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A fatty liver is characterized by the hyperaccumulation of lipids within hepatocytes and is often caused by excessive alcohol intake. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcoholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to a level lower than that seen before HGF treatment. In contrast, serum levels of lipids and lipoproteins increased with HGF administration. Primary cultured hepatocytes prepared from the fatty liver retained lipid droplets during a 48-hour culture. However, when cultured in the presence of HGF, intracellular lipid concentrations decreased and lipid secretion was enhanced. Consistent with these events, HGF stimulated the rate of protein synthesis of apolipoprotein B (apoB) and enhanced subsequent mobilization of lipids into the medium. These results indicate that HGF administration induced recovery from the fatty liver, at least in part, by enhancing apoB synthesis and the subsequent mobilization of lipids from hepatocytes with fatty change. The possibility that HGF can be therapeutic for subjects with an alcohol-related fatty liver warrants further attention.

Background/Aims

The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of ‘hepatotrophic factors’ and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-β, with the pathologic changes caused by PCS in rats.

Methods

PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months.

Results

The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-β concentration that peaked at 1.4 × baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-α and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis.

Conclusions

The development of hepatic atrophy was associated with changes in TGF-β concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-β constrains the amount of hepatocyte proliferation independently from control of liver volume.

Background: Hepatocyte growth factor (HGF) plays an essential role in hepatic development and regeneration, and shows proliferative and antiapoptotic activity in hepatocytes.

Aims: To establish an effective new method for HGF gene transfer in vivo and to investigate its effects in acute experimental liver injury.

Animals: Eight week old female mice were used.

Methods: Rat HGF gene in a modified pKSCX plasmid was transferred to the tibialis anterior muscle by electroporation using a pulse generator. Four days later, plasma HGF concentrations were determined by enzyme linked immunosorbent assay every two days for three weeks. To confirm the efficacy of electroporation, a plasmid bearing green fluorescence protein (GFP) was transferred similarly. Four days after electroporation, carbon tetrachloride (CCl4) was administered to mice to induce acute liver injury. Plasma alanine aminotransferase (ALT) activity was measured. Hepatic apoptosis was assessed by Hoechst 33258 staining and the TUNEL method.

Results: Fluorescence microscopy showed strong green fluorescence where the GFP gene had been transferred into muscle. In mice given the HGF gene, HGF in plasma was increased up to fourfold from pretreatment amounts, peaking 6–9 days after electroporation and quickly decreasing within three weeks. Compared with the group without HGF transfer, the percentage of apoptotic hepatocytes after CCl4 intoxication was significantly lower, as was ALT activity. In addition, ALT activity normalised more rapidly in the HGF gene transfer group.

Conclusions: Naked DNA injection and transfer by electroporation efficiently brings about HGF expression in vivo, which can attenuate acute liver injury.

Myocardial infarction complicates approximately 1 in 10,000 pregnancies. Although coronary artery dissection is the leading cause of pregnancy-related myocardial infarction during the postpartum period, the pathogenesis of coronary dissection during this period remains uncertain.

Herein, we report the case of a 52-year-old black postmenopausal woman with no apparent cardiovascular risk factors who gave birth to twins after in vitro fertilization. Ten days after delivery, she presented with an acute coronary syndrome. Coronary angiography revealed dissection of all 3 coronary arteries. Despite aggressive medical management, the patient experienced recurrent myocardial ischemia. Repeat coronary angiography revealed progression of the dissection process, which required urgent coronary artery bypass surgery. The patient's postoperative course was uneventful. To our knowledge, this report is the 1st description of pregnancy-associated coronary artery dissections in a postmenopausal woman, and the 1st such event in a pregnancy that resulted from in vitro fertilization.

Objective

To investigate the association between chronic exposure to second hand smoke (SHS) and the short‐term prognosis of patients hospitalised with acute coronary syndromes.

Methods

Between 1 October 2003 and 30 September 2004, 2172 consecutive patients enrolled with acute coronary syndromes at the cardiology clinics or the emergency units of six major hospitals, in Greece were studied. Exposure to SHS was measured through a questionnaire administered during a specific interview, after the second day of hospitalisation. The main outcome of interest was the 30‐day status of these patients (death, or rehospitalisation due to coronary heart disease).

