Elevated levels of interleukin-12/23p40 may serve as a potential indicator of dysfunctional heart rate variability in type 2 diabetes.

BACKGROUND: Systemic inflammatory processes plausibly contribute to the development of cardiovascular complications, causing increased morbidity and mortality in type 2 diabetes. Circulating inflammatory markers, i.e., interleukin (IL)-6 and tumour necrosis factor-α, are associated with neurocardiac measures. We examined a broad panel of various inflammatory and inflammation-related serum markers to obtain more detailed insight into the possible neuro-immune interaction between cardiovascular regulation and systemic level of inflammation. METHODS: Serum samples from 100 participants with type 2 diabetes were analysed. Heart rate variability, cardiovascular autonomic reflex tests, and cardiac vagal tone tests were performed based on electrocardiographic readings. Data regarding covariates (demographic-, diabetes-, and cardiovascular risk factors) were registered. RESULTS: Increased serum levels of IL-12/IL-23p40 (p < 0.01) and intercellular adhesion molecule (ICAM)-1 (p < 0.007) were associated with diminished heart rate variability measures. After all adjustments, the associations between IL-12/23p40, SDANN and VLF persisted (p = 0.001). Additionally, serum levels of vascular endothelial growth factor (VEGF)-C were associated with response to standing (p = 0.005). DISCUSSION: The few but robust associations between neurocardiac regulation and serum markers found in this study suggest systemic changes in proinflammatory, endothelial, and lymphatic function, which collectively impacts the systemic cardiovascular function. Our results warrant further exploration of IL-12/IL-23p40, ICAM-1, and VEGF-C as possible cardiovascular biomarkers in T2D that may support future decisions regarding treatment strategies for improved patient care.

Papel do strain no diagnóstico precoce da cardiomiopatia diabética / Role of strain in the early diagnosis of diabetic cardiomyopathy

Fundamento: A ecocardiografia avançada com utilização de strain miocárdico bi e tridimensional propõe identificar a disfunção sistólica subclínica em diversas condições clínicas. No diabetes mellitus, seu papel é de grande interesse para diagnóstico precoce de cardiomiopatia diabética. Contudo, há grande heterogeneidade nos artigos publicados. Objetivo: Realizar uma revisão sistemática, para avaliar o papel atual da avaliação com strain nos pacientes com diabetes mellitus. Métodos: Após revisão sistemática em cinco bancos de dados, 19 estudos que utilizaram strain bidimensional e oito estudos que utilizaram strain tridimensional foram incluídos. Resultados:Na avaliação por strain bidimensional, a amostra totalizou 1.774 indivíduos com diabetes mellitus, com idade média de 57,1 anos e mediana de 55 anos, com equilíbrio em relação ao sexo dos participantes (47,5% do sexo feminino). Nos estudos que utilizaram strain tridimensional, foram incluídos 488 indivíduos com diabetes, com idade média de 55,7 anos e mediana de 63 anos, também com equilíbrio entre o sexo dos pacientes (51% do sexo feminino). O strain global longitudinal foi o marcador de deformação miocárdica que mais frequentemente conseguiu demonstrar diferença entre grupos com indivíduos diabéticos e controles. Conclusão: O strain miocárdico por speckle tracking bi e tridimensional permite identificar disfunção sistólica subclínica em pacientes diabéticos, o que se torna mais marcante nos pacientes com mais fatores de risco associados e com remodelamento ventricular.(AU)

Background: Advanced echocardiography using two- and three-dimensional myocardial strain proposes to identify subclinical systolic dysfunction in different clinical conditions. Strain assessment plays an important role in the early diagnosis of diabetic cardiomyopathy in diabetes mellitus (DM). However, the findings of published articles are heterogeneous. Here we conducted a systematic review to analyze the current role of strain assessment in patients with DM. Methods: This systematic review of five databases identified 19 studies that used twodimensional strain and 8 studies that used three-dimensional strain. Results: The studies of two-dimensional strain included 1,774 DM patients (mean age, 57.1 years; median age, 55 years; 47.5% women), while those of three-dimensional strain included 488 DM patients (mean age, 55.7 years; median age, 63 years; 51% women). Global longitudinal strain was the myocardial deformation marker that differed most frequently between the DM and control groups. Conclusion: Myocardial strain imaging by two- and three-dimensional speckle tracking echocardiography allows the identification of subclinical systolic dysfunction in DM patients, and differences become more marked when associated with risk factors and ventricular remodeling.(AU)

The interplay between mitochondria and store-operated Ca2+ entry: Emerging insights into cardiac diseases.

