Fumiyoshi Watanabe

Increased Nitric Oxide in the Exhaled Air of Patients with Decompensated Liver Cirrhosis

Patients with liver cirrhosis often present with several systemic hemodynamic disturbances, including hypotension, low systemic vascular resistance, and a reduced sensitivity to vasoconstrictors [1]. As cirrhosis progresses, vascular resistance continues to decrease, and the low arterial pressure may lead to secondary disturbances in renal and hepatic blood flow and to ascites [1]. The precise mechanisms of these hemodynamic disorders have not yet been clearly elucidated. Excessive production of vasodilators, such as prostacyclin, bradykinin, substance P, and atrial natriuretic peptide, has been proposed, but there is no clear evidence to show that vasodilators are involved. Vallance and Moncada [2] hypothesized that nitric oxide, originally discovered as an endothelium-derived relaxing factor [3], may be a causative factor in hemodynamic disorders in patients with liver cirrhosis. High concentrations of circulating endotoxin are frequently found in patients with cirrhosis who have no clinical evidence of infection [4]. Thus, the endotoxemia of liver cirrhosis may induce nitric oxide synthase directly in blood vessels or indirectly through cytokines, leading to an increased synthesis and release of nitric oxide that may account for the hemodynamic abnormalities. Recent studies show that nitric oxide concentration in exhaled air can be measured [5-7] and that it is increased in patients with bronchial asthma [5, 6]. To test the hypothesis that an increased synthesis and release of nitric oxide accounts for hemodynamic abnormalities in patients with liver cirrhosis, we investigated whether nitric oxide output in exhaled air is increased in these patients. Methods Patients Fifty-six patients were consecutively selected from those hospitalized in our department. All had biopsy-proven chronic hepatitis or liver cirrhosis; none had primary lung disease, hypertension, or infection. They could walk in the ward unaided and did not need intensive care. Physical examination findings and blood data were analyzed to classify hepatocellular function in liver cirrhosis according to the Child criteria. The clinical background of these patients is summarized in Table 1. Healthy volunteers served as controls (15 men; 34 2 years of age; body surface area, 1.84 0.03 m2). All medications were discontinued 24 hours before each study began. No antihypertensives or vasodilators, including nitrates and angiotensin-converting enzyme inhibitors, were used in these patients. The study was approved by the hospital ethics committee, and informed consent was obtained from each study participant. Table 1. Clinical Background of Patients with Chronic Hepatitis and Liver Cirrhosis Nitric Oxide Measurement The nitric oxide concentration in exhaled air was determined at least 3 hours after meals while each participant was at rest in the sitting position, as previously described [7]. Each participant was asked to inhale synthetic air (Taiyo Sanso Co., Osaka, Japan) free of nitric oxide (< 3 parts per billion [ppb]) through a mask and a T-valve, and to exhale the air into a wide-bore Teflon tube (internal diameter, 25 mm; length, 600 mm). Exhaled air was continuously drawn from this tube with a vacuum pump and was introduced into a chemiluminescence analyzer (APNE-350E, Horiba Co., Kyoto, Japan). Measurement of nitric oxide concentration was based on the reaction of nitric oxide with ozone. The sensitivity of the analyzer to nitric oxide ranged from 2 to 1000 ppb. The system was calibrated with dilutions of certified nitric oxide gas (450 ppb in nitrogen; Taiyo Sanso Co.) using mass flowmeters (Estec Co., Kyoto, Japan). Expired volume was measured with a hot-wire flow meter connected to the T-valve on the expiratory side, and minute ventilation was calculated using a breath-by-breath respirometer (RM-280, Minato Medical Science Co., Tokyo, Japan). The nitric oxide concentration and minute ventilation were recorded with a computer-assisted data recorder (DS1100, Fukuda Denshi Co., Tokyo, Japan), and the output of nitric oxide was calculated as follows: nitric oxide output = (nitric oxideex nitric oxidein) x minute ventilation/body surface area, where nitric oxideex was the nitric oxide concentration in exhaled air, and nitric oxidein was the nitric oxide concentration in inhaled air. Nitric oxide concentration and minute ventilation were monitored simultaneously for 10 minutes, and the data obtained during the last 3 minutes was averaged. During the study period, the ambient levels of nitric oxide concentration were less than 5 ppb. Nitric oxide output was reproducible in patients with cirrhosis and in controls (coefficient of variation, 10.8% [n = 5] for patients and 9.3% [n = 5] for controls) on separate days, and there was no significant time-course change in nitric oxide output at rest. Echocardiographic Measurement To examine the relation between systemic hemodynamics and nitric oxide