The Analgesic Effect of Oxygen in Suspected Acute Myocardial Infarction: A Substudy of the DETO2X-AMI Trial.

OBJECTIVES: In this substudy of the DETO2X-AMI (An Efficacy and Outcome Study of Supplemental Oxygen Treatment in Patients With Suspected Myocardial Infarction) trial, the authors aimed to assess the analgesic effect of moderate-flow oxygen supplementation in patients with suspected acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI) and to study the effect of oxygen supplementation on the use of opiates and sedatives during PCI. BACKGROUND: Routine oxygen in normoxemic patients with AMI does not provide clinical benefit. However, oxygen may relieve ischemic pain. METHODS: Patients were randomly allocated to oxygen or ambient air according to the main study protocol. After PCI, peak level of pain during PCI was measured by the Visual Analogue Scale. The total amount of opiates and sedatives was reported. RESULTS: A total of 622 patients were enrolled: 330 in the oxygen group and 292 in the ambient air group. There was no significant difference in peak level of pain (oxygen 4.0 [1.0 to 6.0] vs. air 3.0 [0.6 to 6.0]; p = 0.37), use of opiates (mg) (oxygen 0.0 [0.0 to 3.0] vs. air 0.0 [0.0 to 3.0]; p = 0.31), or use of sedatives between the groups (median [interquartile range]) (oxygen 2.5 [0.0 to 2.5] vs. air 2.5 [0.0 to 2.5]; p = 0.74). CONCLUSIONS: In the present study, the authors did not find any analgesic effect of routine oxygen as compared with ambient air, and no differences in the use of sedatives and opiates during PCI. Our results indicate that moderate-flow oxygen supplementation does not relieve pain in normoxemic patients with suspected AMI undergoing treatment with PCI and should thus not be used for this purpose.

Both El Tor and classical cholera toxin bind blood group determinants.

Cholera is a disease which shows a clear blood group profile, with blood group O individuals experiencing the most severe symptoms. For a long time, the cholera toxin has been suspected to be the main culprit of this blood group dependence. Here, we show that both El Tor and classical cholera toxin B-pentamers do indeed bind blood group determinants (with equal affinities), using Surface Plasmon Resonance and NMR spectroscopy. Together with previous structural data, this confirms our earlier hypothesis as to the molecular basis of cholera blood group dependence, with an interesting twist: the shorter blood group H-determinant characteristic of blood group O individuals binds with similar binding affinity compared to the A-determinant, however, with different kinetics.

S100A8/A9 complex as a new biomarker in prediction of mortality in elderly patients with severe heart failure.

BACKGROUND: S100A8/A9 complex is a new inflammation-related protein and has a positive correlation with C-reaction protein level. However its role in chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: Circulating levels of S100A8/A9 complex and other biomarkers (IL-6, IL-8, TNF-α, and BNP) were measured in CHF (n = 54) and hypertensive without CHF (n = 31) as well as healthy subjects (n = 23), with follow up to 1480 days. During follow-up, cumulative mortality rate for CHF patients was 63%. Plasma levels of S100A8/A9 complex, IL-6, IL-8 and TNF-α were significantly higher in CHF than the hypertensive patients and healthy subjects. A significant positive correlation was found between S100A8/A9 complex and IL-6 and IL-8 respectively. Cox regression analysis showed that IL-6 and IL-8 were predictors for mortality for 6 months, and S100A8/A9 complex, IL-6, IL-8 and age were predictors for mortality for one year whereas BNP, TNF-α, IL-6 and IL-8 remained predictors for mortality for two years. A combination of S100A8/A9 complex and IL-6 provided powerful predictive value in mortality for both 6 and 12 months. CONCLUSIONS: S100A8/A9 complex is a useful biomarker as a predictor for one year mortality and its combination with IL-6 is able to provide additive prognostic information in this vulnerable heart failure population in the elderly.

Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance.