Store-operated Ca2+ entry (SOCE) machinery, including Orai channels, TRPCs, and STIM1, is key to cellular calcium homeostasis. The following characteristics of mitochondria are involved in the physiological and pathological regulation of cells: mitochondria mediate calcium uptake through calcium uniporters; mitochondria are regulated by mitochondrial dynamic related proteins (OPA1, MFN1/2, and DRP1) and form mitochondrial networks through continuous fission and fusion; mitochondria supply NADH to the electron transport chain through the Krebs cycle to produce ATP; under stress, mitochondria will produce excessive reactive oxygen species to regulate mitochondria-endoplasmic reticulum interactions and the related signalling pathways. Both SOCE and mitochondria play critical roles in mediating cardiac hypertrophy, diabetic cardiomyopathy, and cardiac ischaemia-reperfusion injury. All the mitochondrial characteristics mentioned above are determinants of SOCE activity, and vice versa. Ca2+ signalling dictates the reciprocal regulation between mitochondria and SOCE under the specific pathological conditions of cardiomyocytes. The coupling of mitochondria and SOCE is essential for various pathophysiological processes in the heart. Herein, we review the research focussing on the reciprocal regulation between mitochondria and SOCE and provide potential interplay patterns in cardiac diseases.

Mechanisms of reduced peak oxygen consumption in subjects with uncomplicated type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance (i.e. impaired peak oxygen consumption, or VO2peak). In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations. METHODS: Eighty-eight adults with well-controlled and uncomplicated T2D and no criteria for HF underwent a maximal iCPET with speckle tracking echocardiography, vascular and endothelial function assessment, as well as a comprehensive biohumoral characterization. Effort intolerance was defined by a VO2peak below 80% of maximal predicted oxygen uptake. RESULTS: Forty-eight patients (55%) had effort intolerance reaching a lower VO2peak than T2D controls (16.5 ± 3.2 mL/min/kg, vs 21.7 ± 5.4 mL/min/kg, p < 0.0001). Despite a comparable cardiac output, patients with effort intolerance showed reduced peak peripheral oxygen extraction (11.3 ± 3.1 vs 12.7 ± 3.3 mL/dL, p = 0.002), lower VO2/work slope (9.9 ± 1.2 vs 11.2 ± 1.4, p < 0.0001), impaired left ventricle systolic reserve (peak S' 13.5 ± 2.8 vs 15.2 ± 3.0, p = 0.009) and global longitudinal strain (peak-rest ΔGLS 1.7 ± 1.5 vs 2.5 ± 1.8, p = 0.03) than subjects with VO2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups. CONCLUSIONS: Effort intolerance and reduced VO2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.

Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are antihyperglycemic agents with cardioprotective properties against diabetic cardiomyopathy (DCM). However, the distinctive mechanisms underlying GLP-1RAs and SGLT2is in DCM are not fully elucidated. The purpose of this study was to investigate the impacts of GLP1RAs and/or SGLT2is on myocardial energy metabolism, cardiac function, and apoptosis signaling in DCM. Biochemistry and echocardiograms were studied before and after treatment with empagliflozin (10 mg/kg/day, oral gavage), and/or liraglutide (200 µg/kg every 12 h, subcutaneously) for 4 weeks in male Wistar rats with streptozotocin (65 mg/kg intraperitoneally)-induced diabetes. Cardiac fibrosis, apoptosis, and protein expression of metabolic and inflammatory signaling molecules were evaluated by histopathology and Western blotting in ventricular cardiomyocytes of different groups. Empagliflozin and liraglutide normalized myocardial dysfunction in diabetic rats. Upregulation of phosphorylated-acetyl coenzyme A carboxylase, carnitine palmitoyltransferase 1ß, cluster of differentiation 36, and peroxisome proliferator-activated receptor-gamma coactivator, and downregulation of glucose transporter 4, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α2 to adenosine monophosphate-activated protein kinase α2, and the ratio of phosphorylated protein kinase B to protein kinase B in diabetic cardiomyocytes were restored by treatment with empagliflozin or liraglutide. Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, interleukin-1ß, tumor necrosis factor-α, and cleaved caspase-1 were significantly downregulated in empagliflozin-treated and liraglutide-treated diabetic rats. Both empagliflozin-treated and liraglutide-treated diabetic rats exhibited attenuated myocardial fibrosis and apoptosis. Empagliflozin modulated fatty acid and glucose metabolism, while liraglutide regulated inflammation and apoptosis in DCM. The better effects of combined treatment with GLP-1RAs and SGLT2is may lead to a potential strategy targeting DCM.