production, we measured cardiac output using transthoracic two-dimensional echocardiography (SSD-2200, Aloka Co., Tokyo, Japan) in 19 patients with liver cirrhosis and in 6 controls. This was done on the same day that nitric oxide concentrations were measured. A physician, who was blinded to the patient characteristics and the exhaled nitric oxide output values, obtained echocardiographic views and recorded them on videotape. Another physician, who was also blinded to these data, measured cardiac output using the echocardiographic images. Left ventricular dimension was measured in the long-axis view of the left ventricle while the patient was in the left lateral decubitus position. Left ventricular volume and cardiac index were obtained by the following formulae according to the Teichholz equation [8]: left ventricular volume = 7.0 x dimension3/(2.4 + dimension); cardiac index = (left ventricular end-diastolic volume -end-systolic volume) x heart rate/body surface area. Blood pressure was measured with a sphygmomanometer. Total peripheral resistance index was calculated as mean blood pressure 80/cardiac index. The cardiac index obtained by this method on separate days was reproducible in patients with cirrhosis and in controls (coefficient of variation, 9.1% [n = 6] in patients and 8.6% [n = 5] in controls). Statistical Analysis Values are expressed as the mean SE. Differences between patients and controls were compared using one-way analysis of variance (ANOVA) followed by the Fisher test. The correlation coefficient was calculated using the least-squares method. Statistical significance was set at P < 0.05. Results Patients with decompensated liver cirrhosis had markedly depressed liver function but normal serum creatinine levels (Table 1). There were no intergroup differences in minute ventilation per m2 body surface area (patients with chronic hepatitis, 5.1 0.3 L/min; Child A patients, 5.6 0.3 L/min; Child B patients, 5.4 0.2 L/min; Child C patients, 6.2 0.3 L/min; and controls, 5.4 0.2 L/min; P = 0.12). The level of exhaled nitric oxide output per m2 body surface area was significantly greater in patients with Child C (190 11 nL/min; P < 0.001) or Child B liver cirrhosis (166 12 nL/min; P < 0.001) than in controls (97 8 nL/min) (Figure 1). In patients with Child A liver cirrhosis (119 10 nL/min; P = 0.17) or chronic hepatitis (129 19 nL/min; P = 0.13), the level of nitric oxide output per m2 body surface area was similar to that in controls. Figure 1. Nitric oxide (NO) output in exhaled air in controls, patients with chronic hepatitis (CH), and patients with liver cirrhosis. The results of hemodynamic measurements showed that patients with Child C liver cirrhosis had a greater cardiac index per m2 body surface area (4.3 0.3 L/min compared with 2.9 0.2 L/min; P < 0.001) and a smaller total peripheral resistance per m2 body surface area (1732 125 dyne/s x cm5 compared with 2680 235 dyne/s x cm5; P = 0.004) than controls. There was a positive correlation between the level of nitric oxide output and cardiac index (r = 0.621; P < 0.001) (Figure 2). Figure 2. Relation between nitric oxide (NO) output and cardiac index in patients with liver cirrhosis and controls. Discussion We have shown that nitric oxide output is increased in the air exhaled by patients with cirrhosis, especially patients with decompensated cirrhosis. Although we did not identify the origin of the increased synthesis of nitric oxide, several potential sources can be considered. Patients with liver cirrhosis often have endotoxemia even when they have no signs of infection [4], and elevated concentrations of cytokines, such as tumor necrosis factor-, have been shown in patients with liver diseases [9, 10]. The liver may produce large amounts of nitric oxide in these patients: Hepatocytes and Kupffer cells are known to produce nitric oxide in vitro in response to lipopolysaccharide and several cytokines [11, 12]. The plasma levels of cytokines, including tumor necrosis factor, are much lower in patients with liver cirrhosis than in these in vitro studies [10-15]. However, in vitro studies have also shown that endotoxin and cytokines also induce nitric oxide synthase in other tissues, including vascular endothelium, smooth muscle, and bronchial epithelium [13-15]. Thus, it is possible that vascular and bronchial tissues in the lungs of patients with liver cirrhosis produce nitric oxide as a result of continuous stimulation by the lower concentrations of cytokines, because the plasma levels of cytokines in patients with cirrhosis are similar to those in normal persons who have become hypotensive through the administration of endotoxin [10, 16]. Because most nitric oxide is inactivated by hemoglobin or rapidly metabolized to nitrite and nitrate [3], nitric oxide in exhaled air may be the residual of excessive local production of nitric oxide by the lung rather than a product of the liver. Because plasma nitrite and nitrate levels reflect the sum of nitric oxide production in the entire body, includ