Altered myocardial Ca(2+) and Na(+) handling in congestive heart failure (CHF) may be expected to decrease the tolerance to ischemia by augmenting reperfusion Ca(2+) overload. The aim of the present study was to investigate tolerance to hypoxia-reoxygenation by measuring enzyme release, cell death, ATP level, and cell Ca(2+) and Na(+) in cardiomyocytes from failing rat hearts. CHF was induced in Wistar rats by ligation of the left coronary artery during isoflurane anesthesia, after which cardiac failure developed within 6 wk. Isolated cardiomyocytes were cultured for 24 h and subsequently exposed to 4 h of hypoxia and 2 h of reoxygenation. Cell damage was measured as lactate dehydrogenase (LD) release, cell death as propidium iodide uptake, and ATP by firefly luciferase assay. Cell Ca(2+) and Na(+) were determined with radioactive isotopes, and free intracellular Ca(2+) concentration ([Ca(2+)](i)) with fluo-3 AM. CHF cells showed less increase in LD release and cell death after hypoxia-reoxygenation and had less relative reduction in ATP level after hypoxia than sham cells. CHF cells accumulated less Na(+) than sham cells during hypoxia (117 vs. 267 nmol/mg protein). CHF cells maintained much lower [Ca(2+)](i) than sham cells during hypoxia (423 vs. 1,766 arbitrary units at 4 h of hypoxia), and exchangeable Ca(2+) increased much less in CHF than in sham cells (1.4 vs. 6.7 nmol/mg protein) after 120 min of reoxygenation. Ranolazine, an inhibitor of late Na(+) current, significantly attenuated both the increase in exchangeable Ca(2+) and the increase in LD release in sham cells after reoxygenation. This supports the suggestion that differences in Na(+) accumulation during hypoxia cause the observed differences in Ca(2+) accumulation during reoxygenation. Tolerance to hypoxia and reoxygenation was surprisingly higher in CHF than in sham cardiomyocytes, probably explained by lower hypoxia-mediated Na(+) accumulation and subsequent lower Ca(2+) accumulation in CHF after reoxygenation.

TNFalpha-antagonist neither improve cardiac remodelling or cardiac function at early stage of heart failure in diabetic rats.

OBJECTIVES: Despite tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in patients with heart failure and previous preclinical study with TNFalpha-antagonist has been demonstrated to improve cardiac function in acute heart failure, recent clinical trials using TNFalpha-antagonist in patients with chronic severe heart failure have been disappointing. The aim was to study why TNFalpha-antagonist may not work during long-term treatment in chronic heart failure (CHF) in experimental model. METHODS: 49 rats were used at the age of 26 weeks: healthy Whistar Kyoto rats (WKY, n = 26) and diabetic (WKY+D, n = 23). Rats in each group received either a 12-week treatment with TNFalpha-antagonist (Etanercept) or NaCl injections. RESULTS: In diabetic rats, there were increased plasma glucose level and blood pressure. By use of echocardiography diabetic rats displayed not only enlarged and thinned left ventricles but also decreased both systolic and diastolic functions. Moreover, there are increased interleukin-6 (IL6) mRNA levels. However, TNFalpha-antagonist, etanercept, does not improve either cardiac remodelling or cardiac function. IL6 mRNA level remained unchanged after treatment of etanercept. CONCLUSION: Chronic treatment of TNFalpha-antagonist has no favourable effect on either cardiac remodelling or cardiac function. It is therefore inappropriate to use TNFalpha-antagonist in CHF in diabetes as underlying cause.

Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients.

BACKGROUND: Increased proinflammatory cytokines have mainly been studied in younger patients with heart failure and are regarded as prognostic markers. However, whether this holds true in elderly patients with heart failure remains uncertain. OBJECTIVES: To determine whether inflammation is equally important in the progression of heart failure in the elderly as has been previously reported in younger patients, and whether cytokine level can predict mortality in this population of elderly heart failure patients. METHODS: The cytokine profile in an elderly patient group with severe heart failure (n=54, mean [+/- SD] age of 80.1+/-5.0 years, New York Heart Association class III or IV) was compared with that of age-matched healthy individuals (n=70). Of the 54 study patients, 46% were hypertensive, 54% had coronary artery disease, 43% had atrial fibrillation and 24% had a previous stroke. One-year mortality was 24%. RESULTS: The results showed increased levels of interleukin-6 (IL-6), tumour necrosis factor-alpha and epidermal growth factor in the heart failure patients compared with those in the control group. Moreover, IL-6, tumour necrosis factor-alpha and vascular endothelial growth factor were significantly increased in patients who died within one year. Further logistic regression analyses showed that IL-6 was the only significant predictor of one-year mortality. In a subgroup of heart failure patients with atrial fibrillation, there were significant cytokine activations, whereas in a subgroup with ischemia or diabetes, cytokines were less activated. CONCLUSIONS: In the present octogenarian group with heart failure, there were significant increases of inflammatory cytokines that were associated with mortality, and IL-6 was the only cytokine to predict one-year mortality. Cytokine activation was more pronounced in the subgroup of patients with heart failure and concomitant atrial fibrillation.

