On the basis of thrombolysis in myocardial infarction (TIMI) score, ECG, and a point-of-care biomarker panel of troponin, creatine kinase MB, and myoglobin, Martin Than and colleagues(1) identified patients with chest pain who were at very low risk of a short-term major adverse cardiac event and who might be suitable for early discharge.
We are a little concerned about missing TIMI score data. The score includes “three or more risk factors for coronary artery disease” and “significant coronary stenosis at previous angiography” (yes=1, no=0). We wonder whether a patient without a regular health check was regarded by Than and colleagues as scoring 0 or 1? This could be an important issue considering the threshold considered (TIMI score ≥1=positive). We know, for instance, that people of low socioeconomic status have a lower access to health care, yet they have more risk factors for coronary heart disease.(2—4) Without a regular check-up, these people might have had a lower TIMI score than they should have.
In conclusion, we think that the accelerated diagnostic protocol should take into account the absence of medical follow-up to consider factors such as health inequalities.
We declare that we have no conflicts of interest.
References
1 Than M, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet 2011; 377: 1077-1084. Summary | Full Text | PDF(200KB) | CrossRef | PubMed
2 Kaplan GA, Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation 1993; 88: 1973-1998. PubMed
3 Tyroler HA. The influence of socioeconomic factors on cardiovascular disease risk factor development. Prev Med 1999; 29: S36-S40. CrossRef | PubMed
4 Manrique-Garcia E, Sidorchuk A, Hallqvist J, Moradi T. Socioeconomic position and incidence of acute myocardial infarction: a meta-analysis. J Epidemiol Community Health 2011; 65: 301-309. PubMed
Tuesday
Serum Myoglobin
Serum myoglobin is a test that measures the amount of myoglobin in the blood.
Myoglobin is a protein in heart and skeletal muscles. When you exercise, your muscles use up any available oxygen. Myoglobin has oxygen attached to it, which provides extra oxygen for the muscle to maintain a high level of activity for a longer period of time.
When muscle is damaged, myoglobin is released into the bloodstream. Ultimately, it is removed in the urine.
Myoglobin is a protein in heart and skeletal muscles. When you exercise, your muscles use up any available oxygen. Myoglobin has oxygen attached to it, which provides extra oxygen for the muscle to maintain a high level of activity for a longer period of time.
When muscle is damaged, myoglobin is released into the bloodstream. Ultimately, it is removed in the urine.
Wednesday
Unmasking the Janus face of myoglobin in health and disease.
Abstract
For more than 100 years, myoglobin has been among the most extensively studied proteins. Since the first comprehensive review on myoglobin function as a dioxygen store by Millikan in 1939 and the discovery of its structure 50 years ago, multiple studies have extended our understanding of its occurrence, properties and functions. Beyond the two major roles, the storage and the facilitation of dioxygen diffusion, recent physiological studies have revealed that myoglobin acts as a potent scavenger of nitric oxide (NO(*)) representing a control system that preserves mitochondrial respiration. In addition, myoglobin may also protect the heart against reactive oxygen species (ROS), and, under hypoxic conditions, deoxygenated myoglobin is able to reduce nitrite to NO(*) leading to a downregulation of the cardiac energy status and to a decreased heart injury after reoxygenation. Thus, by controlling the NO(*) bioavailability via scavenging or formation, myoglobin serves as part of a sensitive dioxygen sensory system. In this review, the physiological relevance of these recent findings are delineated for pathological states where NO(*) and ROS bioavailability are known to be critical determinants for the outcome of the disease, e.g. ischemia/reperfusion injury. Detrimental and beneficial effects of the presence of myoglobin are discussed for various states of tissue oxygen tension within the heart and skeletal muscle. Furthermore, the impact of myoglobin on parasite infection, rhabdomyolysis, hindlimb and liver ischemia, angiogenesis and tumor growth are considered
Hendgen-Cotta UB, Flögel U, Kelm M, Rassaf T.
Department of Medicine, Division of Cardiology, Pulmonary Diseases and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany.
For more than 100 years, myoglobin has been among the most extensively studied proteins. Since the first comprehensive review on myoglobin function as a dioxygen store by Millikan in 1939 and the discovery of its structure 50 years ago, multiple studies have extended our understanding of its occurrence, properties and functions. Beyond the two major roles, the storage and the facilitation of dioxygen diffusion, recent physiological studies have revealed that myoglobin acts as a potent scavenger of nitric oxide (NO(*)) representing a control system that preserves mitochondrial respiration. In addition, myoglobin may also protect the heart against reactive oxygen species (ROS), and, under hypoxic conditions, deoxygenated myoglobin is able to reduce nitrite to NO(*) leading to a downregulation of the cardiac energy status and to a decreased heart injury after reoxygenation. Thus, by controlling the NO(*) bioavailability via scavenging or formation, myoglobin serves as part of a sensitive dioxygen sensory system. In this review, the physiological relevance of these recent findings are delineated for pathological states where NO(*) and ROS bioavailability are known to be critical determinants for the outcome of the disease, e.g. ischemia/reperfusion injury. Detrimental and beneficial effects of the presence of myoglobin are discussed for various states of tissue oxygen tension within the heart and skeletal muscle. Furthermore, the impact of myoglobin on parasite infection, rhabdomyolysis, hindlimb and liver ischemia, angiogenesis and tumor growth are considered
Hendgen-Cotta UB, Flögel U, Kelm M, Rassaf T.
