Circulating AIM as an indicator of liver damage and hepatocellular carcinoma in humans.

BACKGROUND: Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC. METHODS AND FINDINGS: Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99 ± 1.8 µg/ml in men and 6.06 ± 2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s-40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis. CONCLUSION: AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

An assessment of risk factors for the complexity of coronary artery disease using the SYNTAX score.

In 2005, the SYNTAX score was reported as "an angiographic tool grading the complexity of coronary artery disease". We investigated risk factors for the complexity of coronary artery disease (CAD) using SYNTAX scores in patients with new-onset CAD. The subjects were 359 consecutive cases that underwent de novo percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery without previous PCI history. Acute myocardial infarction was excluded. The SYNTAX scores were obtained from coronary angiographies performed before PCI. On multivariate linear regression analysis of risk factors for the SYNTAX scores, aging, being a male and having diabetes mellitus were identified as significant independent risk factors (age: multiple regression coefficient 0.27, p = 0.001; male: 4.91, p = 0.004; diabetes: 4.53, p = 0.001). Other coronary risk factors such as hypertension, hypercholesterolemia, smoking and reduced renal function were not identified as significant independent risk factors. In patients undergoing PCI, aging, being a male and having diabetes mellitus are considered to be independent risk factors for the complexity of CAD. Therefore, when patients with CAD have these factors, we expect the CAD of the patient to be more complex and that it will be necessary to provide more careful medical care.

Fatty liver incidence and predictive variables.

Although fatty liver predicts ischemic heart disease, the incidence and predictors of fatty liver need examination. The objective of this study was to determine fatty liver incidence and predictive variables. Using abdominal ultrasonography, we followed biennially through 2007 (mean follow-up, 11.6+/-4.6 years) 1635 Nagasaki atomic bomb survivors (606 men) without fatty liver at baseline (November 1990 through October 1992). We examined potential predictive variables with the Cox proportional hazard model and longitudinal trends with the Wilcoxon rank-sum test. In all, 323 (124 men) new fatty liver cases were diagnosed. The incidence was 19.9/1000 person-years (22.3 for men, 18.6 for women) and peaked in the sixth decade of life. After controlling for age, sex, and smoking and drinking habits, obesity (relative risk (RR), 2.93; 95% confidence interval (CI), 2.33-3.69, P<0.001), low high-density lipoprotein-cholesterol (RR, 1.87; 95% CI, 1.42-2.47; P<0.001), hypertriglyceridemia (RR, 2.49; 95% CI, 1.96-3.15; P<0.001), glucose intolerance (RR, 1.51; 95% CI, 1.09-2.10; P=0.013) and hypertension (RR, 1.63; 95% CI, 1.30-2.04; P<0.001) were predictive of fatty liver. In multivariate analysis including all variables, obesity (RR, 2.55; 95% CI, 1.93-3.38; P<0.001), hypertriglyceridemia (RR, 1.92; 95% CI, 1.41-2.62; P<0.001) and hypertension (RR, 1.31; 95% CI, 1.01-1.71; P=0.046) remained predictive. In fatty liver cases, body mass index and serum triglycerides, but not systolic or diastolic blood pressure, increased significantly and steadily up to the time of the diagnosis. Obesity, hypertriglyceridemia and, to a lesser extent, hypertension might serve as predictive variables for fatty liver.

High prevalence of early repolarization in short QT syndrome.

BACKGROUND: Short QT syndrome (SQTS) is characterized by an abnormally short QT interval and sudden death. Due to the limited number of cases, the characteristics of SQTS are not well understood. It has been reported recently that early repolarization is associated with idiopathic ventricular fibrillation and the QT interval is short in patients with early repolarization. OBJECTIVE: The purpose of this study was to study the association between early repolarization and arrhythmic events in SQTS. METHODS: The study consisted of three cohorts: SQTS cohort (N = 37), control cohort with short QT interval and no arrhythmic events (N = 44), and control cohort with normal QT interval (N = 185). ECG parameters were compared among the study cohorts. RESULTS: Heart rate, PR interval, and QRS duration were similar among the three study cohorts. Early repolarization was more common in the SQTS cohort (65%) than in the short QT control cohort (30%) and the normal QT control cohort (10%). Duration from T-wave peak to T-wave end was longer in the SQTS cohort than in the short QT control cohort, although QT and corrected QT intervals were similar. In the SQTS cohort, there were more males among patients with arrhythmic events than in those with a family history but without arrhythmic events. In multivariate models, early repolarization was associated with arrhythmic events in the SQTS cohort. ECG parameters including QT and QTc intervals were not associated with arrhythmic events in the SQTS cohort. CONCLUSION: There is a high prevalence of early repolarization in patients with SQTS. Early repolarization may be useful in identifying risk of cardiac events in SQTS.

