{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T23:35:18Z","timestamp":1787960118565,"version":"build-2784847793"},"reference-count":107,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,16]],"date-time":"2023-04-16T00:00:00Z","timestamp":1681603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Azienda Provinciale per i Servizi Sanitari (APSS) of Autonomous Province of Trento"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms \u201cpropionic acidemia\u201d OR \u201cpropionate\u201d AND \u201ccardiomyopathy\u201d OR \u201cLong QT syndrome\u201d. We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation\u2013contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin\u2013angiotensin\u2013aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.<\/jats:p>","DOI":"10.3390\/metabo13040563","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T02:26:02Z","timestamp":1681698362000},"page":"563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Understanding the Pathogenesis of Cardiac Complications in Patients with Propionic Acidemia and Exploring Therapeutic Alternatives for Those Who Are Not Eligible or Are Waiting for Liver Transplantation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0445-2974","authenticated-orcid":false,"given":"Evelina","family":"Maines","sequence":"first","affiliation":[{"name":"Division of Pediatrics, Santa Chiara General Hospital, APSS, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Moretti","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Santa Chiara General Hospital, APSS, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5147-4367","authenticated-orcid":false,"given":"Nicola","family":"Vitturi","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases, Department of Medicine-DIMED, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Gugelmo","sequence":"additional","affiliation":[{"name":"Division of Clinical Nutrition, Department of Medicine-DIMED, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Fasan","sequence":"additional","affiliation":[{"name":"Division of Clinical Nutrition, Department of Medicine-DIMED, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-3015","authenticated-orcid":false,"given":"Livia","family":"Lenzini","sequence":"additional","affiliation":[{"name":"Emergency Medicine Unit, Department of Medicine-DIMED, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Piccoli","sequence":"additional","affiliation":[{"name":"CIBIO, Department of Cellular, Computational and Integrative Biology, Italy & Dulbecco Telethon Institute, Universit\u00e0 degli Studi di Trento, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenza","family":"Gragnaniello","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, Department of Women\u2019s and Children\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9986-1385","authenticated-orcid":false,"given":"Arianna","family":"Maiorana","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Ges\u00f9 Children\u2019s Hospital-IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Soffiati","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Santa Chiara General Hospital, APSS, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7724-137X","authenticated-orcid":false,"given":"Alberto","family":"Burlina","sequence":"additional","affiliation":[{"name":"Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, Department of Women\u2019s and Children\u2019s Health, University Hospital, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-7148","authenticated-orcid":false,"given":"Roberto","family":"Franceschi","sequence":"additional","affiliation":[{"name":"Division of Pediatrics, Santa Chiara General Hospital, APSS, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ymgme.2017.10.002","article-title":"Propionyl-CoA carboxylase\u2014A review","volume":"122","author":"Wongkittichote","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13023-014-0130-8","article-title":"Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia","volume":"9","author":"Baumgartner","year":"2014","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s10545-015-9840-x","article-title":"The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: The evolving clinical phenotype","volume":"38","author":"Valayannopoulos","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/jimd.12370","article-title":"Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision","volume":"44","author":"Forny","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/BF01955907","article-title":"Cardiomyopathy in propionic acidaemia","volume":"152","author":"Massoud","year":"1993","journal-title":"Eur. J. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jpeds.2009.07.002","article-title":"Cardiomyopathies in propionic aciduria are reversible after liver transplantation","volume":"156","author":"Romano","year":"2010","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ymgme.2020.02.004","article-title":"Cardiac phenotype in propionic acidemia\u2014Results of an observational monocentric study","volume":"130","author":"Kovacevic","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.jpeds.2006.11.043","article-title":"Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia","volume":"150","author":"Baumgartner","year":"2007","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ymgme.2005.04.004","article-title":"Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy","volume":"85","author":"Mardach","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.1007\/s10545-009-1084-1","article-title":"Unusual presentation of propionic acidaemia as isolated cardiomyopathy","volume":"32","author":"Lee","year":"2009","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1750-1172-8-6","article-title":"Propionic acidemia: Clinical course and outcome in 55 pediatric and adolescent patients","volume":"8","author":"Barth","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1007\/s00246-007-9160-5","article-title":"Cardiac arrest secondary to long QTc in a child with propionic acidemia","volume":"29","author":"Jameson","year":"2008","journal-title":"Pediatr. