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Ectopic fat accumulation in non-adipose tissues is closely related to diabetes-related myocardial dysfunction. Nevertheless, the complete picture of the lipid metabolites involved in the metabolic-related myocardial alterations is not fully characterized. The aim of this study was to characterize the specific lipid profile in hearts in an animal model of obesity/insulin resistance induced by a high-fat diet (HFD). The cardiac lipidome profiles were assessed via liquid chromatography-mass spectrometry (LC-MS)/MS-MS and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging in hearts from C57BL/6J mice fed with an HFD or standard-diet (STD) for 12 weeks. Targeted lipidome analysis identified a total of 63 lipids (i.e., 48 triacylglycerols (TG), 5 diacylglycerols (DG), 1 sphingomyelin (SM), 3 phosphatidylcholines (PC), 1 DihydroPC, and 5 carnitines) modified in hearts from HFD-fed mice compared to animals fed with STD. Whereas most of the TG were up-regulated in hearts from animals fed with an HFD, most of the carnitines were down-regulated, thereby suggesting a reduction in the mitochondrial beta-oxidation. Roughly 30% of the identified metabolites were oxidated, pointing to an increase in lipid peroxidation. Cardiac lipidome was associated with a specific biochemical profile and a specific liver TG pattern. Overall, our study reveals a specific cardiac lipid fingerprint associated with metabolic alterations induced by HFD.

BACKGROUND: The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation. METHODS: To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart. RESULTS: Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver. CONCLUSION: CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopat

Diabetic cardiomyopathy (DCM) is a cardiovascular disease which has been reported as a major cause of mortality worldwide for several years. Berberine (BBR) is a natural compound extracted from a Chinese herb, with a clinically reported anti-DCM effect; however, its molecular mechanisms have not yet been fully elucidated. The present study indicated that BBR markedly alleviated DCM by inhibiting IL-1 beta secretion and the expression of gasdermin D (Gsdmd) at the post-transcriptional level. Considering the importance of microRNAs (miRNAs/miRs) in the regulation of the post-transcriptional process of specific genes, the ability of BBR to upregulate the expression levels of miR-18a-3p by activating its promoter (-1,000/-500) was examined. Notably, miR-18a-3p targeted Gsdmd and abated pyroptosis in high glucose-treated H9C2 cells. Moreover, miR-18a-3p overexpression inhibited Gsdmd expression and improved biomarkers of cardiac function in a rat model of DCM. On the whole, the findings of the present study indicate that BBR alleviates DCM by inhibiting miR-18a-3p-mediated Gsdmd activation; thus, BBR may be considered a potential therapeutic agent for the treatment of DCM.

Elevated blood glucose levels, insulin resistance (IR), hyperinsulinemia and dyslipidemia the key aspects of type 2 diabetes mellitus (T2DM), contribute to the development of a certain form of cardiomyopathy. This cardiomyopathy, also known as diabetic cardiomyopathy (DMCM), typically occurs in the absence of overt coronary artery disease (CAD), hypertension or valvular disease. DMCM encompasses a variety of pathophysiological processes impacting the myocardium, hence increasing the risk for heart failure (HF) and significantly worsening outcomes in this population. Low fat (LF), calorie-restricted diets have been suggested as the preferred eating pattern for patients with HF. However, LF diets are naturally higher in carbohydrates (CHO). We argue that in an insulin resistant state, such as in DMCM, LF diets may worsen glycaemic control and promote further insulin resistance (IR), contributing to a physiological and functional decline in DMCM. We postulate that CHO restriction targeting hyperinsulinemia may be able to improve tissue and systemic IR. In recent years low carbohydrate diets (LC) including ketogenic diets (KD), have emerged as a safe and effective tool for the management of various clinical conditions such as T2DM and other metabolic disorders. CHO restriction achieves sustained glycaemic control, lower insulin levels and successfully reverses IR. In addition to this, its pleiotropic effects may present a metabolic stress defense and facilitate improvement to cardiac function in patients with HF. We therefore hypothesize that patients who adopt a LC diet may require less medications and experience improvements in HF-related symptom burden.

Purpose Exercise-mediated protection from cardiomyopathy in diabetes through myokines raises the question of what volume of exercise should be performed. Irisin pathway molecules (consisting of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), irisin, peroxisome proliferator-activated receptors-alpha (PPAR-alpha) and uncoupling protein 1 (UCP1)), which have been shown to be mostly expressed in the heart, are thought to have beneficial effects on diabetic heart. The aim of the study is to evaluate the effects of different exercise protocols on irisin pathway in Type 1 diabetic heart. Methods Diabetic (60 mg/kg streptozotocin i.p.) and healthy Wistar Albino rats (n = 60) were trained under moderate and high-volume exercise protocols on rat treadmill for 6 weeks. After killing, mRNA transcript and protein abundance of PGC-1 alpha, irisin, PPAR-alpha, and UCP1 were determined in the left ventricles of healthy and diabetic rats. Results PPAR-alpha, FNDC5, and UCP1 mRNA levels increased significantly in healthy moderate-volume exercise group (HMVE) compared to healthy high-volume exercise (HHVE) and diabetic moderate-volume exercise groups (DMVE). Moreover, protein levels of irisin and UCP1 also elevated significantly in the diabetic high-volume exercise group (DHVE) compared to the healthy control group (HC), although there was no significant difference between the groups in PPAR-alpha. Conclusion Irisin and UCP1 protein values increased due to HHEV in the heart of Type 1 diabetic rats, but PPAR-alpha values did not change; it shows that HHEV is suitable for the heart of Type 1 diabetic rats in terms of the benefits of the pathway of irisin., Ankara University Research Funds [17L0230010, 15A0230006], This study was funded by Ankara University Research Funds (17L0230010 and 15A0230006).

Elevated blood glucose levels, insulin resistance (IR), hyperinsulinemia and dyslipidemia the key aspects of type 2 diabetes mellitus (T2DM), contribute to the development of a certain form of cardiomyopathy. This cardiomyopathy, also known as diabetic cardiomyopathy (DMCM), typically occurs in the absence of overt coronary artery disease (CAD), hypertension or valvular disease. DMCM encompasses a variety of pathophysiological processes impacting the myocardium, hence increasing the risk for heart failure (HF) and significantly worsening outcomes in this population. Low fat (LF), calorie-restricted diets have been suggested as the preferred eating pattern for patients with HF. However, LF diets are naturally higher in carbohydrates (CHO). We argue that in an insulin resistant state, such as in DMCM, LF diets may worsen glycaemic control and promote further insulin resistance (IR), contributing to a physiological and functional decline in DMCM. We postulate that CHO restriction targeting hyperinsulinemia may be able to improve tissue and systemic IR. In recent years low carbohydrate diets (LC) including ketogenic diets (KD), have emerged as a safe and effective tool for the management of various clinical conditions such as T2DM and other metabolic disorders. CHO restriction achieves sustained glycaemic control, lower insulin levels and successfully reverses IR. In addition to this, its pleiotropic effects may present a metabolic stress defense and facilitate improvement to cardiac function in patients with HF. We therefore hypothesize that patients who adopt a LC diet may require less medications and experience improvements in HF-related symptom burden.

Diabetes mellitus (DM) is a major and worsening global health problem. Type 2 diabetes mellitus (T2DM) accounts for more than 90% of DM and the global epidemic of obesity largely explains the dramatic increase in the incidence and prevalence of T2DM over the past 20 years. Cardiovascular complications are the major cause of morbidity and mortality in diabetic patients. The electrocardiogram (ECG) of diabetic and obese patients is frequently disturbed. The aim of this project was to characterize and clarify the molecular basis of electro-mechanical dysfunction in the hearts of type 2 diabetic and type 2 diabetic/obese rats. Experiments were performed in Zucker diabetic fatty (ZDF), Zucker fatty (ZF), and Zucker lean (ZL) rats. In vivo, biotelemetry experiments were performed to establish how the ECG was altered by diabetes and diabesity. Experiments were also carried out in isolated hearts to investigate further how diabetes and diabesity affect the electrical conduction system of the heart. Cell imaging was employed to assess ventricular myocyte shortening. Fluorescence photometry and whole-cell patch-clamp techniques were used to assess the effects of diabetes and diabesity on ion channel currents. Molecular biology and electron microscopy techniques were employed to assess proteins and structures associated with cardiac muscle contraction. Heart rate (HR) was reduced by aging and by diabesity in the absence of changes in physical activity and body temperature. Reductions in heart rate variability linked with altered sympathovagal drive may partly underlie disturbed HR in the ZDF rat even in the absence of autonomic nervous system control in the isolated perfused heart. The amplitude of shortening is generally well preserved in ZDF myocytes. There was evidence of altered time course of the Ca2+ transient and shortening in ventricular myocytes from ZDF rats. Molecular and structural defects in the ZF and ZDF rat hearts were observed. The resul

Type 2 diabetes is a chronic disease associated with micro- and macro-vascular complications, including myocardial ischemia, and also with a specific and intrinsic cardiac dysfunction called diabetic cardiomyopathy (DCM). Both clinical and animal studies demonstrate significant sex differences in prevalence, pathophysiology, and outcomes of cardiovascular diseases (CVDs), including those associated with diabetes. The increased risk of CVDs with diabetes is higher in women compared to men with 50% higher risk of coronary artery diseases and increased mortality when exposed to acute myocardial infarction. Clinical studies also reveal a sexual dimorphism in the incidence and outcomes of DCM. Based on these clinical findings, growing experimental research was initiated to understand the impact of sex on CVDs associated with diabetes and to identify the molecular mechanisms involved. Endothelial dysfunction, atherosclerosis, coagulation, and fibrosis are mechanisms found to be sex-differentially modulated in the diabetic cardiovascular system. Recently, impairment of energy metabolism also emerged as a determinant of multiple CVDs associated with diabetes. Therefore, future studies should thoroughly analyze the sex-specific metabolic determinants to propose new therapeutic targets. With current medicine tending toward more personalized care of patients, we finally propose to discuss the importance of sex as determinant in the treatment of diabetes-associated cardiac diseases to promote a more systemic inclusion of both males and females in clinical and preclinical studies.

