Western Diet Causes Heart Failure With Reduced Ejection Fraction and Metabolic Shifts After Diastolic Dysfunction and Novel Cardiac Lipid Derangements.
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ABSTRACT:
SUBMITTER: Maurya SK
PROVIDER: S-EPMC10149654 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
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Western Diet Causes Heart Failure With Reduced Ejection Fraction and Metabolic Shifts After Diastolic Dysfunction and Novel Cardiac Lipid Derangements.
Maurya Santosh K SK Carley Andrew N AN Maurya Chandan K CK Lewandowski E Douglas ED
JACC. Basic to translational science 20230125 4
Western diet (WD) impairs glucose tolerance and cardiac lipid dynamics, preceding heart failure with reduced ejection fraction (HFrEF) in mice. Unlike diabetic db/db mice with high cardiac triglyceride (TG) and rapid TG turnover, WD mice had high TG but slowed turnover, reducing lipolytic PPAR⍺ activation. WD deranged cardiac TG dynamics by imbalancing synthesis and lipolysis, with low cardiac TG lipase (ATGL), low ATGL co-activator, and high ATGL inhibitory peptide. By 24 weeks of WD, hearts sh ...[more]
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Project description:Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a “two-hit” model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat and 0.5% N(ω)-nitro-L-arginine methyl ester (HFD+L-NAME) diet, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME. Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein nicotinamide nucleotide transhydrogenase (Nnt), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background, were challenged with HFD+L-NAME for 9 weeks (n = 6-10). Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e’ (42.8 vs. 21.5, P = 1.2e-10), E/A (2.3 vs 1.4, P = 4.1e-2), diastolic stiffness (0.09 vs 0.04 mmHg/μL, P = 5.1e-3), and myocardial fibrosis (P = 2.3e-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P = 8.4e-3) and a 38.8% reduction in GSH:GSSG (P = 2.6e-2) among Nnt+/+ mice after HFD+L-NAME feeding. Using single-nucleus ligand-receptor analysis, we implicate fibroblast growth factor 1 (Fgf1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis. Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis and position both NNT and Fgf1 as novel therapeutic targets.
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Project description:AimsWe hypothesized that grading of diastolic dysfunction (DDF) according to two DDF grading algorithms and strain imaging yields prognostic information on all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF).Methods and resultsWe enrolled ambulatory HFrEF (left ventricular ejection fraction < 45%; N = 1 065) patients who underwent echocardiography and speckle tracking assessment of global longitudinal strain (GLS). Patients were stratified according to DDF grades (Grades I-III) according to two contemporary DDF grading algorithms. Prognostic performance was assessed by C-statistics. Of the originally 1 065 enrolled patients, a total of 645 (61%) patients (age: 67 ± 11 years, male: 72%, ejection fraction: 27 ± 9%) were classified according to both DDF grading algorithms. Concordance between the algorithms was moderate (kappa = 0.48) and the reclassification rate was 33%. During a median follow-up of 3.3 years (1.9, 4.7 years), 101 (16%) died from all causes. When comparing DDF Grade I vs. Grade III, both algorithms provided prognostic information [Nagueh: (hazard ratio) HR 2.09, 95% confidence interval (CI),1.32-3.31, P = 0.002; Johansen: HR 2.47, 95% CI, 1.57-3.87, P < 0.001]. However, when comparing DDF Grade II vs. Grade III, only the Johansen algorithm yielded prognostic information (Nagueh: HR 1.04, 95% CI, 0.60-1.77, P = 0.90; Johansen: HR 2.26, 95% CI, 1.35-3.77, P = 0.002). We found no difference in prognostic performance between the two algorithms (C-statistics: 0.604 vs. 0.623, P = 0.24). Assessed by C-statistics, the most powerful predictors of the endpoint from the two algorithms were E/e'-ratio (C-statistics: 0.644), tricuspid regurgitation velocity (C-statistics: 0.625) and E/A-ratio (C-statistics: 0.602). When adding GLS to a combination of these predictors, the prognostic performance increased significantly (C-statistics: 0.705 vs. C-statistics: 0.634, P = 0.028).ConclusionsEvaluation of DDF in patients with HFrEF yields prognostic information on all-cause mortality. Furthermore, adding GLS to contemporary algorithms of DDF adds novel prognostic information.
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Project description:Background Heart failure phenotyping in single-ventricle Fontan patients is challenging, particularly in patients with normal ejection fraction (EF). The objective of this study was to identify Fontan patients with abnormal diastolic function, who are high risk for heart failure with preserved ejection fraction (HFpEF), and characterize their cardiac mechanics, exercise function, and functional health status. Methods and Results Data were obtained from the Pediatric Heart Network Fontan Cross-sectional Study database. EF was considered abnormal if <50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e'/end-diastolic volume) was >90th percentile (≥0.26 mL-1). Patients were divided into: controls=normal EF and diastolic function; systolic dysfunction (SD) = abnormal EF with normal diastolic function; diastolic dysfunction (DD) = normal EF with abnormal diastolic pressure:volume quotient. Exercise function was quantified as percent predicted peak VO2. Physical Functioning Summary Score (FSS) was reported from the Child Health Questionnaire. A total of 239 patients were included, 177 (74%) control, 36 (15%) SD, and 26 (11%) DD. Median age was 12.2 (5.4) years. Arterial elastance, a measure of arterial stiffness, was higher in DD (3.6±1.1 mm Hg/mL) compared with controls (2.5±0.8 mm Hg/mL), P<0.01. DD patients had lower predicted peak VO2 compared with controls (52% [20] versus 67% [23], P<0.01). Physical FSS was lower in DD (45±13) and SD (44±13) compared with controls (50±7), P<0.01. Conclusions Fontan patients with abnormal diastolic function and normal EF have decreased exercise tolerance, decreased functional health status, and elevated arterial stiffness. Identification of patients at high risk for HFpEF is feasible and should be considered when evaluating Fontan patients.