Exercise training suppresses Mst1 activation and attenuates myocardial dysfunction in mice with type 1 diabetes.

Our study was to test the effects of aerobic exercise on myocardial function in mice with type 1 diabetes and investigate the underlying mechanism associated with mammalian sterile 20-like kinase 1 (Mst1). Wild-type mice and Mst1(-/-) mice were injected with streptozotocin to induce diabetes and given moderate-intensity exercise for 12 weeks. Phosphorylation of Mst1 was significantly enhanced in the left ventricles of diabetic mice, which was reversed by exercise training. Exercise training or Mst1 deficiency improved myocardial function and reduced myocardial fibrosis in diabetic mice. Exercise training or Mst1 deficiency reduced TUNEL-positive cells and caspase-3 activity in the myocardium of diabetic mice. Exercise training or Mst1 deficiency abated oxidative stress and reduced mitochondrial reactive oxygen species formation, attenuated mitochondrial swelling, and enhanced mitochondrial adenosine triphosphate formation and mitochondrial membrane potential in the myocardium of diabetic mice. Exercise training or Mst1 deficiency suppressed inflammation in the myocardium of diabetic mice. Furthermore, exercise training did not provide further protection in Mst1 knockout mice in diabetes. In conclusion, chronic exercise training attenuated myocardial dysfunction in mice with type 1 diabetes, at least in part, through suppressing Mst1 activation.

Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs.

Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)-effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.

FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes.

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.

[Diabetes mellitus, coronary artery disease und heart disease (Update 2019)]. / Diabetes mellitus, koronare Herzkrankheit und Herzinsuffizienz (Update 2019).

Diabetes mellitus, cardiovascular disease and heart failure are interacting dynamically. Patients being diagnosed with cardiovascular disease should be screened for diabetes mellitus. Enhanced cardiovascular risk stratification based on biomarkers, symptoms and classical risk factors should be performed in patients with pre-existing diabetes mellitus. In patients with previously diagnosed arterosclerotic cardiovascular disease an agent proven to reduce major adverse cardiovascular events or cardiovascular mortality is recommended after therapy failure of metformin.

Current status and strategies of long noncoding RNA research for diabetic cardiomyopathy.

Long noncoding RNAs (lncRNAs) are endogenous RNA transcripts longer than 200 nucleotides which regulate epigenetically the expression of genes but do not have protein-coding potential. They are emerging as potential key regulators of diabetes mellitus and a variety of cardiovascular diseases. Diabetic cardiomyopathy (DCM) refers to diabetes mellitus-elicited structural and functional abnormalities of the myocardium, beyond that caused by ischemia or hypertension. The purpose of this review was to summarize current status of lncRNA research for DCM and discuss the challenges and possible strategies of lncRNA research for DCM. A systemic search was performed using PubMed and Google Scholar databases. Major conference proceedings of diabetes mellitus and cardiovascular disease occurring between January, 2014 to August, 2018 were also searched to identify unpublished studies that may be potentially eligible. The pathogenesis of DCM involves elevated oxidative stress, myocardial inflammation, apoptosis, and autophagy due to metabolic disturbances. Thousands of lncRNAs are aberrantly regulated in DCM. Manipulating the expression of specific lncRNAs, such as H19, metastasis-associated lung adenocarcinoma transcript 1, and myocardial infarction-associated transcript, with genetic approaches regulates potently oxidative stress, myocardial inflammation, apoptosis, and autophagy and ameliorates DCM in experimental animals. The detail data regarding the regulation and function of individual lncRNAs in DCM are limited. However, lncRNAs have been considered as potential diagnostic and therapeutic targets for DCM. Overexpression of protective lncRNAs and knockdown of detrimental lncRNAs in the heart are crucial for defining the role and function of lncRNAs of interest in DCM, however, they are technically challenging due to the length, short life, and location of lncRNAs. Gene delivery vectors can provide exogenous sources of cardioprotective lncRNAs to ameliorate DCM, and CRISPR-Cas9 genome editing technology may be used to knockdown specific lncRNAs in DCM. In summary, current data indicate that LncRNAs are a vital regulator of DCM and act as the promising diagnostic and therapeutic targets for DCM.

Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes.

BACKGROUND: Cardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death. UPR activation is an early event of diabetic cardiomyopathies and deregulated autophagy is associated with CVDs. RESULTS: An upregulation of UPR markers (glucose-regulated protein 78 KDa, glucose-regulated protein 94 KDa, inositol-requiring enzyme 1α, protein kinase RNA-like ER kinase and CCAAT/-enhancer-binding protein homologous protein (CHOP) gene) in EAT compared to subcutaneous adipose tissue (SAT), was observed as well as the UPR-related apoptosis marker caspase-4/procaspase-4 ratio but not in CHOP protein levels. Additionally, levels of ubiquitin and ubiquitinated proteins were decreased in EAT. Moreover, upregulation of autophagy markers (5' adenosine monophosphate-activated protein kinase, mechanistic target of rapamycin, Beclin 1, microtubule-associated protein light chain 3-II, lysosome-associated membrane protein 2, and PTEN-induced putative kinase 1) was observed, as well as an increase in the apoptotic Bim but not the ratio between Bim and the anti-apoptotic Bcl-2 in EAT. Diabetic patients show alterations in UPR activation markers but not in autophagy or apoptosis markers. CONCLUSION: UPR and autophagy are increased in EAT compared to SAT, opening doors to the identification of early biomarkers for cardiomyopathies and novel therapeutic targets.

Arterial-ventricular coupling in type 1 diabetes: arterial stiffness is associated with impaired global longitudinal strain in type 1 diabetes patients-the Thousand & 1 Study.

AIMS: Diabetes is associated with higher arterial stiffness-an early marker of cardiovascular disease. The coupling between arterial stiffness and myocardial function is still unresolved. We investigate associations between arterial stiffness and early myocardial impairment assessed with advanced echocardiography. METHODS: In 305 type 1 diabetes (T1D) patients without known heart disease and with normal left ventricular ejection fraction (LVEF) (biplane LVEF > 45%), we measured arterial stiffness as pulse wave velocity (PWV) and performed conventional and speckle-tracking echocardiography assessing global longitudinal strain (GLS) as a measure of systolic myocardial function. Associations between PWV and myocardial function were reported as standardized beta values from adjusted regression models including age, sex, mean arterial pressure, body mass index, HbA1c, diabetes duration, estimated glomerular filtration rate, degree of albuminuria, total cholesterol, heart rate and smoking. RESULTS: Patients were 54 (12) years [mean (SD)], 152 (50%) females, diabetes duration 31 (16) years, HbA1c 65 (12) mmol/mol, LVEF 58 (5) %, GLS -18.2 (2.6) % and PWV 10.2 (3.4) m/s. There was no association between PWV and LVEF (p = 0.93). Conversely, there was a highly significant association between PWV and GLS in crude and multivariable models (standardized ß-coefficient 0.25, p < 0.001 and 0.16, p = 0.036, respectively). Also, diastolic function measured as E/e' was highly associated with PWV in crude and multivariable models (standardized ß-coefficient 0.43, p < 0.001 and 0.17, p = 0.016, respectively). CONCLUSIONS: In T1D patients with normal LVEF and without known heart disease, higher arterial stiffness is independently associated with early systolic and diastolic myocardial impairment detectable by advanced echocardiography. Although unable to demonstrate causality, we display a relationship between diabetic angiopathy and diabetic cardiomyopathy (H-3-2009-139 and PROFIL-H-B-2009-056).

