Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

New candidate genes for ST-elevation myocardial infarction.

BACKGROUND: Despite extensive research in atherosclerosis, the mechanisms of coronary atherothrombosis in ST-elevation myocardial infarction (STEMI) patients are undetermined. OBJECTIVES: Our aim was to find candidate genes involved in STEMI by analysing leucocyte gene expression in STEMI patients, without the influence of secondary inflammation from innate immunity, which was assumed to be a consequence rather than the cause of coronary atherothrombosis. METHODS: Fifty-one patients were included at coronary angiography because of STEMI. Arterial blood was sampled in the acute phase (P1), at 24-48 h (P2) and at 3 months (P3). Leucocyte RNA was isolated and gene expression analysis was performed by Affymetrix Human Transcriptome Array 2.0. By omission of up- or downregulated genes at P2, secondary changes from innate immunity were excluded. Genes differentially expressed in P1 when compared to the convalescent sample in P3 were determined as genes involved in STEMI. RESULTS: Three genes were upregulated at P1 compared to P3; ABCG1 (P = 5.81 × 10-5 ), RAB20 (P = 3.69 × 10-5 ) and TMEM2 (P = 7.75 × 10-6 ) whilst four were downregulated; ACVR1 (P = 9.01 × 10-5 ), NFATC2IP (P = 8.86 × 10-5 ), SUN1 (P = 3.87 × 10-5 ) and TTC9C (P = 7.18 × 10-6 ). These genes were also highly expressed in carotid atherosclerotic plaques. CONCLUSIONS: We found seven genes involved in STEMI. The study is unique regarding the blood sampling in the acute phase and omission of secondary expressed genes from innate immunity. However, the results need to be replicated by future studies.

Prevalence and cumulative incidence of cancer, and mortality in patients with Takotsubo syndrome with focus on the index event.

BACKGROUND: It has been suggested that Takotsubo syndrome (TS) is associated with cancer but previous studies have limitations. AIM: To make a comprehensive analysis of prevalence and cumulative incidence of cancer, and mortality among TS patients with focus on the index event. DESIGN: A register-based case-control study. METHODS: The first new cancer occurrences (International Classification of Diseases C00-C75, C81-C96) were compared between 505 patients with TS without obstructive coronary artery disease (CAD) and four age- and gender-matched controls comprising patients with acute coronary syndrome with obstructive CAD (CAD controls), respectively, with chest-pain without obstructive CAD at coronary angiography (controls without CAD). RESULTS: The prevalence of cancer before the index event was non-significantly (P = 0.052) higher in TS patients (15.8%) than in CAD controls (11.5%), respectively, higher (P = 0.028) than in controls without CAD (11.1%). There were no differences between the groups in cumulative incidence of cancer after the index event but a higher mortality in TS patients who developed cancer when compared with controls without CAD that developed cancer after the index event (P = 0.018). CONCLUSIONS: There is an increased prevalence of first diagnosed cancer in TS patients before the index event but no increased cumulative incidence of cancer after the index event. The results does not support investigation for the possibility of a malignancy specifically in TS patients but in the event of cancer this patient group might need special care. However, if there is lack of a clear stressor it could be of importance to investigate the possibility of a malignancy.

Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries.

BACKGROUND: Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI-CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA. METHODS: This is a registry-based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69 267 patients with first-time MI-CAD. RESULTS: Almost all event rates (median follow-up 3.8 years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n = 268 (6.6%), n = 1563 (21.5%), n = 17 777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk. CONCLUSIONS: Patients with first-time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up.

Supplemental oxygen therapy does not affect the systemic inflammatory response to acute myocardial infarction.

BACKGROUND: Oxygen therapy has been used routinely in normoxemic patients with suspected acute myocardial infarction (AMI) despite limited evidence supporting a beneficial effect. AMI is associated with a systemic inflammation. Here, we hypothesized that the inflammatory response to AMI is potentiated by oxygen therapy. METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) multicentre trial randomized patients with suspected AMI to receive oxygen at 6 L min-1 for 6-12 h or ambient air. For this prespecified subgroup analysis, we recruited patients with confirmed AMI from two sites for evaluation of inflammatory biomarkers at randomization and 5-7 h later. Ninety-two inflammatory biomarkers were analysed using proximity extension assay technology, to evaluate the effect of oxygen on the systemic inflammatory response to AMI. RESULTS: Plasma from 144 AMI patients was analysed whereof 76 (53%) were randomized to oxygen and 68 (47%) to air. Eight biomarkers showed a significant increase, whereas 13 were decreased 5-7 h after randomization. The inflammatory response did not differ between the two treatment groups neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age and sex, the release of inflammation-related biomarkers was still similar in the groups. CONCLUSIONS: In a randomized controlled setting of normoxemic patients with AMI, the use of supplemental oxygen did not have any significant impact on the early release of systemic inflammatory markers.