The obesity epidemic has increased type II diabetes mellitus (T2DM) across developed countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia-reperfusion (I-R) injury, and refractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opioid receptor stimulus may overcome diabetes mellitus-induced cardiac dysfunction via membrane/mitochondrial-dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I-R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochondrial function. T2DM induced 25% weight gain, hyperglycemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca2+ -induced swelling, and cell death were all evident. Morphine administration for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I-R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contractile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short-term, but high-dose morphine administration in diabetic patients undergoing or recovering from acute ischemic cardiovascular events.

Background: The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes. Methods: In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 μg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m2 were excluded. Results: Median (Q1-Q3) FGF-23 was 74 (58-91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e*(8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R2 = 0.11) and increased E/e*(P < 0.01, R2 = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57-86) vs. 80 (60-98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues. Conclusions: In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated w

The rise of type 2 diabetes (T2DM) increases the risk of diabetic cardiomyopathy. Worsened cardiovascular outcomes have been clinically observed in female diabetic patients; however, there is a lack of sex specific treatments for diabetes associated heart complications. Caveolins are integral membrane proteins expressed in caveolae and mitochondria that act as cellular signaling platforms to regulate stress responses. The cardiac-specific caveolin-3 overexpression (Cav3 OE) has been shown to protect the heart from morphological changes induced by stressors and preserve mitochondrial function, but this has not yet been shown in a diabetic heart. We tested the rationale that Cav3 will protect the heart from diabetes-induced metabolic injury and be especially advantageous for females. Mid-aged male and female Cav3 OE mice and transgene-negative (Tg-Neg) littermates were either injected with streptozotocin (STZ) and fed a 60% kcal high-fat diet (HFD) to induce diabetes or injected with citrate buffer and fed a 4% kcal low-fat diet for controls. STZ/HFD significantly increased weight and impaired glucose tolerance of male and female mice, with worsened glucose tolerance in males. Tg-Neg T2DM mice presented cardiac hypertrophy in males and females, mitochondrial dysfunction in females, diastolic dysfunction in males, and cardiac mitochondrial disarray in males and females. Meanwhile, Cav3 OE prevented these incidences in T2DM mice. Therefore, Cav3 may be a novel target to protect diabetic mice, especially females, from cardiac complications.

Allopurinol (ALP) attenuates oxidative stress and diabetic cardiomyopathy (DCM), but the mechanism is unclear. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) following the disassociation with its repressor Keap1 under oxidative stress can maintain inner redox homeostasis and attenuate DCM with concomitant attenuation of autophagy. We postulated that ALP treatment may activate Nrf2 to mitigate autophagy over-activation and consequently attenuate DCM. Streptozotocin-induced type 1 diabetic rats were untreated or treated with ALP (100 mg/kg/d) for 4 weeks and terminated after heart function measurements by echocardiography and pressure-volume conductance system. Cardiomyocyte H9C2 cells infected with Nrf2 siRNA or not were incubated with high glucose (HG, 25 mmol/L) concomitantly with ALP treatment. Cell viability, lactate dehydrogenase, 15-F2t-Isoprostane and superoxide dismutase (SOD) were measured with colorimetric enzyme-linked immunosorbent assays. ROS, apoptosis, was assessed by dihydroethidium staining and TUNEL, respectively. The Western blot and qRT-PCR were used to assess protein and mRNA variations. Diabetic rats showed significant reductions in heart rate (HR), left ventricular eject fraction (LVEF), stroke work (SW) and cardiac output (CO), left ventricular end-systolic volume (LVVs) as compared to non-diabetic control and ALP improved or normalized HR, LVEF, SW, CO and LVVs in diabetic rats (all P < .05). Hearts of diabetic rats displayed excessive oxidative stress manifested as increased levels of 15-F2t-Isoprostane and superoxide anion production, increased apoptotic cell death and cardiomyocytes autophagy that were concomitant with reduced expressions of Nrf2, heme oxygenase-1 (HO-1) and Keap1. ALP reverted all the above-mentioned diabetes-induced biochemical changes except that it did not affect the levels of Keap1. In vitro, ALP increased Nrf2 and reduced the hyperglycaemia-induced increases of H9C2 cardiomyocyte hypertrophy, oxi

В обзоре детально проанализированы современные взгляды на эпидемиологию, этиологию и патогенез диабетической кардиомиопатии. Сахарный диабет вызывает различные структурные и функциональные модификации ткани миокарда. Эти патофизиологические изменения возникают в результате метаболических нарушений, вызванных гипергликемией, инсулинорезистентностью и дислипидемией. Свободные жирные кислоты могут стимулировать окисление и накапливаться в цитозоле, что приводит к липотоксическим эффектам путем образования церамидов, диацилглицерола и реактивных форм кислорода. Гипергликемия также вызывает увеличение содержания реактивных форм кислорода и образования конечных продуктов гликирования, что сопровождается развитием сердечной глюкотоксичности. Сочетание этих патофизиологических процессов, дефицит АТФ и липо-/глюкотоксичность являются промоторами дисбаланса Ca2+, стресса митохондриального/эндоплазматического ретикулума и развития апоптоза, активации сигнальных путей протеинкиназы С, митоген-активируемой протеинкиназы, убиквитин-протеасомной системы, протеотоксического стресса, активации циклического модулятора аденозиновых 5’-монофосфатов, ренин-ангиотензиновой системы, вызывают хроническое воспаление низкой интенсивности, диастолическую, а в дальнейшем систолическую дисфункцию, фиброз миокарда. Хроническая гипергликемия, инсулиновая резистентность и гиперинсулинемия вызывают резистентность кардиомиоцитов к инсулину и метаболические расстройства, которые усиливают дисфункцию митохондрий, оксидативный стресс, выработку конечных продуктов гликирования, нарушение обмена Ca2+ в митохондриях, хроническое воспаление низкой интенсивности, активацию системы «ренин — ангиотензин — альдостерон», стресс эндоплазматического ретикулума, гибель кардиомиоцитов, а также микрососудистую дисфункцию. Эти патофизиологические нарушения способствуют жесткости сердца, гипертрофии и фиброзу, развитию диастолической и систолической дисфункции миокарда и сердечной недостаточности., В огляді детально проаналізовані сучасні погляди на епідеміологію, етіологію та патогенез діабетичної кардіоміопатії. Цукровий діабет спричиняє різні структурні та функціональні модифікації тканини міокарда. Ці патофізіологічні зміни виникають внаслідок метаболічних порушень, викликаних гіперглікемією, інсулінорезистентністю і дисліпідемією. Вільні жирні кислоти можуть стимулювати окиснення і накопичуватися в цитозолі, що призводить до ліпотоксичних ефектів шляхом утворення церамідів, діацилгліцеролу і реактивних форм кисню. Гіперглікемія також викликає збільшення вмісту реактивних форм кисню та утворення кінцевих продуктів глікування, що супроводжується розвитком серцевої глюкотоксичності. Поєднання цих патофізіологічних процесів, нестача АТФ і ліпо-/глюкотоксичність є промоторами дисбалансу Ca2+, стресу мітохондріального/ендоплазматичного ретикулуму та розвитку апоптозу, активації сигнальних шляхів протеїнкінази С, мітоген-активованих протеїнкіназ, убіквітин-протеасомної системи, протеотоксичного стресу, активації циклічного модулятора аденозинових 5'-монофосфатів, ренін-ангіотензинової системи, що викликають хронічне запалення низької інтенсивності, діастолічну, а в подальшому систолічну дисфункцію, фіброз міокарда. Хронічна гіперглікемія, інсулінова резистентність і гіперінсулінемія викликають резистентність кардіоміоцитів до інсуліну та метаболічні розлади, що посилюють дисфункцію мітохондрій, оксидативний стрес, вироблення кінцевих продуктів глікування, порушення обміну Ca2+ в мітохондріях, хронічне запалення низької інтенсивності, активацію системи «ренін — ангіотензин — альдостерон», стрес ендоплазматичного ретикулуму, загибель кардіоміоцитів, а також мікросудинну дисфункцію. Ці патофізіологічні порушення сприяють жорсткості серця, гіпертрофії та фіброзу, розвитку діастолічної та систолічної дисфункції міокарда і серцевої недостатності., This paper presents detailed analysis of current views on the epidemiology, etiology and pathogenesis of diabetic cardiomyopathy. Diabetes mellitus causes various structural and functional modifications of myocardial tissue. These pathophysiological changes occur due to metabolic disorders caused by hyperglycemia, insulin resistance and dyslipidemia. Free fatty acids can stimulate oxidation and accumulate in the cytosol, leading to lipotoxic effects through the formation of ceramides, diacylglycerol and reactive oxygen species. Hyperglycemia also causes an increase in reactive oxygen species and the formation of end products of glycation, which is accompanied by the development of cardiac glucose toxicity. The combination of these pathophysiological processes, adenosine triphosphate deficiency and lipo-/glucose toxicity are promoters of Ca2+ imbalance, mitochondrial/endoplasmic reticulum stress and apoptosis, activation of protein kinase C signaling pathways, mitogen-activated protein kinases, ubiquitin-proteasome system, proteotoxic stress, activation of the cyclic modulator of adenosine 5’-monophosphates, renin-angiotensin system, causing low-grade chronic inflammation, development of diastolic and, subsequently, systolic dysfunction, myocardial fibrosis. Chronic hyperglycemia, insulin resistance and hyperinsulinemia cause cardiomyocyte resistance to insulin and metabolic disorders that exacerbate mitochondrial dysfunction, oxidative stress, production of glycation end products, alteration of Ca2+ metabolism in the mitochondria, chronic low-grade inflammation, activation of the renin-angiotensin-aldosterone system, stress of the endoplasmic reticulum, death of cardiomyocytes, as well as microvascular dysfunction. These pathophysiological disorders contribute to cardiac stiffness, hypertrophy and fibrosis, the development of diastolic and systolic myocardial dysfunction and heart failure.