A case report: 201Tl/99mTc-Pyrophosphate dual-isotope myocardial SPECT for detecting annular subendocardial infarction induced by a transient shock.

The patient was a 74-year-old woman with angina pectoris, who had undergone percutaneous coronary intervention with stent placement in the right coronary artery on October 2, 2007. On November 12 of the same year, she suffered from paroxysmal atrial fibrillation. She was treated with pilsicainide hydrochloride administered by intravenous injection, which was followed by a sudden sinus standstill, with marked bradycardia and a shock state. The patient was then treated with a catecholamine, however, the shock state persisted for about an hour. An electrocardiogram revealed persistent ST depression in leads V4-6 along with elevation of the serum creatinine kinase. A coronary angiography performed on the admission day revealed no abnormality. On the third hospital day, a dual-isotope myocardial SPECT using 201Tl and 99mTc-pyrophosphate demonstrated an annular accumulation of 99mTc-pyrophosphate concordant with the endocardium from apex to the mid-portion of the left ventricle, suggestive of subendocardial infarction. The case is reported here, as there are few reports of subendocardial infarction developing due to ischemia arising from a shock state.

Men with Brugada-like electrocardiogram have higher risk of prostate cancer.

BACKGROUND: Elevated plasma testosterone levels are thought to play a role in the male preponderance of cases of Brugada syndrome (BS) and the development of prostate cancer. METHODS AND RESULTS: The 34 Brugada-like electrocardiogram (ECG) cases were identified among 2,681 male survivors of the atomic bomb who had undergone at least 1 biennial health examination between July 1958 and December 1999 in Nagasaki, Japan. They were followed for incident prostate cancer from July 1958 through December 2004, and the risk of prostate cancer for Brugada-like ECG, age, smoking habit, and radiation exposure was analyzed using Cox proportional hazards analysis. Among the men with or without Brugada-like ECG there were 4 (11.8%) and 54 (2.0%) cases of prostate cancer, respectively. With age adjustment there was a higher risk of prostate cancer for Brugada-like ECG (relative risk (RR): 5.42, 95% confidence interval (CI) 1.96-15.00, P=0.001). With further adjustment for smoking habit and radiation dose, Brugada-like ECG remained a significant risk factor for prostate cancer (RR: 6.47, 95%CI 1.97-21.21, P=0.002). CONCLUSIONS: Brugada-like ECG confers a higher risk of prostate cancer independent of age, smoking habit, and radiation exposure. Men with a Brugada-like ECG should be regularly examined for prostate cancer and vice versa, especially elderly subjects.

A case of mixed connective tissue disease complicated with hypertrophic obstructive cardiomyopathy.

A 54-year-old female was diagnosed as mixed connective tissue disease (MCTD) complicated with secondary Sjögren's syndrome. Although she had no dyspnea on exertion, the chest X-ray showed cardiomegaly with interstitial pneumonia. The echocardiogram demonstrated asymmetric hypertrophy of the interventricular septum. Diagnosis of hypertrophic obstructive cardiomyopathy (HOCM) was confirmed by left ventriculography and myocardial biopsy. She was treated with prednisolone, resulting in improvement of swollen hand, elevated muscle enzymes and interstitial pneumonia. A rare complication of HOCM with MCTD was described.

Two cases of short QT interval.

BACKGROUND: The epidemiology of short QT interval remains unclear. We attempted to determine the incidence and clinical characteristics of short QT interval in a longitudinal cohort study. METHODS: A total of 19,153 subjects (7,525 male, 11,628 female) were enrolled in the study and all available electrocardiograms (ECGs) were investigated longitudinally from 1958 through 2003. We defined short QT interval as QTc of less than 350 ms. RESULTS: Of the 19,153 subjects, two met the criteria of short QT interval and allowed for prevalence and incidence estimates for short QT interval as 0.01% and 0.39/100,000 person-years, respectively. Both cases had neither a family history of sudden cardiac death, nor a history of drug use that might have affected for QT interval. Case 1 was a female with history of ischemic heart disease. Case 2 was a 60-year-old male who exhibited a short QT interval for the first time when he was 26 years of age. He had sick sinus syndrome as an underlying heart disease. CONCLUSIONS: Of the 19,153 subjects in this study, none were identified as having the short QT syndrome, with associated high risk of ventricular tachyarrhythmia, atrial fibrillation, and sudden death. Two subjects were identified as having QTc of less than 350 ms, and allowed prevalence and incidence estimates to be made of short QT interval. There observations were suggestive of clinical relationships between short QT interval and organic or electrophysiological heart disease.

