Are fatty acids associated with disease activity and biomarkers in patients with psoriatic arthritis? Data from a multicenter clinical trial.

The pathogenesis of psoriatic arthritis (PsA) involves inflammation and bone and soft tissue turnover. Dietary fatty acids have previously been associated with pro-inflammatory effects induced by saturated fatty acids (SFA) and anti-inflammatory effects achieved by at least some polyunsaturated fatty acids (PUFA). The aim of the study was to investigate the correlations between the content of fatty acids in granulocytes and clinical and biochemical markers of PsA. A total of 140 patients with PsA were included. Skin and joint disease activity were assessed. Fatty acid composition in granulocytes was determined by gas chromatography. Competitive enzyme-linked immunosorbent assays were used to assess bone and soft tissue turnover. The content of SFA, n-6 PUFA or n-3 PUFA in granulocytes was not associated with disease activity. Marine n-3 PUFA was significantly positively correlated with collagen degradation. In contrast, n-6 PUFA was significantly positively correlated with collagen formation and negatively correlated with collagen degradation. However, the correlations were all weak. No association was found between the content of fatty acids in granulocytes and disease activity in this population of patients with PsA. The correlation between fatty acids and biomarkers of bone and soft tissue turnover needs further investigation.

Effect of n-3 PUFA on extracellular matrix protein turnover in patients with psoriatic arthritis: a randomized, double-blind, placebo-controlled trial.

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by involvement of skin, axial and peripheral skeleton. An altered balance between extracellular matrix (ECM) formation and breakdown is a key event in PsA, and changes in ECM protein metabolites may provide insight to tissue changes. Dietary fish oils (n-3 PUFA) might affect the inflammation driven tissue turnover. The aim was to evaluate ECM metabolites in patients with PsA compared to healthy individuals and investigate the effects of n-3 PUFA. The 24-week randomized, double-blind, placebo-controlled trial of PUFA included 142 patients with PsA. Fifty-seven healthy individuals were included for comparison. This study is a sub-study investigating biomarkers of tissue remodelling as secondary outcomes. Serum samples at baseline and 24 weeks and healthy individuals were obtained, while a panel of ECM metabolites reflecting bone and soft tissue turnover were measured by ELISAs: PRO-C1, PRO-C3, PRO-C4, C1M, C3M, C4M, CTX-I and Osteocalcin (OC). C1M, PRO-C3, PRO-C4 and C4M was found to be elevated in PsA patients compared to the healthy individuals (from 56 to 792%, all p < 0.0001), where no differences were found for OC, CTX-I, PRO-C1 and C3M. PRO-C3 was increased by 7% in patients receiving n-3 PUFA after 24 weeks compared to baseline levels (p = 0.002). None of the other biomarkers was changed with n-3 PUFA treatment. This indicates that tissue turnover is increased in PsA patients compared to healthy individuals, while n-3 PUFA treatment for 24 weeks did not have an effect on tissue turnover. Trial registration NCT01818804. Registered 27 March 2013-Completed 18 February 2016. https://clinicaltrials.gov/ct2/show/NCT01818804?term=NCT01818804&rank=1.

The Effect of Marine n-3 Polyunsaturated Fatty Acids on Heart Rate Variability in Renal Transplant Recipients: A Randomized Controlled Trial.

Resting heart rate (rHR) and heart rate variability (HRV) are non-invasive measurements that predict the risk of sudden cardiac death (SCD). Marine n-3 polyunsaturated fatty acid (PUFA) supplementation may decrease rHR, increase HRV, and reduce the risk of SCD. To date, no studies have investigated the effect of marine n-3 PUFA on HRV in renal transplant recipients. In a randomized controlled trial, 132 renal transplant recipients were randomized to receive either three 1 g capsules of marine n-3 PUFA, each containing 460 mg/g EPA and 380 mg/g DHA, or control (olive oil) for 44 weeks. HRV was calculated in the time and frequency domains during a conventional cardiovascular reflex test (response to standing, deep breathing, and Valsalva maneuver) and during 2 min of resting in the supine position. There was no significant effect of marine n-3 PUFA supplementation on time-domain HRV compared with controls. rHR decreased 3.1 bpm (± 13.1) for patients receiving marine n-3 PUFA compared to 0.8 (± 11.0) in controls (p = 0.28). In the frequency domain HRV analyses, there was a significant change in response to standing in both high and low frequency measures, 2.9 (p = 0.04, 95% CI (1.1;8)) and 2.7 (p = 0.04, 95% CI (1.1;6.5)), respectively. In conclusion, 44 weeks of supplemental marine n-3 PUFAs in renal transplant recipients significantly improved the cardiac autonomic function, assessed by measuring HRV during conventional cardiovascular reflex tests.