With the aim of describing echocardiographic findings in type 1 diabetic patients with hyperglycemia admitted to the Intermediate Care Unit of the Hospital Central Universitario Dr. Antonio Maria Pineda during the December 2018-January 2019 period, a cross-sectional descriptive study was done in 25 patients with an average age of 20.28 ± 3.49 years, 56% were males, 92% were asymptomatic and had a mean time of diagnosis of 4.96 ± 3.29 years. The results show that 20% of patients had mild diastolic dysfunction and 44% regional motility alterations. Mean glycemic values of these patients was 209 mg/dL. Echocardiographic functional findings were not associated with time of diagnosis of diabetes. Subclinical findings of cardiovascular disease associated with persistent hyperglycemia was found in this group of patients It is important to implement measures that prevent micro and macrovascular complications of this disease., Con el objetivo de describir las características ecocardiográficas de pacientes con diabetes tipo 1 (DT1) descompensados en hiperglucemia de la Unidad de Cuidados Intermedios del Hospital Central Universitario Dr. Antonio María Pineda durante el mes de diciembre 2018-enero 2019, se desarrolló una investigación tipo descriptiva transversal con un total de 25 pacientes los cuales se caracterizaron por un promedio de edad de 20,28 años ± 3,49 años, 56% eran del sexo masculino, 92% asintomáticos cardiovasculares y con un promedio de años de diagnóstico de DT1 de 4,96 ± 3,29 años. Los resultados indican que 20% de los pacientes presentaron disfunción diastólica leve y 44% trastornos de motilidad regional. El promedio de glicemia basal en estos pacientes fue de 209 mg/dL. Los hallazgos funcionales ecocardiográficos no guardaron relación con los años de diagnóstico de la DT1. En conclusión, en estos pacientes se pueden encontrar hallazgos subclínicos de enfermedad cardiovascular en asociación a hiperglucemia persistente por lo que es importante implementar medidas de prevención que retarden las complicaciones micro y macrovasculares de esta enfermedad.

We read with interest your letter to the editor expressing concern about using ROCK2 inhibition for diabetic cardiomyopathy (DCM) management, as it may promote tumor metastasis and disturb some physiological functions. However, the effect of ROCK2 on metastasis seems to be tumor and context specific. In fact, numerous studies reported a metastasis-promoting role for ROCK2 in tumors like gastric cancer [ 1 ] hepatocellular carcinoma [ 2 ] and osteosarcoma [ 3 ], and that ROCK2 inhibition produced beneficial effects. Therefore, as it remains unclear how ROCK2 inhibition affects cancer spread, especially in vivo, we agree that, as with new drugs, thorough tumorigenicity and metastasis studies are needed.

Both human and animal studies have shown mitochondrial and contractile dysfunction in hearts of type 2 diabetes mellitus (T2DM). Exercise training has shown positive effects on cardiac function, but its effect on the mitochondria have been insufficiently explored. The aim of this study was to assess the effect of exercise training on mitochondrial function in T2DM hearts. We divided T2DM mice (db/db) into a sedentary and an interval training group at 8 weeks of age and used heterozygote db/+ as controls. After 8 weeks of training, we evaluated mitochondrial structure and function, as well as the levels of mRNA and proteins involved in key metabolic processes from the left ventricle. db/db animals showed decreased oxidative phosphorylation capacity and fragmented mitochondria. Mitochondrial respiration showed a blunted response to Ca2+ along with reduced protein levels of the mitochondrial calcium uniporter. Exercise training ameliorated the reduced oxidative phosphorylation in complex (C) I + II, CII and CIV, but not CI or Ca2+ response. Mitochondrial fragmentation was partially restored. mRNA levels of isocitrate, succinate and oxoglutarate dehydrogenase were increased in db/db mice and normalized by exercise training. Exercise training induced an upregulation of two transcripts of peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α1 and PGC1α4) previously linked to endurance training adaptations and strength training adaptations, respectively. The T2DM heart showed mitochondrial dysfunction at multiple levels and exercise training ameliorated some, but not all mitochondrial dysfunctions.

The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished.

Introduction: Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Furthermore, inflammation and injury in diabetic kidneys and hearts is dependent on infiltrating macrophages. Therefore, we hypothesized that the tissue protective effects of MRAs in diabetes is partially due to inhibition of MR signaling in macrophages. In this study, we used mice genetically deficient in myeloid MR to evaluate whether macrophage mineralocorticoid receptor signaling contributes to the development of kidney and cardiac disease in hypertensive diabetic mice. Method(s): Transgenic mice with intact myeloid MR (MRflox/flox) or myeloid MR deficiency (MRflox/flox LysMCre) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice (n=13) were made diabetic with multiple low dose injections of streptozotocin (STZ) and were assessed after 15 weeks for the development of hypertension (systolic blood pressure), nephropathy (albuminuria, renal function impairment and kidney damage) and cardiomyopathy (cardiac dysfunction-echocardiography and cardiac damage). Result(s): MR intact Nos3-/- mice with diabetes developed hypertension, kidney damage (macrophage accumulation, albuminuria, renal function impairment, hypertrophy, tubular injury, fibrosis), and cardiac damage (Left ventricular (LV) fractional shortening, macrophage accumulation, fibrosis), but no neutrophil infiltrate. In comparison, myeloid MR deficient Nos3-/- mice had equivalent diabetes, hypertension and albuminuria, but showed protection against loss of renal function (plasma cystatin-C reduced 48% vs MR intact mice with diabetes, p<0.01) and cardiac dysfunction (LV fractional shortening reduced 26% in MR intact mice with diabetes, p<0.01, but not in myeloid MR deficient mice with diabetes). The cardiac protection resulting from myeloid MR deficiency included the prevention of a diabetes-ind

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.

Diabetes mellitus (DM), and in particular type 2 DM (T2DM), is approaching epidemic proportions globally. Relative to people without diabetes, exercise performance is reduced by approximately 20% in T2DM subjects universally, whereas impairment in type 1 DM (T1DM) is less consistently reported. Risk of cardiovascular disease (CVD) is significantly elevated in both T1DM and T2DM, and thus emphasis is placed on cardiovascular constraints to exercise capacity, including subclinical cardiac dysfunction and the entity of diabetic cardiomyopathy (DMC). A clear bidirectional association between heart failure and T2DM exists, with numerous pathophysiological mechanisms identified in animal models. Longitudinal data suggests a low prevalence of heart failure in T1DM, on the other hand, which insinuates the pathological mechanisms thought to underpin DMC may be exclusive of chronic hyperglycemia which unifies the diagnosis of T1DM and T2DM. The pulmonary microvasculature is targeted in diabetes, meanwhile, and may be an under-appreciated contributor to exercise limitation. It is thought that the lungs are protected from deleterious effects of subclinical microvascular disease by virtue of their substantial size, although the ability to assess pulmonary microvascular function during exercise has been limited. This thesis assesses exercise performance (VO2peak) in people with T1DM and T2DM, evaluates the contribution of cardiac function and the pulmonary circulation using comprehensive traditional and novel echocardiographic analyses, and investigates the effect of phosphodiesterase type 5 (PDE5) inhibitor Sildenafil on exercise capacity. VO2peak is demonstrated to be impaired in only the T2DM cohort of the study group, and independently associated with sedentary lifestyle and reduced left ventricular end diastolic volume. Comprehensive resting and exercise echocardiographic measurements of biventricular systolic function and LV diastolic function, in addition to speckle-tracki

Cardiomyocytes inside the heart are densely packed with parallel columns of myofibrils and mitochondria. Growing evidence indicates a strong correlation between alterations in this sub-cellular ultrastructure and the alterations in energy metabolism during various pathological conditions of heart. The central hypothesis explored in this thesis is that changes in cardiac sub-cellular architecture in pathological conditions can also affect cardiac bioenergetics by interfering with various mechanisms of intracellular energy transport. Type 1 diabetic cardiomyopathy is an ideal candidate for a model disease state to understand this hypothesized interplay between ultrastructure and metabolism. It exhibits many common conditions which accompany heart failure, such as increased mitochondrial reactive oxygen species production and decreased reserve of creatine phosphate. In a preliminary study, 2D electron microscope images collected from control and streptozotocin induced type I diabetic rat hearts were analysed. It was found that diabetic cardiomyopathy leads to an increased mitochondrial fission and formation of large mitochondrial clusters. Further analysis showed that effective surface-to-volume ratio of mitochondrial clusters increases by 22.5% in diabetic cells. Subsequently, a compartmental model of cardiac energy transfer was developed. This simple model predicted that this increase in the surface-to-volume ratio can have a moderate compensatory effect by elevating the availability of adenosine triphosphate (ATP) in the cytosol when ATP synthesis within the mitochondria is compromised. Next, 3D electron microscope images from control animals were investigated. The analysis revealed that cardiac mitochondria are arranged non-uniformly in parallel columns of varying sizes. Following this, the compartmental model was extended to a reaction diffusion based 2D finite element model incorporating a realistic description of the observed sub-cellular ultrastructure. The new

Aims: Type 1 diabetes entails increased cardiovascular morbidity and cardiac chamber sizes are associated with cardiovascular disease. The aim of this study was to compare cardiac chamber sizes in normoalbuminuric persons with type 1 diabetes to a background population without diabetes. Methods: In a cross-sectional study, we examined 71 normoalbuminuric persons with long-term type 1 diabetes without known cardiovascular disease using cardiac multi-detector computed tomography. Cardiac chamber sizes and left ventricular remodelling were compared to persons without diabetes from the Copenhagen General Population Study. Results: Participants were median (interquartile range) 54 (48–60) (type 1 diabetes) and 57 (50–64) (without diabetes) years old and 59% were men (both groups). Participants with type 1 diabetes had smaller left ventricular mass (−3.5 g/m2, 95% confidence interval −5.8 to −1.3) and left (−4.0 mL/m2, 95% confidence interval −6.9 to −1.0) and right (−11.7 mL/m2, 95% confidence interval −15.4 to −7.9) ventricular volumes in multivariable analyses (adjusted for age, sex, body composition, blood pressure and antihypertensive medication), but no differences in atrial volumes. Conclusion: Persons with long-term type 1 diabetes had smaller left ventricular mass and biventricular volumes, yet similar atrial sizes, compared to a background population without diabetes. These findings may reflect subclinical development of diabetic cardiomyopathy.

The pathophysiology linking diabetes and cardiovascular disease (CVD) is complex and multifactorial. The specific type of cardiomyopathy associated with diabetes, known as diabetic cardiomyopathy (DCM), is recognized as asymptomatic progression of structural and functional remodeling in the heart of diabetic patients in the absence of coronary atherosclerosis and hypertension. In other words, the presence of heart disease specifically in diabetic patients is also known as diabetic heart disease. This article reviews the impact of diabetes in heart and vascular beds focusing on molecular mechanisms involving the oxidative stress, the inflammation, the endothelium dysfunction and the alteration of the homeostasis of calcium, among others mechanisms. Understanding these mechanisms will help identify and treat CVD in patients with diabetes, as well as to plan efficient strategies to mitigate DCM impact in those patients.

