Dietary omega-3 fatty acid reverses age-linked heart failure with preserved ejection fraction

Abstract Objectives:To evaluate the association of Omega-3 fatty-acid (O3-FA) blood levels with cardiometabolic risk markers, functional capacity and cardiac function/morphology in HFpEF patients.Background:O3-FA demonstrated favorable effects on heart failure and associated phenotypic traits in experimental/clinical studies. In patients with heart failure with preserved ejection fraction (HFpEF), the association of O3-FA status with patient characteristics is unknown.Methods:This is a cross-sectional analysis of baseline data from the Aldo-DHF-RCT. From 422 patients, the omega-3-index (O3I=EPA+DHA) was analyzed in n=404 using the HS-Omega-3-Index® methodology. Patient characteristics were; 67±8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥50%, E/e´ 7.1±1.5; median NT-proBNP 158 ng/L (IQR 82-298). Pearson's correlation coefficient was used to describe associations of the O3I with metabolic phenotype, exercise capacity, echocardiographic markers for LVDF, and neurohumoral activation.Results:The O3I was below(<8%)/within(8-11%)/higher >11%) than the target range in 374 (93%)/29 (7%)/1 (0.2%) patients respectively. Mean O3I was 5.7±1.7%. The O3I was inversely associated with HbA1c (r=-0.139, p=0.006), triglycerides-to-HDL-C ratio (r=-0.12, p=0.017), triglycerides (r=-0.117, p=0.02), non-HDL-C (r=-0.101, p=0.044), body-mass-index (r=-0.149, p=0.003), waist circumference (r=-0.121, p=0.015), waist-to-height ratio (r=-0.141, p=0.005), and positively associated with submaximal aerobic capacity (r=0.113, p=0.023) and LVEF (r=0.211, p<0.001). We did not observe an association between the =3I and maximal functional capacity, echocardiographic markers of LVDF or NT-proBNP.Conclusions:Higher O3I was associated with a more favorable cardiometabolic risk profile and better submaximal aerobic capacity in HFpEF patients but did not correlate with echocardiographic markers for left ventricular filling pressures, left ventricular relaxation or neurohumoral activation.

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Daily Omega-3 Fatty Acid Improves Heart Failure Symptoms

Internal Medicine News ◽

10.1016/s1097-8690(11)70067-1 ◽

2011 ◽

Vol 44 (2) ◽

pp. 20

Author(s):

ROBERT FINN

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Omega 3 ◽

Omega 3 Fatty Acid

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Skeletal Muscle Function, Structure, and Metabolism in Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction

Circulation Heart Failure ◽

10.1161/circheartfailure.120.007198 ◽

2020 ◽

Vol 13 (12) ◽

Author(s):

Tarek Bekfani ◽

Mohamed Bekhite Elsaied ◽

Steffen Derlien ◽

Jenny Nisser ◽

Martin Westermann ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Fatty Acid ◽

Ejection Fraction ◽

Oral Anticoagulation ◽

Muscle Function ◽

Muscle Endurance ◽

Acid Oxidation ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction

Background: Reduced exercise capacity in patients with heart failure (HF) could be partially explained by skeletal muscle dysfunction. We compared skeletal muscle function, structure, and metabolism among clinically stable outpatients with HF with preserved ejection fraction, HF with reduced ejection fraction, and healthy controls (HC). Furthermore, the molecular, metabolic, and clinical profile of patients with reduced muscle endurance was described. Methods: Fifty-five participants were recruited prospectively at the University Hospital Jena (17 HF with preserved ejection fraction, 18 HF with reduced ejection fraction, and 20 HC). All participants underwent echocardiography, cardiopulmonary exercise testing, 6-minute walking test, isokinetic muscle function, and skeletal muscle biopsies. Expression levels of fatty acid oxidation, glucose metabolism, atrophy genes, and proteins as well as inflammatory biomarkers were assessed. Mitochondria were evaluated using electron microscopy. Results: Patients with HF with preserved ejection fraction showed compared with HF with reduced ejection fraction and HC reduced muscle strength (eccentric extension: 13.3±5.0 versus 18.0±5.9 versus 17.9±5.1 Nm/kg, P =0.04), elevated levels of MSTN-2 (myostatin-2), FBXO-32 (F-box only protein 32 [Atrogin1]) gene and protein, and smaller mitochondrial size ( P <0.05). Mitochondrial function and fatty acid and glucose metabolism were impaired in HF-patients compared with HC ( P <0.05). In a multiple regression analysis, GDF-15 (growth and differentiation factor 15), CPT1B (carnitine palmitoyltransferase IB)-protein and oral anticoagulation were independent factors for predicting reduced muscle endurance after adjusting for age (log10 GDF-15 [pg/mL] [B, −54.3 (95% CI, −106 to −2.00), P =0.043], log10 CPT1B per fold increase [B, 49.3 (95% CI, 1.90–96.77), P =0.042]; oral anticoagulation present [B, 44.8 (95% CI, 27.90–61.78), P <0.001]). Conclusions: Patients with HF with preserved ejection fraction have worse muscle function and predominant muscle atrophy compared with those with HF with reduced ejection fraction and HC. Inflammatory biomarkers, fatty acid oxidation, and oral anticoagulation were independent factors for predicting reduced muscle endurance.