The effect of marine n-3 polyunsaturated fatty acids on cardiac autonomic and hemodynamic function in patients with psoriatic arthritis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The aim of this study was to investigate the effect of marine n-3 polyunsaturated fatty acids (PUFA) on cardiac autonomic function and vascular function in patients with psoriatic arthritis. METHODS: The study was conducted as a randomized, double-blind, placebo-controlled trial, where 145 patients with psoriatic arthritis were supplemented with 3 g of n-3 PUFA or olive oil (control) daily for 24 weeks. Blood pressure, heart rate, heart rate variability (HRV), central blood pressure, pulse wave velocity (PWV) and fatty acid composition of granulocytes, were determined at baseline and after supplementation. RESULTS: At baseline we found a significant difference in the mean of all normal RR intervals (inverse of heart rate, vary from beat to beat) when comparing subjects with the highest vs the lowest fish intake (p = 0.03). After supplementation for 24 weeks there was a trend towards an increase in RR (p = 0.13) and decrease in heart rate (p = 0.12) comparing the n-3 PUFA group with the control group. However, per-protocol analysis showed significantly increased RR (p = 0.01) and lowered heart rate (p = 0.01) in the n-3 PUFA supplemented patients compared with controls. Blood pressure, PWV and Central blood pressure did not change after supplementation with n-3 PUFA. Adjustment for disease activity and conventional cardiovascular risk factors did not change the results. CONCLUSIONS: Marine n-3 PUFA increased RR intervals in patients with psoriatic arthritis which may suggest a protective effect of n-3 PUFA against cardiovascular disease in this population. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01818804.

Plasma n-3 Polyunsaturated Fatty Acids and Bone Mineral Density in Renal Transplant Recipients.

OBJECTIVE: Renal transplant recipients (RTR) suffer high rates of bone loss and increased risk of fracture. Marine n-3 polyunsaturated fatty acids (n-3 PUFA), found mainly in fish and seafood, may have beneficial effects on bone and are positively associated with bone mineral density (BMD) in healthy elderly. The aim of this study was to investigate if this association prevails despite the more complex causes of bone loss in RTR. DESIGN, SUBJECTS, AND METHODS: A total of 701 RTR were included in a cross-sectional analysis. BMD of lumbar spine, proximal femur, and distal forearm were measured by dual energy x-ray absorptiometry scan, and blood samples were drawn in the fasting state for measurement of plasma fatty acid composition 10 weeks posttransplant. Multiple linear regression analysis was used to assess the association between plasma marine n-3 PUFA levels and BMD. RESULTS: Mean age was 52.2 years, and two-thirds were men. Based on femoral neck T-scores, 26% of patients were osteoporotic and 52% osteopenic. Z-scores increased significantly across quartiles of marine n-3 PUFA levels, and marine n-3 PUFA was a positive predictor of BMD at total hip and lumbar spine after multivariate adjustment. No association was found between n-6 PUFA content and BMD. CONCLUSIONS: Plasma marine n-3 PUFA levels were positively associated with BMD at the hip and lumbar spine 10 weeks posttransplant.

The autonomic nervous system and cardiovascular disease: role of n-3 PUFAs.

