Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical siabetic cardiomyopathy.

INTRODUCTION: Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. METHODS: In this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. RESULTS: The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E', or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = - 0.10; p = 0.007), the Physical Activity Scale in the Elderly (rho = - 0.12; p = 0.004), duration of cardiopulmonary exercise testing (rho = - 0.28; p < 0.001), peak VO2 (rho = - 0.26; p < 0.001), and ratio of minute ventilation/carbon dioxide production (rho = 0.12; p = 0.002). After adjustment for known confounders, the correlation with Physical Activity Scale in the Elderly and overall Kansas City Cardiomyopathy Questionnaire score was no longer significant. CONCLUSION: Among patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals. TRIAL REGISTRATION: ARISE-HF, NCT04083339 Date Registered August 23, 2019.

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. METHODS: Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. RESULTS: Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. CONCLUSIONS: Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. TRIAL REGISTRATION: ARISE-HF, NCT04083339.

Additive effect of metabolic dysfunction-associated fatty liver disease on left ventricular function and global strain in type 2 diabetes mellitus patients: a 3.0 T cardiac magnetic resonance feature tracking study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are both metabolic disorders that negatively impact the cardiovascular system. This study comprehensively analyzed the additive effect of MAFLD on left ventricular function and global strain in T2DM patients by cardiac magnetic resonance (CMR). METHODS: Data of 261 T2DM patients, including 109 with and 152 without MAFLD, as well as 73 matched normal controls from our medical center between June 2015 and March 2022 were retrospectively analyzed. CMR-derived parameters, including LV function and global strain parameters, were compared among different groups. Univariate and multivariate linear regression analyses were conducted to investigate the impact of various factors on LV function and global strain. RESULTS: Our investigation revealed a progressive deterioration in LV functional parameters across three groups: control subjects, T2DM patients without MAFLD, and T2DM patients with MAFLD. Statistically significant increases in left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular mass index (LVMI) were observed, along with decreases in left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI). Among these three groups, significant reductions were also noted in the absolute values of LV global radial, circumferential, and longitudinal peak strains (GRPS, GCPS, and GLPS), as well as in peak systolic (PSSR) and peak diastolic strain rates (PDSR). MAFLD was identified as an independent predictor of LVEF, LVMI, LVGFI, GRPS, GCPS, and GLPS in multivariate linear analysis. Besides, the incidence of late gadolinium enhancement was higher in MAFLD patients than in non-MAFLD patients (50/109 [45.9%] vs. 42/152 [27.6%], p = 0.003). Furthermore, escalating MAFLD severity was associated with a numerical deterioration in both LV function parameters and global strain values. CONCLUSIONS: This study thoroughly compared CMR parameters in T2DM patients with and without MAFLD, uncovering MAFLD's adverse impact on LV function and deformation in T2DM patients. These findings highlight the critical need for early detection and comprehensive management of cardiac function in T2DM patients with MAFLD.

The differential effects of dyslipidemia status and triglyceride-glucose index on left ventricular global function and myocardial microcirculation in diabetic individuals: a cardiac magnetic resonance study.

BACKGROUND: It remains unclear whether the association between dyslipidemia status and triglyceride-glucose (TyG) index with myocardial damage varies in the context of type 2 diabetes mellitus (T2DM). This study aimed to determine the differential effects of dyslipidemia status and TyG index on left ventricular (LV) global function and myocardial microcirculation in patients with T2DM using cardiac magnetic resonance (CMR) imaging. METHODS: A total of 226 T2DM patients and 72 controls who underwent CMR examination were included. The T2DM group was further categorized into subgroups based on the presence or absence of dyslipidemia (referred to as T2DM (DysL+) and T2DM (DysL-)) or whether the TyG index exceeded 9.06. CMR-derived LV perfusion parameters, remodeling index, and global function index (GFI) were assessed and compared among groups. A multivariable linear regression model was employed to evaluate the effects of various variables on LV myocardial microcirculation, remodeling index, and GFI. RESULTS: The LV GFI sequentially decreased in controls, T2DM (DysL-), and T2DM (DysL+) groups (p < 0.001), and was lower (p = 0.003) in T2DM with higher TyG index group than in lower TyG index group. The LV remodeling index was higher in higher TyG index group than in lower TyG index group (p = 0.002), but there was no significant difference in whether the subgroup was accompanied by dyslipidemia. Multivariable analysis revealed that the TyG index, but not dyslipidemia status, was independently associated with LV remodeling index (ß coefficient[95% confidence interval], 0.152[0.025, 0.268], p = 0.007) and LV GFI (- 0.159[- 0.281, - 0.032], p = 0.014). For LV myocardial microcirculation, perfusion index, upslope, and max signal intensity sequentially decreased in controls, T2DM (DysL-), and T2DM (DysL+) groups (all p < 0.001). Dyslipidemia status independently correlated with perfusion index (- 0.147[- 0.272, - 0.024], p = 0.02) and upslope (- 0.200[- 0.320, 0.083], p = 0.001), while TyG index was independently correlated with time to maximum signal intensity (0.141[0.019, 0.257], p = 0.023). CONCLUSIONS: Both dyslipidemia status and higher TyG index were associated with further deterioration of LV global function and myocardial microvascular function in the context of T2DM. The effects of dyslipidemia and a higher TyG index appear to be differential, which indicates that not only the amount of blood lipids and glucose but also the quality of blood lipids are therapeutic targets for preventing further myocardial damage.