Učestalost subkliničke sistolne i dijastolne disfunkcije leve komore (LV) kod dijabetičara može biti velika i često neblagovremeno pepoznata. Kod normotenzivnih bolesnika sa Diabetes mellitus-om tip 2 noćni pad krvnog pritiska može biti manji od 10% (non-dipperi), što se može pokazati ambulatornim monitoringom krvnog pritiska (ABPM). Ovi bolesnici su u visokom riziku od neželjenih kardijalnih događaja. Cilj: Istražiti dijagnostičku i prognostičku ulogu tkivnog Doppler-a i parametara miokardne deformacije za rano otkrivanje disfunkcije leve komore. Odrediti značaj Doppler ehokardiografije i AMBP za prognozu i ishod tokom tri godine praćenja. Metode: U istraživanje je bio uključen 121 asimptomatski dijabetičar i grupa od 41 zdravih, po starosti i polu uporedivih ispitanika. Dimenzije, volumeni leve pretkomore i komore procenjeni su ehokardiografski, kao i svi konvencionalni Doppler parametri. Metodom tkivnog Doppler-a merene su brzine u nivou medijalnog anulusa (Em, Am, Sm), uključujući brzinu izovolumetrijske kontrakcije (IVCv), vreme akceleracije IVCv i akceleraciju tokom izovolumetrijske kontrakcije (IVA), odnos E/Em i tkivni indeks miokardne performanse (tMPI). Globalni longitudinalni strejn (GLS) određivan je dvodimenzionalnom speckle-tracking metodom. Svim ispitanicima je urađen ABPM. Tokom perioda od tri godine praćena je pojava nekog od neželjenih kardijalnih događaja. Rezultati: Značajne korelacije između mehanike i funkcije leve komore nađene su u odnosu na sledeće parametre: GLS sa E/Em (r=0.402; p=0.0001), IVCv (r= -0.358; p<0.001) i tMPI (r=0,289; p<0,001) sa signifikantno nižim vrednostima GLS (-17.5 ± 2.1 vs -24.4 ± 2.4; p<0.001), IVCv (0.07 ± 0.02m/s vs 0.09 ± 0.03m/s; p<0.001) i signifikantno višim E/Em (10.3 ± 2.24 vs 7.4 ± 1.8; p<0.001) kod dijabetičara. ABPM je pokazao da je procentualni pad sistolnog krvnog pritiska u toku noći bio očekivano signifikantno niži u grupi dijabetičara, gde je čak 38 bolesnika (31%) imalo noćni pad sistolnog krvnog pri, Subclinical left ventricular (LV) systolic and diastolic dysfunction is prevalent in diabetic subjects. In normotensive type 2 diabetic patients ambulatory blood pressure monitoring (ABPM) can show a non-dipping nocturnal pattern of blood pressure. This patients are at risk of cardiovascular morbidity and mortality. Aim: To explore the diagnostic and prognostic role of Tissue Doppler and myocardial deformation parameters for early detection of left ventricular dysfunction. To determine the significance of Doppler echocardiography and AMBP for prognosis and outcome during three years follow up. Methods: The study included 121 asymptomatic normotensive typ 2 diabetic patients and 41 age and sex matched healthy subject. Dimensions and left atrial and left ventricular volumes were assessed by echocardiography and all conventional Doppler parameters. Tissue Doppler velocities were measured from medial annulus (Em, Am, Sm), including isovolumic contraction velocity (IVCv), acceleration time of IVCv and acceleration during isovolumic contraction (IVA), E/Em and Doppler tissue myocardial performance index (tMPI) Global longitudinal strain (GLS) was derived from two-dimensional speckle-tracking. ABPM was performed in all patients. All patients were followed up for three years. The end point was some of the cardiac events. Results: There was close correlations between values of GLS and E/Em (r=0.402, p<0.001), IVCv (r= -0.358; p<0.001) and tMPI (r=0,289; p<0,001) with significantly lower values of GLS (-17.5 ± 2.1 vs -24.4 ± 2.4; p<0.001), IVCv (0.07 ± 0.02m/s vs 0.09 ± 0.03m/s; p<0.001), and significantly higher value of E/Em (10.3 ± 2.24 vs 7.4 ± 1.8; p<0.001) in group of diabetic patients. ABPM showed that 38 diabetic patients (31,4%) had a non-dipping pattern, despite the fact that they are considered normotensive and as many as 14 had an increase in blood pressure during the night (inverse-dipper). During of three years of follow up only 9 of 121 diabetic patients (7.4%)

Aim: To evaluate whether macrophage mineralocorticoid receptor signaling contributes to the development of kidney and cardiac disease in hypertensive diabetic mice. Background(s): Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Furthermore, inflammation and injury in diabetic kidneys and hearts is dependent on infiltrating macrophages. Therefore, we hypothesized that the tissue protective effects of MRAs in diabetes is partially due to inhibition of MR signaling in macrophages. Method(s): Transgenic mice with intact myeloid MR (MRflox/flox =WT) or myeloid MR deficiency (MRflox/flox LysMCre = MyMRKO) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice (n=13) were made diabetic with low dose streptozotocin (STZ) and were assessed after 15 weeks for the development of hypertension (systolic blood pressure), nephropathy (renal function impairment, albuminuria, renal injury) and cardiomyopathy (cardiac dysfunction-echocardiography). Result(s): MR intact Nos3-/- mice with diabetes developed hypertension, albuminuria, renal function impairment (elevated cystatin-C), tubular injury (increased KIM-1 gene expression), and reduced cardiac function (LV fractional shortening: Diabetic 21% versus non-diabetic 31%), but no neutrophil infiltrate. In comparison, myeloid MR deficient Nos3-/- mice with similar diabetes had equivalent levels of hypertension, albuminuria and tubular injury, but showed improved renal function (plasma cystatin-C 48%#, p<0.01) and improved cardiac function (LV fractional shortening 28%, p<0.01). Conclusion(s): MR signaling in macrophages promotes injury in the diabetic kidneys and hearts of Nos3-/- mice without affecting hypertension. Therefore, MRAs can suppress diabetic nephropathy and diabetic cardiomyopathy by reducing macrophage-mediated injury independent of their ability to lower blood pressure

Актуальність. Висока захворюваність та поширеність цукрового діабету (ЦД) зумовлює ранню інвалідизацію та смертність через розвиток хронічних ускладнень. При цьому головна причина смерті при ЦД 2-го типу пов’язана із серцево-судинними захворюваннями. Мета дослідження: з’ясувати частоту, механізми та прояви уражень серцево-судинної системи у хворих на ЦД 2-го типу. Матеріали та методи. Обстежено 49 пацієнтів з ЦД 2-го типу віком понад 50 років, у тому числі 25 чоловіків, 24 жінки. Визначали показники метаболізму, зміни електрокардіограми. Результати. У групі спостереження у 55,1 % пацієнтів виявлена ішемічна хвороба серця (ІХС), у 77,6 % — артеріальна гіпертензія, у 28,6 % — перенесені кардіоваскулярні події. Переважали хворі (83,7 %) з надлишковою масою тіла і ожирінням. У 57,1 % виявлені порушення ліпідного обміну за наявної декомпенсації ЦД в 61,2 %, що підтверджено збільшенням рівня глікованого гемоглобіну до 8,8 ± 0,3 %. Зареєстровані порушення процесів автоматизму, збудливості та провідності серця: у 12,2 % — синусова тахікардія, у 6,1 % — синусова брадикардія, у 4,1 % — синусова аритмія, у 10,2 % — миготлива аритмія, у 8,2 % — суправентрикулярна і шлуночкова екстрасистолія, у 30,6 % — внутрішньошлуночкові блокади. Прояви гіпоксії мали 32,7 % пацієнтів, зміни зубця Q — 8,2 %, зміни інтервалу ST — 8,2 %. Висновки. Дисметаболічні порушення є підґрунтям для розвитку хронічних діабетичних ускладнень, що формують, зокрема, кардіальну автономну нейропатію, діабетичну кардіоміопатію та атеросклеротичні ураження серцево-судинної системи з маніфестацією ІХС, артеріальної гіпертензії, синдрому порушень ритму і провідності, гіпоксії., Актуальность. Высокая заболеваемость и распространенность сахарного диабета (СД) обусловливают раннюю инвалидизацию и смертность из-за развития хронических осложнений. При этом главная причина смерти при СД 2-го типа связана с сердечно-сосудистыми заболеваниями. Цель исследования: выяснить частоту, механизмы и проявления поражений сердечно-сосудистой системы у больных СД 2-го типа. Материалы и методы. Обследовано 49 пациентов с СД 2-го типа в возрасте старше 50 лет, в том числе 25 мужчин, 24 женщины. Определялись показатели метаболизма, изменения электрокардиограммы. Результаты. В группе наблюдения у 55,1 % пациентов выявлена ишемическая болезнь сердца (ИБС), у 77,6 % — артериальная гипертензия, у 28,6 % — перенесенные кардиоваскулярные cобытия. Преобладали больные (83,7 %) с избыточной массой тела и ожирением. У 57,1 % выявлялись нарушения липидного обмена при наличии декомпенсации СД у 61,2 %, что подтверждено повышением уровня гликированного гемоглобина в среднем до 8,8 ± 0,3 %. Зарегистрированы нарушения процессов автоматизма, возбудимости и проводимости сердца: у 12,2 % — синусовая тахикардия, у 6,1 % — синусовая брадикардия, у 4,1 % — синусовая аритмия, у 10,2 % — мерцательная аритмия, у 8,2 % — суправентрикулярная и желудочковая экстрасистолия, у 30,6 % — внутрижелудочковые блокады. Проявления гипоксии имели 32,7 % пациентов, изменения зубца Q — 8,2 %, изменения интервала ST — 8,2 %. Выводы. Дисметаболические нарушения являются основой развития хронических диабетических осложнений, формируют, в частности, кардиальную автономную нейропатию, диабетическую кардиомиопатию и атеросклеротические поражения сердечно-сосудистой системы с манифестацией ИБС, артериальной гипертензии, синдрома нарушений ритма и проводимости, гипоксии., Background. A high morbidity and prevalence of diabetes mellitus (DM) cause early disability and mortality due to the development of chronic complications. The main cause of death in type 2 DM is associated with cardiovascular di­seases. The purpose of the study: to determine the incidence, mechanisms and manifestations of cardiovascular disorders in patients with type 2 DM. Materials and methods. Forty-nine individuals with type 2 DM aged over 50 years were exami­ned, including 25 men and 24 women. Metabolic parameters, changes in the electrocardiogram were determined. Results. In the observation group, 55.1 % of patients had coronary heart disease, 77.6 % — arterial hypertension and 28.6 % — cardiovascular events. An overweight and obesity were prevalent in 83.7 % of patients. In 57.1 %, disorders of lipid metabolism were detected, with the presence of diabetes decompensation in 61.2 %, confirmed by an increased level of glycosylated hemoglobin on average to 8.8 ± 0.3 %. Disorders of the automatism processes, excitability and cardiac conduction were detected: in 12.2 % of cases — sinus tachycardia, in 6.1 % — sinus bradycardia, in 4.1 % — sinus arrhythmia, in 10.2 % — atrial fibrillation, in 8.2 % — supraventricular and ventricular extrasystole, in 30.6 % — intraventricular blockades. 32.7 % of patients had hypoxia manifestations, 8.2 % — changes in the Q wave, 8.2 % — changes in the ST interval. Conclusions. Dysmetabolic disorders are the basis for the development of chronic diabetic complications forming, in particular, cardiac autonomic neuropathy, diabetic cardiomyopathy and atherosclerotic lesions of the cardiovascular system with manifestation of coronary heart disease, arterial hypertension, syndrome of rhythm and conduction disorders, hypoxia.