In the last decades, a large body of experimental and clinical evidence has been accumulated showing that cardiovascular diseases are often accompanied by an imbalance in the sympathetic-vagal outflow to the heart, resulting in a chronic adrenergic activation. The arterial baroreceptor system is a key component of mechanisms contributing to the neural regulation of the cardiovascular system. Several methods have been proposed to assess autonomic activity by analyzing heart rate and blood pressure changes either spontaneously occurring or following provocations. The autonomic nervous system has been regarded as one of the putative mechanisms involved into the beneficial effects of exposure to n-3 fatty acids observed in epidemiological studies. The aim of the present review is to provide an update on the clinical evidence proposed so far linking exposure to n-3 fatty acids to autonomic nervous system modulation.

Marine n-3 fatty acids, atrial fibrillation and QT interval in haemodialysis patients.

Patients treated with haemodialysis are at high risk of sudden cardiac death (SCD) often caused by arrhythmias. Atrial fibrillation (AF) is frequent among haemodialysis patients and is associated with increased mortality. Prolonged QTc is a risk marker of ventricular arrhythmia and is thereby associated with SCD. Studies have suggested that n-3 PUFA may have an antiarrhythmic effect, but the exact mechanism is not clear. The aim of this study was to examine whether AF was associated with n-3 PUFA in plasma phospholipids and whether supplementation with n-3 PUFA would shorten the QTc interval in haemodialysis patients compared to placebo. In a double-blinded randomised, placebo-controlled intervention trial 206 haemodialysis patients with CVD were treated with 1·7 g n-3 PUFA or placebo (olive oil) daily for 3 months. Blood samples and electrocardiogram evaluations were carried out at baseline and after 3 months. The QT interval, PQ interval and heart rate were measured in all patients with sinus rhythm (SR). At baseline 13 % of patients had AF. The content of the n-3 PUFA, DHA, was significantly lower (P < 0·05) in serum of patients with AF compared with patients with SR. Thus, the DHA content was independently negatively associated with AF. Supplementation with n-3 PUFA did not shorten the QT interval significantly compared to the placebo group (P = 0·42), although subgroup analysis within the n-3 PUFA group revealed a shortening effects on QTc (P = 0·01). In conclusion, an inverse association was found between the presence of AF and the plasma DHA in haemodialysis patients. Intervention with n-3 PUFA did not shorten the QTc interval compared to placebo.

Omega-3 polyunsaturated Fatty acids and heart rate variability.

Omega-3 polyunsaturated fatty acids (PUFA) may modulate autonomic control of the heart because omega-3 PUFA is abundant in the brain and other nervous tissue as well as in cardiac tissue. This might partly explain why omega-3 PUFA offer some protection against sudden cardiac death (SCD). The autonomic nervous system is involved in the pathogenesis of SCD. Heart rate variability (HRV) can be used as a non-invasive marker of cardiac autonomic control and a low HRV is a predictor for SCD and arrhythmic events. Studies on HRV and omega-3 PUFA have been performed in several populations such as patients with ischemic heart disease, patients with diabetes mellitus, patients with chronic renal failure, and in healthy subjects as well as in children. The studies have demonstrated a positive association between cellular content of omega-3 PUFA and HRV and supplementation with omega-3 PUFA seems to increase HRV which could be a possible explanation for decreased risk of arrhythmic events and SCD sometimes observed after omega-3 PUFA supplementation. However, the results are not consistent and further research is needed.

Effect of intravenous omega-3 fatty acid infusion and hemodialysis on fatty acid composition of free fatty acids and phospholipids in patients with end-stage renal disease.

BACKGROUND: Patients treated with hemodialysis (HD) have been reported to have decreased levels of ω-3 polyunsaturated fatty acids (PUFAs) in plasma and cells. The aim of this study was to investigate the effect of ω-3 PUFAs administered intravenously during HD, as well as the effect of HD treatment, on the fatty acid composition of plasma free fatty acids (FFAs), plasma phospholipids, and platelet phospholipids. METHODS: Forty-four HD patients were randomized to groups receiving either a single dose of a lipid emulsion containing 4.1 g of ω-3 PUFAs or placebo (saline) administered intravenously during HD. Blood was drawn immediately before (baseline) and after (4 hours) HD and before the next HD session (48 hours). Fatty acid composition was measured using gas chromatography. RESULTS: The increase in ω-3 FFAs was greater in the ω-3 PUFA group compared with the placebo group, whereas the increase in total FFAs was similar between the 2 groups. In the ω-3 PUFA group, ω-3 PUFAs in plasma phospholipids were higher after 48 hours than at baseline, and in platelet phospholipids, ω-3 PUFAs increased after 4 hours. In the placebo group, no changes were observed in ω-3 PUFAs in plasma and platelet phospholipids. CONCLUSIONS: Intravenous ω-3 PUFAs administered during HD caused a transient selective increase in ω-3 FFA concentration. Furthermore, ω-3 PUFAs were rapidly incorporated into platelets, and the content of ω-3 PUFAs in plasma phospholipids increased after 48 hours.

