Diabetic Cardiomyopathy

HomeCirculation ResearchVol. 124, No. 8Diabetic Cardiomyopathy Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBDiabetic CardiomyopathyWhat Is It and Can It Be Fixed? Wolfgang H. Dillmann Wolfgang H. DillmannWolfgang H. Dillmann Correspondence to Wolfgang H. Dillmann, MD, Division of Endocrinology/Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Dr. MC0618, La Jolla, CA 92093. Email E-mail Address: [email protected] Search for more papers by this author Originally published11 Apr 2019https://doi.org/10.1161/CIRCRESAHA.118.314665Circulation Research. 2019;124:1160–1162Diabetic cardiomyopathy was initially described as a human pathophysiological condition in which heart failure occurred in the absence of coronary artery disease, hypertension, and valvular heart disease. Recent studies in diabetic animal models identify decreased cardiomyocyte function as an important mediating mechanism for heart failure. Decreased cardiomyocyte function is in part mediated by abnormal mitochondrial calcium handling and a decreased free matrix calcium level which could be a good target for new therapeutic interventions.Diabetic cardiomyopathy (DC) is a diabetes mellitus (DM)-induced pathophysiological condition that can result in heart failure (HF). Here, we present the point of view that diminished cardiomyocyte contraction is a significant contributor which is currently not included among the contributing mechanisms for DC and is largely mediated by changes in either the level or post-translational modification of specific cardiomyocyte proteins, or both. Correcting these changes may lead to novel therapeutic approaches.HF, DM, and Cardiovascular DiseaseDM occurs in 9.3% of the US population. The prevalence of HF is high in patients with DM, ranging from 19% to 26%.1 HF occurs in both type 1 DM (T1D) and type 2 DM (T2D). T2D accounts for 90% to 95% of DM cases and is frequently linked to obesity.In patients with DM, cardiovascular disease is the leading cause of death with coronary artery disease and ischemic cardiomyopathy as main contributors. In addition to coronary artery disease, small vessel disease and diminished cardiac capillary density occurs. Patients with DM can present initially with normal systolic contraction, but impaired diastolic cardiac function,1 a condition termed HF with preserved ejection fraction (HFpEF) which may account for 50% of all HF.In 1972, Rubler et al2 identified a new type of cardiomyopathy in patients with DM termed DC. These patients had a history of HF in the absence of coronary artery disease, hypertension, or valvular heart disease, and it was postulated that the myocardial disease is due to diffuse myocardial fibrosis, cardiac hypertrophy, and diabetic microangiopathy. This definition does not include abnormal cardiomyocyte function and fits the data available at that time. The role of DM in HF was found in the Framingham study.3 Human DC has become a well-documented condition. In T1D and T2D experimental animal models, decreased diastolic and systolic contractile function accompanied by diminished cardiomyocyte contraction and changes in specific cardiomyocyte proteins have been demonstrated.4,5 This leads to the point of view that abnormal contractile function of the diabetic cardiomyocyte could be included in the definition of DC to make it more integrated and conclusive.In contrast to earlier trials,6 more recent trials in patients with DM using sodium/glucose exchange inhibitors and glucagon-like peptide receptor agonists show significant improvements in cardiac contractile function.1 In addition, if myocardial infarct area is adjusted to equal size in patients without DM and patients with DM, the incidence of HF is significantly higher in patients with DM than in those without the disease. These findings also suggest that ischemic and DC are frequently interrelated entities amplifying maladaptive contractile effects in patients with DM.Mechanisms Contributing to the Development of DCMultiple mechanisms contribute to decreased performance of the diabetic heart and have been reviewed.1 They include exposure of the heart to the diabetic milieu of hyperglycemia along with increased fatty acids (FA) and cytokines. Hyperglycemia enhances enzymatic O-GlcNAcylation of cardiomyocyte proteins and is maladaptive. Increased chemical nonenzymatic AGE (advanced glycation end-product) formation also occurs with detrimental effects. A diabetic autonomic neuropathy is present and linked to hyperglycemia. Exposure to increased lipid levels including FA and triglycerides causes increased fat droplet accumulation in cardiomyocytes mediating cardiac lipotoxicity. Decreased insulin signaling is a hallmark of T1D and T2D, and alterations in other signaling cascades occur, including decreased AMPK (AMP-activated protein kinase) signaling and increased PKC (protein kinase C) and MAPK (mitogen-activated protein kinase) signaling with maladaptive consequences.DM-Induced Changes in Specific Cardiomyocyte Proteins Linked to Calcium (Ca2+) HandlingExploring DM-induced changes in molecular mechanisms mediating cytosolic and mitochondrial