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E883","DOI":"10.1503\/cmaj.180240","article-title":"Metabolic cardiomyopathy from propionic acidemia precipitating cardiac arrest in a 25-year-old man","volume":"190","author":"Tan","year":"2018","journal-title":"CMAJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_15","first-page":"e895","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.healun.2014.06.002","article-title":"The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary","volume":"33","author":"Kirk","year":"2014","journal-title":"J. Heart Lung Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1097\/TP.0000000000003501","article-title":"Liver Transplantation for Propionic Acidemia: Evidence From a Systematic Review and Meta-analysis","volume":"105","author":"Zhou","year":"2021","journal-title":"Transplantation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/jmd2.12119","article-title":"The re-occurrence of cardiomyopathy in propionic acidemia after liver transplantation","volume":"54","author":"Berry","year":"2020","journal-title":"JIMD Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1017\/S104795112200035X","article-title":"The re-occurrence of dilated cardiomyopathy in propionic acidemia after liver transplantation requiring heart transplant, first case from Middle East","volume":"33","author":"Hejazi","year":"2023","journal-title":"Cardiol. Young"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1146\/annurev.bioeng.3.1.57","article-title":"Cardiac energy metabolism: Models of cellular respiration","volume":"3","author":"Jafri","year":"2001","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/jimd.12287","article-title":"Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia","volume":"43","author":"Maines","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ymgme.2005.11.016","article-title":"Metabolic changes associated with hyperammonemia in patients with propionic acidemia","volume":"88","author":"Filipowicz","year":"2006","journal-title":"Mol. Genet. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"165682","DOI":"10.1016\/j.bbadis.2020.165682","article-title":"Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats","volume":"1866","author":"Roginski","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E622","DOI":"10.1152\/ajpendo.00081.2018","article-title":"Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine","volume":"315","author":"Wang","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bordugo, A., Salvetti, E., Rodella, G., Piazza, M., Dianin, A., Amoruso, A., Piacentini, G., Pane, M., Torriani, S., and Vitulo, N. (2021). Assessing Gut Microbiota in an Infant with Congenital Propionic Acidemia before and after Probiotic Supplementation. Microorganisms, 9.","DOI":"10.3390\/microorganisms9122599"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1515\/jpem-2012-0148","article-title":"Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia","volume":"26","author":"Siekmeyer","year":"2013","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ymgme.2017.07.003","article-title":"Anaplerotic therapy in propionic acidemia","volume":"122","author":"Longo","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1203\/PDR.0b013e3181a7c270","article-title":"Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria","volume":"66","author":"Valayannopoulos","year":"2009","journal-title":"Pediatr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.mito.2014.07.001","article-title":"Successful reversal of propionic acidaemia associated cardiomyopathy: Evidence for low myocardial coenzyme Q10 status and secondary mitochondrial dysfunction as an underlying pathophysiological mechanism","volume":"17","author":"Baruteau","year":"2014","journal-title":"Mitochondrion"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2016.04.007","article-title":"In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder","volume":"96","author":"Guenzel","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Alonso-Barroso, E., P\u00e9rez, B., Desviat, L.R., and Richard, E. (2021). Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031161"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.mito.2011.02.002","article-title":"Fatal heart failure associated with CoQ10 and multiple OXPHOS deficiency in a child with propionic acidemia","volume":"11","author":"Fragaki","year":"2011","journal-title":"Mitochondrion"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10545-012-9545-3","article-title":"Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia","volume":"36","author":"Abia","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ymgme.2009.06.007","article-title":"Profiling of oxidative stress in patients with inborn errors of metabolism","volume":"98","author":"Parikh","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1042\/BJ20060221","article-title":"Secondary mitochondrial dysfunction in propionic aciduria: A pathogenic role for endogenous mitochondrial toxins","volume":"398","author":"Schwab","year":"2006","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1161\/01.HYP.0000254415.31362.a7","article-title":"Role of oxidative stress in cardiac hypertrophy and remodeling","volume":"49","author":"Takimoto","year":"2007","journal-title":"Hypertension"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ymgme.2017.07.009","article-title":"Treatment with antioxidants ameliorates oxidative damage in a mouse model of propionic acidemia","volume":"122","author":"Murphy","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.bbrc.2014.08.091","article-title":"Antioxidants successfully reduce ROS production in propionic acidemia fibroblasts","volume":"452","author":"Ugarte","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e13667","DOI":"10.14814\/phy2.13667","article-title":"The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue","volume":"6","author":"Gottwald","year":"2018","journal-title":"Physiol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pokrzywinski, K.L., Biel, T.G., Kryndushkin, D., and Rao, V.A. (2016). Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity. PLoS ONE., 11.","DOI":"10.1371\/journal.pone.0168283"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14","DOI":"10.20463\/jenb.2018.0019","article-title":"The effects of coenzyme Q10 on oxidative stress and heat shock proteins in rats subjected to acute and chronic exercise","volume":"22","author":"Pala","year":"2018","journal-title":"J. Exerc. Nutr. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.jacc.2010.02.075","article-title":"Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: A pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure)","volume":"56","author":"McMurray","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/joim.13456","article-title":"Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?","volume":"291","author":"Bomer","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S134","DOI":"10.1007\/BF00226854","article-title":"Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study","volume":"71","author":"Morisco","year":"1993","journal-title":"Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Alehagen, U., Aaseth, J., and Johansson, P. (2015). Reduced Cardiovascular Mortality 10 Years after Supplementation with Selenium and Coenzyme Q10 for Four Years: Follow-Up Results of a Prospective Randomized Double-Blind Placebo-Controlled Trial in Elderly Citizens. PLoS ONE., 10.","DOI":"10.1371\/journal.pone.0141641"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1056\/NEJMra063052","article-title":"The failing heart--an engine out of fuel","volume":"356","author":"Neubauer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/jimd.12365","article-title":"Enantiomer-specific pharmacokinetics of, D,L-3-hydroxybutyrate: Implications for the treatment of multiple acyl-CoA dehydrogenase deficiency","volume":"44","author":"Vaz","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1203\/PDR.0b013e318232154f","article-title":"Successful treatment of severe cardiomyopathy in glycogen storage disease type III With, D,L-3-hydroxybutyrate, ketogenic and high-protein diet","volume":"70","author":"Valayannopoulos","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s10545-013-9600-8","article-title":"Current concepts in organic acidurias: Understanding intra- and extracerebral disease manifestation","volume":"36","author":"Burgard","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.ymgme.2021.09.009","article-title":"Metabolic perturbations mediated by propionyl-CoA accumulation in organs of mouse model of propionic acidemia","volume":"134","author":"He","year":"2021","journal-title":"Mol. Genet. Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1540-8159.2004.00507.x","article-title":"Ventricular fibrillation without overt cardiomyopathy as first presentation of organic cation transporter 2-deficiency in adolescence","volume":"27","author":"Rijlaarsdam","year":"2004","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ymgme.2011.08.034","article-title":"Chronic management and health supervision of individuals with propionic acidemia","volume":"105","author":"Sutton","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and Excitation-Contraction Coupling in the Heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"165586","DOI":"10.1016\/j.bbadis.2019.165586","article-title":"Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia","volume":"1866","author":"Tamayo","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1161\/CIRCRESAHA.117.310083","article-title":"Calcium Signaling and Cardiac Arrhythmias","volume":"120","author":"Landstrom","year":"2017","journal-title":"Circ. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.hrthm.2016.02.003","article-title":"Mechanisms of acquired long QT syndrome in patients with propionic academia","volume":"13","author":"Bodi","year":"2016","journal-title":"Heart Rhythm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.jacbts.2019.05.011","article-title":"Epigenetics in Cardiac Hypertrophy and Heart Failure","volume":"4","author":"Liu","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"617451","DOI":"10.3389\/fcvm.2020.617451","article-title":"Cardiac Complications of Propionic and Other Inherited Organic Acidemias","volume":"7","author":"Park","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nrm.2016.140","article-title":"Metabolic regulation of gene expression through histone acylations","volume":"18","author":"Sabari","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jnutbio.2007.08.002","article-title":"Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon","volume":"19","author":"Waldecker","year":"2008","journal-title":"J. Nutr. Biochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.yjmcc.2019.04.003","article-title":"Histone deacetylases in cardiovascular and metabolic diseases","volume":"130","author":"Bagchi","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/nsmb.3490","article-title":"Histone propionylation is a mark of active chromatin","volume":"24","author":"Kebede","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nrg3965","article-title":"Towards