Increased adiponectin level in parallel with increased NT-pro BNP in patients with severe heart failure in the elderly: A hospital cohort study.

BACKGROUND: Adiponectin, which is a collagen-like plasma protein produced by adipose tissue, has in general anti-atherogenic and anti-inflammatory effects. Recently it was shown to be elevated in chronic heart failure patients. However whether this holds true in the elderly heart failure patients who are often associated with malnutrition remains unknown. MATERIALS AND METHODS: Patients with severe heart failure (n=92, average age >70 years, NYHA III-IV) and age-matched healthy volunteers (n=70) as control were enrolled in the present study. Serum levels of adiponectin and NT-pro BNP were measured. RESULTS: Adiponectin levels were significantly increased in heart failure patients for those >70 years old as compared with control group. There were higher adiponectin levels in non-ischemic heart failure as compared with those with ischemic cause. Serum adiponectin levels were positively associated with serum NT-pro BNP levels. There was a strong trend of higher adiponectin levels in those who died as compared with those who survived. CONCLUSION: Serum adiponectin levels were increased in the very elderly heart failure patients, and particularly in those with underlying non-ischemic origin. Adiponectin levels appear to be associated with increased mortality.

TNFalpha antagonist upregulates interleukin-6 in rats with hypertensive heart failure.

BACKGROUND: Tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in heart failure, but recent clinical trials using TNFalpha antagonists in patients with severe heart failure have been disappointing. Hypertension is one of most common causes to chronic heart failure in humans. HYPOTHESIS: Suppression of a single cytokine in CHF is not an effective treatment strategy because it leads to the upregulation of other proinflammatory cytokines. OBJECTIVES: The aim of the present study was to investigate the effect of chronic treatment with a TNFalpha antagonist in a rat model of the early stage of heart failure due to hypertension. METHODS: Spontaneously hypertensive rats (SHR, n=30) and healthy Wistar Kyoto rats (WKY, n=30) were treated with either the TNFalpha antagonist etanercept or placebo for 12 weeks. At the end of the study, the rats were 26 weeks old and indices of cardiac structure, function and cytokines were analyzed. RESULTS: SHR displayed early stage of heart failure as shown by increased heart weight/body weight ratio and relative wall thickness by echocardiography, downregulated myocardial beta(1)-adrenoceptor, and upregulated myocardial brain natriuretic peptide and interleukin-6 (IL6). Chronic treatment with etanercept in SHR resulted in decreased relative wall thickness but also increased cardiac reserve and higher blood pressure. In addition, IL6 was further upregulated compared with placebo treatment. CONCLUSION: Chronic treatment with etanercept in SHR resulted in favorable cardiac remodeling, but also had a positive inotropic effect and was associated with an upregulation of IL6. These findings indicate that chronic treatment with TNFalpha antagonists is not an effective treatment strategy and may aggravate heart failure in the long term.

Effects of autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy on neonatal rat cardiomyocytes.

INTRODUCTION: Immunoadsorption has been shown to improve cardiac performance and reduce mortality in patients with dilated cardiomyopathy. In this study, the underlying mechanism for these beneficial effects was investigated in cultured rat cardiomyocytes. METHODS AND RESULTS: Immunoadsorption was performed in patients with dilated cardiomyopathy (n=7). Antibody-induced complement-dependent cytotoxicity was investigated by colorimetric MTT. Autoantibodies against the beta(1)-adrenoceptor were detected by ELISA and purified. Column eluent from six patients exhibited a cytotoxic effect, three patients were positive for the beta(1)-adrenoceptor autoantibodies. The purified autoantibodies were able to visualize the beta(1)-adrenoceptors by immunocytofluorescence on rat cardiomyocytes, and also displayed partial agonist properties and induced a positive chronotropic effect, which were blocked by the beta(1)-selective antagonist bisoprolol and the peptide corresponding to the beta(1)-adrenoceptor. Column eluent from one patient induced apoptosis in nick end labelling test (8.1+/-1.7% vs. 2.9+/-1.2% in control, p<0.05). CONCLUSION: Autoantibodies removed by immunoadsorption from patients with dilated cardiomyopathy have a pathophysiological role, as shown by the complement-dependent cytotoxicity and chronotropic action on rat cardiomyocytes. This implies that removal of circulating autoantibodies might be part of the underlying mechanism for improved cardiac function.