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Abstract P389: Free Fatty Acid Receptor 4 Is Necessary For An Adaptive Response Following Heart Failure Induced By Metabolic Syndrome In Mice

Circulation Research ◽

10.1161/res.129.suppl_1.p389 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Naixin Zhang ◽

Katherine A Murphy ◽

Dylan J Gyberg ◽

Timothy D O'Connell

Keyword(s):

Heart Failure ◽

Metabolic Syndrome ◽

Fatty Acid ◽

Free Fatty Acid ◽

Ejection Fraction ◽

Mouse Model ◽

Diastolic Dysfunction ◽

Preserved Ejection Fraction ◽

Acid Receptor ◽

Free Fatty Acid Receptor

Non-resolving inflammation is central to the pathogenesis of heart failure (HF). Heart failure preserved ejection fraction (HFpEF) is a type of HF that is particularly associated with inflammation provoked by metabolic syndrome (MetS). The G-protein coupled receptor, free fatty acid receptor 4 (Ffar4), is a receptor for medium and long chain fatty acids (FA) that regulates metabolism and attenuates inflammation. Ffar4 is expressed in the human heart, and downregulated in heart failure. Furthermore, polymorphisms in Ffar4 have been associated with eccentric remodeling in a patient cohort. Previously, Ffar4 was shown to protect the heart from pathologic stress by attenuating oxidative stress in a mouse model of pressure overload. Here, we tested the hypothesis that Ffar4 would attenuate the development of heart failure using a mouse model of MetS-induced HFpEF. Metabolic syndrome was induced in mice by feeding a high-fat, high-sucrose diet (42% fat, 30% sucrose) to produce obesity and delivering the nitric oxide synthase inhibitor, L-NAME, in the drinking water to induce hypertension. The combined intervention (referred to as HFpEF diet) resulted in mice developing excessive adiposity, glucose intolerance (in males only), and mild hypertension. After 20 weeks on the HFpEF diet, both male and female WT mice, developed diastolic dysfunction (increased E/A and E/e’) and preserved ejection fraction (EF), consistent with clinical HFpEF. In Ffar4KO male mice HFpEF diet induced a greater degree of diastolic dysfunction compared to WT mice, despite equivalent metabolic parameters. Female Ffar4KO mice fed the HFpEF diet had a greater increase in weight gain and adiposity compared to WT female mice. Surprisingly, diastolic function was equivalent between WT and FFAR4KO female mice, suggesting a sex-based difference in FFAR4 cardioprotection. Our data show that Ffar4 attenuates HFpEF secondary to MetS.

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Lifelong dietary omega-3 fatty acid reverses cardiac and vascular dysfunction via MMP-2 modulation in aged mice

European Heart Journal ◽

10.1093/eurheartj/ehab724.3303 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

S S Saeedi Saravi ◽

N R Bonetti ◽

A Vukolic ◽

L Liberale ◽

D Vdovenko ◽

...

Keyword(s):

Fatty Acid ◽

Arterial Stiffness ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Interstitial Fibrosis ◽