a molecular understanding of microRNA-mediated gene silencing","volume":"16","author":"Jonas","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"E729","DOI":"10.1152\/ajpendo.00194.2014","article-title":"MicroRNA regulation of mitochondrial and ER stress signaling pathways: Implications for lipoprotein metabolism in metabolic syndrome","volume":"307","author":"Christian","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/j.1440-1681.2009.05245.x","article-title":"MicroRNAs and apoptosis: Implications in the molecular therapy of human disease","volume":"36","author":"Yang","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nrd3864","article-title":"MicroRNA therapeutics for cardiovascular disease: Opportunities and obstacles","volume":"11","author":"Olson","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5727","DOI":"10.1038\/s41598-017-06420-8","article-title":"Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia","volume":"7","author":"Ramos","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.trsl.2019.12.004","article-title":"Pathogenic implications of dysregulated miRNAs in propionic acidemia related cardiomyopathy","volume":"218","author":"Guenzel","year":"2020","journal-title":"Transl. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1017\/S0954422420000049","article-title":"Nutraceutical support in heart failure: A position paper of the International Lipid Expert Panel (ILEP)","volume":"33","author":"Cicero","year":"2020","journal-title":"Nutr. Res. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1159\/000415560","article-title":"Selenium-related endemic diseases and the daily selenium requirement of humans","volume":"55","author":"Yang","year":"1988","journal-title":"World Rev. Nutr. Diet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1056\/NEJMcibr1402199","article-title":"Keshan disease, selenium deficiency, and the selenoproteome","volume":"370","author":"Loscalzo","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1002\/ejhf.1644","article-title":"Selenium and outcome in heart failure","volume":"22","author":"Bomer","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_73","first-page":"6","article-title":"Combination effects of selenium and coenzyme Q10 on left ventricular systolic function in patients with heart failure","volume":"15","author":"Garakyaraghi","year":"2015","journal-title":"Iran. Heart J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1093\/ajcn\/nqaa245","article-title":"Selenium, antioxidants, cardiovascular disease, and all-cause mortality: A systematic review and meta-analysis of randomized controlled trials","volume":"112","author":"Jenkins","year":"2020","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3616","DOI":"10.1080\/10408398.2020.1803200","article-title":"Selenium status in the body and cardiovascular disease: A systematic review and meta-analysis","volume":"61","author":"Kuria","year":"2021","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/ejhf.1154","article-title":"Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function","volume":"20","author":"Hoes","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1053\/euhj.1997.0727","article-title":"A non-invasive selective assessment of type I fibre mitochondrial function using 31P NMR spectroscopy. Evidence for impaired oxidative phosphorylation rate in skeletal muscle in patients with chronic heart failure","volume":"19","author":"Jeneson","year":"1998","journal-title":"Eur. Heart J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e004129","DOI":"10.1161\/CIRCHEARTFAILURE.117.004129","article-title":"Fatigability, exercise intolerance, and abnormal skeletal muscle energetics in heart failure","volume":"10","author":"Weiss","year":"2017","journal-title":"Circ. Heart Fail."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e004800","DOI":"10.1161\/CIRCHEARTFAILURE.117.004800","article-title":"Skeletal muscle abnormalities and iron deficiency in chronic heart failure (an exercise (31)P magnetic resonance spectroscopy study of calf muscle)","volume":"11","author":"Melenovsky","year":"2018","journal-title":"Circ. Heart Fail."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"Ferric carboxymaltose in patients with heart failure and iron deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.117.027497","article-title":"Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency","volume":"136","author":"Ponikowski","year":"2017","journal-title":"Circulation"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/eurheartj\/ehu385","article-title":"Beneficial effects of longterm intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency","volume":"36","author":"Ponikowski","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1136\/hrt.2007.119792","article-title":"Hypocalcaemia and vitamin D deficiency: An important, but preventable, cause of life-threatening infant heart failure","volume":"94","author":"Maiya","year":"2008","journal-title":"Heart"},{"key":"ref_84","first-page":"e10840","article-title":"Role of Vitamin D Supplementation in Heart Failure Patients With Vitamin D Deficiency and Its Effects on Clinical Outcomes: A Literature Review","volume":"12","author":"Busa","year":"2020","journal-title":"Cureus"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.cardfail.2020.01.005","article-title":"Zinc Deficiency and Heart Failure: A Systematic Review of the Current Literature","volume":"26","author":"Rosenblum","year":"2020","journal-title":"J. Card. Fail."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/eurjhf\/hfr167","article-title":"Selenium- and zinc-deficient cardiomyopathy in human intestinal malabsorption: Preliminary results of selenium\/zinc infusion","volume":"14","author":"Frustaci","year":"2012","journal-title":"Eur. J. Heart Fail."