Cardiomiopatía diabética / Diabetic cardiomyopathy

La enfermedad coronaria, la hipertensión arterial y la diabetes son factores de riesgo independientes para el desarrollo de insuficiencia cardíaca y muerte. La cardiomiopatía diabética (CMD) es una de las etiologías frecuentes de cardiopatía en pacientes con diabetes tipo 1 y tipo 2. Si bien se suele plantear la CMD como la causa de la cardiopatía cuando se excluyen la hipertensión arterial, las valvulopatías y la enfermedad arterial coronaria aterotrombótica, estas coexisten con frecuencia e incluso también con la neuropatía autónoma cardiovascular. En los pacientes con CMD se puede demostrar mediante tests serológicos y por imagen alteraciones a nivel molecular, metabólico, mitocondrial, celular y tisular con infiltración grasa del músculo cardíaco, vinculadas a hiperglicemia, hiperinsulinemia y resistencia a la insulina, así como a lipotoxicidad por ácidos grasos libres, que son responsables del desarrollo de la CMD. Esta entidad primero determina disfunción diastólica del ventrículo izquierdo, más tarde disfunción sistólica e insuficiencia cardíaca. Se diagnostica mediante estudios serológicos de marcadores biológicos múltiples y por técnicas de imagen que evidencian la disfunción ventricular y mejoran la predicción pronóstica de enfermedad cardiovascular en diabéticos. En base a dichas pruebas se ha propuesto una clasificación por estadios o fenotipos clínicos de la CMD, que apunta a su diagnóstico precoz. Puede ser asintomática o ser responsable de síntomas y manifestaciones severas tales como insuficiencia cardíaca, arritmias y muerte súbita. Se puede asociar a hipertensión arterial, a enfermedad coronaria, a otras manifestaciones de microangiopatía y macroangiopatía aterotrombótica y a mortalidad cardiovascular. La prevención y el tratamiento intensivo multifactorial y personalizado de la diabetes, de todas sus alteraciones metabólicas y de la cardiopatía, mejoran la calidad y prolongan la vida. Se espera que investigaciones recientes, en proceso y futuras, determinen portentosos avances en la prevención y en el tratamiento de la CMD, que constituye una de las serias amenazas a la salud de la humanidad.

Coronary heart disease, hypertension and diabetes mellitus are independent risk factors for heart failure and death. Diabetic cardiomyopathy (DCM) is one of the common etiologies of cardiac disease in patients with diabetes type 1 or 2. Although DCM is often considered as the cause of heart disease when arterial hypertension, valvulopathies and atherothrombotic coronary artery are excluded, they coexist frequently, as well as with cardiovascular neuropathy. In patients with DCM, serological and imaging tests can show alterations at the molecular, metabolic, mitochondrial, cellular and tissue levels with fatty infiltration of the heart muscle, linked to hyperglycemia, hyperinsulinemia, insulin resistance, and lipotoxicity by fatty free acids, which are responsible for the development of the cardiomyopathy. The DCM first determines left ventricular diastolic dysfunction, later systolic dysfunction and heart failure. It is diagnosed by serological tests of multiple biological markers and by imaging tests that demonstrate ventricular dysfunction and improve the prognostic prediction of cardiovascular disease in diabetics. Based on these tests, a classification by stages or clinical phenotypes of DCM, which aims at its early diagnosis, has been proposed. It can be asymptomatic or be responsible for symptoms and severe manifestations such as heart failure, arrhythmias and sudden death, and may associate hypertension, coronary disease, other manifestations of microangiopathy and atherothrombotic macroangiopathy and cardiovascular mortality. The prevention and intensive multifactorial and personalized treatment of diabetes and all its metabolic and cardiac alterations, improve quality and prolong life. It is expected that ongoing and future research will determine breakthroughs in the prevention and treatment of DCM, which is one of the serious threats to the health of mankind.

A large frontal QRS-T angle is a strong predictor of the long-term risk of myocardial infarction and all-cause mortality in the diabetic population.

BACKGROUND: A large angle between the QRS vector and the T-wave vector (QRS-T angle) in electrocardiograms (ECGs) has recently been introduced as a marker of poor prognosis. The prognostic value in diabetes is unknown. We assessed the long-term predictive power of the frontal plane QRS-T angle in the diabetic population. METHODS: In 1992-93, the diabetic population of the municipality of Horsens, Denmark, was delineated by the prescription method, and an age- and gender-stratified sample of 240 diabetic persons was randomly selected. In 2015, 12-lead ECGs taken in 1993-94 were analyzed. Vital statistics were obtained from the Danish Civil Registration System and data regarding hospitalizations taken from The National Patient Registry in July 2015. RESULTS: In total, 178 people agreed to participate (74%) in the study, with the mean (sd) age being 58.9 (10.2) years and 56% being male. The total observation time was 21.5 (0.18) years, during which time 122 (69%) persons died, 32 (18%) suffered a myocardial infarction (MI) and 126 (71%) reached the composite endpoint of non-fatal MI or all-cause death. In Cox regression multivariate analysis a QRS-T angle above 90° was found to be an independent predictor of all-cause death (HR=2.2 (95% CI: 1.3-3.8)), MI (HR=2.95 (95% CI: 1.1-7.7)) and MI or all-cause death (HR=2.0 (95% CI: 1.2-3.5)) (all p<0.05), when adjusting for the effects of co-variates (gender, age, length of diabetes, BMI, total cholesterol, diabetes type, hemoglobin A1c, smoking, hypertension and previous MI). CONCLUSION: A large QRS-T angle is a strong, independent long-term predictor of all-cause mortality, MI and MI or all-cause death in the diabetic population.