Long-chain fatty acids are the main cardiac substrates from which ATP is generated continually to serve the high energy demand and sustain the normal function of the heart. Under healthy conditions, fatty acid beta-oxidation produces 50-70% of the energy demands with the remainder largely accounted for by glucose. Chronically increased dietary lipid supply often leads to excess lipid accumulation in the heart, which is linked to a variety of maladaptive phenomena, such as insulin resistance, cardiac hypertrophy and contractile dysfunction. CD36, the predominant cardiac fatty acid transporter, has a key role in setting the heart on a road to contractile dysfunction upon the onset of chronic lipid oversupply by translocating to the cell surface and opening the cellular 'doors' for fatty acids. The sequence of events after the CD36-mediated myocellular lipid accumulation is less understood, but in general it has been accepted that the excessively imported lipids cause insulin resistance, which in turn leads to contractile dysfunction. There are several gaps of knowledge in this proposed order of events which this review aims to discuss. First, the molecular mechanisms underlying lipid-induced insulin resistance are not yet completely disclosed. Specifically, several mediators have been proposed, such as diacylglycerols, ceramides, peroxisome proliferator-activated receptors (PPAR), inflammatory kinases and reactive oxygen species (ROS), but their relative contributions to the onset of insulin resistance and their putatively synergistic actions are topics of controversy. Second, there are also pieces of evidence that lipids can induce contractile dysfunction independently of insulin resistance. Perhaps, a more integrative view is needed, in which several lipid-induced pathways operate synergistically or in parallel to induce contractile dysfunction. Unraveling of these processes is expected to be important in designing effective therapeutic strategies to protect the

Left ventricular (LV) diastolic dysfunction and longitudinal systolic dysfunction were identified in patients with diabetes mellitus (DM). This study's aim was to investigate the impact of LV longitudinal systolic function on LV diastolic function in DM patients with preserved LV ejection fraction (LVEF). We studied 177 DM patients with preserved LVEF (all ≥50%), and 82 age-, gender- and LVEF-matched healthy volunteers as control. Global longitudinal strain (GLS) was defined as the average peak strain of 18 segments from standard apical views, GLS <18% as subclinical LV systolic dysfunction (LVSD), and LV dispersion as the standard deviation of time-to-peak strain from the same views. For DM patients with LVSD (n = 74), E/A and E' were lower, and E/E' and isovolumic relaxation time (IVRT) were greater than for DM patients without LVSD (n = 103) and normal controls (n = 82). Moreover, these parameters were lower for DM patients without LVSD than for normal controls. Multivariate analysis revealed that GLS was a strong determinative factor for E' and E/E' (β = 0.30, p < 0.001 and β = -0.25, p < 0.001, respectively), as was LV dispersion for E-wave deceleration time and IVRT (β = 0.21, p = 0.002 and β = 0.30, p < 0.001, respectively) independently of age. For normal subjects, however, only age was associated with all LV diastolic parameters. In conclusions, in contrast to age-related LV diastolic dysfunction in normal subjects, in DM patients with preserved LVEF, LV diastolic function was associated with LV longitudinal systolic function and LV dispersion independently of age. Our findings have obvious clinical implications for the management of DM patients., info:eu-repo/semantics/published

Izvod: Dijabetes karakteriše pojačana aktivnost RAAS. Hiperglikemija je najznačajniji metabolički uzročnik tkivnih promena i aktivacije RAAS. Posledice aktivacije RAAS u srčanom tkivu su oksidacioni stres, fibroza i apoptoza. U poslednje vreme se uviđa da modulacija RAAS, inhibitorima ASE i blokatorima AT1 receptora, nije dovoljno efikasna, dok direktni inhibitor renina pokazuje efekat i na intracelularni i ekstracelularni tkivni RAAS. Kombinovana primena modulatora RAAS dovodi do povećanog kardiovaskularnog mortaliteta što je ukazalo na postojanje neželjenih efekata na miokard. Mehanizam kardijalnog oštećenja nakon primene modulatora RAAS je važno istraživačko pitanje. Ovim istraživanjem su sagledavani akutni efekti perfuzije modulatorima RAAS na zdrav i miokard u dijabetesu. Utvrditi razlike u kardiodinamskim parametrima, koronarnom protoku, stvaranju NO i parametrima oksidacionog stresa između srca zdravih i pacova nakon 4 nedelje hiperglikemije. Utvrditi akutne efekte perfuzije modulatorima RAAS (zofenopril, valsartan, spironolakton i aliskiren) na srca zdravih i pacova nakon četiri nedelje hiperglikemije. Korišteni su pacovi soja Wistar albino podeljeni u 8 grupa po 12 životinja. Životinje su žrtvovane a srce je izolovano i postavljeno na Lagendorf-ov aparat. Četiri grupe su činile zdrave životinje kojima su kroz izolovano srce perfuzijom puštani pojedinačno zofenopril 1.5 μM, valsartan 1μM, spironolakton 0.1 μM i aliskiren 1 μM. Na isti način su tretirani i pacovi kojima je 4 nedelje pred eksperiment hemisjki indukovan dijabetes upotrebom streptozotocina. Određivani su kardiodinamski parametri: brzine promene pristiska u levoj komori (dp/dt max i dp/dt min), pritisak u levoj komori (SLVP i DLVP), srčana frekvenca (NR) i koronarni protok (CF). Iz koronarnog efluenta određivana koncentracija NO i parametara oksidacionog stresa: O2.-, H2O2 i TBARS. Svi parametri su određivani pri različitim perfuzionim pritiscima od 40-120 cm H20. Hronična hiperglikemija je dovel, Diabetes is characterized by an increase in the activity of RAAS. Hyperglycemia is the most important metabolic cause of tissue changes and RAAS activation. The consequences of RAAS activation in the cardiac tissue are oxidative stress, fibrosis and apoptosis. Recently, it has been noted that RAAS modulation with ACE inhibitors and blockers of AT1 receptors is not effective enough, while a direct renin inhibitor proved to have effect on both, intracellular and extracellular tissue RAAS. A combined use of RAAS modulators leads to an increased cardiovascular mortality, which indicates the presence of adverse effects on myocardium. The 166 mechanism of cardiac damage after the administration of RAAS modulators is an important research issue. This research examined the acute effects of perfusion with RAAS modulators on healthy and diabetic myocardium. To identify the differences in cardiodynamic parameters, coronary flow, NO production and oxidative stress parameters between the hearts of healthy rats and the hearts of rats that had been hyperglycemic for 4 weeks. To determine the acute effects of perfusion with RAAS modulators (zofenopril, valsartan, spironolactone and aliskiren) on the hearts of healthy rats and the hearts of rats after four weeks of hyperglycemia. We used rats of albino Wistar strain, divided into 8 groups of 12 animals each. The animals were sacrificed and the hearts were isolated and mounted on Langendorff' apparatus. Four groups consisted of healthy animals into whose isolated hearts were by perfusion separately released zofenopril 1.5 uM, 1μM valsartan, spironolactone 0.1 uM and 1 uM aliskiren. In the same way were treated the rats to which diabetes had been induced chemically, using streptozotocin, 4 weeks before the experiment. The cardiodynamic parameters were measured: rate of the change of the left ventricular pressure (dp / dt max and dp / dt min), left ventricular pressure (SLVP and DLVP), heart rate (HR) and coronary flow (CF).