New subtype of apical hypertrophic cardiomyopathy identified with nuclear magnetic resonance imaging as an underlying cause of markedly inverted T waves

OBJECTIVES The aim of this study was to elucidate the clinical importance of a new subtype of apical hypertrophic cardiomyopathy that could not be diagnosed with the classical diagnostic criteria. BACKGROUND Apical hypertrophic cardiomyopathy is recognized by a characteristic spade-shaped intraventricular cavity on the end-diastolic left ventriculogram in the right anterior oblique projection, often associated with giant negative T waves [negativity > or = 1.0 mV (10 mm)]. As an underlying cause of giant negative T waves, an additional new subtype of apical hypertrophic cardiomyopathy has been identified. METHODS In 40 patients with inverted T waves (negativity > or = 0.5 mV), including 26 patients with giant negative T waves, nuclear magnetic resonance (NMR) long-axis images corresponding to the left ventriculogram in the right anterior oblique projection and short-axis images at various levels, including the apical level, were obtained to define the site of hypertrophied myocardium. RESULTS Long-axis images indicated a spadelike configuration in 17 patients, whereas this diagnostic configuration was not present in the other 23 patients. Nine of these 23 patients had significantly hypertrophied myocardium at the basal level. In the 14 remaining patients, short-axis images indicated no hypertrophy at the basal level and proved that the area of hypertrophied myocardium was confined to a narrow region of the septum or the anterior or lateral wall at the apical level (nonspade apical hypertrophic cardiomyopathy). The hypertrophied myocardium of the nonspade type was so narrowly confined that the mass did not form a spadelike configuration or could not be detected on the long-axis image. CONCLUSIONS Nonspade apical hypertrophic cardiomyopathy was newly identified on NMR short-axis images, and this could be an additional, important underlying cause of moderately to severely inverted T waves.

Relationship between distribution of hypertrophy and electrocardiographic changes in hypertrophic cardiomyopathy

To assess the relationship between the distribution of hypertrophy and electrocardiographic changes in patients with hypertrophic cardiomyopathy, magnetic resonance imaging and ECG findings were correlated in 25 patients with apical hypertrophy (group I), 15 patients with both apical and basal hypertrophy (group II), and 11 patients with hypertrophy localized to the basal left ventricle (group III). The number of precordial leads with negative T waves (-0.5 mV or more) was greater in group I than in groups II and III (I = 3.0 +/- 1.5, II = 1.7 +/- 1.5, III = 0.3 +/- 0.6; p < 0.01). Giant negative T waves (-1.0 mV or more) in precordial leads were found in 13 patients (52%) in group I and five patients (33%) in group II but were not found in group III. In contrast, tall positive T waves (> or = 1.0 mV) in precordial leads were found in two patients (13%) in group II and five (45%) in group III but were not found in group I. These results suggest that the distribution of hypertrophy in patients with hypertrophic cardiomyopathy produces a particular T wave polarity in precordial leads.

Visualization of Sinus Venosus-type Atrial Septal Defect by Biplane Transesophageal Echocardiography

In this article we describe three patients in whom biplane transesophageal echocardiography was useful in diagnosing sinus venosus type atrial septal defects. In two patients, diagnosis of anomalous pulmonary venous drainage was made correctly by biplane transesophageal echocardiography.