Myocarditis or "true" infarction by cardiac magnetic resonance in patients with a clinical diagnosis of myocardial infarction without obstructive coronary disease: A meta-analysis of individual patient data.

OBJECTIVE: Myocardial Infarction with Non-Obstructed Coronary Arteries (MINOCA) is common, but the causes are to a large extent unknown. Thus, we aimed to study the prevalence of myocarditis and "true" myocardial infarction determined by cardiac magnetic resonance (CMR) imaging in MINOCA patients, and risk markers for these two conditions in this population. METHODS: A search was made in the PubMed and Cochrane databases using the search terms "Myocardial infarction", "Coronary angiography", "Normal coronary arteries" and "MRI". All relevant abstracts were read and seven of the studies fulfilled the inclusion criteria; studies describing case series of patients fulfilling the diagnosis of acute myocardial infarction with normal or non-obstructive coronary arteries on coronary angiography that were investigated with CMR imaging. Data from five of these studies are presented. RESULTS: A total of 556 patients from 5 different sites were included. Fifty-one percent were men with a mean age of 52 ± 16 years. Thirty-three per cent of the patients had myocarditis (n = 183), whereas 21% of the patients had infarction on CMR (n = 115). Young age and a high CRP were associated with myocarditis whereas male sex, treated hyperlipidemia, high troponin ratio and low CRP were associated with "true" myocardial infarction. CONCLUSION AND RELEVANCE: The results of this meta-analysis of individual data showed that myocarditis and "true" myocardial infarction are common in MINOCA when determined by CMR imaging. This information emphasizes the importance of performing CMR imaging in MINOCA patients and can be used clinically to guide diagnostics and treatment of MINOCA patients.

Myocardial infarction with normal coronary arteries is common and associated with normal findings on cardiovascular magnetic resonance imaging: results from the Stockholm Myocardial Infarction with Normal Coronaries study.

OBJECTIVES: Myocardial infarction with angiographically normal coronary arteries (MINCA) is an important subtype of myocardial infarction; however, the prevalence, underlying pathophysiology, prognosis and optimal management of this condition are still largely unknown. Cardiovascular magnetic resonance (CMR) imaging has the potential to clarify the underlying pathology in patients with MINCA. The objective of this study was to investigate the diagnostic value of CMR imaging in this group of patients. DESIGN: The prospective, multicentre, observational Stockholm Myocardial Infarction with Normal Coronaries (SMINC) study. SETTING: Coronary care units in the Stockholm metropolitan area. SUBJECTS: Patients between 35 and 70 years of age with MINCA were consecutively included in the screening phase of the SMINC study. All patients had a typical clinical presentation, fulfilling the universal definition of myocardial infarction and had normal coronary angiography finding. Patients with known structural or coronary heart disease or other known causes of elevated troponin levels were excluded. RESULTS: In total, 176 patients with MINCA were screened from 2007 to 2011. Of these, 152 underwent CMR imaging. The investigation was performed a median of 12 (interquartile range 6-28) days after hospital admission; 67% of the findings were normal, whereas 19% of patients had signs of myocardial necrosis and 7% had signs of myocarditis. The remaining patients (7%) had either unrecognized hypertrophic cardiomyopathy or could not be classified. CONCLUSION: In this consecutive series of patients with MINCA, CMR imaging may help to differentiate between those with myocarditis, myocardial necrosis and normal myocardium. The incidence of MINCA was higher than previously reported. After excluding cases of myocarditis, MINCA consists of a large group of patients with normal CMR imaging results and a smaller group with myocardial necrosis. The aetiologies of these different imaging findings need to be explored.

Coronary artery bypass graft surgery up-regulates genes involved in platelet aggregation.