Department of Medicine, Division of Cardiology, Pulmonary Diseases and Angiology, University Hospital Düsseldorf, Düsseldorf, Germany.
Thursday
mass spectrometric comparison of the interactions of cisplatin and transplatin with myoglobin
Abstract
Mass spectrometric studies of the interactions of cisplatin and transplatin with myoglobin (Mb) provide information concerning interaction kinetics, Mb adduct identity, and cisplatin and transplatin binding sites on Mb.
Although the Mb–cisplatin interaction is faster than the Mb–transplatin interaction, monoadducts and diadducts were formed in both the interactions over 30 h. In order to locate the binding sites of cisplatin and transplatin on Mb, digests of free Mb, Mb–cisplatin and Mb–transplatin adducts were subjected to analysis by Fourier transform mass spectrometry (FT-MS). This analysis revealed that two fragment ions, 1313.275+ and 1316.685+, were obtained only from the Mb–cisplatin and Mb–transplatin adduct digests.
Tandem mass spectrometry (MS/MS and MS3) of the 1313.275+ and 1316.685+ ions indicate that these ions arise from [Pt(NH3)]2+ and [Pt(NH3)2]2+, respectively, bound to peptide His97-Gly153. The product-ion spectra of the MS/MS and MS3 analyses of the 1313.275+ ion indicate a common binding site of cisplatin and transplatin on His116-His119 residues. The interactions of cisplatin and transplatin with a dipeptide His-Ser and the three dimensional (3D) structure of native Mb suggest that cisplatin and transplatin coordinate to His116 and His119.
Ting Zhaoa and Fred L. King, a,
a C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
Mass spectrometric studies of the interactions of cisplatin and transplatin with myoglobin (Mb) provide information concerning interaction kinetics, Mb adduct identity, and cisplatin and transplatin binding sites on Mb.
Although the Mb–cisplatin interaction is faster than the Mb–transplatin interaction, monoadducts and diadducts were formed in both the interactions over 30 h. In order to locate the binding sites of cisplatin and transplatin on Mb, digests of free Mb, Mb–cisplatin and Mb–transplatin adducts were subjected to analysis by Fourier transform mass spectrometry (FT-MS). This analysis revealed that two fragment ions, 1313.275+ and 1316.685+, were obtained only from the Mb–cisplatin and Mb–transplatin adduct digests.
Tandem mass spectrometry (MS/MS and MS3) of the 1313.275+ and 1316.685+ ions indicate that these ions arise from [Pt(NH3)]2+ and [Pt(NH3)2]2+, respectively, bound to peptide His97-Gly153. The product-ion spectra of the MS/MS and MS3 analyses of the 1313.275+ ion indicate a common binding site of cisplatin and transplatin on His116-His119 residues. The interactions of cisplatin and transplatin with a dipeptide His-Ser and the three dimensional (3D) structure of native Mb suggest that cisplatin and transplatin coordinate to His116 and His119.
Ting Zhaoa and Fred L. King, a,
a C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
Tuesday
Expression and Functional Regulation of Myoglobin in Epithelial Cancers
(American Journal of Pathology. 2009;175:201-206.)
Myoglobin is a multifunctional heme protein that is thought to be expressed exclusively in myocytes. Its importance in both oxygen transport and free radical scavenging has been extensively characterized. We hypothesized that solid tumors could take advantage of proteins such as myoglobin to cope with hypoxic conditions and to control the metabolism of reactive oxygen and nitrogen species.
We therefore sought to establish whether myoglobin might be expressed and functionally regulated in epithelial tumors that are known to face hypoxia and oxidative stress during disease progression. We analyzed the expression of myoglobin in human epithelial cancers at both transcriptional and protein levels; moreover, we investigated the expression levels of myoglobin in cancer cell lines subjected to different conditions, including hypoxia, oxidative stress, and mitogenic stimuli. We provide evidence that human epithelial tumors, including breast, lung, ovary, and colon carcinomas, express high levels of myoglobin from the earliest stages of disease development.