Fatty liver and uric acid levels predict incident coronary heart disease but not stroke among atomic bomb survivors in Nagasaki.

Relationships between fatty liver and coronary heart disease (CHD) and stroke risk remain ill defined. We investigated whether fatty liver is a predictor of CHD and stroke risk. Until December 2000 we followed 2,024 atomic bomb survivors (775 men: 62.0 +/- 9.9 years old; 1,249 women: 63.2 +/- 8.4 years old) who had basic examinations between November 1990 and October 1992 for clinical and laboratory CHD risk factors and fatty liver and who were initially free of CHD and stroke. Forty-nine cases of CHD and 84 cases of stroke were observed. At the time of the baseline examinations, significant clinical associations were found between fatty liver and obesity (p<0.001), hypertension (p<0.001), dyslipidemia (p<0.001), and glucose intolerance (p<0.001). A slight but nonsignificant association was found between fatty liver and hyperuricemia (p=0.07) as well. By using multiple Cox regression analyses, age (relative risk [RR] 1.05, 95% confidence interval [CI] 1.01-1.08), smoking (RR 2.20, 95% CI 1.02-4.74), hyperuricemia (RR 2.30, 95% CI 1.08-4.89), and fatty liver (RR 2.53, 95% CI 1.06-6.06) were shown to be significant predictors of CHD, whereas age (RR 1.08, 95% CI 1.06-1.10), smoking (RR 2.06, 95% CI 1.14-3.72), and hypertension (RR 2.14, 95% CI 1.38-3.30) predicted stroke risk. Fatty liver, which clusters clinical and laboratory CHD risk factors, is an independent predictor of CHD, but not of stroke. Fatty liver should be followed as a feature of metabolic syndrome, with the aim of preventing CHD.

Bedtime administration of cilnidipine controls morning hypertension.

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.

Aldosterone induces circadian gene expression of clock genes in H9c2 cardiomyoblasts.

We examined mRNA expression of the clock genes (Per1, Per2, and Bmal1) and PAI-1 (plasminogen activator inhibitor-1) after aldosterone treatment every 4 h up to 48 h in H9c2 cardiomyoblasts by reverse transcription-polymerase chain reaction. To block the MR (mineralocorticoid receptor), the MR antagonist, spironolactone, was added to the medium 1 h before aldosterone treatment. Aldosterone induced an initial increase and rhythmic expression of Per1, while spironolactone attenuated the acute increase in Per1 mRNA induced by aldosterone. On the other hand, aldosterone did not increase the Per2 mRNA in the acute phase, but thereafter induced a rhythmic expression of Per2. Aldosterone also induced rhythmic expression of Bmal1, a positive element of the clock genes. The rhythm of Bmal1 mRNA was anti-phase of that of Per2 mRNA. Aldosterone induced an acute increase in PAI-1 mRNA, but did not induce rhythmic expression of PAI-1. The present study demonstrated first that aldosterone regulates expression of the clock genes Per1, Per2, and Bmal1, and increases PAI-1 expression in H9c2 cardiomyoblasts. Second, an acute increase in Per1 mRNA after aldosterone treatment is mediated through MR. Third, clock genes are not related to PAI-1 expression in H9c2 cardiomyoblasts.

Serum adiponectin and leptin in a patient with Cushing's syndrome before and after adrenalectomy.

We measured the serum adiponectin and leptin concentrations before and after successful removal of a left adrenal adenoma in a 46-year-old woman with Cushing's syndrome. The serum adiponectin level was 6.0 microg/ml before the operation and rose to 8.1 microg/ml after adrenalectomy. However, the serum leptin level was markedly high (24.8 ng/ml) before the operation and decreased to within the normal range (6.0 ng/ml) 6 months after adrenalectomy, concomitant with weight reduction and normalization of the serum cortisol level.

Longitudinal analysis of blood pressure trends and prognosis in isolated systolic hypertension in elderly individuals.