Intravenous infusion of n-3 polyunsaturated fatty acids and inducibility of ventricular tachycardia in patients with implantable cardioverter defibrillator.

AIMS: Marine n-3 polyunsaturated fatty acids (PUFA) may have antiarrhythmic effects. The aim of this study was to investigate the effect of intravenously administered n-3 PUFA on the inducibility of ventricular tachycardia (VT) in patients with an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: In a randomized, placebo-controlled cross-over study, patients with an ICD underwent two electrophysiological studies using the stimulation possibilities in the ICD preceded by intravenous infusion of either a lipid emulsion delivering 3.9 g n-3 PUFA or placebo (0.9% saline). The level of stimulation required to induce sustained monomorphic VT was ranked in order from least to most aggressive, and non-inducibility was ranked highest. The content of n-3 PUFA in plasma free fatty acids (FFA), plasma phospholipids, and platelet phospholipids was measured by gas chromatography. Eight patients were included, and six of these completed the study. The content of n-3 PUFA as FFA and in platelet phospholipids increased more after n-3 PUFA infusion than after placebo (P<0.001). Of the five patients who were inducible after placebo, two were no longer inducible after n-3 PUFA infusion and another two required stronger stimulation to induce VT. The difference in the stimulation required after placebo and after n-3 PUFA was borderline significant (P=0.063, Wilcoxon signed-rank test). CONCLUSION: Intravenous n-3 PUFA tended to decrease VT inducibility, but a larger study is warranted.

The effect of marine n-3 fatty acids in different doses on plasma concentrations of Lp-PLA2 in healthy adults.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging independent risk factor for cardiovascular disease (CVD). Lp-PLA(2) can be modified by lipid lowering drugs, but it is unknown whether diet can reduce plasma levels of Lp-PLA(2). AIM OF THE STUDY: The aim of the trial was to study the effect of marine n-3 polyunsaturated fatty acids (PUFA) on plasma Lp-PLA(2) levels in healthy subjects. METHODS: Sixty healthy subjects were randomized to a moderate dose (2 g) of n-3 PUFA, a high dose (6.6 g) of n-3 PUFA or olive oil (control) daily for 12 weeks. Plasma Lp-PLA(2) was measured at baseline and after the interventions. RESULTS: Plasma Lp-PLA(2) levels were unchanged in all three groups before and after the supplements. Neither did the results differ between groups. There was no correlation between the content of n-3 PUFA in platelets or granulocytes or plasma Lp-PLA(2). CONCLUSION: Marine n-3 PUFA had no effect on plasma levels of Lp-PLA(2) in healthy adults and relatively young people.

Adiponectin and marine n-3 fatty acids in patients referred for coronary angiography.

Marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may reduce the risk of coronary heart disease (CHD) and have anti-inflammatory effects. We examined whether levels of serum adiponectin were related to the occurrence and extent of CHD, and whether intake of n-3 PUFAs was associated to high levels of adiponectin. Serum adiponectin and the content of n-3 PUFAs in subcutaneous adipose tissue, platelets and granulocytes were measured in 291 patients referred to elective coronary angiography. Significantly lower levels of serum adiponectin were observed in patients with coronary stenoses compared to patients without stenoses (7336+/-3598 ng/ml vs 10,203+/-8396 ng/ml; p=0.003), but no significant correlation was seen between serum adiponectin and the extent of CHD. In men, serum adiponectin correlated to levels of the content of EPA in platelets (r=0.26; p<0.01) and in granulocytes (r=0.23; p<0.01) and to the content of DHA in subcutaneous adipose tissue (r=0.15; p<0.05) and granulocytes (r=0.17; p<0.05). After regression analysis EPA in platelets (p=0.017) and granulocytes (p=0.030) remained an independent correlate of adiponectin levels, while DHA was no longer an independent correlate. In conclusion, serum levels of adiponectin were lower in patients with angiographically documented coronary artery disease. Also, intake of EPA may increase serum adiponectin and through this exert a protective effect on CHD.

Effect of the administration of n-3 polyunsaturated fatty acids on circulating levels of microparticles in patients with a previous myocardial infarction.

BACKGROUND: Increased levels of microparticles exposing tissue factor circulate in the blood of patients with coronary heart disease, possibly disseminating their pro-thrombotic and pro-inflammatory potential. Because diets rich in n-3 (polyunsaturated) fatty acids have been associated with reduced incidence of coronary heart disease-related events, we investigated the in vivo effects of treatments with n-3 fatty acids on levels of circulating microparticles and their tissue factor- dependent procoagulant activity in patients with a previous myocardial infarction. DESIGN AND METHODS: Forty-six post-myocardial infarction patients were assigned to receive either 5.2 g of n-3 fatty acids daily (n=23) or an olive oil placebo (n = 23) for 12 weeks. Circulating microparticles were isolated from peripheral blood. The number of microparticles, their cellular source and tissue factor antigen were determined by flow cytometry, and their procoagulant potential assayed by a fibrin generation test. RESULTS: The total number of microparticles, endothelium-derived microparticles and microparticle tissue factor antigen were not significantly different between the two groups. However, the number of platelet-derived microparticles [from a median of 431 (126-1796, range) x 10(6)/L to a median of 226 (87-677, range)] x 10(6)/L and monocyte-derived microparticles [from a median of 388 (9-1681, range) x 10(6)/L to a median of 265 (7-984, range) x 10(6)/L] in plasma were significantly (p < 0.05) decreased by n-3 fatty acids, while they were unchanged in the placebo group. Total microparticle tissue factor-procoagulant activity was also reduced in the n-3 fatty acid group compared to that in the placebo group. CONCLUSIONS: Treatment with n-3 fatty acids after myocardial infarction exerts favorable effects on levels of platelet- and monocyte-derived microparticles, thus possibly explaining some of the anti-inflammatory and anti-thrombotic properties of these natural compounds.

Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor for cardiovascular disease. In the present study, plasma levels of Lp-PLA(2) were measured in patients (n=301) admitted to elective coronary angiography because of suspected coronary artery disease (CAD). In a multiple linear regression analysis, the degree of CAD (0-, 1-, 2- or 3-vessel disease) and plasma LDL cholesterol significantly correlated to Lp-PLA(2) levels. Also the content of the marine n-3 fatty acid, eicosapentaenoic acid (EPA) in adipose tissue, a measure of long-term intake of seafood independently and inversely (r=-0.18, p<0.01) correlated with plasma levels of Lp-PLA(2). The results support the view that Lp-PLA(2) may relate to CAD and that intake of marine n-3 fatty acids might reduce plasma Lp-PLA(2) suggesting another mechanism by which n-3 fatty acids could reduce the risk of cardiovascular disease.

Autonomic nervous system, heart rate variability and n-3 fatty acids.

Animal and in-vitro studies have shown profound antiarrhythmic effects of n-3 polyunsaturated fatty acids (PUFAs) on the heart. Because n-3 PUFAs (in particular docosahexaenoic acid) are abundant in nervous tissue, this antiarrhythmic effect may be mediated by effects of n-3 PUFAs on autonomic control or tone. This paper reviews the effect of n-3 PUFAs on heart rate variability, a noninvasive indicator of cardiac autonomic function. In most, although not all, studies, dietary n-3 PUFA levels and n-3 PUFA supplementation are related to improved heart rate variability. Although further research is required to confirm these relationships, the results support a beneficial effect of n-3 PUFAs on autonomic tone in humans, specifically an increase in vagal tone, which may reduce the risk of arrhythmias. The modulation of heart rate variability by n-3 PUFAs may partly explain the reduction in sudden cardiac death observed in subjects with a regular intake of n-3 PUFAs.