Results

1003 (46%) of the patients were exposed to SHS. Patients reporting exposure to SHS had 61% (95% CI 14% to 118%) higher risk of having an event during the first 30 days after hospitalisation as compared with patients who were not exposed to SHS, after taking into account the effect of several potential confounders. A dose–response linear relationship was observed between the risk of having recurrent events and the years of exposure to SHS (ρ = 0.17, p<0.001).

Conclusions

Exposure to SHS increases considerably the risk of recurrent events in patients who had survived a cardiac event.

Aims

To determine whether circulating levels of chromogranin A (CgA) provide prognostic information independently of conventional risk markers in acute coronary syndromes (ACSs).

Methods and results

We measured circulating CgA levels on day 1 in 1268 patients (median age 67 years, 70% male) with ACS admitted to a single coronary care unit of a Scandinavian teaching hospital. The merit of CgA as a biomarker was evaluated after adjusting for conventional cardiovascular risk factors. During a median follow-up of 92 months, 389 patients (31%) died. The baseline CgA concentration was strongly associated with increased long-term mortality [hazard ratio per 1 standard deviation increase in logarithmically transformed CgA level: 1.57 (1.44–1.70), P < 0.001], heart failure hospitalizations [1.54 (1.35–1.76), P < 0.001], and recurrent myocardial infarction (MI) [1.27 (1.10–1.47), P < 0.001], but not stroke. After adjustment for conventional cardiovascular risk markers, the association remained significant for mortality [hazard ratio 1.28 (1.15–1.42), P < 0.001] and heart failure hospitalization [hazard ratio 1.24 (1.04–1.47), P = 0.02], but not recurrent MI.

Conclusion

CgA is an independent predictor of long-term mortality and heart failure hospitalizations across the spectrum of ACSs and provides incremental prognostic information to conventional cardiovascular risk markers.

Kawasaki disease (KD) is an acute vasculitis syndrome of unknown etiology. It occurs in infants and young children, affecting mainly small and medium-sized arteries, particularly the coronary arteries. Generalized microvasculitis occurs in the first 10 days, and the inflammation persists in the walls of medium and small arteries, especially the coronary arteries, and changes to coronary artery aneurysms.

We report the case of a 10-month-old girl referred to our center three months after the onset of disease due to the aneurysms of the coronary arteries. During the acute phase of her illness, she received 2 gr/kg intravenous gamma globulin; and after her referral to us, the patient was treated by antiaggregant doses of acetylsalicylic acid (ASA) (5 mg/kg) and Warfarin (1 mg/daily). At three months’ follow-up, the aneurysms still persisted in the echocardiogram.

Background

The prevalence of depression in patients with acute coronary syndrome, i.e. myocardial infarction and unstable angina, is higher than in the general population. The prevalence of anxiety is higher as well. Both depression and anxiety are associated with poor cardiac outcomes and higher mortality. Comorbid depression in patients with acute coronary syndrome often goes undiagnosed, and it is therefore a challenging task to prevent this risk factor. The study of DEpression in Coronary ARtery Disease (DECARD) is designed to examine if it is possible to prevent depression in patients with acute coronary syndrome.

Methods

Two hundred forty non-depressed patients with acute coronary syndrome are randomized to treatment with either escitalopram or placebo for 1 year. Psychiatric and cardiac assessment of patients is performed to evaluate the possibility of preventing depression. Diagnosis of depression and Hamilton Depression Scale are the primary outcome measures.

Discussion

This is the first study of prevention of depression in patients after acute coronary syndrome with a selective serotonin reuptake inhibitor.

Trial Registration

Identifier: NCT00140257

Background

Apoptosis plays an important role in the development of heart failure. The aim of the prospectively designed study was to assess whether the concentration of apoptotic markers apoptosis-stimulating fragment (Fas, CD95/APO-1) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can predict prognosis in patients with acute coronary syndromes.

Methods

The concentrations of soluble Fas and TRAIL were determined in 295 patients with acute coronary syndromes. The status of all patients was evaluated at 6 months. The primary goal was a composite end-point of death and hospitalization for heart failure. The secondary end-points were re-MI, death alone and stroke alone.