BACKGROUND: During and shortly after coronary artery bypass graft (CABG) surgery, there is an increase in thromboembolic events. CABG, a strong inflammatory stimulus, is associated with a hypercoaguable state. Platelets might contribute to this hypercoaguable state because they have a pivotal role in thrombosis. In the days following surgery there is augmented platelet regeneration in response to the inflammatory stimulus. OBJECTIVES: The aim of this study was to investigate any changes in platelet mRNA profiles to test the hypothesis that post-CABG surgery platelets are associated with a prothrombotic state. METHODS: Blood was sampled and platelets purified from 11 patients before and 3-6 days after CABG. Gene expression profiling was performed using low density array (LDA) plates for seven of the patients. RESULTS: Forty-five genes were examined and those significantly up-regulated were glycoprotein (GP)IIb, GPIIIa and cyclooxygenase-1 (COX-1). These findings were confirmed in four more patients, including flow cytometry analysis of the GPIIb/IIIa receptor. CONCLUSIONS: CABG surgery up-regulates mRNA and protein levels of proteins that are key players in platelet aggregation. Marked elevation of GPIIb/IIIa mRNA levels results in significantly increased GPIIb/IIIa expression in platelets post-CABG surgery, which may be a reason for increased thrombus formation and myocardial infarction after CABG.

Risk factors for myocardial infarction with normal coronary arteries and myocarditis compared with myocardial infarction with coronary artery stenosis.

The interest and awareness of myocardial infarction with normal coronary arteries (MINCA) have increased recently due to the frequent use of coronary angiography, the description of Takotsubo stress cardiomyopathy, and new sensitive troponin analyses. The prevalence of MINCA in all patients with myocardial infarction (MI) was registered during a 3-month period in the Stockholm metropolitan area in Sweden. The results showed that MINCA is more common than previously thought (7%) and affecting one third of every woman with MI. Patients with myocarditis were younger and more often presented with signs of inflammation such as elevated C-reactive protein and fever. Myocarditis constitutes an important differential diagnosis for coronary artery disease. There is a need for larger studies of MINCA, including investigation with cardiac magnetic resonance imaging, to establish prevalence and pathological process in this important subgroup of MI.

Myocardial infarction with angiographically normal coronary arteries.

Myocardial Infarction with Normal Coronary Arteries (MINCA) is an important subgroup of myocardial infarction with a frequency of at least 3-4% of all myocardial infarctions. The interest and awareness of MINCA have increased recently due to the frequent use of coronary angiography, the description of Takotsubo stress cardiomyopathy and new sensitive troponin assays. Since myocarditis may mimic myocardial infarction it is essential to exclude this in patients with myocardial infarction with angiographically normal coronary arteries. Cardiac magnetic resonance imaging is a cornerstone not only to establish the diagnosis but also an important tool in the search for different causes of myocardial damage. In the future, atherosclerotic burden, hemostatic function, characterization of stressors and inflammation will be important targets for research in this group of patients.

Cardiovascular disease associated with radiotherapy: activation of nuclear factor kappa-B.

There have been several recent reports of an increased risk of cardiovascular disease after radiotherapy. Hence, with an increasing number of cancer survivors, the incidence of cardiovascular disease caused by radiotherapy will increase. The existence of a type of vascular disease, or vasculopathy, induced by radiotherapy has been known for decades. It is important to identify and understand the molecular causes of this vasculopathy to determine preventive strategies. Recently, a chronic inflammation with similarities to atherosclerosis has been observed, with activation of the transcription factor nuclear factor kappa-B (NF-κB) as a possible cause. However, the trigger for NF-κB activation is unclear although it may be that reactive oxygen species or direct DNA damage is involved. To minimize the risk of cardiovascular disease in vulnerable patients, careful selection of patients, radiation dose and fractionation are important, together with the development of new techniques that reduce radiation dose to the blood vessels. In the light of the finding of an interaction between risk factors for cardiovascular disease and radiotherapy, it is reasonable to modify these factors including diabetes mellitus, hyperlipidaemia, hypertension and smoking. We believe that preventive strategies focusing on NF-κB can reduce the risk of future adverse cardiovascular events.

Use of the whole leucocyte population in the study of the NFκB pathway.

The nuclear factor NF-{kappa}B (NFκB) is involved in the regulation of innate immunity and in particular, inflammatory genes. It is associated with the pathogenesis of many chronic diseases such as coronary heart disease (CHD). It is believed that individual susceptibility to CHD might be affected by differences in gene transcription and therefore gene expression in circulating cell populations such as leucocytes is of interest. The aim of this study was to investigate whether the total white blood cell population (leucocytes) could be used to study the effect of lipopolysaccharide (LPS) treatment on the expression of genes of the NFκB pathway. Gene expression of the NFκB pathway was examined in total leucocyte, monocyte and neutrophil populations. The majority of the 84 genes examined were up-regulated after treatment with LPS for 12 h in all cell populations examined. The total leucocyte population behaved in a similar manner to both neutrophils and monocytic cells, indicating that it alone could be used in studies, therefore avoiding cell separation, which is time-consuming and can result in cell activation. Furthermore, in clinical studies, it enables a larger number of patient samples to be studied simultaneously, while also reducing the amount of blood required from each. This will provide enough starting material for use with molecular techniques, such as chromatin immunoprecipitation (ChIP) and ChIP-sequencing, and allow large-scale gene expression studies of the NFκB pathway in patients with chronic and acute inflammation with established CHD.

