A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation.

BACKGROUND: There is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα). METHODS: hTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma. RESULTS: The n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal ß-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice. CONCLUSIONS: The FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.

Coronary calcium score in the initial evaluation of suspected coronary artery disease.

OBJECTIVE: We evaluated coronary artery calcium (CAC) scoring as an initial diagnostic tool in outpatients and in patients presenting at the emergency department due to suspected coronary artery disease (CAD). METHODS: 10 857 patients underwent CAC scoring and coronary CT angiography (CCTA) at Haukeland University Hospital in Norway during 2013-2020. Based on CCTA, obstructive CAD was defined as at least one coronary stenosis ≥50%. High-risk CAD included obstructive stenoses of the left main stem, the proximal left ascending artery or affecting all three major vascular territories with at least one proximal segment involved. RESULTS: Median age was 58 years and 49.5% were women. The overall prevalence of CAC=0 was 45.0%. Among those with CAC=0, 1.8% had obstructive CAD and 0.6% had high-risk CAD on CCTA. Overall, the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of CAC=0 for obstructive CAD were 95.3%, 53.4%, 30.0% and 98.2%, respectively. However, among patients <45 years of age, although the NPV was high at 98.9%, the sensitivity of CAC=0 for obstructive CAD was only 82.3%. CONCLUSIONS: In symptomatic patients, CAC=0 correctly ruled out obstructive CAD and high-risk CAD in 98.2% and 99.4% of cases. This large registry-based cross-sectional study supports the incorporation of CAC testing in the early triage of patients with chest pain and as a gatekeeper to further cardiac testing. However, a full CCTA may be needed for safely ruling out obstructive CAD in the youngest patients (<45 years of age).

Long-term treatment with the pan-PPAR agonist tetradecylthioacetic acid or fish oil is associated with increased cardiac content of n-3 fatty acids in rat.

BACKGROUND: Excess peroxisome proliferator-activated receptor (PPAR) stimulation has been associated with detrimental health effects including impaired myocardial function. Recently, supplementation with n-3 polyunsaturated fatty acids (PUFA) has been associated with improved left ventricular function and functional capacity in patients with dilated cardiomyopathy. We investigated the long-term effects of the pan-PPAR agonist tetradecylthioacetic acid (TTA) and/or high-dose fish oil (FO) on cardiac fatty acid (FA) composition and lipid metabolism. Male Wistar rats were given one out of four different 25% (w/v) fat diets: control diet; TTA diet; FO diet; or diet containing both TTA and FO. RESULTS: After 50 weeks n-3 PUFA levels were increased by TTA and FO in the heart, whereas liver levels were reduced following TTA administration. TTA was associated with a decrease in arachidonic acid, increased activities of carnitine palmitoyltransferase II, fatty acyl-CoA oxidase, glycerol-3-phosphate acyltransferase, and fatty acid synthase in the heart. Furthermore, cardiac Ucp3 and Cact mRNA was upregulated. CONCLUSIONS: Long-term treatment with the pan-PPAR agonist TTA or high-dose FO induced marked changes in PUFA composition and enzymatic activity involved in FA metabolism in the heart, different from liver. Changes included increased FA oxidation and a selective increase in cardiac n-3 PUFA.

Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia.

BACKGROUND AND AIMS: Women with heterozygous familial hypercholesterolemia (FH) are recommended to initiate statin treatment at the same age as men (from 8 to 10 years of age). However, statins are contraindicated when pregnancy is planned, during pregnancy and breastfeeding. The aim of the study was to determine the duration of pregnancy-related off-statin periods and breastfeeding in FH women. METHODS: A cross-sectional study using an anonymous online self-administered questionnaire was conducted. Women with FH were recruited through Lipid Clinics in Norway and Netherlands and national FH patient organizations. RESULTS: 102 women with FH (n = 70 Norwegian and n = 32 Dutch) were included in the analysis. Total length of pregnancy-related off-statin periods was estimated for 80 women where data were available, and was median (min-max) 2.3 (0-14.2) years. Lost statin treatment time was estimated for 67 women where data were available, and was median (min-max) 18 (0-100)% at mean (SD) age of 31 (4.3) years at last pregnancy. More women breastfed in Norway (83%) and for longer time [8.5 [1-42] months] compared to the Netherlands [63%, p = 0.03; 3.6 (0-14) months, p < 0.001]. Eighty-six percent of the women reported need for more information on pregnancy and breastfeeding in relation to FH. CONCLUSIONS: Young FH women lose years of treatment when discontinuing statins in relation to pregnancy and breastfeeding periods and should be closely followed up to minimize the duration of these off-statin periods. Whether these periods of interrupted treatment increase the cardiovascular risk in FH women needs to be further elucidated.

A complex role of activin A in non-alcoholic fatty liver disease.

OBJECTIVES: Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes. RESULTS: Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A-follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-beta(1), promoted matrix metalloproteinase activity, induced mitochondrial beta-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs. CONCLUSIONS: Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.

Use of Loop Diuretics is Associated with Increased Mortality in Patients with Suspected Coronary Artery Disease, but without Systolic Heart Failure or Renal Impairment: An Observational Study Using Propensity Score Matching.

BACKGROUND: Loop diuretics are widely used in patients with heart and renal failure, as well as to treat hypertension and peripheral edema. However, there are no randomized, controlled trials (RCT) evaluating their long term safety, and several observational reports have indicated adverse effects. We sought to evaluate the impact of loop diuretics on long term survival in patients with suspected coronary artery disease, but without clinical heart failure, reduced left ventricular ejection fraction or impaired renal function. METHOD AND FINDINGS: From 3101 patients undergoing coronary angiography for suspected stable angina pectoris, subjects taking loop diuretics (n=109) were matched with controls (n=198) in an attempted 1:2 ratio, using propensity scores based on 59 baseline variables. During median follow-up of 10.1 years, 37.6% in the loop diuretics group and 23.7% in the control group died (log-rank p-value 0.005). Treatment with loop diuretics was associated with a hazard ratio (95% confidence interval) of 1.82 (1.20, 2.76), and the number needed to harm was 7.2 (4.1, 30.3). Inclusion of all 3101 patients using propensity score weighting and adjustment for numerous covariates provided similar estimates. The main limitation is the potential of confounding from unmeasured patient characteristics. CONCLUSIONS: The use of loop diuretics in patients with suspected coronary artery disease, but without systolic heart failure or renal impairment, is associated with increased risk of all-cause mortality. Considering the lack of randomized controlled trials to evaluate long term safety of loop diuretics, our data suggest caution when prescribing these drugs to patients without a clear indication.