Results

During the median follow-up of 6 months, 26 patients experienced the composite end-point. Using multivariate logistic regression, the concentration of TRAIL was the strongest significant and independent predictor of composite end-point (OR 0.11 (95% CI 0.03–0.45), p = 0.002). Low concentration was associated with poor prognosis of patients. Other significant predictors of composite end-point were serum creatinine (OR 7.7 (95% CI 1.1–54.5, p = 0.041) and complete revascularization (OR 0.19 (95% CI 0.05–0.78, p = 0.02). Independent significant predictors of death in the multivariate analysis were the concentration of TRAIL (OR 0.053 (95% CI 0.004–0.744), p = 0.029), older age (OR 1.20 (95% CI 1.02–1.41, p = 0.026) and serum creatinine (OR 15.1 (95% CI 1.56–145.2), p = 0.0193). Re-MI or stroke could not be predicted by any combination of obtained parameters.

Conclusions

Low concentrations of soluble TRAIL represent a strong predictor of a poor prognosis in patients with acute coronary syndrome. The predictive value of TRAIL concentration is independent of age, ejection fraction, index peak troponin level, concentration of BNP or serum creatinine.

BACKGROUND—Raised plasma homocysteine is a risk factor for coronary artery disease. Patients with myocardial infarction or unstable angina show greater activation of coagulation, greater troponin release, and a worse outcome.
OBJECTIVE—To examine variations in plasma homocysteine concentration in relation to C reactive protein (CRP) in patients presenting with acute coronary syndromes.
METHODS—Consecutive patients presenting with acute myocardial infarction (22) and unstable angina pectoris (12) were studied. Plasma samples were obtained on admission (before clinical intervention), on days 2, 7, and 28, and again six months after admission. Plasma homocysteine, assayed by high performance liquid chromatography, and CRP were both determined at the same time points. Changes were assessed by analysis of variance.
RESULTS—CRP concentrations showed a classical rise on day 2, followed by a gradual decline to normal values taken at six months from admission in both myocardial infarction (p < 0.0001) and unstable angina (p = 0.02). Homocysteine concentrations in myocardial infarction (median, 25th to 75th interquartile range) were: 11.9 (10.7 to 12.6), 11.5 (9.1 to 13.4), 12.1 (11.4 to 14.1), 12.4 (11.1 to 14.4), and 12.1 (11.2 to 14.0) µmol/l, for days 1, 2, 7, 28, and 180, respectively (p = 0.02). Significant differences were observed only between day 2 and day 7 (p < 0.05). The final homocysteine measurement was not different from the admission level. Homocysteine concentrations in unstable angina did not differ between admission and convalescence (12.5 (9.1 to 14.5) µmol/l and 12.3 (7.7 to 14.9) µmol/l, respectively).
CONCLUSIONS—Plasma homocysteine concentrations are minimally influenced by acute phase variations with reliable measurements obtained on admission in patients with myocardial infarction and unstable angina.


Keywords: myocardial infarction; unstable angina; homocysteine; sample timing

Objective

To investigate the relation between serum high sensitivity (hs) C reactive protein (CRP), proinflammatory cytokine concentrations, proinflammatory to anti‐inflammatory cytokine ratios and long‐term prognosis in patients with non‐ST elevation acute coronary syndrome (NSTEACS).

Design

Prospective follow‐up study for the first six months and then for the first year after admission to hospital.

Setting

Tertiary referral centre.

Patients

80 patients (60 men, 20 women, mean age 60 (SD 10) years) with NSTEACS and moderate to high TIMI (Thrombolysis In Myocardial Infarction) risk scores.

Interventions

Blood samples from patients with NSTEACS were obtained at the time of admission. Serum concentrations of hs‐CRP, (hs) pro‐inflammatory (interleukin (IL) ‐1β, IL‐6, tumour necrosis factor α) and (hs) anti‐inflammatory (IL‐10) cytokines were analysed and proinflammatory to anti‐inflammatory cytokine ratios were calculated by dividing proinflammatory cytokine concentrations by anti‐inflammatory cytokine IL‐10.

