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Olsson, Anders
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Pitts, R., Gunzburger, E., Ballantyne, C. M., Barter, P. J., Kallend, D., Leiter, L. A., . . . Schwartz, G. G. (2017). Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 6(1), Article ID e004119.
Open this publication in new window or tab >>Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure
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2017 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 1, article id e004119Article in journal (Refereed) Published
Abstract [en]

Background- Aldosterone may have adverse effects in the myocardium and vasculature. Treatment with an aldosterone antagonist reduces cardiovascular risk in patients with acute myocardial infarction complicated by heart failure (HF) and left ventricular systolic dysfunction. However, most patients with acute coronary syndrome do not have advanced HF. Among such patients, it is unknown whether aldosterone predicts cardiovascular risk. Methods and Results- To address this question, we examined data from the dal-OUTCOMES trial that compared the cholesteryl ester transfer protein inhibitor dalcetrapib with placebo, beginning 4 to 12 weeks after an index acute coronary syndrome. Patients with New York Heart Association class II (with LVEF amp;lt; 40%), III, or IV HF were excluded. Aldosterone was measured at randomization in 4073 patients. The primary outcome was a composite of coronary heart disease death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. Hospitalization for HF was a secondary endpoint. Over a median follow-up of 37 months, the primary outcome occurred in 366 patients (9.0%), and hospitalization for HF occurred in 72 patients (1.8%). There was no association between aldosterone and either the time to first occurrence of a primary outcome (hazard ratio for doubling of aldosterone 0.92, 95% confidence interval 0.78-1.09, P=0.34) or hospitalization for HF (hazard ratio 1.38, 95% CI 0.96-1.99, P=0.08) in Cox regression models adjusted for covariates. Conclusions- In patients with recent acute coronary syndrome but without advanced HF, aldosterone does not predict major cardiovascular events.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2017
Keywords
acute coronary syndrome; aldosterone; morbidity/mortality
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-135708 (URN)10.1161/JAHA.116.004119 (DOI)000393593300008 ()28073769 (PubMedID)
Note

Funding Agencies|F. Hoffmann-La Roche

Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-04-16
Olsson, A., Angelin, B., Assmann, G., Binder, C. J., Bjoerkhem, I., Cedazo-Minguez, A., . . . Yvan-Charvet, L. (2017). Can LDL cholesterol be too low? Possible risks of extremely low levels. Journal of Internal Medicine, 281(6), 534-553
Open this publication in new window or tab >>Can LDL cholesterol be too low? Possible risks of extremely low levels
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2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 6, p. 534-553Article, review/survey (Refereed) Published
Abstract [en]

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important. This is an article from the symposium: Risks and benefits of Extremely Low LDL Cholesterol.

Place, publisher, year, edition, pages
WILEY, 2017
Keywords
abetalipoproteinaemia; adverse effects; hypocholesterolaemia; low-density lipoprotein; safety
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-138220 (URN)10.1111/joim.12614 (DOI)000401715800001 ()28295777 (PubMedID)
Note

Funding Agencies|Foundation of Old Servants; International Task Force for The Prevention of Cardiometabolic Diseases

Available from: 2017-06-14 Created: 2017-06-14 Last updated: 2018-04-16
Schwartz, G. G., Abt, M., Bao, W., DeMicco, D., Kallend, D., Miller, M., . . . Olsson, A. (2015). Fasting Triglycerides Predict Recurrent Ischemic Events in Patients With Acute Coronary Syndrome Treated With Statins. Journal of the American College of Cardiology, 65(21), 2267-2275
Open this publication in new window or tab >>Fasting Triglycerides Predict Recurrent Ischemic Events in Patients With Acute Coronary Syndrome Treated With Statins
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2015 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 65, no 21, p. 2267-2275Article in journal (Refereed) Published
Abstract [en]

BACKGROUND Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dalOUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p less than 0.001). The hazard ratio in the highest/lowest quintile (greater than 175/less than= 80 mg/dl) was 1.50 (95% confidence interval: 1.05 to 2.15). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p = 0.03), with a hazard ratio of 1.51 (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (greater than195/less than= 135 mg/dl). The relationship of triglycerides to risk was independent of lowdensity lipoprotein cholesterol in both studies. CONCLUSIONS Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (C) 2015 by the American College of Cardiology Foundation.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
lipids; myocardial infarction; unstable angina
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-119573 (URN)10.1016/j.jacc.2015.03.544 (DOI)000355196300001 ()26022813 (PubMedID)
Note

Funding Agencies|F. Hoffmann-La Roche Ltd.; Pfizer; Anthera; Resverlogix; Roche; Sanofi; Amgen; AstraZeneca; Karobio; Merck

