Electrical features of the diabetic myocardium. Arrhythmic and cardiovascular Safety considerations in diabetes

[EN] Diabetes is a chronic metabolic disease characterized by hyperglycemia in the absence of treatment. Among the diabetes-associated complications, cardiovascular disease is the major cause of mortality and morbidity in diabetic patients. Diabetes causes a complex myocardial dysfunction, referred as diabetic cardiomyopathy, which even in the absence of other cardiac risk factors results in abnormal diastolic and systolic function. Besides mechanical abnormalities, altered electrical function is another major feature of the diabetic myocardium. Both type 1 and type 2 diabetic patients often show cardiac electrical remodeling, mainly a prolonged ventricular repolarization visible in the electrocardiogram as a lengthening of the QT interval duration. The underlying mechanisms at the cellular level involve alterations on the expression and activity of several cardiac ion channels and their associated regulatory proteins. Consequent changes in sodium, calcium and potassium currents collectively lead to a delay in repolarization that can increase the risk of developing life-threatening ventricular arrhythmias and sudden death. QT duration correlates strongly with the risk of developing torsade de pointes, a form of ventricular tachycardia that can degenerate into ventricular fibrillation. Therefore, QT prolongation is a qualitative marker of proarrhythmic risk, and analysis of ventricular repolarization is therefore required for the approval of new drugs. To that end, the Thorough QT/QTc analysis evaluates QT interval prolongation to assess potential proarrhythmic effects. In addition, since diabetic patients have a higher risk to die from cardiovascular causes than individuals without diabetes, cardiovascular safety of the new antidiabetic drugs must be carefully evaluated in type 2 diabetic patients. These cardiovascular outcome trials reveal that some glucose-lowering drugs actually reduce cardiovascular risk. The mechanism of cardioprotection might involve a reduction of the risk of developing arrhythmia.This work was supported by grants from the Basque Government: Govierno Vasco PIBA2018-58, GIC18/150 and IT1196-19. AA received a predoctoral fellowship from the Basque Government

Molecular and Electrophysiological Role of Diabetes-Associated Circulating Inflammatory Factors in Cardiac Arrhythmia Remodeling in a Metabolic-Induced Model of Type 2 Diabetic Rat

Background: Diabetic patients have prolonged cardiac repolarization and higher risk of arrhythmia. Besides, diabetes activates the innate immune system, resulting in higher levels of plasmatic cytokines, which are described to prolong ventricular repolarization. Methods: We characterize a metabolic model of type 2 diabetes (T2D) with prolonged cardiac repolarization. Sprague-Dawley rats were fed on a high-fat diet (45% Kcal from fat) for 6 weeks, and a low dose of streptozotozin intraperitoneally injected at week 2. Body weight and fasting blood glucose were measured and electrocardiograms of conscious animals were recorded weekly. Plasmatic lipid profile, insulin, cytokines, and arrhythmia susceptibility were determined at the end of the experimental period. Outward K+ currents and action potentials were recorded in isolated ventricular myocytes by patch-clamp. Results: T2D animals showed insulin resistance, hyperglycemia, and elevated levels of plasma cholesterol, triglycerides, TNFα, and IL-1b. They also developed bradycardia and prolonged QTc-interval duration that resulted in increased susceptibility to severe ventricular tachycardia under cardiac challenge. Action potential duration (APD) was prolonged in control cardiomyocytes incubated 24 h with plasma isolated from diabetic rats. However, adding TNFα and IL-1b receptor blockers to the serum of diabetic animals prevented the increased APD. Conclusions: The elevation of the circulating levels of TNFα and IL-1b are responsible for impaired ventricular repolarization and higher susceptibility to cardiac arrhythmia in our metabolic model of T2D.This work was supported by grants from the Gobierno Vasco PIBA2018-58 and GIC18/150 and MICINN PID2020-118814RB-I00. JZ-A is a predoctoral Fellow of the UPV/EHU and had a STSM from the EU COST Action CA16225