Main outcome measure

The primary end point of the study was new coronary events (NCE) defined as the combination of cardiac death, non‐fatal myocardial infarction and recurrent rest angina that required hospitalisation within 12 months of follow up.

Results

During the one‐year follow‐up period, 23 patients (29%) met the NCE criteria. Concentrations of hs‐CRP, IL‐1β and IL‐6 and ratios of IL‐1β:IL‐10 and IL‐6:IL‐10 were significantly higher in patients with NCE than in patients without NCE. In the logistic regression analysis, IL‐6:IL‐10 ratio was the most important predictor for NCE (p  =  0.006) with an odds ratio of 2.24 (95% CI 1.26 to 3.97).

Conclusions

Cytokine concentrations and proinflammatory to anti‐inflammatory cytokine ratios may be useful markers for predicting vascular risk in patients with NSTEACS.

OBJECTIVE—To investigate the clinical significance of circulating hepatocyte growth factor (HGF) and the role of peripheral blood mononuclear cells (monocytes), which are a possible source of HGF, in patients with acute myocardial infarction.
DESIGN AND PATIENTS—37 patients with acute myocardial infarction and 13 normal control subjects were recruited. Peripheral venous blood samples were drawn from the infarct patients 1, 7, 14, and 21 days after onset. Monocytes were isolated from peripheral blood at those times. HGF concentrations in serum and in a culture medium of monocytes after incubation for 24 hours (monocyte HGF levels) were measured by enzyme linked immunosorbent assay.
RESULTS—Serum HGF and monocyte HGF values within seven days after onset of myocardial infarction were significantly higher than those of control subjects and decreased by day 14. There were significant positive correlations between serum HGF and monocyte HGF levels on day 7; between maximum plasma creatine phosphokinase levels and serum HGF levels on day 1; between maximum plasma C reactive protein and serum HGF levels; and between maximum C reactive protein and monocyte HGF levels. Monocyte HGF levels were raised in the patients with progression of ventricular enlargement in the course of acute myocardial infarction.
CONCLUSIONS—Early serum HGF concentrations reflect the extent of myocardial damage in acute myocardial infarction patients. Inflammation after acute myocardial infarction is supposed to be involved in enhanced HGF production. Monocytes may play an important role in ventricular remodelling after acute myocardial infarction by releasing the cardiovascular protective mitogen HGF.


Keywords: C reactive protein; cytokines; ischaemic heart disease; remodelling; hepatocyte growth factor

Background

Hepatocyte growth factor (HGF) is one of the major angiogenic factors being studied for the treatment of ischemic heart diseases. Our previous study demonstrated adenovirus-HGF was effective in myocardial ischemia models. The first clinical safety study showed a positive effect in patients with severe and diffused triple coronary disease.

Methods

12 Pigs were randomized (1∶1) to receive HGF, which was administered as five injections into the infarcted myocardium, or saline (control group). The injections were guided by EnSite NavX left ventricular electroanatomical mapping.

Results

The catheter-based injections caused no pericardial effusion, malignant arrhythmia or death. During mapping and injection, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine and creatine kinase-MB levels have no significant increase as compared to those before and after the injection in HGF group(P>0.05). HGF group has high HGF expression with Western blot, less myocardial infarct sizes by electroanatomical mapping (HGF group versus after saline group, 5.28±0.55 cm2 versus 9.06±1.06 cm2, P<0.01), better cardiac function with Gated-Single Photon Emission Computed Tomography compared with those in saline group. Histological, strongly increased lectin–positive microvessels and microvessel density were found in the myocardial ischemic regions in HGF group.

Conclusion

Intramyocardial injection guided by NavX system provides a method of feasible and safe percutaneous gene transfer to myocardial infarct regions.

Anoop Shah and colleagues performed a retrospective cohort study and a systematic review, and show evidence that in people with stable coronary disease there were threshold hemoglobin values below which mortality increased in a graded, continuous fashion.

Background

Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated.

