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. 2018 Dec 21;39(48):4243-4254.
doi: 10.1093/eurheartj/ehy596.

Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology

Christoph Maack  1 , Michael Lehrke  2 , Johannes Backs  3 , Frank R Heinzel  4 , Jean-Sebastien Hulot  5   6 , Nikolaus Marx  2 , Walter J Paulus  7 , Patrick Rossignol  8 , Heinrich Taegtmeyer  9 , Johann Bauersachs  10 , Antoni Bayes-Genis  11   12 , Dirk Brutsaert  13 , Heiko Bugger  14 , Kieran Clarke  15 , Francesco Cosentino  16 , Gilles De Keulenaer  17 , Alessandra Dei Cas  18   19 , Arantxa González  20 , Martin Huelsmann  21 , Guido Iaccarino  22 , Ida Gjervold Lunde  23 , Alexander R Lyon  24 , Piero Pollesello  25 , Graham Rena  26 , Niels P Riksen  27 , Giuseppe Rosano  28   29 , Bart Staels  30   31   32   33 , Linda W van Laake  34 , Christoph Wanner  35 , Dimitrios Farmakis  36 , Gerasimos Filippatos  36 , Frank Ruschitzka  37 , Petar Seferovic  38 , Rudolf A de Boer  39 , Stephane Heymans  40   41   42
Affiliations

Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology

Christoph Maack et al. Eur Heart J. .
No abstract available

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Figures

Figure 1
Figure 1
Systemic interdependence of heart failure and type 2 diabetes mellitus. In heart failure, neuroendocrine activation alters haemodynamics and metabolism, predisposing to the development of diabetes through insulin resistance. In diabetes, hyperglycaemia induces macro- and microvascular dysfunction, and myocardial ischaemia and/or infarction bias towards systolic dysfunction (heart failure with reduced ejection fraction), while in the absence of ischaemia, diastolic dysfunction (heart failure with preserved ejection fraction) prevails through a combination of sarcomere stiffness and fibrosis. Inflammation is a key systemic factor that contributes to several of these processes. The specific points of intervention by glucose-lowering drugs are indicated (all have in common that they lowed hyperglycaemia). AGEs, advanced glycation end products; AMP, adenosine monophosphate; AMPK, AMP-kinase; DPP4/GLP1, DPP4-inhibitors/GLP-1 analogons; SGLT2, SGLT2-inhibitors.
Figure 2
Figure 2
Cardiac metabolic alterations in heart failure. In heart failure, increased uptake of free fatty acids and glucose into the cytosol is uncoupled from mitochondrial uptake and oxidation of free fatty acid and pyruvate, respectively. This provokes accumulation of metabolic intermediates in the cytosol which can trigger lipo- and glucotoxicity. Instead, utilization of ketone bodies is increased in heart failure. Impaired overall substrate oxidation reduces Krebs cycle (TCA) activity, oxidizing electron donors NADH and FADH2 for the electron transport chain (ETC). This reduces metabolic flux through creatine kinase (CK), thereby the phosphocreatine (PCr) to ATP ratio. β-Ox., β-oxidation; CPT-1/2, carnitine palmitoyltransferase type 1/2; FA-CoA, fatty acyl-coenzyme A; FACS, fatty acyl-coenzyme A synthetase; FAT/CD36, fatty acid translocase; GLUT 1/4, glucose transporters 1/4; G6P, glucose-6-phosphate; PDH, pyruvate dehydrogenase complex; PPP, pentose phosphate pathway; Polyol P., Polyol pathway; TAG, triacylglycerol; UDPGlcNac, UDP-glycnacylation. Red arrows (↓↑) indicate the changes in heart failure.
Figure 3
Figure 3
Cardiac metabolic alterations in diabetes. In diabetes, strongly increased free fatty acid activate peroxisome proliferator-activated receptor α (PPARα), which up-regulates expression of genes involved in fatty acid (FA) oxidation. Increased FA oxidation shuts down glucose uptake and oxidation (insulin resistance), thereby blunts metabolic flexibility. Excessive FA are stored as triacylglycerol (TAG), which can mediate lipotoxicity. FA and reactive oxygen species (ROS) activate uncoupling protein 3 (UCP3), which makes ATP production less efficient. Abbreviations see legend of Figure 2.
Figure 4
Figure 4
Metabolic interventions in diabetes and heart failure. For details see text. DPP4/GLP1, DPP4-inhibitors/GLP-1 analogons; SGLT2, SGLT2-inhibitors.
Figure 5
Figure 5
Basic concepts concerning the use of anti-diabetic drugs in patients with heart failure.
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References

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