Diabetes mellitus tip 2 (DM) ima značajan uticaj na morfologiju i funkciju leve komore nezavisno od drugih faktora rizika i komorbiditeta kao što su hipertenzija (HTA) i koronarna bolest (AP). Cilj rada je bio da se ispitaju mogućnosti dopunskih i strain ehokardiografskih parametara u otkrivanju dijabetesne kardiomiopatije (DCM) u odnosu na klasične, da se proceni prediktivna vrednost pojedinih parametara na razvoj neželjenih događaja, i prediktivna vrednost strain i strain rate analiza kod asimptomatskih pacijenata sa DM i mikroalbuminurijom. Metod: Ispitivano je 210 pacijenata sa DM i to: (grupa I:70 samo DM, grupa II:70 DM i AP i grupa III:70 DM i HTA), i 80 zdravih dobrovoljaca bez DM koji su služili kao kontrolna grupa. Svim pacijentima određivani su klasični faktori rizika, rađena laboratorijska ispitivanja, testovi na mikroalbuminuriju, pregled očnog dna, klinički pregled, ergo test, klasična ultrazvučna merenja, tkivni Doppler, longitudinali, cirkumferencijalni strain i strain rate. Kontrolna ultrazvučna merenja rađena su nakon godinu dana. Rezultati: u poređenju sa kontrolama pacijenti u grupi I imali su povećanu masu leve komore (LK),oštećenu relaksaciju LK, nižu ejekcionu frakciju (EF), frakciono skraćenje (FS) i manju ekskurziju mitralnog anulusa (MAPSE). Prisustvo HTA dodatno oštećuje EF, FS i MAPSE i pogoršava dijastolnu disfunkciju.Maksimalni globalni longitudinalni strain (Slong) i rani dijastolni strain rate (SRlong E) sniženi su u grupi I u odnosu na kontrole, dok je cirkumferencijalni strain (Scirc) smanjen samo ako je DM udružen sa HTA ili AP. Prediktivna vrednost u predviđanju neželjenih događaja postoji za: EF, indeks mitralnog protoka (E/A), indeks volumena leve pretkomore (LAVindeks; ml/m2), vreme deceleracije E talasa (EDT), brzinu propagacije mitrlanog protoka (Vp),MAPSE, Slong, SRlong E, Scirc. Zaključak: DM je nezavistan determinator morfologije i funkcije leve komore što se može dokazati primenom klasične i strain rate ehokardiografije., Diabetes mellitus type 2 (DM) has a significant impact on the morphology and left ventricular function independent of other risk factors and co-morbidities such as hypertension (HTA) and coronary heart disease (AP).The aim of this study was to examine the possibility of additional strain and echocardiographic parameters in the detection of diabetic cardiomyopathy (DCM) in relation to classical, to assess the predictive value of the parameters on the development of adverse events, and the predictive value of strain and strain rate analysis in asymptomatic patients with DM and microalbuminuria. Method: 210 patients with DM divided in: (group I: 70 DM Group II: 70 DM and AP and Group III: 70 DM and HTA), and 80 healthy subjects without DM who served as a control group. All patients were determined by conventional risk factors, conducted laboratory tests, tests for microalbuminuria, fundus examination, clinical examination, ergo test, conventional ultrasonic measurements, tissue Doppler, longitudinal, circumferential strain and strain rate. Control ultrasound measurements were made after one year. Results: Compared with control group, patients in group I had increased mass of the left ventricle (LK), damaged LK relaxation, lower ejection fraction (EF), fractional shortening (FS) and mitral annular plane excursion (MAPSE). The presence of HTA further damaged EF, FS and MAPSE and deteriorating diastolic disfunction. Peak global longitudinal strain (Slong) and early diastolic longitudinal strain rate (SRlong E) decreased in group I compared to controls, while the circumferential strain (Scirc) reduced only if DM is associated with hypertension or AP. The predictive value in predicting adverse events exist for: EF, the index of the mitral flow (E / A), left atrial volume index (LAV index), E wave deceleration time (EDT), the speed of propagation of mitral flow (Vp), MAPSE, Slong, SRlong E, Scirc. Conclusion: DM is an independent determinant of morphology and function of the

Diabetic cardiomyopathy is a major contributor to the increasing burden of heart failure globally. Effective therapies remain elusive, in part due to the incomplete understanding of the mechanisms underlying diabetes-induced myocardial injury. The objective of this study was to assess the direct impact of insulin replacement on left ventricle structure and function in a rat model of diabetes. Male Sprague-Dawley rats were administered streptozotocin (55 mg/kg i.v.) or citrate vehicle and were followed for 8 weeks. A subset of diabetic rats were allocated to insulin replacement (6 IU/day insulin s.c.) for the final 4 weeks of the 8-week time period. Diabetes induced the characteristic systemic complications of diabetes (hyperglycaemia, polyuria, kidney hypertrophy) and was accompanied by marked left ventricle remodelling (cardiomyocyte hypertrophy, left ventricle collagen content) and diastolic dysfunction (transmitral E/A, left ventricle-dP/dt). Importantly, these systemic and cardiac impairments were ameliorated markedly following insulin replacement, and moreover, markers of the diabetic cardiomyopathy phenotype were significantly correlated with the extent of hyperglycaemia. In summary, these data suggest that poor glucose control directly contributes towards the underlying features of experimental diabetic cardiomyopathy, at least in the early stages, and that adequate replacement ameliorates this.Copyright © The Author(s) 2017.

Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced ART and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500 mu M/100 nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (similar to 6.2 fold; p

This study aims at investigating the epigenetic landscape of cardiomyocytes exposed to long elevated glucose levels in vitro and in vivo Exposure of mouse HL-1 and rat differentiated H9C2 cardiomyocyte cell lines to high glucose (30 mM) for 72 hours determined some epigenetic changes including upregulation of class I and III HDAC protein levels and activity, inhibition of histone acetylase p300 activity, increase in histone H3 lysine (K) 27 trimethylation (H3K27me3) and reduction in H3K9 acetylation (H3K9Ac). Gene expression analysis focused on cardiotoxicity, revealed that high glucose induced markers associated with tissue damage, fibrosis and cardiac remodelling such as Nexilin, Versican, CREM and ADRA2. Notably, the transcription factor CREM was found to be important in the regulation of cardiotoxicity-associated genes as assessed by specific siRNA and chromatin immunoprecipitation experiments. In CD1 mice, made hyperglycaemic by STZ injection, cardiac structural alterations were evident at six months after STZ treatment and were associated with a significant increase of H3K27me3 and reduction of H3K9Ac. Consistently, Nexilin, CREM and ADRA2 expression was significantly induced at RNA and protein level. Confocal microscopy analysis of Nexilin localization showed this protein irregularly distributed along the sarcomeres in the heart of hyperglycaemic mice. This evidence suggested for a structural alteration of cardiac Z-disk with potential consequences on contractility. In conclusion, high glucose may alter the epigenetic landscape of cardiac cells. Sildenafil, restoring cGMP levels, counteracted the increase of CREM and Nexilin providing a protective effect in the presence of hyperglycemia.

Despite diabetes being an independent predictor of poor prognosis of heart failure (2.5-fold), therapies specifically targeting the diabetic heart remain elusive. The STZ-induced diabetic rodent is a commonly-utilised model for the study of DCM, exhibiting overt hyperglycaemia due to insulin deficiency. This study sought to make a comprehensive assessment of systemic characteristics, myocardial structure and cardiac function following insulin replacement in STZinduced DCM. After four weeks untreated STZ-induced diabetes in adult male Sprague-Dawley rats (55 mg/kg i.v. in 280 g rats), 6IU/day insulin s.c. was administered for a further 4wks. Results were compared to citrate vehicle-treated sham and untreated STZ rats. After a total of eight weeks diabetes (Table), insulin replacement attenuated hyperglycaemia and increased urine excretion, with ameliorated left ventricular (LV) diastolic function, LV superoxide levels and LV remodelling. In summary, these data infer that insulin deficiency per se directly contributes towards the underlying phenotypic and pathological features of DCM in the STZ diabetic rat. (Table presented).

Актуальність. Концепція про діабетичну кардіоміопатію вперше була запропонована С. Рублер та співавт. понад 100 років тому, але цей діагноз рідко використовується клініцистами через існування, переважно в пацієнтів із цукровим діабетом (ЦД), таких коморбідних захворювань, як ішемічна хвороба серця (ІХС) і гіпертонічна хвороба. Різноманітні механізми спричинюють патогенез діабетичної кардіоміопатії, але її специфічні ознаки досі остаточно не встановлені. Мета дослідження — з’ясувати ультраструктурні особливості ремоделювання кардіоміоцитів, характерні для діабетичної кардіоміопатії, за наявності коморбідної ІХС та артеріальної гіпертензії (АГ). Матеріали і методи. Були порівняні результати клінічного обстеження та ультраструктурного дослідження експрес-некропсій та періопераційних біопсій міокарда в 25 пацієнтів із ЦД 2-го типу за наявності супутньої АГ та ІХС. Результати. Виявлені ультраструктурні особливості гібернації кардіоміоцитів, характерні для ЦД 2-го типу, відмінні від їх гібернації за наявності ІХС та АГ. З’ясовано, що гібернація кардіоміоцитів за ЦД виникає вже на ранніх стадіях захворювання, ще до розвитку АГ та ІХС, тобто за відсутності гіпертрофії кардіоміоцитів та їх оглушеності, характерних для серцево-судинних захворювань. Висновки. Діабетична кардіоміопатія виникає в результаті дисметаболічних і мікроциркуляційних розладів, що призводить до гібернації кардіоміоцитів. Тригерами розвитку діабетичної кардіоміопатії є декомпенсація ЦД і серцево-судинні захворювання. Гіберновані кардіоміоцити гинуть шляхом апоптозу або вторинного некрозу, що обумовлює трансформацію діастолічної дисфункції лівого шлуночка в систолічну., Актуальность. Концепция о диабетической кардиомиопатии впервые была предложена С. Рублер и соавт. более 100 лет назад, но этот диагноз редко применяется клиницистами из-за существования, преимущественно у пациентов с сахарным диабетом (СД), таких коморбидных заболеваний, как ишемическая болезнь сердца (ИБС) и гипертоническая болезнь. Различные механизмы влияют на патогенез диабетической кардиомиопатии, но ее специфические признаки до сих пор не установлены. Цель исследования — выявить ультраструктурные особенности ремоделирования кардиомиоцитов, типичные для диабетической кардиомиопатии, при наличии коморбидной ИБС и артериальной гипертензии (АГ). Материал и методы. Были сопоставлены результаты клинического обследования и ультраструктурного исследования экспресс-некропсий и периоперационных биопсий миокарда 25 пациентов с СД 2-го типа, сопутствующей АГ, а также ИБС. Результаты. Выявлены ультраструктурные особенности гибернации кардиомиоцитов, характерные для СД, отличные от их гибернации при ИБС и АГ. Установлено, что гибернация кардиомиоцитов при СД возникает уже на ранних стадиях заболевания, еще до развития АГ и ИБС, то есть при отсутствии гипертрофии кардиомиоцитов и их оглушенности, характерных для сердечно-сосудистых заболеваний. Выводы. Диабетическая кардиомиопатия является результатом дисметаболических и микроциркуляторных расстройств, которые приводят к гибернации кардиомиоцитов. Триггерами развития диабетической кардиомиопатии является декомпенсация СД и сердечно-сосудистые заболевания. Гибернированные кардиомиоциты погибают путем апоптоза или вторичного некроза, что способствует трансформации диастолической дисфункции левого желудочка в систолическую., Introduction. The concept of diabetic cardiomyopathy was first proposed by S. Rubler et al. more than 100 years ago, but this diagnosis іs rarely used by clinicians because of the existence of such co-morbidities as ischemic heart disease and arterial hypertension in those patients. Different mechanisms have been implicated in the pathogenesis of diabetic cardiomyopathy, however its specific features are not revealed till now. The aim of the investigation was to reveal the ultrastructural features of cardiomyocyte remodeling, typical for diabetic cardiomyopathy in the cases of concomitant ischemic heart disease and arterial hypertension. Material and methods. Ultrastructure of express-necropsies and intraoperative myocardial biopsies of 25 patients suffering from diabetes mellitus, arterial hypertension and different forms of ishemic heart disease were examined. Results. The ultrastractural mechanisms of cardiomyocyte hibernation, specific for diabetic cardiomyopathy, in comparison with changes characteristic for ischemic heart disease and arterial hypertension, were revealed. Cardiomyocyte hibernation in the cases of diabetes mellitus emergences on the early stages of the illness, prior the appearance of arterial hypertension and ischemic heart disease which cause predominantly their hypertrophy and stunning. Conclusions. Diabetic cardiomyopathy is a consequence of dysmetabolic and microcirculatory disorders causing cardiomyocyte hibernation. Decompensation of diabetes mellitus and the presence of ischemic heart disease or arterial hypertension are the main triggers of diabetic cardiomyopathy development. Hibernated cardiomyocytes die due to apoptosis or secondary necrosis transforming diastolic dysfunction of the left ventricle, typical for diabetes mellitus, into systolic type.