Methods and findings

A retrospective cohort study was carried out using the UK General Practice Research Database. 20,131 people with a new diagnosis of stable angina and no previous acute coronary syndrome, and 14,171 people with first MI who survived for at least 7 days were followed up for a mean of 3.2 years. Using semi-parametric Cox regression and multiple adjustment, there was evidence of threshold haemoglobin values below which mortality increased in a graded continuous fashion. For men with MI, the threshold value was 13.5 g/dl (95% confidence interval [CI] 13.2–13.9); the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 (95% CI 1.76–2.29) compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl; 95% CI 12.1–13.5) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI. We did a systematic review and meta-analysis that identified ten previously published studies, reporting a total of only 1,127 endpoints, but none evaluated thresholds of risk.

Conclusions

There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here. Intervention trials would clarify whether increasing the haemoglobin concentration reduces mortality.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries, accounting for 16.3%, 13.9%, and 9.4% of all deaths, respectively, in 2004. Many risks factors, such as high blood pressure and high blood cholesterol level, are known to be associated with coronary artery disease, and prevention and treatment of such factors remains one of the key strategies in the management of coronary artery disease. Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.

Why was This Study Done?

Much more needs to be understood about the relationship between low hemoglobin and coronary artery disease before hemoglobin levels can potentially be used as a clinical prognostic biomarker. Previous studies have been limited in their ability to describe the shape of this relationship—which means that it is uncertain whether there is a “best” hemoglobin threshold or a continuous graded relationship from “good” to “bad”—to assess gender differences, and to compare patients with angina or who have experienced previous myocardial infarction. In order to inform these knowledge gaps, the researchers conducted a retrospective analysis of patients from a prospective observational cohort as well as a systematic review and meta-analysis (statistical analysis) of previous studies.

What Did the Researchers Do and Find?

The researchers conducted a systematic review and meta-analysis of previous studies and found ten relevant studies, but none evaluated thresholds of risk, only linear relationships.

The researchers carried out a new study using the UK's General Practice Research Database—a national research tool that uses anonymized electronic clinical records of a representative sample of the UK population, with details of consultations, diagnoses, referrals, prescriptions, and test results—as the basis for their analysis. They identified and collected information from two cohorts of patients: those with new onset stable angina and no previous acute coronary syndrome; and those with a first myocardial infarction (heart attack). For these patients, the researchers also looked at all values of routinely recorded blood parameters (including hemoglobin) and information on established cardiovascular risk factors, such as smoking. The researchers followed up patients using death of any cause as a primary endpoint and put this data into a statistical model to identify upper and lower thresholds of an optimal hemoglobin range beyond which mortality risk increased.

The researchers found that there was a threshold hemoglobin value below which mortality continuously increased in a graded manner. For men with myocardial infarction, the threshold value was 13.5 g/dl: 29.5% of patients had hemoglobin below this threshold and had a hazard ratio for mortality of 2.00 compared to those with hemoglobin values in the lowest risk range. Women had a lower threshold hemoglobin value than men: 12.8 g/dl for women with myocardial infarction, but the shape and strength of association did not differ between the genders, or between patients with angina and myocardial infarction.

What Do These Findings Mean?

These findings suggest that there are thresholds of hemoglobin that are associated with increased risk of mortality in patients with angina or myocardial infarction. A substantial proportion of patients (15%–30%) have a hemoglobin level that places them at markedly higher risk of death compared to patients with lowest risk hemoglobin levels and importantly, these thresholds are higher than clinicians might anticipate—and are remarkably similar to World Health Organization anemia thresholds of 12 g/dl for women and 13 g/dl for men. Despite the limitations of these observational findings, this study supports the rationale for conducting future randomized controlled trials to assess whether hemoglobin levels are causal and whether clinicians should intervene to increase hemoglobin levels, for example by oral iron supplementation.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000439.

Wikipedia provides information about hemoglobin (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

The World Health Organization provides an overview of the global prevalence of coronary artery disease, a factsheet on the top ten causes of death, as well as information on anemia