QTc prolongation in Black diabetic subjects with cardiac autonomic neuropathy.

BACKGROUND: Prolonged corrected QT (QTc) has been identified as a risk factor for malignant arrhythmias and sudden cardiac death. Caucasian studies have shown a definite relationship between QTc prolongation and Cardiac Autonomic Neuropathy (CAN) in diabetic subjects. OBJECTIVE: To determine the prevalence of prolonged QTc in Black diabetic individuals with CAN and to ascertain how prolonged QTc correlated with the severity of CAN among these patients. METHODS: A total of 176 adult diabetic subjects were studied, 87 males and 89 females. There was a control group of non-diabetic individuals. Cardiac autonomic function was assessed using five cardiovascular autonomic function tests. CAN was diagnosed if 2 or more of these tests were abnormal. Severity of CAN was determined according to the number of abnormal tests. QTc > 0.440 was regarded as prolonged. RESULTS: Fifty-one out of the 176 diabetic subjects (29%) had CAN. The prevalence of prolonged QTc in diabetic subjects with CAN was 12%. QTc was prolonged in 1.6% and 0.6% of diabetic individuals without CAN and controls respectively. Although QTc correlated strongly with cardiac autonomic function neuropathy, there was no definite relationship between QTc prolongation and severity of CAN. CONCLUSION: This study in a Black population is in agreement with the well-known relationship between QTc prolongation and CAN reported in Caucasian studies. In view of the wide variability of QTc in this study population, it is suggested that relative QTc increase may be a better indicator of CAN than a definite QTc prolongation of greater than 0.440.

Cardiovascular Screening for the Asymptomatic Patient with Diabetes: More Cons Than Pros.

Diabetes mellitus is associated with an increased risk of coronary heart disease (CHD) morbidity and mortality. Although it frequently coexists with other cardiovascular disease (CVD) risk factors, it confers an increased risk for CVD events on its own. Coronary atherosclerosis is generally more aggressive and widespread in people with diabetes (PWD) and is frequently asymptomatic. Screening for silent myocardial ischaemia can be applied in a wide variety of ways. In nearly all asymptomatic PWD, however, the results of screening will generally not change medical therapy, since aggressive preventive measures, such as control of blood pressure and lipids, would have been already indicated, and above all, invasive revascularization procedures (either with percutaneous coronary intervention or coronary artery bypass grafting) have not been shown in randomized clinical trials to confer any benefit on morbidity and mortality. Still, unresolved issues remain regarding the extent of the underlying ischaemia that might affect the risk and the benefit of revascularization (on top of optimal medical therapy) in ameliorating this risk in patients with moderate to severe ischaemia. The issues related to the detection of coronary atherosclerosis and ischaemia, as well as the studies related to management of CHD in asymptomatic PWD, will be reviewed here.

PI3Kγ Inhibition Protects Against Diabetic Cardiomyopathy in Mice.

