Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy

Alexander, Danny; Lombardi, Raffaella; Rodrı́guez, Gabriela; Mitchell, Matthew; Marian, Ali J.

doi:10.1111/j.1365-2362.2010.02441.x

Cited by 81 publications

(74 citation statements)

References 24 publications

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“…5). Elevated 3-methylhistidine has been known to associate with cardiomyopathy (30) and is considered to be a marker for muscle degradation (31). These metabolic findings were suggestive of carnitine deficiency.…”

Section: Resultsmentioning

confidence: 82%

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Guo

Milburn

Ryals

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

144

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Precision medicine, taking account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy, has shown great promise to transform medical care. Nontargeted metabolomics, with the ability to detect broad classes of biochemicals, can provide a comprehensive functional phenotype integrating clinical phenotypes with genetic and nongenetic factors. To test the application of metabolomics in individual diagnosis, we conducted a metabolomics analysis on plasma samples collected from 80 volunteers of normal health with complete medical records and three-generation pedigrees. Using a broadspectrum metabolomics platform consisting of liquid chromatography and GC coupled with MS, we profiled nearly 600 metabolites covering 72 biochemical pathways in all major branches of biosynthesis, catabolism, gut microbiome activities, and xenobiotics. Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort. Examination of the convergence of metabolomics profiles with whole-exon sequences (WESs) provided an effective approach to assess and interpret clinical significance of genetic mutations, as shown in a number of cases, including fructose intolerance, xanthinuria, and carnitine deficiency. Metabolic abnormalities consistent with early indications of diabetes, liver dysfunction, and disruption of gut microbiome homeostasis were identified in several volunteers. Additionally, diverse metabolic responses to medications among the volunteers may assist to identify therapeutic effects and sensitivity to toxicity. The results of this study demonstrate that metabolomics could be an effective approach to complement next generation sequencing (NGS) for disease risk analysis, disease monitoring, and drug management in our goal toward precision care.metabolomics | whole-exome sequencing | functional phenotyping | gene penetrance | disease assessment T he rapid progression of next generation sequencing (NGS) technology in recent years has significantly reduced the cost and time required to query a patient's genome accurately. The ability to comprehensively survey genetic variations and their associations with diseases is currently central to personalized medicine and can potentially transform clinical diagnosis and disease management. Indeed, whole-genome sequencing and whole-exome sequencing (WES) have been used successfully to investigate both common and rare diseases (1-7), as well as to provide guidance for drug treatment (8). Despite these successes, significant limitations remain on applying NGS in clinical settings for patient care (9-11). One of the key challenges is the proper interpretation of NGS data. It is known that human exome sequencing identifies ∼10,000 nonsynonymous single-nucleotide variants (12). The computational algorithms and databases for predicting and prioritizing functional pathogenic variants are not yet fully effective. More importantly, the impact of nongenetic factors, such ...

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Section: Resultsmentioning

confidence: 82%

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Guo

Milburn

Ryals

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

158

144

View full text Add to dashboard Cite

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“…Although these metabolites represent a small portion of the human metabolome in terms of absolute numbers, they report on pathways critical for cellular and organism‐level homeostasis: fatty acid, carbohydrate, amino acid, and urea metabolism. These particular metabolites were chosen for several reasons: (1) An expanding body of evidence has implicated impairments in fatty acid and carbohydrate oxidation in HF pathophysiology, which could be reflected in acylcarnitine elevations13, 50, 73, 74, 75, 76, 77; (2) previous metabolomics investigations have identified derangements in plasma levels of these metabolites in HF patients49, 50, 78, 79, 80; and (3) acylcarnitines and their derivatives have been suggested to have intrinsic physiological effects that could contribute to the HF phenotype 66, 67, 68, 81, 82…”

Section: Discussionmentioning

confidence: 99%

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

Kelly

McGarrah

et al. 2016

JAHA

186

137

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BackgroundMetabolic 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 ResultsWe 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.ConclusionsWe 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.

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“…Apart from the metabolic shift from free FAs to glucose metabolism, significant alterations in a Krebs' cycle and anaplerotic intermediates including elevated levels of succinate or malate and decreased citrate [68,14] have been already described. Alexander et al observed interesting changes in plasma levels of steroid metabolites in male patients with dilated cardiomyopathy -DCM [69]. Females in the control and DCM groups had a similar plasma metabolites profile, whereas dehydroepiandrosterone sulfate (DHEA-S) and epiandrosterone sulfate were significantly reduced in the male DCM group.…”

Section: Heart Failure -A Multisystemic Diseasementioning

confidence: 93%

“…Authors suggested that there may be a metabolic "feminization" of male patients with primary DCM. Apart from changes in steroid metabolites profile, increased levels of citric acid cycle intermediates and lipid β-oxidation products were observed in all DCM patients [69]. Taking into consideration multiplicity of lipid fractions and their various physiological functions, current clinical serum lipids profile examination does not provide detailed information on lipids metabolism abnormalities [70].…”

Section: Heart Failure -A Multisystemic Diseasementioning

confidence: 98%

Metabolomics — A wide-open door to personalized treatment in chronic heart failure?

Marcinkiewicz-Siemion

Ciborowski

Krętowski

et al. 2016

International Journal of Cardiology

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Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy

Abstract: Background-Metabolomics, the comprehensive profile of small molecule metabolites found in biological specimens, has the potential to provide insights into the pathogenesis of disease states and lead to identification of new biomarkers.

Cited by 81 publications

References 24 publications

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

Plasma metabolomic profiles enhance precision medicine for volunteers of normal health

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

Metabolomics — A wide-open door to personalized treatment in chronic heart failure?

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