The aim of the study was to develop a new strategy for the differentiation of hematopoietic stem cell (HSC) derived from UCB into hepatocyte like cells and also to estimate the effects of combination of fibroblast growth factor 4 (FGF 4) and hepatocyte growth factor (HGF) on hematopoietic stem cell differentiation. HSCs were isolated and purified by magnetic activated cell sorting. HSCs were induced to hepatocyte like cells under a 2-step protocol with combination of growth factors. Reverse transcription polymerase chain reaction was performed to detect multiple genes related to hepatocyte like cells development and function. Hepatocyte like morphology was illustrated by inverted repeat microscope and the secretion of albumin and α- fetoprotein by these cells was confirmed by enzyme linked immunosorbent assay. Hepatocyte like cells was observed at the end of the protocol (days 14). These differentiated cells were observed to show high expression of genes related to hepatocytes (tryptophan 2, 3-dioxygenase [TO], glucose 6-phosphate [G6P], cytokeratin 18 [CK 18], albumin and α- fetoprotein [AFP]). The quantities of albumin and AFP at day 0 were low and upon differentiation the cells were able to produce albumin and AFP at high levels. Our results show a new strategy for differentiation in a short duration, using a combination of growth factors for the differentiation of umbilical cord blood derived HSC into hepatocyte like cells under certain in vitro conditions. After further studies this approach has the potency, for widespread cell replacement therapy for liver diseases.

At present, the study into inflammatory markers has become a new tool which is most useful for establishing the prognosis of patients with acute coronary syndrome. The inflammatory substrate involved is acute coronary syndrome is extremely complex, with a large number of factors involved both in its activation and its modulation. It is known that C-reactive protein play a key role in the physiopathology of the atherosclerosis. Furthermore, scientific literature reports that the existence of a circadian rhythm in the triggering of cardiovascular accidents can suggest the implication of, or association with these physiological rhythms that show activity peaks at particular times of the day or night. Keeping in mind the potential association between inflammation and circadian rhythm, a better understanding of the kinetics of said markers could lead to improvements in their use in cardiovascular diseases. Considering the diversity of the diurnal variations in the intrinsic properties of the cardiovascular system, these should be kept in mind during the design of in vivo experimental studies. As such, the information available reinforces our opinion when suitably validating the biomarkers and the need to demonstrate their reliability, stability, and lack of variability and standardise the methodology of their measurement.

Mice lacking hepatocyte IKKβ (IkkβΔhep) are defective in TNFα-activation of hepatocellular transcription factor NF-κB, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, IkkβΔhep mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that IkkβΔhep hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G0 → G1 transitions), and enhanced recovery efficiency, cyclin D1 expression and cell proliferation after plating. Ex vivo deletion of Ikkβ also accelerates hepatocyte growth. IkkβΔhep hepatocyte proliferative responses show heightened sensitivity to TGFα and TNFα, and heightened expression of fibronectin, collagens I/III, nidogen, β-actin and integrin β1 mRNAs. These findings suggest that altered mitogen signaling and expression of extracellular matrix and its associated components underlie growth advantages. Increased HCC development in IkkβΔhep mice may also be caused by growth advantages of surviving Ikkβ-deleted hepatocytes.

Backgound

Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD). We hypothesize, that hemostatic and rheological risk factors may be of major relevance for the incidence and the risk stratification of these patients.

Methods

In 243 patients with coronary artery disease and stable angina pectoris parameters of metabolism, hemostasis, blood rheology and endogenous fibrinolysis were assessed. Patients were prospectively followed for 2 years in respect to elective revascularizations and acute coronary syndromes.

Results

During follow-up 88 patients presented with cardiac events, 22 of those were admitted to the hospital because of acute events, 5 Patients were excluded due to non- cardiac death. Patients with clinical events were found to be more frequently diabetic and presented with a more progressed coronary atherosclerosis. Even though patients with diabetes mellitus demonstrated a comparable level of multivessel disease (71% vs. 70%) the rate of elective revascularization was higher (41% vs. 28%, p < 0.05). The results were also unfavorable for the incidence of acute cardiovascular events (18% vs. 8%, p < 0.01). In comparison to non-diabetic patients diabetics demonstrated significantly elevated levels of fibrinogen (352 ± 76 vs. 312 ± 64 mg/dl, p < 0.01), plasma viscosity (1.38 ± 0.23 vs. 1.31 ± 0.16 mPas, p < 0.01), red blood cell aggregation (13.2 ± 2.5 vs. 12.1 ± 3.1 E, p < 0.05) and plasmin-activator-inhibitor (6.11 ± 3.4 vs. 4.7 ± 2.7 U/l, p < 0.05).