Fish, marine n-3 polyunsaturated fatty acids and coronary heart disease: a minireview with focus on clinical trial data.

In this paper, we will briefly deal with the background for the possible effects of long-chain marine n-3 (also called omega-3) polyunsaturated fatty acids (PUFA) in coronary heart disease (CHD) and then focus on findings from clinical trials in humans. We will not deal with effects of alpha-linolenic acid, the non-marine type of n-3 PUFA derived from plant oils.

Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer.

OBJECTIVE: To compare the levels of n-3 polyunsaturated fatty acids (PUFAs) in leukocytes and prostate tissue in men with prostate cancer or benign prostatic hyperplasia (BPH), as dietary intake of n-3 PUFAs has been linked to the risk of prostate cancer; the prostate-specific antigen (PSA) level was also compared to prostate tissue levels of n-3 PUFAs. PATIENTS AND METHODS: Prostate tissue was obtained and leukocytes isolated from 20 men with prostate cancer and 35 with BPH. The n-3 PUFAs alpha-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) were measured in prostate tissue and in peripheral blood leukocytes using gas chromatography. PSA levels were measured in all of the men. RESULTS: There was a strong positive correlation between EPA and DHA in leukocytes and in prostate tissue (EPA: r = 0.80, DHA: r = 0.53, both P < 0.001) in all the men, whereas there was no association between the content of ALA in leukocytes and in prostate tissue (r = -0.15). Men with BPH had similar levels of ALA in leukocytes and in prostate tissue, but men with prostate cancer had more ALA in prostate tissue than in leukocytes. The PSA level was significantly positively correlated with ALA level in prostate tissue (r = 0.42, P < 0.01) but there was no significant correlation between PSA level and EPA and DHA levels. There were no significant correlations between PSA level and n-3 PUFA levels in leukocytes. CONCLUSION: Dietary intake of the marine n-3 PUFAs reflected in EPA and DHA levels in leukocytes are also reflected in EPA and DHA levels in prostate tissue in men with and without prostate cancer. However, there is a discrepancy between the levels of ALA in leukocytes and in prostate tissue, with higher levels in men with prostate cancer. This is in accordance with the strong positive association between PSA and ALA levels in prostate tissue. This study therefore does not support the hypothesis that intake of marine n-3 PUFAs might protect against prostate cancer, but lends support to the deleterious role of ALA in the development of prostate cancer.

N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial.

Patients who are treated with chronic hemodialysis (HD) experience premature cardiovascular disease and an increased mortality. N-3 polyunsaturated fatty acids (PUFA) may be effective in the secondary prevention of cardiovascular disease, but the effects of n-3 PUFA has not previously been examined in HD patients. It was hypothesized that secondary prevention with n-3 PUFA would reduce the number of cardiovascular events and death in patients who are treated with chronic HD. A randomized, double-blind, placebo-controlled intervention trial compared the effect of n-3 PUFA and a control treatment as secondary prevention of cardiovascular events in HD patients. The primary outcome was a composite of total cardiovascular events and death. A total of 206 patients were randomly assigned to treatment with n-3 PUFA or control treatment and followed for 2 yr or until reaching a predefined end point. During the trial, 121 (59%) of 206 patients reached a primary end point. N-3 PUFA had no significant effect on the primary composite end point of cardiovascular events and death (62 versus 59; NS). In the n-3 PUFA group, a significant reduction was seen in the number of myocardial infarctions (four versus 13; P = 0.036). This trial was limited by a relatively small number of patients and a large number of withdrawals. However, it is concluded that treatment with n-3 PUFA did not reduce the total number of cardiovascular events and death in this high-risk population. N-3 PUFA significantly reduced the number of myocardial infarctions as a secondary outcome, a finding that might be of clinical interest.