INTRODUCTION AND OBJECTIVES: Cardiovascular diseases, including cardiomyopathy, are the major complications in diabetes. A deeper understanding of the molecular mechanisms leading to cardiomyopathy is critical for developing novel therapies. We proposed phosphoinositide3-kinase gamma (PI3Kγ) as a molecular target against diabetic cardiomyopathy, given the role of PI3Kγ in cardiac remodeling to pressure overload. Given the availability of a pharmacological inhibitor of this molecular target GE21, we tested the validity of our hypothesis by inducing diabetes in mice with genetic ablation of PI3Kγ or knock-in for a catalytically inactive PI3Kγ. METHODS: Mice were made diabetic by streptozotocin. Cardiac function was assessed by serial echocardiographic analyses, while fibrosis and inflammation were evaluated by histological analysis. RESULTS: Diabetes induced cardiac dysfunction in wild-type mice. Systolic dysfunction was completely prevented, and diastolic dysfunction was partially blocked, in both PI3Kγ knock-out and kinase-dead mice. Cardiac dysfunction was similarly rescued by administration of the PI3Kγ inhibitor GE21 in a dose-dependent manner. These actions of genetic and pharmacological PI3Kγ inhibition were associated with a decrease in inflammation and fibrosis in diabetic hearts. CONCLUSIONS: Our study demonstrates a fundamental role of PI3Kγ in diabetic cardiomyopathy in mice and the beneficial effect of pharmacological PI3Kγ inhibition, highlighting its potential as a promising strategy for clinical treatment of cardiac complications of diabetic patients.

[Diabetes mellitus, coronary artery disease and heart disease]. / Diabetes mellitus, koronare Herzkrankheit und Herzinsuffizienz.

Diabetes mellitus, cardiovascular disease and heart failure are interacting dynamically. Patients being diagnosed with cardiovascular disease should be screened for diabetes mellitus. Enhanced cardiovascular risk stratification based on biomarkers, symptoms and classical risk factors should be performed in patients with pre-existing diabetes mellitus.

Efficacy of CD34+ Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Is Absent in Patients With Diabetes but Preserved in Patients With Insulin Resistance.

UNLABELLED: We evaluated the association of diabetes and insulin resistance with the response to cell therapy in patients with nonischemic dilated cardiomyopathy (DCM). A total of 45 outpatients with DCM received granulocyte colony-stimulating factor for 5 days. CD34(+) cells were then collected by apheresis and injected transendocardially. Twelve patients had diabetes mellitus (DM group), 17 had insulin resistance (IR group), and 16 displayed normal glucose metabolism (no-IR group). After stimulation, we found higher numbers of CD34(+) cells in the IR group (94 ± 73 × 10(6) cells per liter) than in the no-IR group (54 ± 35 × 10(6) cells per liter) or DM group (31 ± 20 × 10(6) cells per liter; p = .005). Similarly, apheresis yielded the highest numbers of CD34(+) cells in the IR group (IR group, 216 ± 110 × 10(6) cells; no-IR group, 127 ± 82 × 10(6) cells; DM group, 77 ± 83 × 10(6) cells; p = .002). Six months after cell therapy, we found an increase in left ventricular ejection fraction in the IR group (+5.6% ± 6.9%) and the no-IR group (+4.4% ± 7.2%) but not in the DM group (-0.9% ± 5.4%; p = .035). The N-terminal pro-brain natriuretic peptide levels decreased in the IR and no-IR groups, but not in the DM group (-606 ± 850 pg/ml; -698 ± 1,105 pg/ml; and +238 ± 963 pg/ml, respectively; p = .034). Transendocardial CD34(+) cell therapy appears to be ineffective in DCM patients with diabetes. IR was associated with improved CD34(+) stem cell mobilization and a preserved clinical response to cell therapy. SIGNIFICANCE: The present study is the first clinical study directly evaluating the effects of altered glucose metabolism on the efficacy of CD34(+) stem cell therapy in patients with nonischemic dilated cardiomyopathy. The results offer critical insights into the physiology of stem cell mobilization in heart failure and possibly an explanation for the often conflicting results obtained with stem cell therapy for heart failure. These results demonstrate that patients with dilated cardiomyopathy and diabetes do not benefit from autologous CD34(+) cell therapy. This finding could serve as a useful tool when selecting heart failure patients for future clinical studies in the field of stem cell therapy.

Forkhead box transcription factor 1: role in the pathogenesis of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle in people with diabetes that can occur independent of hypertension or vascular disease. The underlying mechanism of DCM is incompletely understood. Some transcription factors have been suggested to regulate the gene program intricate in the pathogenesis of diabetes prompted cardiac injury. Forkhead box transcription factor 1 is a pleiotropic transcription factor that plays a pivotal role in a variety of physiological processes. Altered FOXO1 expression and function have been associated with cardiovascular diseases, and the important role of FOXO1 in DCM has begun to attract attention. In this review, we focus on the FOXO1 pathway and its role in various processes that have been related to DCM, such as metabolism, oxidative stress, endothelial dysfunction, inflammation and apoptosis.