Conclusion

Pathological alterations of fibrinogen, blood rheology and plasminogen-activator-inhibtor as indicators of a procoagulant state are of major relevance for the short-term incidence of cardiac events, especially in patients with diabetes mellitus type 2, and may be used to stratify patients to specific therapies.

This case report describes for the first time acute coronary syndrome in a 67-year old patient after oral intake of naratriptan for migraine. So far in the literature, only sumatriptan, zolmitriptan and frovatriptan have been described to cause acute coronary syndromes.

A 67-year old Swiss woman with thoracic pain after intake of 2.5 mg naratriptan presented with T-wave inversions in the ECG and a positive troponin-T at our hospital. Coronary angiography showed normal coronary arteries. Naratriptan-induced coronary vasospasms were thought to have caused the acute coronary syndrome.

Triptans should not be prescribed in patients with pre-existing coronary heart disease. However, triptans can also cause acute coronary syndromes in patients without coronary heart disease – as described in our case report. Severe or persistent thoracic pain after intake of triptans should therefore be investigated accordingly.

Spontaneous coronary artery dissection is a rare cause of acute myocardial ischaemia. Eight consecutive fatal cases which occurred in women aged 34-54 years (mean 43) are described. The dissection involved the left anterior descending coronary artery in four, the left main trunk in two, the right coronary artery in one, and both left anterior descending and circumflex arteries in one. The clinical presentation was sudden death in six cases, and acute myocardial infarction in two. Diagnosis was made at necropsy in every case but one, in which coronary dissection was diagnosed during life by selective coronary angiography. The only ascertained risk factor was hypertension in one patient; none of the women was in the puerperium, and Marfan syndrome was excluded in all. Histology showed a haematoma between the coronary tunica media and adventitia, that flattened and occluded the lumen; a coronary intimal tear was detected in only two cases. Unusual histological findings were cystic medial necrosis in one case, eosinophilic inflammatory infiltrates in four, and angiomatosis of the tunica adventitia in one. Patients dying of spontaneous coronary dissection are usually middle aged women, with no coronary atherosclerosis and apparently no risk factors. Spontaneous coronary artery dissection is unpredictable, and sudden death is the usual mode of clinical presentation. Prompt diagnosis and life saving treatment is far from being achieved.

Images

Background

Several inflammatory mediators such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are known to play a critical role in the regulation of vascular permeability and angiogenesis. We studied the serum levels of growth factors and gene expression profiles of genes involved in the growth factor signaling in the peripheral blood of diabetic (DM) and non-diabetic (ND) patients following cardiopulmonary bypass (CPB) and cardioplegic-arrest (C).

Methods and Results

Serum and total RNA were obtained from the blood samples collected from DM and matched ND patients (n=7 patients each) who underwent coronary artery bypass graft (CABG); before (pre), 6-hours (6h), and 4-days (4d) after CPB/C. The cytokine panel consisting of growth factors such as VEGF, HGF, FGF, and EGF was quantified in DM and ND patients; pre, 6h, and 4d post-CPB/C using multiplex cytokine quantification system. cDNA microarray analysis was performed and fold-change was calculated. Length of hospitalization (10 vs. 6 days; p=0.04) and weight gain (5 vs. 2.5 kg; p=0.001) were significantly greater for DM compared to ND patients. The serum levels of VEGF and HGF were significantly elevated in DM patients when compared to ND patients; pre vs. 6h post-CPB/C. In addition, significantly elevated mRNA expression of HIF1α, CREB, and EP300 (> 2 fold) was observed, 4d post-CPB/C exclusively in DM patients.

Conclusions

The differential profile of gene and protein expression of growth factors and their related genes in DM vs. ND patients could be associated with increased edema and weight gain in DM patients after CPB/C.

Background

A diagnosis of Kawasaki syndrome is based on clinical criteria with nonspecific laboratory findings, and there is a substantial risk of coronary artery aneurysms if treatment with intravenous immunoglobulin is delayed. In this study, we examined the contributions of sociodemographic factors and parent and physician behavior to the development of coronary artery aneurysms in children with Kawasaki syndrome.