Left Ventricular ◽

Omega 3 ◽

Omega 3 Fatty Acid ◽

Aged Mice ◽

Age Related

Abstract Background Aging has a remarkable effect on the cardiovascular system, and negatively causes structural and functional changes in the heart including diastolic/systolic dysfunction and left ventricular (LV) dyssynchrony, as well as, arterial stiffness which may develop to heart failure with preserved ejection fraction (HFpEF) in aged adults. We recently showed that the plant-derived omega-3-fatty-acid α-linolenic-acid (ALA) has emerged to confer potential protective effects against cardiovascular disease. Since cardiovascular aging is a chronic process, we hypothesized that a lifelong effective dietary supplementation with ALA will reverse or prevent age-related diastolic and arterial dysfunction during aging. Purpose Here, we test the hypotheses that (1) lifelong dietary ALA will prevent LV diastolic and arterial dysfunction in aged mice and that (2) lifelong dietary ALA will prevent the age-related cardiovascular dysfunction through modiulation of matrix-metalloproteinase-2 (MMP-2) in the heart and arteries. Methods and results 6-month-old (young) wild-type C57BL/6J mice were fed a low (0.03%), as control, or high ALA (7.3%) diet for more than 12 months. Our results show that aged (>18 months) mice on low ALA diet recapitulate major hallmarks of HFpEF, including diastolic dysfunction with preserved left ventricular ejection fraction, cardiac interstitial fibrosis, impaired acetylcholine-induced relaxation of aortic segments, and arterial stiffness. Intriguingly, we revealed that lifelong ALA-rich diet prevents diastolic dysfunction, vascular relaxation capacity, reduced pulse wave velocity, interstitial fibrosis, and coincident hemodynamic abnormalities in aged mice. Lifelong dietary ALA-in the prevention strategy-was associated with remarkably reduced cardiac and aortic MMP-2 and COX-2 expression, lower levels of pro-inflammatory cytokine TNF-α, and increased isocitrate dehydrogenase 2 (Idh2) expression, decreased function of which has previously been associated with cardiac dysfunction. Conclusions Our data support that lifelong ALA-rich diet restores normal cardiac and vascular function in aged mice with LV diastolic and arterial dysfunction and prevents development of age-related cardiovascular dysfunction through the modulation of MMP-2 signaling. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): 1. Swiss National Science Foundation (number 324730_182328)2. the Kardio Stiftung, Baden, Switzerland

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Omega-3 Red Blood Cell Content Is Associated with Fat Mass Index and Leptin in Subjects with Obesity and Heart Failure with Preserved Ejection Fraction (P21-001-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz041.p21-001-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Hayley Billingsley ◽

Salvatore Carbone ◽

Justin Canada ◽

Leo Buckley ◽

Dave Dixon ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Blood Cell ◽

Fat Mass ◽

Red Blood Cell ◽

Overweight And Obesity ◽

Exercise Intolerance ◽

Preserved Ejection Fraction ◽

Omega 3 ◽

Pufa Content

Abstract Objectives Overweight and obesity affect 80% of patients with heart failure and preserved ejection fraction (HFpEF). Exercise intolerance is a cardinal manifestation of HFpEF and is associated with excess fat mass (FM). Dietary polyunsaturated fatty acids (PUFA) have been associated with lower FM. However, the relationship between Omega-3 (N-3) PUFA and FM in HFpEF remains unclear. Red blood cell membrane (RBC) N-3 and omega-6 (N-6) PUFA content may serve as better objective measures of intake than subject-reported data. We hypothesized that increased RBC omega-3 (N-3) content is associated with lower FM and leptin in subjects with obesity and HFpEF. Methods Twenty-four consecutive subjects with HFpEF underwent body composition measurement with bioelectrical impedance analysis to obtain FM Index (FMI; kg/m2) and venipuncture to obtain RBC total percentage of N-3 PUFA content (RBC N-3%) as well as the ratio of N-6 to N-3 PUFA (N-6/N-3 ratio). Results Fourteen subjects were female (58%) with a median age of 53 (interquartile range [IQR] 48–63). Median BMI was 42.4 kg/m2 (38.1–47.4) and FMI was 18.7 kg/m2 (14.2–22.7). Median leptin was 82.5 ng/mL (63.5–116.5), RBC N-3% was 7.4% (6.6–8.9), and N-6/N-3 ratio was 5.00 (4.03–5.70). RBC N-3% was inversely associated with FMI (r = −0.406, P = 0.049), while N-6/N-3 ratio was positively associated with FMI (r = +0.472, P = 0.020) (Figure 1A and B). N-6/N-3 ratio was also associated with leptin (r = +0.462, P = 0.023), while RBC N-3% presented an inverse trend with leptin (r = −0.388, r = 0.061) (Figure 1C and D). Conclusions Higher percentage of N-3 PUFA in RBC membranes is associated with lower FMI and leptin in subjects with obesity and HFpEF. These findings suggest that increasing dietary N-3 intake and reducing N-6/N-3 ratio may protect against adiposity in HFpEF. Funding Sources This cross-sectional analysis was performed from baseline data of the DHART2 clinical trial (NCT02173548) and was funded by the NIH (1R34HL11348-01A1). Supporting Tables, Images and/or Graphs

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