Available from: 2015-06-23 Created: 2015-06-22 Last updated: 2017-12-04
Raal, F. J., Stein, E. A., Dufour, R., Turner, T., Civeira, F., Burgess, L., . . . Gaudet, D. (2015). PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. The Lancet, 385(9965), 331-340
Open this publication in new window or tab >>PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial
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2015 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 385, no 9965, p. 331-340Article in journal (Refereed) Published
Abstract [en]

Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19,2013.331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2.6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59.2% reduction [95% CI 53.4-65.1], monthly dose: 61.3% reduction [53.6-69.0]; both pless than0.0001) and at the mean of weeks 10 and 12 (60.2% reduction [95% CI 54.5-65.8] and 65.6% reduction [59.8-71.3]; both pless than0.0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). Interpretation In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.

Place, publisher, year, edition, pages
Elsevier: Lancet, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-114580 (URN)10.1016/S0140-6736(14)61399-4 (DOI)000348509000026 ()
Available from: 2015-02-27 Created: 2015-02-26 Last updated: 2017-12-04
Angelin, B., Kristensen, J. D., Eriksson, M., Carlsson, B., Klein, I., Olsson, A., . . . Ladenson, P. W. (2015). Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome. Journal of Internal Medicine, 277(3), 331-342
Open this publication in new window or tab >>Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome
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2015 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, no 3, p. 331-342Article in journal (Refereed) Published
Abstract [en]

BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200gday(-1) eprotirome or placebo for 12weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures. ResultsEprotirome treatment at 100 and 200g daily reduced serum LDL cholesterol levels by 235% and 31 +/- 4%, respectively, compared with 2 +/- 6% for placebo (Pless than0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients. ConclusionIn hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia.

Place, publisher, year, edition, pages
Wiley: 12 months, 2015
Keywords
cholesterol; hypercholesterolaemia; lipoprotein; liver; thyroid
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116513 (URN)10.1111/joim.12261 (DOI)000349977300005 ()24754313 (PubMedID)
Note

Funding Agencies|Karo Bio

Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2017-12-04
Sjouke, B., Langslet, G., Ceska, R., Nicholls, S. J., Nissen, S. E., Ohlander, M., . . . Kastelein, J. J. P. (2014). Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. LANCET DIABETES and ENDOCRINOLOGY, 2(6), 455-463
Open this publication in new window or tab >>Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study
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2014 (English)In: LANCET DIABETES and ENDOCRINOLOGY, ISSN 2213-8587, Vol. 2, no 6, p. 455-463Article in journal (Refereed) Published
Abstract [en]

Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 mu g and 100 mu g eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 mu g eprotirome, 100 mu g eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 mu g eprotirome, and 77 to receive 100 mu g eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 mu g eprotirome, and 22 given 100 mu g eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs placebo) in the 50 mu g eprotirome group, and decreased by 22% (-32 to -13%; p=0.0045 vs placebo) in the 100 mu g eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; pless than0.0001), alanine aminotransferase (ALT; pless than0.0001), conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (pless than0.0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 mu g eprotirome group and 27% (30 to 23) in the 100 mu g eprotirome group (pless than0.0001 vs placebo for both groups). Interpretation Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations.

Place, publisher, year, edition, pages
Elsevier: Lancet, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-108164 (URN)10.1016/S2213-8587(14)70006-3 (DOI)000336724300022 ()
Available from: 2014-06-26 Created: 2014-06-26 Last updated: 2014-06-26
Olsson, A. G. (2014). [Guidelines for cholesterol treatment--the obstacle remains in Stockholm]. [Letter to the editor]. Läkartidningen, 111(20), 885
Open this publication in new window or tab >>[Guidelines for cholesterol treatment--the obstacle remains in Stockholm].
2014 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 20, p. 885-Article in journal, Letter (Other academic) Published
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116860 (URN)24908807 (PubMedID)
Available from: 2015-04-08 Created: 2015-04-08 Last updated: 2017-12-04
Tikkanen, M. J., Fayyad, R., Faergeman, O., Olsson, A., Wun, C.-C., Laskey, R., . . . Pedersen, T. R. (2013). Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. International Journal of Cardiology, 168(4), 3846-3852
Open this publication in new window or tab >>Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels
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2013 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 168, no 4, p. 3846-3852Article in journal (Refereed) Published
Abstract [en]