Methods

We performed a retrospective, case-control chart review of Kawasaki syndrome patients treated at our institution during an 11-year period (1991–2002). Of 324 patients, 21 patients had coronary artery aneurysms and were matched with 81 Kawasaki syndrome control patients without coronary artery aneurysms.

Results

Patients who developed coronary artery aneurysms were more likely to have had their diagnosis established after 10 days of fever as a result of a delay in physician recognition of Kawasaki syndrome. In addition, these patients were also more likely to have been hospitalized at an outside facility with an erroneous diagnosis, to have had a greater number of healthcare visits before diagnosis, to have sought medical care in Mexico, to lack medical insurance and to speak Spanish as a primary language. Independent predictors of delayed diagnosis included incomplete clinical signs of Kawasaki syndrome, seeking health care in Mexico, and being hospitalized at an outside facility with a different diagnosis.

Conclusions

Increased risk of coronary artery aneurysms is associated with a delay in diagnosis by physicians and not with a delay in seeking medical consultation by parents. Sociodemographic factors influence the likelihood that patients will have a delayed diagnosis.

Loss of proliferative capacity is common in many tissue types during aging. We have shown that mitogenic signaling through the epidermal growth factor (EGF) receptor declines in hepatocytes from old rats. Specifically, we showed that in old hepatocytes there is a decrease in autophosphorylation of EGF receptor at Tyr-1173. This results in loss of recruitment of the adapter protein Shc to the membrane and decreased ERK MAP kinase pathway activation. Because EGF receptor signaling also requires intracellular generation of H202, we next questioned whether altering the intracellular GSH/thiol concentration may also affect the age-dependent decline in EGF receptor signaling. Surprisingly, decreased intracellular GSH had no effect on EGF receptor signaling in hepatocytes from either young or old animals. However, increasing the thiol concentration dramatically attenuated EGF receptor signaling in hepatocytes from both young and old animals. Unexpectedly, loss of EGF receptor signaling was due to a specific decrease in EGF receptor number, but not in other components of the EGF receptor signaling pathway such as ERK MAP kinase. These results suggest that age-dependent mechanisms of alteration in EGF receptor signaling are independent of thiol regulation of EGF receptor signaling.

Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome, particularly seen in women during pregnancy or in the puerperium. It has a high acute phase mortality. The etiology is uncertain. Hormonal changes during pregnancy, hemodynamic stress and changes in the autoimmune status have been considered as possible etiological factors. A timely diagnosis and institution of appropriate treatment is important for a successful outcome. There is no consensus of opinion for optimal treatment. Conservative management, coronary artery bypass graft surgery, and percutaneous coronary intervention, all have been described in the literature as possible therapeutic options. Spontaneous coronary artery dissection should be considered as a differential in any young woman presenting with chest pain associated with pregnancy. We report two cases of pregnancy-associated spontaneous coronary artery dissection, both successfully managed, along with a comprehensive review of the previously published literature.

AIM: To investigate whether the function of hepatocytes co-cultured with bone marrow mesenchymal stem cells (MSCs) could be maintained in serum from acute-on-chronic liver failure (ACLF) patients.

METHODS: Hepatocyte supportive functions and cytotoxicity of sera from 18 patients with viral hepatitis B-induced ACLF and 18 healthy volunteers were evaluated for porcine hepatocytes co-cultured with MSCs and hepatocyte mono-layered culture, respectively. Chemokine profile was also examined for the normal serum and liver failure serum.

RESULTS: Hepatocyte growth factor (HGF) and Tumor necrosis factor; tumor necrosis factor (TNF)-α were remarkably elevated in response to ACLF while epidermal growth factor (EGF) and VEGF levels were significantly decreased. Liver failure serum samples induced a higher detachment rate, lower viability and decreased liver support functions in the homo-hepatocyte culture. Hepatocytes co-cultured with MSCs could tolerate the cytotoxicity of the serum from ACLF patients and had similar liver support functions compared with the hepatocytes cultured with healthy human serum in vitro. In addition, co-cultured hepatocytes maintained a proliferative capability despite of the insult from liver failure serum.

CONCLUSION: ACLF serum does not impair the cell morphology, viability, proliferation and overall metabolic capacities of hepatocyte co-cultured with MSCs in vitro.