Objective: This study was to develop a strain analysis method to evaluate the left ventricular (LV) functions in type 2 diabetic patients with an asymptomatic LV diastolic dysfunction. Methods: Two groups (10 asymptomatic type 2 diabetic subjects and 10 control ones) were considered. All of the subjects had normal ejection fraction values but impaired diastolic functions assessed by the transmitral blood flow velocity. For each subject, based on cardiac MRI, global indexes including LV volume, LV myocardial mass, cardiac index (CI), and transmitral peak velocity, were measured, and regional indexes (i.e., LV deformation, strain and strain rate) were calculated through an image-registration technology. Results: Most of the global indexes did not differentiate between the two groups, except for the CI, LV myocardial mass and transmitral peak velocity. While for the regional indexes, the global LV diastolic dysfunction of the diabetic indicated an increased strain (0.08 ± 0.044 vs. −0.031 ± 0.077, p = 0.001) and a reduced strain rate (1.834 ± 0.909 vs. 3.791 ± 2.394, p = 0.033) compared to the controls, moreover, the local LV diastolic dysfunction reflected by the strain and strain rate varied, and the degree of dysfunction gradually decreased from the basal level to the apical level. Conclusions: The results showed that the strain and strain rates are effective to capture the subtle alterations of the LV functions, and the proposed method can be used to estimate the LV myocardial function based on cardiac MRI.

BackgroundWe examined the relationship between glucose homeostasis and comprehensive measures of cardiac structure and function among a representative sample of US Hispanics.Methods and resultsECHO-SOL (Echocardiographic Study of Latinos), an echocardiographic ancillary study of the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), enrolled 1818 Hispanic/Latino men (43%) and women (57%) aged ≥45 years (mean=56). Glucose intolerance was defined as follows: (1) prediabetes: hemoglobin (HbA1c) ≥5.7 and <6.5% and (2) diabetes mellitus: fasting plasma glucose ≥126 mg/dL, 2-hour postload glucose ≥200 mg/dL, HbA1c ≥6.5%, or hypoglycemic agent use. Uncontrolled diabetes mellitus was defined as HbA1c ≥7.0%. Insulin resistance was defined using the homeostatic model assessment for insulin resistance. Echocardiography examinations assessed left ventricular structure and systolic/diastolic function. Multivariable linear and logistic regression models were used. Prediabetes prevalence was 42%, and diabetes mellitus prevalence was 28% (47% uncontrolled). Glucose intolerance was associated with increased left ventricular posterior wall and interventricular septal and relative wall thicknesses (all P<0.05), reduced ejection fraction (P<0.01), reduced stroke and end-diastolic volumes (both P<0.001), decreased peak E' velocity (lateral and septal P<0.001), and increased E/E' ratio (lateral and septal P<0.01). The odds ratios (95% confidence intervals) for diastolic dysfunction among individuals with prediabetes and diabetes mellitus (versus diabetes mellitus free) were 1.36 (0.96-1.9) and 1.90 (1.3-2.8), respectively(P=0.006). Results were consistent for uncontrolled diabetes mellitus versus diabetes mellitus. Homeostatic model assessment for insulin resistance was associated with increased E/E' (P<0.001), and greater relative wall thickness and septal thickness (both P<0.05); lower stroke volume (P<0.0001); and lower peak lateral and septal E' v

The prevalence of heart failure, especially heart failure with preserved ejection (HFpEF), is increasing annually in part due to an ageing population and the dramatically increased incidence of obesity, insulin resistance, prediabetes and diabetes worldwide. It is well established that patients with type-1 diabetes (T1DM) and type-2 diabetes (T2DM) are at a significantly increased risk of developing HFpEF. HFpEF is a progressive condition and its earliest manifestations are subtly impaired myocardial function that is termed diabetic cardiomyopathy (DCM). At present, there is only a limited understanding of the underlying pathophysiological mechanisms that drive the development of DCM and eventual HFpEF in early T1DM and T2DM. Therefore, the aim of this thesis was to further explore mechanisms that could drive the development of DCM and HFpEF using rat models of early T1DM and T2DM. Using synchrotron radiation as a source for small angle x-ray scattering (SAXS) in the in situ beating rat heart, we are able to measure actin-myosin cross-bridge (CB) dynamics in the entire cardiac cycle, in real time. In the first part of this thesis, we were able to demonstrate that chronic inhibition of the RhoA/Rho-kinase (ROCK) pathway with fasudil improved regionally impaired diastolic myosin head extension and depressed systolic mass transfer in the myocardium of rats with early T1DM. Further, we were also able to demonstrate that global left ventricular (LV) systolic performance was significantly improved in diabetic rats treated with fasudil. These results suggest that the activation of the ROCK pathway is involved in the development of early DCM in the context of T1DM. The Goto-Kakizaki (GK) rat is a non-obese model of spontaneous T2DM, which makes it a useful model to examine the effects of early T2DM on the myocardium without the added complication of obesity. Utilising the synchrotron radiation SAXS technique in the in situ beating heart preparation, we are able to demonstra

Introduction: The cardiomyopathy in diabetes mellitus (DM) is the disorders in cardiac muscle due to prolonged exposure of vascular tissues to hyperglycemia in DM; and is termed as diabetic cardiomyopathy (DC). The early pre-clinical features of DC are the left ventricular diastolic dysfunction (LVDD), preceding the systolic dysfunction and being able to evolve to symptomatic heart failure. Methods: A cross-sectional study was done including 50 DM-2 patients without any feature of cardiovascular involvement and blood pressure less than 130/80 mmHg. Doppler echocardiography was done to evaluate LVDD. Results: In this study results showed diastolic dysfunction was more common among female than male. The prevalence of diastolic dysfunction is more in cases of longer duration of DM. Conclusion: Our study supports other studies that myocardial damage in DM-2 affects diastolic dysfunction before systolic dysfunction. As Doppler echocardiography is a simple non-invasive procedure to assess cardiac function, so in diabetes it should be done routinely in DM for early diagnosis and prevention of further complications.

Background Different from other indicators of cardiac function, such as ejection fraction and transmitral early diastolic velocity, myocardial strain is promising to capture subtle alterations that result from early diseases of the myocardium. In order to extract the left ventricle (LV) myocardial strain and strain rate from cardiac cine-MRI, a modified hierarchical transformation model was proposed. Methods A hierarchical transformation model including the global and local LV deformations was employed to analyze the strain and strain rate of the left ventricle by cine-MRI image registration. The endocardial and epicardial contour information was introduced to enhance the registration accuracy by combining the original hierarchical algorithm with an Iterative Closest Points using Invariant Features algorithm. The hierarchical model was validated by a normal volunteer first and then applied to two clinical cases (i.e., the normal volunteer and a diabetic patient) to evaluate their respective function. Results Based on the two clinical cases, by comparing the displacement fields of two selected landmarks in the normal volunteer, the proposed method showed a better performance than the original or unmodified model. Meanwhile, the comparison of the radial strain between the volunteer and patient demonstrated their apparent functional difference. Conclusions The present method could be used to estimate the LV myocardial strain and strain rate during a cardiac cycle and thus to quantify the analysis of the LV motion function.

The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) continues to increase with the general aging of the population. In patients with chronic HF, prevalence of DM is 24% compared with 40% in those hospitalized with worsening HF. Patients with concomitant HF and DM have diverse pathophysiologic, metabolic, and neurohormonal abnormalities that potentially contribute to worse outcomes than those without comorbid DM. In addition, although stable HF outpatients with DM show responses that are similar to those of patients without DM undergoing evidence-based therapies, it is unclear whether hospitalized HF patients with DM will respond similarly to novel investigational therapies. These data support the need to re-evaluate the epidemiology, pathophysiology, and therapy of HF patients with concomitant DM. This paper discusses the role of DM in HF patients and underscores the potential need for the development of targeted therapies.