Background: Statins may reduce cardiovascular (CV) morbidity in patients with mild-to-moderate elevations in liver enzyme levels. This post-hoc analysis of the IDEAL study compared intensive versus moderate statin therapy for the prevention of CV events in coronary heart disease patients with normal and elevated baseline levels of serum alanine aminotransferase (ALT). less thanbrgreater than less thanbrgreater thanMethods: Cox regression analysis was used to investigate the effect of atorvastatin 80 mg/day versus simvastatin 20-40 mg/day on the risk of IDEAL study end points in patients with normal baseline ALT (defined as ALT andlt; ULN [upper limit of normal]) versus elevated baseline ALT (ALT andgt;= ULN). less thanbrgreater than less thanbrgreater thanResults: Of 8863 IDEAL patients with non-missing baseline ALT values, 7782 (87.8%) had an ALT andlt; ULN and 1081 (12.2%) had an ALT andgt;= ULN. In patients with elevated baseline ALT, major CV event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard ratio, 0.556; 95% confidence interval, 0.367-0.842; p = 0.0056). Significant heterogeneity of treatment effect was observed for major CV events, cerebrovascular events, and major coronary events, with a trend towards treatment difference for the other outcomes, indicating a greater benefit with atorvastatin in the elevated ALT group. less thanbrgreater than less thanbrgreater thanConclusions: The CV benefit of intensive lipid lowering with atorvastatin compared with a more moderate regimen with simvastatin was generally greater in patients with mildly-to-moderately elevated baseline ALT than patients with normal baseline ALT. Moderate elevations in liver enzyme levels should not present a barrier to prescribing statins, even at higher doses, in high-risk patients.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Coronary heart disease, Statins, Cardiovascular risk, Liver enzymes, Alanine aminotransferase, Fatty liver disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102400 (URN)10.1016/j.ijcard.2013.06.024 (DOI)000326219600114 ()
Note

Funding Agencies|Pfizer Inc.||

Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
Zamani, P., Schwartz, G. G., Olsson, A., Rifai, N., Bao, W., Libby, P., . . . Kinlay, S. (2013). Inflammatory Biomarkers, Death, and Recurrent Nonfatal Coronary Events After an Acute Coronary Syndrome in the MIRACL Study. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2(1)
Open this publication in new window or tab >>Inflammatory Biomarkers, Death, and Recurrent Nonfatal Coronary Events After an Acute Coronary Syndrome in the MIRACL Study
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2013 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 2, no 1Article in journal (Refereed) Published
Abstract [en]

Background-In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. less thanbrgreater than less thanbrgreater thanMethods and Results-We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E-selectin, P-selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.006), SAA (P=0.012), and IL-6 (Pandlt;0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes. VCAM and tPA related to the risk of death (Pandlt;0.001, P=0.021, respectively) and to nonfatal acute coronary syndromes (P=0.021, P=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however, CRP and SAA continued to relate to death. less thanbrgreater than less thanbrgreater thanConclusions-In acute coronary syndromes, the CRP inflammatory axis relates to the risk of death and may reflect myocardial injury. VCAM and tPA may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2013
Keywords
acute coronary syndromes, biomarkers, CRP, death, nonfatal events, risk
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102096 (URN)10.1161/JAHA.112.003103 (DOI)000326336800041 ()
Note

Funding Agencies|Pfizer, Inc.||

Available from: 2013-11-29 Created: 2013-11-29 Last updated: 2017-12-06
Holmes, M. V., Simon, T., J Exeter, H., Folkersen, L., Asselbergs, F. W., Guardiola, M., . . . Talmud, P. J. (2013). Secretory Phospholipase A(2)-IIA and Cardiovascular Disease. Journal of the American College of Cardiology, 62(21), 1966-1976
Open this publication in new window or tab >>Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
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2013 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 62, no 21, p. 1966-1976Article in journal (Refereed) Published
Abstract [en]

Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
cardiovascular diseases, drug development, epidemiology, genetics, Mendelian randomization
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-102496 (URN)10.1016/j.jacc.2013.06.044 (DOI)000326939500010 ()
Note

Funding Agencies|BHG programme grant|RG/10/12/28456|UK Medical Research Council (Population Health Scientist Fellowship)|G0802432|British Heart Foundation|RG 10/12/28456RG008/014RG/10/001/27643PG07/133/24260FS 08/ 048/25628|National Institute of Health Research University College London Hospitals Biomedical Research Centre||Dutch Kidney Foundation|E033|Netherlands Organisation for Health Research and Development (NWO VENI)|916.761.70|Dutch Inter University Cardiology Institute Netherlands (ICIN)||Canada Research Chair in Genetic and Molecular Epidemiology||Europe Against Cancer Programme of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society|||EU-LSHM-CT-2006037697|

Available from: 2013-12-12 Created: 2013-12-12 Last updated: 2017-12-06
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