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cardfail.2018.02.011","article-title":"Association of Serum Zinc Level with Prognosis in Patients with Heart Failure","volume":"24","author":"Yoshihisa","year":"2018","journal-title":"J. Card. Fail."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"152","DOI":"10.14503\/THIJ-17-6586","article-title":"Zinc Deficiency as a Reversible Cause of Heart Failure","volume":"47","author":"Rosenblum","year":"2020","journal-title":"Tex. Heart Inst. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s10557-018-6808-8","article-title":"Thiamine Therapy for Heart Failure: A Promise or Fiction?","volume":"32","author":"Kattoor","year":"2018","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cardfail.2015.10.005","article-title":"Determining the role of thiamine deficiency in systolic heart failure: A meta-analysis and systematic review","volume":"21","author":"Jain","year":"2015","journal-title":"J. Card. Fail."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Piquereau, J., Boitard, S.E., Ventura-Clapier, R., and Mericskay, M. (2021). Metabolic Therapy of Heart Failure: Is There a Future for B Vitamins?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010030"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.4081\/hi.2011.e21","article-title":"Riboflavin alleviates cardiac failure in Type I diabetic cardiomyopathy","volume":"6","author":"Wang","year":"2011","journal-title":"Heart Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1016\/j.jada.2009.05.011","article-title":"B-vitamin deficiency in hospitalized patients with heart failure","volume":"109","author":"Keith","year":"2009","journal-title":"J. Am. Diet. Assoc."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.ymgme.2019.02.007","article-title":"Nutrition management guideline for propionic acidemia: An evidence- and consensus-based approach","volume":"126","author":"Jurecki","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s10545-006-0267-2","article-title":"Nutrition therapy of organic acidaemias with amino acid-based formulas: Emphasis on methylmalonic and propionic acidaemia","volume":"29","author":"Yannicelli","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/HYPERTENSIONAHA.118.11065","article-title":"Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness","volume":"72","author":"Jia","year":"2018","journal-title":"Hypertension"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1002\/j.1552-4604.1993.tb03901.x","article-title":"Evidence of a partial escape of renin-angiotensin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors","volume":"33","author":"Borghi","year":"1993","journal-title":"J. Clin. Pharmacol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.yjmcc.2022.03.005","article-title":"Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects","volume":"167","author":"Dyck","year":"2022","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_99","unstructured":"(2022, February 09). FDA Drug Safety Communication: FDA Warns That SGLT2 Inhibitors for Diabetes May Result in a Serious Condition of Too Much Acid in the Blood, Available online: https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious."},{"key":"ref_100","unstructured":"European Medicines Agency (2022, February 09). Review of Diabetes Medicines Called SGLT2 Inhibitors Started. Risk of Diabetic Ketoacidosis to Be Examined, Available online: http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/referrals\/SGLT2_inhibitors\/human_referral_prac_000052.jsp&mid=WC0b01ac05805c516f."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Zeppenfeld, K., Tfelt-Hansen, J., de Riva, M., Winkel, B.G., Behr, E.R., Blom, N.A., Charron, P., Corrado, D., Dagres, N., and de Chillou, C. (2022). 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J., Epub ahead of print.","DOI":"10.1093\/eurheartj\/ehac699"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1515\/jpem-2016-0469","article-title":"Long QT syndrome diagnosed in two sisters with propionic acidemia: A case report","volume":"30","author":"Duras","year":"2017","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"785","DOI":"10.4070\/kcj.2013.43.12.785","article-title":"Primary carnitine deficiency and cardiomyopathy","volume":"43","author":"Fu","year":"2013","journal-title":"Korean Circ. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0008-6363(97)00141-7","article-title":"Cardiomyopathies in disorders of oxidative metabolism","volume":"35","author":"Antozzi","year":"1997","journal-title":"Cardiovasc. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/mt.2013.68","article-title":"Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing","volume":"21","author":"Guenzel","year":"2013","journal-title":"Mol Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physiolgenomics.00033.2003","article-title":"Developmental anatomy of the heart: A tale of mice and man","volume":"15","author":"Wessels","year":"2003","journal-title":"Physiol. Genom."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1242\/dmm.005017","article-title":"Heart failure and mouse models","volume":"3","author":"Breckenridge","year":"2010","journal-title":"Dis. Model Mech."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/4\/563\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:16:46Z","timestamp":1760123806000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/4\/563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,16]]},"references-count":107,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["metabo13040563"],"URL":"https:\/\/doi.org\/10.3390\/metabo13040563","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,16]]}}}