BACKGROUND: With age, a larger proportion of elderly individuals have isolated systolic hypertension (ISH). However, because of a lack of longitudinal studies, much less is known about the incidence and prognosis of ISH in elderly individuals. The aims of this study were to document blood pressure (BP) trends in development of ISH in elderly individuals, and to investigate the incidence and prognosis for those with ISH. METHODS: Retrograde longitudinal analysis was conducted on 3284 subjects during 1958 to 1984. The presence of ISH in elderly individuals was defined as systolic BP of >or=160 and diastolic BP of or=60 years. Prognosis was subsequently investigated until 2002 and compared with that for age- and sex-matched non-ISH control subjects. RESULTS: Selected as ISH in elderly individuals were 185 subjects. Three subtypes were documented by BP trends: 71 subjects with "de novo" ISH, 68 with "burned out" ISH, and 46 subjects with "unclassifiable" ISH. Incidence of ISH increased with age. Mean onset age of ISH was 71.0 years. Subsequent follow-up revealed that the subjects with ISH lived long lives: 83.2% of ISH subjects and 76.2% of control subjects lived to be >80 years old. However, 58.9% of ISH subjects were found to have cardiovascular disease during the follow-up, showing a higher prevalence than among control subjects (42.2%, P = .0013). In more than 40% of subjects with ISH, cardiovascular disease occurred at >or=80 years of age. CONCLUSIONS: In this study, the incidence of ISH increased with age. Persons with ISH have good prognoses in terms of longevity, but many have late-onset cardiovascular complications, suggesting the importance of BP control even in very elderly individuals.

Serum levels of S-glutathionylated proteins as a risk-marker for arteriosclerosis obliterans.

BACKGROUND: Oxidative stress plays a role in the development of chronic peripheral arterial disease (PAD) because under these conditions redox regulation is impaired, inducing the S-glutathionylation of proteins. A method of estimating the levels of S-glutathionylated proteins has been developed using biotinylated glutathione S-transferase, which allows the study of their crucial role in the oxidative stress-related progression of PAD. METHODS AND RESULTS: The serum levels of S-glutathionylated proteins were examined in 41 patients with arteriosclerosis obliterans (ASO) and 38 age-matched non-ASO patients using biotinylated glutathione S-transferase. The levels were higher in the patients with ASO, even early on, and positively correlated with the ankle/brachial index. In vitro, the levels of S-glutathionylated proteins were reduced in the presence of glutathione and glutaredoxin. CONCLUSIONS: Serum levels of S-glutathionylated proteins are a sensitive risk-marker for ASO at an early stage.

Fibrotic response to angiotensin II is blunted in the kidney, but not in the heart, in insulin-sensitive long-lived transgenic dwarf rats.

Insulin resistance is a characteristic feature of cardiovascular and renal diseases, and angiotensin II (Ang II) has been suggested to induce insulin resistance. The aims of this study were to elucidate the effect of chronic Ang II infusion on vascular reactivity and organ damage in insulin-sensitive rats. We confirmed the following three points. First, there was no significant difference in pressor response to chronic Ang II infusion (600 ng/kg/min) between insulin-sensitive transgenic rats (Tg) and control rats (C). Second, there was no significant difference in cardiac hypertrophy and fibrosis by chronic Ang II infusion between the two groups. However, third, fibrotic response to chronic Ang II infusion evaluated by histopathological scoring in the kidney was significantly decreased in insulin-sensitive transgenic rats (renal fibrosis and nephropathy score: C+Ang II vs Tg+Ang II; 2.5 vs 1.3; p<0.05). Furthermore, the expression of TGF-beta, a fibrosis indicator, was also significantly suppressed in the kidneys of the transgenic rats (TGF-beta1/GAPDH ratio: C+Ang II vs Tg+Ang II; 1.15 vs 0.81; p<0.05). This result indicates that the growth hormone/insulin-like growth factor-1 axis is critically involved in the development of renal injury and fibrosis, rather than hypertension, cardiac hypertrophy, and cardiac fibrosis induced by chronic Ang II administration.

Ventricular fibrillation in a patient with prominent j wave in the inferior and lateral electrocardiographic leads after gastrostomy.

We describe the case of a 39-year-old man who experienced a ventricular fibrillation storm related to a prominent J wave in the inferior and lateral electrocardiographic leads on the day after gastrostomy. The J wave slowly decreased after amiodarone therapy (400 mg/day) was started, and ventricular fibrillation disappeared.