Jan-Håkan Jansson

High Plasminogen Activator Inhibitor and Tissue Plasminogen Activator Levels in Plasma Precede a First Acute Myocardial Infarction in Both Men and Women Evidence for the Fibrinolytic System as an Independent Primary Risk Factor

BACKGROUND In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1. METHODS AND RESULTS The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men. CONCLUSIONS The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors.

Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

BACKGROUND Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

Leptin is associated with increased risk of myocardial infarction

Abstract. Söderberg S, Ahrén B, Jansson J‐H, Johnson O, Hallmans G, Asplund K, Olsson T (Umeå University, Umeå; and Lund University, Malmö, Sweden). Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999; 246: 409–418.

Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up.

BackgroundThe fibrinolytic system is part of the defense against thrombotic and cardiovascular events, but so far no study has shown that clinical measurements of fibrinolytic key components such as tissue plasminogen activator (t-PA) or plasminogen activator inhibitor type 1 (PAI-1) have any predictive value beyond 3 years. Methods and ResultsIn 1983 through 1985, 213 consecutive patients with angina pectoris and angiographically verified coronary artery disease were sampled, and the mass concentration of t-PA and the activity of PAI-1 were measured in citrated plasma samples. At a mean follow-up time of 7 years, the all-cause mortality was checked. No patient was lost to follow-up. The data were analyzed by Cox regression, and t-PA mass concentration was found to be the only laboratory risk factor significantly related to mortality in all patients (P<.022) and also in the major subgroup (78% of all patients) subjected to coronary bypass surgery (P<.027). In the latter subgroup, body mass index was also related to mortality. ConclusionsAn increased mass concentration of t-PA is a new risk factor of long-term mortality in patients with angina pectoris and coronary artery stenosis. This paradoxical effect probably reflects increased t-PA levels attributable to enzyme inhibitor complex formation in subjects with increased plasma levels of t-PA inhibitors.

Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort - evaluation of risk factors and their interactions.

The purpose of this paper is, first, to describe the organization, sampling procedures, availability of samples/database, ethical considerations, and quality control program of the Northern Sweden Health and Disease Study Cohort. Secondly, some examples are given of studies on cardiovascular disease and diabetes with a focus on the biomarker programme. The cohort has been positioned as a national and international resource for scientific research.

Markers of high fish intake are associated with decreased risk of a first myocardial infarction

High intake of fish has been associated with reduced risk of CHD. The high content of n-3 polyunsaturated fatty acids (PUFA) in fish has been suggested to be a protective factor. In addition, fish is the entirely dominating source of methylmercury for the general population, and the concentration of Hg in erythrocytes (Ery-Hg) is often used as an index of fish consumption. Our aim was to study the relationships between a first-ever myocardial infarction, Ery-Hg, activity of gluthathione peroxidase in erythrocytes (Ery-GSH-Px) and plasma concentration of the n-3 PUFA eicosapentaenoic and docosahexaenoic acids (P-PUFA). In a population-based prospective nested case-control study within Northern Sweden seventy-eight cases of a first-ever myocardial infarction were compared with 156 controls with respect to Ery-Hg, P-PUFA and Ery-GSH-Px. Both Ery-Hg and P-PUFA, but not Ery-GSH-Px, were significantly higher in subjects reporting high fish intake (at least one meal per week) than in those with lower intake. This finding suggests that Ery-Hg and P-PUFA reflect previous long-term fish intake. Low risk of myocardial infarction was associated with high Ery-Hg or high P-PUFA. In a multivariate model the risk of myocardial infarction was further reduced in subjects with both high Ery-Hg and high P-PUFA (odds ratio 0.16, 95 % CI 0.04, 0.65). In conclusion, there is a strong inverse association between the risk of a first myocardial infarction and the biomarkers of fish intake, Ery-Hg and P-PUFA, and this association is independent of traditional risk factors.

Large improvements in major cardiovascular risk factors in the population of northern Sweden: the MONICA study 1986–2009

Abstract.  Eriksson M, Holmgren L, Janlert U, Jansson J‐H, Lundblad D, Stegmayr B, Söderberg S, Eliasson M (Department of Public Health and Clinical Medicine, Umeå University, Umeå; Research Department, Norrbotten County Council, Luleå; Department of Medicine, Skellefteå Hospital, Skellefteå; Department of Medicine, Sunderby Hospital, Luleå; and National Board of Health and Welfare, Stockholm, Sweden). Large improvements in major cardiovascular risk factors in the population of northern Sweden: the MONICA study 1986–2009. J Intern Med 2011; 269: 219–231.

ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies.

IMPORTANCE The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5ω-3), docosapentaenoic acid (DPA; 22:5ω-3), and docosahexaenoic acid (DHA; 22:6ω-3) and plant-derived α-linolenic acid (ALA; 18:3ω-3) for incident CHD. DATA SOURCES A global consortium of 19 studies identified by November 2014. STUDY SELECTION Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.

Time trends in population cholesterol levels 1986-2004: influence of lipid-lowering drugs, obesity, smoking and educational level. The northern Sweden MONICA study.

Objectives.  To explore time trends in population total cholesterol.

Fish intake, mercury, long-chain n-3 polyunsaturated fatty acids and risk of stroke in northern Sweden

Results of previous studies on fish intake and stroke risk have been inconclusive. Different stroke types have often not been separated. Our aim was to elucidate whether intake of fish, Hg or the sum of proportions of fatty acids EPA (20 : 5n-3) and DHA (22 : 6n-3) influence the risk of haemorrhagic or ischaemic stroke. Within a population-based cohort from a community intervention programme, 369 stroke cases and 738 matched controls were identified and included in the present nested case-control study. Information on fish intake had been recorded at recruitment, i.e. before diagnosis. Hg levels were determined in erythrocyte membranes, also collected at recruitment, and the relative content of fatty acids was measured in erythrocyte membranes or plasma phospholipids. The results showed that in women there was a non-significant decrease in stroke risk with increasing fish intake (OR 0.90 (95 % CI 0.73, 1.11) per meal per week). The risk in women differed significantly (P = 0.03) from that in men, in whom the OR for stroke rose with increasing fish intake (OR 1.24 (95 % CI 1.01, 1.51) per meal per week). The corresponding risk in men for Hg was 0.99 (95 % CI 0.93, 1.06), and for the sum of proportions of EPA and DHA 1.08 (95 % CI 0.92, 1.28). We conclude that the relationship between stroke risk and fish intake seems to be different in men and women. Increased levels of EPA and DHA do not decrease the risk for stroke and there is no association between stroke risk and Hg at these low levels.