Diabetesa gaixotasun inflamatorio gisa

Diabetesa gaixotasun kronikoa da, prebalentzia handikoa, zeinetan pankreak ez duen behar adina intsulina sortzen edo organismoak sortzen duen intsulina ez duen eraginkortasunez erabiltzen. Kontrolatu gabeko diabetesaren ondorioa hipergluzemia da, denborarekin organo eta sistema asko larriki kaltetzen dituena, nerbioak eta odol-hodiak batez ere. 2 motako diabetesa (DT2) diabetes motarik ohikoena da, non ehunek ez dioten intsulinari eraginkortasunez erantzuten. Egoera horri intsulinarekiko erresistentzia deritzo. Obesitatea, munduko asaldura metabolikorik ohikoena da, eta DT2 garatzeko arrisku-faktore nagusienetako bat. Obesitatea diabetesarekin lotzen duten mekanismoak oraindik argi ez badaude ere, azken urteotan hanturak indarra hartu du funtsezko faktore gisa. Paziente diabetikoek zitokina proinflamatorioen maila altuak dituzte, eta horrek gradu baxuko hantura kroniko orokortua eragiten du, gantz-ehunean sortzen duena. Hantura kroniko horrek alterazioak eragiten ditu intsulinaren seinaleztapen-jauzian eta, ondorioz, intsulinarekiko erresistentzia eta hipergluzemia dakar. Gaur egungo tratamenduaren helburu nagusia gluzemia normalizatzea da, farmako hipogluzemiatzaileen bidez. Hala ere, sistema immunearen modulazioak, TNF-α eta IL-b bezalako zitokinen blokeoaren bidez, medikamentuak garatzeko aukera berri interesgarriak irekitzen ditu.; Diabetes is a chronic, highly prevalent disease that occurs when the pancreas does not produce enough insulin or does not effectively use the insulin it produces. The effect of uncontrolled diabetes is hyperglycemia, which over time severely damages many organs and systems, especially nerves and blood vessels. Type 2 diabetes is the most common type of diabetes, in which the tissues do not respond effectively to insulin, a condition known as insulin resistance. Obesity is the most common metabolic disorder in the world and is one of the main risk factors for the development of T2DM. Although the mechanisms linking obesity and diabetes are still unclear, inflammation has emerged in the last years as a key factor. Diabetic patients have high levels of pro-inflammatory cytokines, originating in adipose tissue, leading to chronic generalized low-grade inflammation. This chronic inflammation causes alterations in insulin signaling, leading to insulin resistance and hyperglycemia. Although the main goal of current treatment is to normalize glycaemia withhypoglycemic drugs, modulation of the immune system, by blocking cytokines such as TNF-α or IL-1β, is an interesting therapeutic target that may open up new possibilities for drug development

Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

Purpose Kv1.3 channel regulates the activity of lymphocytes, macrophages, or adipose tissue and its blockade reduces inflammatory cytokine secretion and improves insulin sensitivity in animals with metabolic syndrome and in genetically obese mice. Thus, Kv1.3 blockade could be a strategy for the treatment of type 2 diabetes. Elevated circulating levels of TNF alpha and IL-1b mediate the higher susceptibility to cardiac arrhythmia in type 2 diabetic rats. We hypothesized that Kv1.3 channel blockade with the psoralen PAP1 could have immunomodulatory properties that prevent QTc prolongation and reduce the risk of arrhythmia in type 2 diabetic rats. Methods Type 2 diabetes was induced to Sprague-Dawley rats by high-fat diet and streptozotocin injection. Diabetic animals were untreated, treated with metformin, or treated with PAP1 for 4 weeks. Plasma glucose, insulin, cholesterol, triglycerides, and cytokine levels were measured using commercial kits. ECG were recorded weekly, and an arrhythmia-inducing protocol was performed at the end of the experimental period. Action potentials were recorded in isolated ventricular cardiomyocytes. Results In diabetic animals, PAP1 normalized glycaemia, insulin resistance, adiposity, and lipid profile. In addition, PAP1 prevented the diabetes-induced repolarization defects through reducing the secretion of the inflammatory cytokines IL-10, IL-12p70, GM-CSF, IFN gamma, and TNF alpha. Moreover, compared to diabetic untreated and metformin-treated animals, those treated with PAP1 had the lowest risk of developing the life-threatening arrhythmia Torsade de Pointes under cardiac challenge. Conclusion Kv1.3 inhibition improves diabetes and diabetes-associated low-grade inflammation and cardiac electrical remodeling, resulting in more protection against cardiac arrhythmia compared to metformin.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from the Gobierno Vasco (PIBA2018-58 and GIC18/150), and MICINN (PID2020-118814RB-I00). V. F.-L. is a predoctoral Fellow of the UPV/EHU and A. A. is a predoctoral Fellow of the Gobierno Vasco. J.Z.-A. is a predoctoral Fellow of the UPV/EHU and had a STSM from the EU-CARDIOPROTECTION COST Action CA16225