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Project description:Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.
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Project description:AimsWe aim to investigate the association between kidney dysfunction and left ventricular diastolic dysfunction parameters and heart failure with preserved ejection fraction (HFpEF) and whether this is sex-specific.Methods and resultsWe included participants from the HELPFul observational study. Outpatient clinical care data, including echocardiography, and an expert panel judgement on HFpEF was collected. Estimated glomerular filtration rate (eGFR) was calculated by creatinine and cystatin C without race. The association between eGFR with E/e', left ventricular mass index, relative wall thickness, and stage C/D heart failure was tested by multivariable adjusted regression models, stratified by sex, reporting odds ratios and 95% confidence intervals (95% confidence interval). We analysed 880 participants, mean age 62.9 (standard deviation: 9.3) years, 69% female. Four hundred six participants had mild (37.6%) kidney dysfunction (eGFR: 60-89 mL/min/1.73 m2 ) or moderate (8.5%) kidney dysfunction (eGFR: 30-59 mL/min/1.73 m2 ). HFpEF was significantly more prevalent in participants with mild and moderate kidney dysfunction (10.3% and 16.0%, respectively) than participants with normal kidney function (3.4%). A lower kidney function was associated with higher E/e' and higher relative wall thickness values. Participants with moderate kidney dysfunction had a higher likelihood of American College of Cardiology/American Heart Association stage C/D HF (odds ratio: 2.07, 95% confidence interval: 1.23, 3.49) than participants with normal kidney functions.ConclusionsBoth mild and moderate kidney dysfunction are independently associated with left ventricular diastolic dysfunction parameters and HFpEF. This association is independent of sex and strongest for moderate kidney dysfunction. Considering mild-to-moderate kidney dysfunction as risk factor for HFpEF may help identify high-risk groups benefiting most from early intervention.
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Project description:AimLeft ventricular diastolic dysfunction (DD), a common finding in the general population, is considered to be associated with heart failure with preserved ejection faction (HFpEF). Here we evaluate the prevalence and correlates of DD in subjects with and without HFpEF in a middle-aged sample of the general population.Methods and resultsFrom the first 10,000 participants of the population-based Hamburg City Health Study (HCHS), 5913 subjects (mean age 64.4 ± 8.3 years, 51.3% females), qualified for the current analysis. Diastolic dysfunction (DD) was identified in 753 (12.7%) participants. Of those, 11.2% showed DD without HFpEF (ALVDD) while 1.3% suffered from DD with HFpEF (DDwHFpEF). In multivariable regression analysis adjusted for major cardiovascular risk factors, ALVDD was associated with arterial hypertension (OR 2.0, p < 0.001) and HbA1c (OR 1.2, p = 0.007). Associations of both ALVDD and DDwHFpEF were: age (OR 1.7, p < 0.001; OR 2.7, p < 0.001), BMI (OR 1.2, p < 0.001; OR 1.6, p = 0.001), and left ventricular mass index (LVMI). In contrast, female sex (OR 2.5, p = 0.006), atrial fibrillation (OR 2.6, p = 0.024), CAD (OR 7.2, p < 0.001) COPD (OR 3.9, p < 0.001), and QRS duration (OR 1.4, p = 0.005) were strongly associated with DDwHFpEF but not with ALVDD.ConclusionThe prevalence of DD in a sample from the first 10,000 participants of the population-based HCHS was 12.7% of whom 1.3% suffered from HFpEF. DD with and without HFpEF showed significant associations with different major cardiovascular risk factors and comorbidities warranting further research for their possible role in the formation of both ALVDD and DDwHFpEF.
| S-EPMC8971165 | biostudies-literature
Project description:AimsSome patients with apparent heart failure (HF) have an ejection fraction (EF) ≥ 50% and elevated levels of natriuretic peptides (NPs), but no significant diastolic dysfunction. Among these, some may have HF, others may not. Myocardial strain is an excellent prognostic factor.Methods and resultsAmong 4312 consecutive patients with acute HF from three tertiary hospitals, we included 355 patients with EF of ≥50% and elevated levels of NPs, without significant diastolic dysfunction. Patients were classified as having impaired global longitudinal strain (GLS < 16%) or normal GLS (GLS ≥ 16%). The primary endpoint was 5 year all-cause mortality. The mean age was 70.3 years and 49% were female. Overall, 107 patients (30.1%) died at 5 years. As per the definition, 176 (49.6%) patients had impaired GLS and 179 (50.4%) had normal GLS. Patients with normal GLS had lower 5 year all-cause mortality than those with impaired GLS (P < 0.001). When comparing with the 11 365 age-matched and sex-matched controls, patients with normal GLS had the same long-term survival as the controls (P = 0.834), whereas those with impaired GLS had 48% increased risk of all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.17-1.89).ConclusionsAmong patients with apparent HF and preserved EF but without diastolic dysfunction, those with impaired GLS may be considered to have HF.
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