptor-dependent manner in post-ischemic rat heart. ImK has tyrosine phosphorylation sequence in the C-terminus and motifs for NFkappaB and AP1 in the promoter. While statin inhibits AII-mediated vascular remodeling via anti-inflammatory effect independent of cholesterol lowering. To test the possible effect of statin on expression of ImK, Wistar-Kyoto rats received L-nitro-arginine methyl ester (LNAME: 1 mg/ml in drinking water) for 4 weeks in group L. While in L+P group, rats received both LNAME and pitavastatin (PTV: 1 mg/kg/day in drinking water). Temporal profile of ImK mRNA was examined by RT-PCR using specific primers for ImK. RESULTS: Long-term LNAME administration produced significant hypertension and resulted in marked microvascular remodeling characterized by medial thickening and perivascular fibrosis of coronary arterioles (100-200 microm in diameter). RT-PCR revealed significant up-regulation of ImK mRNA with two distinct peaks in L group in the early phase (days 3-7) and the late phase (4 weeks). PTV partially inhibited a rise in systolic blood pressure, but completely abolished the first peak of ImK upregulation (0.76 +/- 0.04 vs. 3.96 +/- 1.43 folds at day 7, p < 0.001). Co-treatments with PTV also significantly inhibited medial thickening and perivascular fibrosis. These findings indicate that statin inhibits microvascular remodeling induced by chronic inhibition of NO synthesis through the action independent of cholesterol lowering.