In human cancer cells, myoglobin is induced by a variety of signals associated with tumor progression, including mitogenic stimuli, oxidative stress, and hypoxia. This study provides evidence that myoglobin, previously thought to be restricted to myocytes, is expressed at high levels by human carcinoma cells. We suggest that myoglobin expression is part of a cellular program aimed at coping with changed metabolic and environmental conditions associated with neoplastic growth.
Expression and Functional Regulation of Myoglobin in Epithelial Cancers
Simona Emilia Flonta*, Sabrina Arena*, Alberto Pisacane, Paolo Michieli and Alberto Bardelli* From the Laboratory of Molecular Genetics,* the Unit of Pathology, and the Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Turin Medical School, Turin; and the FIRC Institute of Molecular Oncology, Milan, Italy
Myoglobin is a multifunctional heme protein that is thought to be expressed exclusively in myocytes. Its importance in both oxygen transport and free radical scavenging has been extensively characterized. We hypothesized that solid tumors could take advantage of proteins such as myoglobin to cope with hypoxic conditions and to control the metabolism of reactive oxygen and nitrogen species.
We therefore sought to establish whether myoglobin might be expressed and functionally regulated in epithelial tumors that are known to face hypoxia and oxidative stress during disease progression. We analyzed the expression of myoglobin in human epithelial cancers at both transcriptional and protein levels; moreover, we investigated the expression levels of myoglobin in cancer cell lines subjected to different conditions, including hypoxia, oxidative stress, and mitogenic stimuli. We provide evidence that human epithelial tumors, including breast, lung, ovary, and colon carcinomas, express high levels of myoglobin from the earliest stages of disease development.
In human cancer cells, myoglobin is induced by a variety of signals associated with tumor progression, including mitogenic stimuli, oxidative stress, and hypoxia. This study provides evidence that myoglobin, previously thought to be restricted to myocytes, is expressed at high levels by human carcinoma cells. We suggest that myoglobin expression is part of a cellular program aimed at coping with changed metabolic and environmental conditions associated with neoplastic growth.
Expression and Functional Regulation of Myoglobin in Epithelial Cancers
Simona Emilia Flonta*, Sabrina Arena*, Alberto Pisacane, Paolo Michieli and Alberto Bardelli* From the Laboratory of Molecular Genetics,* the Unit of Pathology, and the Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Turin Medical School, Turin; and the FIRC Institute of Molecular Oncology, Milan, Italy
Thursday
Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria
Plotnikov EY, Chupyrkina AA, Pevzner IB, Isaev NK, Zorov DB.
A.N.Belozersky Institute of Physico-Chemical Biology, and Institute of Mitoingeneering, Moscow State University, Moscow 119991, Russia.
Rhabdomyolysis or crush syndrome is a pathology caused by muscle injury resulting in acute renal failure. The latest data give strong evidence that this syndrome caused by accumulation of muscle breakdown products in the blood stream is associated with oxidative stress with primary role of mitochondria. In order to evaluate the significance of oxidative stress under rhabdomyolysis we explored the direct effect of myoglobin on renal tubules and isolated kidney mitochondria while measuring mitochondrial respiratory control, production of reactive oxygen and nitrogen species and lipid peroxidation. In parallel, we evaluated mitochondrial damage under myoglobinurea in vivo. An increase of lipid peroxidation products in kidney mitochondria and release of cytochrome c was detected on the first day of myoglobinuria. In mitochondria incubated with myoglobin we detected respiratory control drop, uncoupling of oxidative phosphorylation, an increase of lipid peroxidation products and stimulated NO synthesis. Mitochondrial pore inhibitor, cyclosporine A, mitochondria-targeted antioxidant (SkQ1) and deferoxamine (Fe-chelator and ferryl-myoglobin reducer) abrogated these events. Similar effects (oxidative stress and mitochondrial dysfunction) were revealed when myoglobin was added to isolated renal tubules. Thus, rhabdomyolysis can be considered as oxidative stress-mediated pathology with mitochondria to be the primary target and possibly the source of reactive oxygen and nitrogen species. We speculate that rhabdomyolysis-induced kidney damage involves direct interaction of myoglobin with mitochondria possibly resulting in iron ions release from myoglobin's heme, which promotes the peroxidation of mitochondrial membranes. Usage of mitochondrial permeability transition blockers, Fe-chelators or mitochondria-targeted antioxidants, may bring salvage from this pathology
A.N.Belozersky Institute of Physico-Chemical Biology, and Institute of Mitoingeneering, Moscow State University, Moscow 119991, Russia.