This thesis examined the central concepts of left ventricular (LV) deformation and functional reserve in patients with diabetes (DM). The studies evaluated LV systolic contractile reserve (CR) and coronary microvascular function and identified determinants and patterns of coronary microvascular dysfunction. LV diastolic reserve and its relationship with endothelial function and impact of strict metabolic control on LV mechanics were studied. LV systolic CR at low dose dobutamine of ≥10% identified an index of microcirculatory resistance (IMR) of <25 with 100% accuracy. There was differential involvement of coronary vascular beds in patients with vascular risk factors: DM patients had worse microvascular function in the anterior circulation than patients without DM. The opposite was observed in those without DM. DM patients with dyslipidaemia, hypertension, worse glycaemic control and higher body mass index had worse microvascular function, whereas those treated with metformin had better microvascular function. Flow mediated dilatation (FMD) of the brachial artery was an independent predictor of LV diastolic reserve and exercise capacity. Patients with DM had impaired ability to improve LV diastolic function and maintain normal LV pressures with exercise. This is demonstrated by a higher increase in E/e’, after adjusting for differences in the resting values, with the increase in the ratio persisting up to 10 minutes into recovery. Patients with DM and hypertension, longer duration of insulin therapy, worse glycaemic control, worse renal function and lower septal e’ had more impaired diastolic reserve. Patients with DM have impaired LV systolic and diastolic function manifested by an impaired LV global longitudinal strain of -14.9±3.2% and septal e’ velocities of 6±2 cm/sec, respectively, despite a normal LV ejection fraction. Improvements in glycaemic control over a 12-month period were associated with improvements in LV systolic and diastolic function measure

Obesity is a major global health issue. Obese patients develop metabolic syndrome, which is a cluster of clinical features characterized by insulin resistance and dyslipidemia. Its cardiac manifestation, diabetic cardiomyopathy, leads to heart failure. Bone marrow-derived multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSC) are envisioned as a therapeutic tool not only for cardiovascular diseases but also for other degenerative conditions. Our aim was to evaluate whether the intravenous administration of MSC modifies cardiac dysfunction in obese mice. To this end, C57BL/6 mice were fed a regular (normal) or high-fat diet (obese). Obese animals received the vehicle (obese), a single dose (obese + 1x MSC) or three doses (obese + 3x MSC) of 0.5x10(6) syngeneic MSC. Two to three months following MSC administration, cardiac function was assessed by cardiac catheterization, at basal condition and after a pharmacological stress. Compared to normal mice, obese mice presented hyperglycemia, hyperinsulinemia, hypercholesterolemia and cardiac dysfunction after stress condition. Exogenous MSC neither improved nor impaired this cardiac dysfunction. Thus, intravenous administration of MSC has neutral effect on obesity-induced diabetic cardiomyopathy

RationaleHyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart.ObjectiveTo test whether amylin accumulates in the heart of obese and type 2 diabetic patients and to uncover the effects of amylin accumulation on cardiac morphology and function.Methods and resultsWe compared amylin deposition in failing and nonfailing hearts from lean, obese, and type 2 diabetic humans using immunohistochemistry and Western blots. We found significant accumulation of large amylin oligomers, fibrils, and plaques in failing hearts from obese and diabetic patients but not in normal hearts and failing hearts from lean, nondiabetic humans. Small amylin oligomers were even elevated in nonfailing hearts from overweight/obese patients, suggesting an early state of accumulation. Using a rat model of hyperamylinemia transgenic for human amylin, we observed that amylin oligomers attach to the sarcolemma, leading to myocyte Ca(2+) dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from prediabetes. In contrast, prediabetic rats expressing the same level of wild-type rat amylin, a nonamyloidogenic isoform, exhibited normal heart structure and function.ConclusionsHyperamylinemia promotes amylin deposition in the heart, causing alterations of cardiac myocyte structure and function. We propose that detection and disruption of cardiac amylin buildup may be both a predictor of heart dysfunction and a novel therapeutic strategy in diabetic cardiomyopathy.

The prevalence of diabetes is increasing worldwide. This poses a significant threat to human health, as diabetes is associated with an increased risk of mortality due to cardiovascular disease. In particular, diabetic patients develop diabetic cardiomyopathy (DCM), characterised by impaired cardiac muscle contraction and relaxation, leading to left ventricle (LV) muscle stiffness and congestive heart failure. Previous studies suggest that changes in the coronary vasculature and cardiac subcellular function may account for the progression to DCM, however as yet this has not been assessed in vivo. Synchrotron radiation (SR) now makes possible novel imaging and diffraction techniques, to investigate the role these mechanisms play in the early development of DCM, where clinical intervention is most efficacious. To assess coronary function in vivo we validated the use of SR imaging to detect and quantify regional differences in resistance microvessel calibre. In type 1 diabetic rodents we found that although endothelium-dependent and –independent vasodilatory responses in individual coronary vessels are preserved, following inhibition of NO and PGI2 production, there is evidence of localised focal and segmental constrictions. This demonstrates, for the first time, localised coronary microvascular endothelial dysfunction in early-stage type 1 diabets (T1D). Contributing to this diabetic coronary impairment is the RhoA/Rho-kinase (ROCK) pathway, which had previously been shown to play a role in endothelial dysfunction and coronary vasospasm. Our data further support a role for ROCK in early diabetic coronary dysfunction, as following nitric oxide synthase/cyclooxygenase blockade, ROCK inhibition greatly reduced regional segmental constrictions and completely alleviated persistent focal stenoses in diabetic animals. Together, these findings provide strong evidence that early vascular dysfunction may contribute to the development of DCM. In addition, although characterised b

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.

It was analysed the state of structurally — functional changes of cells membranes, basal membrane, pericapillarity space in 29 Type 2 diabetes mellitus patients with cardiomyopathy. It is established that diabetic cardiomyopathy is accompanied with activation of compensatory-adaptative processes, intensification of intracellular organelles activity, edema and hyperplasia of endotheliocytes that are accompanied by progressing of destructive endothelium changes. Simultaneously it is observed depressing of Na+, K+ -ATPase activity in the erythrocytes membranes, accumulation of lisosomes, triglicerides, lipofuscin in the cytoplasm, activation of lipid peroxidation. Progressing of diabetic cardiomyopathy is accompanied by compaction, but in some parts by loosening of basal membrane. Edema of interstitial spaces and accumulation of desintegration products of cells, triglicerides and glycoproteins are observed. This caused damaging of endothelial cells, rheological disorders and, insuring of vascular wall., Проведен анализ структурно-функциональных изменений в мембранах клеток, базальной мембране, перикапиллярном пространстве у 29 больных сахарным диабетом 2-го типа и кардиомиопатией. Выявлено, что диабетическая кардиомиопатия сопровождается активацией компенсаторно-адаптационных процессов, усилением активности клеточных органелл, отеком и гиперплазией эндотелиоцитов, изменениями эндотелия кровеносных капилляров, форменных элементов крови, что сопровождается прогрессированием деструктивных изменений. Одновременно наблюдаются угнетение активности Na+,K+-ATРазы и уменьшение продуктов Na+,K+-ATРазной реакции в мембранах эритроцитов, накопление в цитоплазме фаголизосом, триацилглицеринов и продуктов распада, липофусцина, а также активация процессов перекисного окисления липидов. Прогрессирование диабетической кардиомиопатии сопровождается уплотнением, а местами разрыхленностью базальной мембраны. Наблюдается отек интерстициального пространства и накопление продуктов распада клеток, триацилглицеринов и гликопротеинов. Выявленные изменения способствуют повреждению эндотелиальных клеток, ухудшению реологических свойств крови и, соответственно, повреждению сосудистой стенки.

The aim of this study was to investigate the features of circulation insulin, leptin concentrations, parameters of insulin resistance in Type 2 diabetes mellitus patients (DM) with cardiomyopathy. 38 patients with Type 2 DM and cardiomyopathy without arterial hypertension (AH); 32 patients with Type 2 DM and AH; 14 patients with Type 2 DM without cardiomyopathy and AH; 15 patients with hypertonic disease I stage, I degree of AH and physiological values of glucose tolerance test were examined. It was established a consider able increase of insulin, C-peptide, leptin, triglycerides concentrations in blood plasma, indexes of HOMA-insulin resistance and decrease of QUICKI; correlation between C-peptide, leptin, triglycerides concentrations and parameters of insulin resistance was found., Целью работы было изучение концентрации циркулирующего инсулина, С-пептида, лептина, параметров инсулиновой резистентности у больных сахарным диабетом 2-го типа с диабетической кардиомиопатией. Обследованы 38 больных СД 2-го типа с ДКМП без артериальной гипертензии; 32 пациента с СД 2-го типа и АГ; 14 пациентов с СД 2-го типа без АГ и ДКМП; 15 больных с диагнозом "гипертоническая болезнь І стадия, І степень АГ" и физиологическими показателями глюкозотолерантного теста. У больных СД 2-го типа с ДКМП наблюдается значительное увеличение концентрации иммунореактивного инсулина, С-пептида и лептина в плазме крови, индекса инсулиновой резистентности и уменьшение параметров QUICKI; выявлена корреляционная взаимосвязь между показателями концентрации С-пептида, лептина и параметрами инсулиновой резистентности.

Results of 24 hours blood pressure monitoring of 38 patients with Type 2 diabetes mellitus (DM) with diabetic cardiomyopathy (DCMP) without arterial hypertension (AH); 32 patients with Type 2 DM and AH; 14 patients with Type 2 DM without AH and DCMP; 15 patients with Hypertonic disease I stage, I degree of AH and physiological values of glucosetolerance test were analyzed. It was established that patients with Type 2 DM and DCMP have more high average systolic and diastolic blood pressure during 24 hours, day and night, increased variability parameters of systolic and diastolic blood pressure during 24 hours, day and night, that may be mediated with sympathetic parasympathetic disbalance. Patients with Type 2 DM and DCMP without AH have tendency to insufficient night blood pressure decrease, formation of disproportional daily blood pressure rhythm with normal average values of systolic and diastolic blood pressure. In this patient group more often were "non dippers" in comparison with patients with Type 2 DM without DCMP and AH., Проведен анализ данных суточного мониторинга артериального давления у 38 больных СД 2 с ДКМП без артериальной гипертензии; у 32 пациентов с СД 2 и АГ; у 14 пациентов с СД 2 без АГ и ДКМП; у 15 больных с диагнозом "гипертоническая болезнь І стадия, І степень АГ" и физиологическими показателями глюкозотолерантного теста. Установлено, что у больных СД 2 с ДКМП отмечаются более высокие средние уровни САД и ДАД на протяжении суток, дневного и ночного периодов суток, повышение показателей вариабельности САД и ДАД в течение дневного и ночного периодов, что может быть опосредовано дисбалансом симпатико парасимпатической системы. У больных СД 2 с ДКМП без сопутствующей АГ выявлена тенденция к недостаточному снижению АД в ночной период, формирование диспропорционального суточного ритма АД при нормальных средних показателях САД и ДАД. Среди больных этой группы чаще регистрируются "non dippers" по сравнению с больными СД 2 без ДКМП и сопутствующей АГ.