Ca2+ handling may identify novel therapeutic approaches.Cytosolic Ca2+ Handling in Diabetic CardiomyocytesIn a T1D rat model, depressed sarcoplasmic reticulum function was reported by Penpargkul et al4 in 1981. Subsequent studies in a T1D mouse model found a significant decrease in SERCA2a (sarcoplasmic/endoplasmic reticulum calcium ATPase 2) protein. Decreased contractile function occurred and was rescued by expressing a SERCA2a transgene.5 These findings support that cardiomyocyte dysfunction can be included in the definition of DC and suggest that enhancing SERCA2a function can be a therapeutic target.Decreased contractile function also occurs in the T2D db/db mouse model. An abnormal cytosolic Ca2+ transient and increased sarcoplasmic reticulum Ca2+ leak occur, accompanied by decreases in SERCA2a and RyR2 (ryanodine receptor 2) levels (not statistically significant). Increased Pln (phospholamban) and decreased Pln phosphorylation mediate increased SERCA2a inhibition. In addition, an abnormal cardiomyocyte Ca2+ transient and a marked decrease in RyR2 protein levels were identified.7 T2D db/db mice are leptin receptor deficient. Leptin has adaptive cardiovascular effects making it difficult to distinguish if decreased cardiac function is only because of DM or if absent leptin signaling contributes.The T2D model of Otsuka Long Evans Tokushima Fatty rats have reduced SERCA2a protein levels and exhibit impaired diastolic function. Treatment with adenoviral vector–based SERCA2a transgene expression improves contractile function. Increased cardiomyocyte size in T2D hearts is restored to normal, but no influence on collagen production occurs. Although the exact mechanism(s) for these effects are uncertain, increased SERCA2a levels in isolated cardiomyocytes has been shown to increase the expression of genes linked to insulin signaling.8For human DC, only limited results for myocardial contractile function or the level of cardiomyocyte proteins are available. Actomyosin cross-bridge kinetics and work output at varying calcium concentrations were determined in male and female patients with DM. The findings suggest that changes in diabetic cardiac muscle function contribute to the incidence and mortality of DM-induced HF.9Conclusion for DM and Cytosolic Ca2+ HandlingThe data from T1D and T2D animals justify the inclusion of abnormal cytosolic Ca2+ handling in cardiomyocytes as an important contributor to DC. Studies in specific T1D and T2D animal models imply that different proteins linked to Ca2+ handling are potential targets. Data from T1D mice and T2D rats point to SERCA2a, whereas results from T2D db/db mice also identify proteins linked to sarcoplasmic reticulum Ca2+ release by the ryanodine receptor and its regulatory proteins.Although quantitation of proteins linked to cytosolic Ca2+ handling in human diabetic hearts is not available, patients with HF owing to other causes exhibit decreased SERCA2a expression and diminished contractile function. Based on findings in animals, restoring cytosolic Ca2+ handling in human diabetic cardiomyocytes may be a promising strategy. Discussing the CUPID trials (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Patients With Cardiac Disease), using AAV1 (adeno-associated virus 1) SERCA2a transgene expression in human HF patients, is relevant because nearly half of the patients had DM. CUPID1 enrolled 39 patients with HF and was a phase1/2 trial using percutaneous intracoronary infusion of AAV1/SERCA2a.10 Improvements in clinical and cardiac measurements occurred in the high dose AAV1/SERCA2a group. A subsequent larger phase2b CUPID2 trial, however, failed to demonstrate a reduction in recurrent HF hospitalization. A specific cause for the different results of CUPID1 versus CUPID2 is difficult to identify, but the patient numbers in CUPID1 were small, and the improvements may have been the play of chance despite positive statistics. Alternatively, a low level of cardiac AAV1/SERCA2a expression occurred in CUPID2 and is, therefore, a potential contributor to the failure to demonstrate benefit. The preparation of AAV1/SERCA2a for CUPID1 versus CUPID2 was different and may have contributed to the discrepant results.10 In contrast to humans, successful peripheral intravenous administration of AAV9. Forty-five transgenes occurs in rodents, with transgene expression in a high percent of cardiomyocytes. For humans, the AAV transgene approach needs further development but has been curtailed by limited funding.11 HF is a multifactorial condition, and focusing only on SERCA2a rectification may be insufficient.Mitochondrial Ca2+ Handling in Diabetic CardiomyocytesMCUC (mitochondrial calcium uniporter complex)-based cardiomyocyte mitochondrial Ca2+ import, as well as mitochondrial Ca2+ export by the mitochondrial sodium calcium lithium exchanger, and the influence which the free mitochondrial matrix calcium level ([Ca2+]m) has on mitochondrial energetic function have been reviewed.12 The MCUC is a highly selective channel that moves Ca2+ ions across the mitochondrial inner membrane driven by the mitochondrial membrane potential (Δψm). Four