Timing of radiotherapy in head and neck free flap reconstruction--a study of postoperative complications.

The local treatment protocol of preoperative radiotherapy in head and neck cancer treatment at the Karolinska University Hospital has resulted in a unique cohort of preoperatively high dose-irradiated patients. In total 216 consecutive patients were reviewed, of whom 221 free flaps, for head and neck cancer reconstruction, were operated between 1984 and 2002. In 194 cases radiotherapy was administered preoperatively and 27 operations were performed without prior radiation. The radiation dose was 64 Gy in 147 cases, 54 Gy or less in 45 cases and uncertain in two cases. In order to study whether the time elapsed between the end of radiotherapy and surgery had any significance regarding postoperative events, the cohort was subsequently divided into three groups: patients operated on within 4 weeks (n=27), between 4 and 6 weeks (n=88) and more than 6 weeks (n=78) after the last radiotherapy session. Postoperative complications were analysed in relation to preoperative dose and timing of radiotherapy. Preoperative radiotherapy was related to an increased risk of free flap necrosis as 22 complete and eight partial flap necroses occurred in the group that had received preoperative radiotherapy and none were observed in the non-irradiated group (P<0.05). Furthermore, a linear trend of increased flap loss (P<0.001), infections (P<0.001) and delayed wound healing (P<0.001) was seen when time increased between the last radiotherapy session and surgery. The largest increase in all complication rates was seen when more than 6 weeks elapsed between last radiotherapy session and surgery. Postoperative complications were independent of the radiation dose given. Our data show an increased morbidity in free flap surgery in the head and neck region after preoperative radiotherapy. Furthermore, time elapsed between the last radiotherapy session and surgery is associated with the risk of developing postoperative complications. We strongly suggest that free flap reconstruction should be performed within 6 weeks of the last radiotherapy session.

Effects on mortality of abciximab in ST-elevation myocardial infarction treated with percutaneous coronary intervention including stent implantation.

OBJECTIVES: To investigate the effects of abciximab on mortality in ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) including stent implantation. DESIGN: Meta-analysis of three selected randomized studies and analysis of data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). SUBJECTS: Pooled data from randomized studies containing in total 1,736 patients undergoing PCI with stent implantation because of STEMI with duration between symptom and treatment <12 h, and 7,436 patients from SCAAR treated with PCI because of STEMI (52% treated with abciximab) in Sweden 2000-2004. RESULTS: Analyses of pooled data showed that abciximab was associated with a decreased risk of reinfarction [odds ratio (OR) 0.38] and urgent target vessel revascularization (OR 0.38) at 30 days. No effect was seen on mortality at 30 days or 6 months. Multivariate analysis of data from SCAAR showed that abciximab reduced the risk of death during 14 months of follow-up (hazard ratio 0.82). CONCLUSIONS: The results are encouraging and support the ACC/AHA and ESC recommendation to use abciximab in treatment of STEMI with PCI including stent implantation. Considering that the pooled results from previous trials showed no effect of abciximab on mortality and the registry part of the present study was observational, the results encourage carrying out new randomized studies of abciximab in STEMI treated with PCI, including stent implantation, with sufficient size and length of follow-up.

Clinical and angiographic follow-up after coronary drug-eluting and bare metal stent implantation. Do drug-eluting stents hold the promise?

