Dataset Information

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

ABSTRACT:

Background

Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).

Methods and results

We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ?45%, diastolic dysfunction grade ?1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ?45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.

Conclusions

We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

SUBMITTER: Hunter WG

PROVIDER: S-EPMC5015273 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

Hunter Wynn G WG Kelly Jacob P JP McGarrah Robert W RW Khouri Michel G MG Craig Damian D Haynes Carol C Ilkayeva Olga O Stevens Robert D RD Bain James R JR Muehlbauer Michael J MJ Newgard Christopher B CB Felker G Michael GM Hernandez Adrian F AF Velazquez Eric J EJ Kraus William E WE Shah Svati H SH

Journal of the American Heart Association 20160729 8

<h4>Background</h4>Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).<h4>Methods and results</h4>We identified HFpEF cases, HFrEF controls, and no-HF controls from the C ...[more]

PMID: 27473038

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Project description:Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results.To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF.Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites).Sildenafil (n?=?79) or a placebo (n?=?81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score.No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], -38.26 [-100.3 to 28.19] and -28.24 [-56.29 to 12.08], respectively; false discovery rate-adjusted P?=?.01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [-3.37 to 14.18], 2.72 [-3 to 12.57], and 10.72 [-11.23 to 29.57], respectively; false discovery rate-adjusted P?=?.01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [-5.64 to 26.99]; false discovery rate-adjusted P?=?.03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (?, -96.60, P?=?.001 and ?, -0.02, P?=?.01; after renal adjustment, P?=?.09 and .02, respectively).Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF.

Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

Project description:Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine, and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase activators and If current inhibitors have shown benefit in improving diastolic function, and there is a rationale for assessing matrix metalloproteinase 9 inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research and drugs currently in clinical trial that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.

Dataset Information

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

Background

Methods and results

Conclusions

Publications

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

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