Rhabdomyolysis or crush syndrome is a pathology caused by muscle injury resulting in acute renal failure. The latest data give strong evidence that this syndrome caused by accumulation of muscle breakdown products in the blood stream is associated with oxidative stress with primary role of mitochondria. In order to evaluate the significance of oxidative stress under rhabdomyolysis we explored the direct effect of myoglobin on renal tubules and isolated kidney mitochondria while measuring mitochondrial respiratory control, production of reactive oxygen and nitrogen species and lipid peroxidation. In parallel, we evaluated mitochondrial damage under myoglobinurea in vivo. An increase of lipid peroxidation products in kidney mitochondria and release of cytochrome c was detected on the first day of myoglobinuria. In mitochondria incubated with myoglobin we detected respiratory control drop, uncoupling of oxidative phosphorylation, an increase of lipid peroxidation products and stimulated NO synthesis. Mitochondrial pore inhibitor, cyclosporine A, mitochondria-targeted antioxidant (SkQ1) and deferoxamine (Fe-chelator and ferryl-myoglobin reducer) abrogated these events. Similar effects (oxidative stress and mitochondrial dysfunction) were revealed when myoglobin was added to isolated renal tubules. Thus, rhabdomyolysis can be considered as oxidative stress-mediated pathology with mitochondria to be the primary target and possibly the source of reactive oxygen and nitrogen species. We speculate that rhabdomyolysis-induced kidney damage involves direct interaction of myoglobin with mitochondria possibly resulting in iron ions release from myoglobin's heme, which promotes the peroxidation of mitochondrial membranes. Usage of mitochondrial permeability transition blockers, Fe-chelators or mitochondria-targeted antioxidants, may bring salvage from this pathology
Monday
Serum myoglobin and renal morbidity and mortality
OBJECTIVES: The intractability of renal dysfunction following thoracic and thoraco-abdominal aortic repair leads us to believe that the accepted mechanisms of renal injury - ischaemia and embolism - are incompletely explanatory. We studied postoperative myoglobinaemia and renal dysfunction following aortic surgery.
METHODS: Between September 2006 and February 2008, we studied serum myoglobin in 109 patients requiring thoracic/thoraco-abdominal repair for three postoperative days. Forty-two of the 109 (38%) patients were female. The median age was 67 years (range 23-84 years). As we have focussed more attention on renal function, our independent renal consultants have dialysed more aggressively. We divided dialysis into: (1) creatinine indication, (2) non-creatinine indication and (3) no dialysis.
RESULTS: Thirteen of the 109 (12%) patients met creatinine indication for dialysis (>4 mg dl(-1)) and an additional 28 (26%) were dialysed for other reasons. Overall mortality was 12 out of 109 (11%) cases: 11 out of 41 (27%) in dialysed patients and one out of 68 (1.5%) in non-dialysed patients. Mortality did not differ between the indications for dialysis. Predictors of mortality were baseline glomerular filtration rate (GFR), postoperative myoglobin and dialysis. The only predictor of dialysis was postoperative myoglobin.
CONCLUSION: A strong relationship between postoperative serum myoglobin and renal failure suggests a rhabdomyolysis-like contributing aetiology following thoraco-abdominal aortic repair. We postulate a novel mechanism of renal injury for which mitigation strategies should be developed.
Miller CC 3rd, Villa MA, Sutton J, Lau D, Keyhani K, Estrera AL, Azizzadeh A, Coogan SM, Safi HJ.
Department of Cardiothoracic and Vascular Surgery, University of Texas Medical School at Houston, Memorial Hermann Heart and Vascular Institute, Houston, TX 77030,
METHODS: Between September 2006 and February 2008, we studied serum myoglobin in 109 patients requiring thoracic/thoraco-abdominal repair for three postoperative days. Forty-two of the 109 (38%) patients were female. The median age was 67 years (range 23-84 years). As we have focussed more attention on renal function, our independent renal consultants have dialysed more aggressively. We divided dialysis into: (1) creatinine indication, (2) non-creatinine indication and (3) no dialysis.
RESULTS: Thirteen of the 109 (12%) patients met creatinine indication for dialysis (>4 mg dl(-1)) and an additional 28 (26%) were dialysed for other reasons. Overall mortality was 12 out of 109 (11%) cases: 11 out of 41 (27%) in dialysed patients and one out of 68 (1.5%) in non-dialysed patients. Mortality did not differ between the indications for dialysis. Predictors of mortality were baseline glomerular filtration rate (GFR), postoperative myoglobin and dialysis. The only predictor of dialysis was postoperative myoglobin.
CONCLUSION: A strong relationship between postoperative serum myoglobin and renal failure suggests a rhabdomyolysis-like contributing aetiology following thoraco-abdominal aortic repair. We postulate a novel mechanism of renal injury for which mitigation strategies should be developed.
Miller CC 3rd, Villa MA, Sutton J, Lau D, Keyhani K, Estrera AL, Azizzadeh A, Coogan SM, Safi HJ.
Department of Cardiothoracic and Vascular Surgery, University of Texas Medical School at Houston, Memorial Hermann Heart and Vascular Institute, Houston, TX 77030,
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