OBJECTIVES: To investigate the influence of drug-eluting stent (DES) implantation on clinical and angiographic restenosis. DESIGN: Registry study of data from the Swedish Coronary Angiography and Angioplasty Registry with a coronary angiographic substudy. SETTING: Multi-centre study. SUBJECTS: During October 2002 to May 2004 a total of 23 590 percutaneous coronary intervention (PCI) procedures were performed at 25 hospitals. After selection, to achieve comparable groups, a total of 5068 patients of whom 4111 had a bare metal stent (BMS) implanted and 957 had a DES implanted, remained. End-point in the registry follow-up was >50% diameter restenosis at clinically driven reangiography within 12 months after index PCI. The primary end-point in the angiographic substudy was late loss in patients' DES at 6-month angiographic follow-up. RESULTS: The rate of clinically driven restenosis, within 12 months, in patients receiving DES was less (3.9%) compared with those who received BMS (7.0%). In multivariate analysis the risk of clinical restenosis was one-third for DES compared with BMS (HR 0.36, 95% CI 0.25-0.52). In the angiographic substudy late loss was 0.07+/-0.53 mm (range -0.88 to 1.62). The amount of late loss was related to the presence of diabetes mellitus or not (0.19+/-0.45 mm vs. -0.12+/-0.58 mm), and lack of postdilatation of the stent or not (0.23+/-0.51 mm vs. -0.09+/-0.50 mm). CONCLUSIONS: The use of DES in the Swedish 'real world' is effective in reducing the clinically driven restenosis rate, when compared with patients with BMS treatment. In the angiographic follow-up the average late loss was as low as observed in recent randomized multi-centre trials.

Lower serum concentration of matrix metalloproteinase-3 in the acute stage of myocardial infarction.

OBJECTIVES: The importance of matrix metalloproteinases (MMPs) in the progression and rupture of the atherosclerotic plaque is gaining increasing recognition but the mechanisms are not yet fully understood. The aim of this study was to investigate the significance of MMP-3 in the acute phase of myocardial infarction (MI) and the influence of the -1612 5A/6A MMP-3 gene promoter polymorphism on serum MMP-3 concentration. SUBJECTS: One-hundred and sixty-four patients admitted with ST-elevation MI and receiving thrombolysis treatment were included in this study. Serum MMP-3 was analysed at admission, after 48 h and at 3 months. RESULTS: Serum MMP-3 concentration was significantly increased at 3 months when compared with admission and 48 h (19.5 ng mL(-1) [14.4-24.7] vs. 15.5 ng mL(-1) [10.5-21.8] at admission, P < 0.001; and 14.7 ng mL(-1) [9.9-23.8] at 48 h, P < 0.001). Furthermore, we found the -1612 5A/6A polymorphism to influence the serum concentration of MMP-3 at all time-points: 14.1 ng mL(-1) [10.2-18.8] in 5A/5A; 19.6 ng mL(-1) [15.0-24.4] in 5A/6A; and 24.0 ng mL(-1) [20.1-32.3] in 6A/6A genotype at 3 months (P < 0.001 between all groups). Female patients had lower serum MMP-3 concentration than male patients at all time-points (14.8 ng mL(-1) [9.4-20.8] vs. 19.9 ng mL(-1) [16.0-26.9], P < 0.0001 at 3 months). CONCLUSIONS: Serum concentration of MMP-3 is significantly lower in the acute stage of MI than during recovery and is significantly influenced by -1612 5A/6A genotype and gender. Together with previous findings, these results primarily implicate MMP-3 in atherosclerosis progression rather than in acute MI.

Serum matrix metalloproteinase-3 concentration is influenced by MMP-3 -1612 5A/6A promoter genotype and associated with myocardial infarction.

OBJECTIVES: Matrix metalloproteinase-3 (MMP-3) is implicated in the formation of atherosclerotic plaques, and the MMP-3 -1612 5A/6A polymorphism is associated with myocardial infarction (MI) and stable coronary artery disease (CAD). The present study examined whether the -1612 5A/6A polymorphism in the promoter region of the MMP-3 gene influences serum concentrations of MMP-3 and whether serum concentrations of MMP-3 are related to extent of coronary atherosclerosis and risk of MI. DESIGN AND SUBJECTS: This case-control study was conducted in three hospitals in the northern part of Stockholm. A total of 755 MI patients aged below 60 were screened, 433 entered and 387 completed the study. Three hundred and eighty-seven sex- and age-matched control subjects were recruited from the general population of the same county. METHODS: The MMP-3 genotype was determined by Pyrosequencing(TM) and the serum MMP-3 concentration was quantified with an immunoassay. Severity and extension of CAD was assessed by quantitative coronary angiography in a subgroup of patients (n=243). RESULTS: Patients had lower serum MMP-3 concentration than controls. There was a strong association between MMP-3 -1612 5A/6A genotype and serum concentrations of MMP-3. The presence of one or two copies of the 6A-allele was associated with a graded increase in serum MMP-3. In female patients there was an inverse correlation (r=-0.39, P<0.05) between serum MMP-3 concentration and plaque area. Conclusion. In conclusion, the serum concentration of MMP-3 is influenced by MMP-3 -1612 5A/6A genotype and associated with MI.