MCU homodimers form the Ca2+ channel pore. EMRE (essential MCU regulator) is a 7 kDa protein which is essential for MCUC Ca2+ conductance. The Ca2+-sensing proteins MICU1 (mitochondrial calcium uptake 1) and MICU2 form dimers and interact electrostatically with EMRE and directly with MCU. Mitochondrial Ca2+ import and export determine [Ca2+]m which stimulates oxidative phosphorylation by enhancing the activity of complex I, III, IV, and the Vmax of complex V, leading to increased ATP formation. The PDC (pyruvate dehydrogenase complex), mediating glucose oxidation, is also activated by [Ca2+]m. With increased glucose oxidation, the oxidation of FA decreases, diminishing oxygen consumption for contractile work, making it more energetically efficient.In T1D hearts, MCU and EMRE are significantly decreased. Decreased transcriptional expression of the MCU gene is mediated by high glucose exposure. Maladaptive consequences resulting from decreased [Ca2+]m include decreased PDC activity with diminished glucose oxidation, increased oxidation of FA, decreased Δψm, increased oxidative stress, and increased apoptotic cardiomyocyte death. Adenoviral vector–based MCU transgene expression in cardiomyocytes eliminates all of the high glucose–induced maladaptive effects. Similar results are obtained by in vivo studies in T1D mice with AAV9.45 MCU transgene expression restoring [Ca2+]m.13 The beneficial energetic, metabolic, and contractile effects occur, and myocardial infarct size is significantly smaller in T1D+AAV-MCU mice versus T1D mice without MCU restoration. Restoration of [Ca2+]m in T2D hearts resulted in similar adaptive effects, including restoration of cardiac contractile function (unpublished results). No maladaptive consequences could be identified from MCU restoration.Conclusion for DM and Mitochondrial Ca2+ HandlingRestoring [Ca2+]m in T1D and T2D hearts improves several functions, including enhanced mitochondrial energetic and metabolic activity, as well as improved metabolic fuel flux with increased glucose oxidation and decreased oxidation of FA with less oxygen consumption for increased cardiac work. In addition, SERCA2a gene expression and protein levels increase in DM cardiomyocytes improving cytosolic Ca2+ flux with enhanced diastolic and systolic cardiac function. In contrast, restoring SERCA2a protein levels in DM cardiomyocytes results in a more limited response primarily enhancing cytosolic Ca2+ handling and contractile function. It is, therefore, our point of view that restoring mitochondrial Ca2+ handling is the preferred approach over improving only cytosolic Ca2+ flux. One potential mechanism for increased SERCA2a gene expression with improved mitochondrial Ca2+ handling may be retrograde mitochondrial-nuclear signaling, but the precise nature of this signal is currently unclear.A potential problem with the restoration of MCUC in diabetic cardiomyocytes could be mitochondrial Ca2+ overload triggering apoptotic cardiomyocyte death. We have not observed this detrimental consequence, and the approach for the restoration of MCUC function may make a difference. For example, restoring the decreased levels of the MCU-bracketing protein EMRE, instead of MCU, may make it less likely that MCUC levels exceed the normal range and excessive [Ca2+]m results with detrimental effects.SummaryHF due to DC was described over 40 years ago, and in the past 3 decades, new knowledge, largely derived from diabetic animal models, has accumulated. These results have shown that decreased function of diabetic cardiomyocytes is a significant contributor to the development of HF. Decreased cardiomyocyte function of the diabetic heart was, however, not included amongst the contributing factors in the original description.2 Currently, only a small number of studies from patients with DM exploring myocardial function and the molecular mechanisms mediating it have been reported. If one accepts guidance from T1D and T2D animal models, improving cytosolic Ca2+ and especially mitochondrial Ca2+ handling of the human diabetic heart are appropriate targets for future therapeutic interventions.Sources of FundingI acknowledge funding as coinvestigator from R01 AR068601 (National Institutes of Health), AC1 07764 (California Institute for Regenerative Medicine), and as Principal Investigator from Veteran Affairs System Merit Award I01 BX003429 (Office of Research and Development), as well as philanthropic support from the P. Robert Majumder Foundation.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Wolfgang H. Dillmann, MD, Division of Endocrinology/Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Dr. MC0618, La Jolla, CA 92093. Email [email protected]eduReferences1. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity.Circ Res. 2018; 122:624–638. doi: 10.1161/CIRCRESAHA.117.311586LinkGoogle Scholar2. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis.Am J Cardiol. 1972; 30:595–602.CrossrefMedlineGoogle Scholar3. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study.Am J Cardiol. 1974; 34:29–34.CrossrefMedlineGoogle Scholar4. 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