Assessment of subclinical LV myocardial dysfunction in T2DM patients with diabetic peripheral neuropathy: a cardiovascular magnetic resonance study.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, and has been demonstrated to be independently associated with cardiovascular events and mortality. This aim of this study was to investigate the subclinical left ventricular (LV) myocardial dysfunction in type 2 diabetes mellitus (T2DM) patients with and without DPN. METHODS: One hundred and thirty T2DM patients without DPN, 61 patients with DPN and 65 age and sex-matched controls who underwent cardiovascular magnetic resonance (CMR) imaging were included, all subjects had no symptoms of heart failure and LV ejection fraction ≥ 50%. LV myocardial non-infarct late gadolinium enhancement (LGE) was determined. LV global strains, including radial, circumferential and longitudinal peak strain (PS) and peak systolic and diastolic strain rates (PSSR and PDSR, respectively), were evaluated using CMR feature tracking and compared among the three groups. Multivariable linear regression analyses were performed to determine the independent factors of reduced LV global myocardial strains in T2DM patients. RESULTS: The prevalence of non-infarct LGE was higher in patients with DPN than those without DPN (37.7% vs. 19.2%, p = 0.008). The LV radial and longitudinal PS (radial: 36.60 ± 7.24% vs. 33.57 ± 7.30% vs. 30.72 ± 8.68%; longitudinal: - 15.03 ± 2.52% vs. - 13.39 ± 2.48% vs. - 11.89 ± 3.02%), as well as longitudinal PDSR [0.89 (0.76, 1.05) 1/s vs. 0.80 (0.71, 0.93) 1/s vs. 0.77 (0.63, 0.87) 1/s] were decreased significantly from controls through T2DM patients without DPN to patients with DPN (all p < 0.001). LV radial and circumferential PDSR, as well as circumferential PS were reduced in both patient groups (all p < 0.05), but were not different between the two groups (all p > 0.05). Radial and longitudinal PSSR were decreased in patients with DPN (p = 0.006 and 0.003, respectively) but preserved in those without DPN (all p > 0.05). Multivariable linear regression analyses adjusting for confounders demonstrated that DPN was independently associated with LV radial and longitudinal PS (ß = - 3.025 and 1.187, p = 0.014 and 0.003, respectively) and PDSR (ß = 0.283 and - 0.086, p = 0.016 and 0.001, respectively), as well as radial PSSR (ß = - 0.266, p = 0.007). CONCLUSIONS: There was more severe subclinical LV dysfunction in T2DM patients complicated with DPN than those without DPN, suggesting further prospective study with more active intervention in this cohort of patients.

Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure.

OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.

Early longitudinal changes in left ventricular function and morphology in diabetic pigs: evaluation by 3.0T magnetic resonance imaging.

BACKGROUND: Previous researches on large animal models of diabetic cardiomyopathy were insufficient. The aim of this study was to evaluate early changes in left ventricular (LV) function and morphology in diabetic pigs using a cardiac magnetic resonance (CMR) time-volume curve and feature tracking technique. METHODS: Streptozotocin (STZ) was used to induce diabetic in sixteen pigs. 3.0T MRI scanned the pig's heart before and 2, 6, 10 and 16 months after modelling. CMR biomarkers, including time-volume curve and myocardial strain, were compared to analyse the longitudinal changes in LV function and morphology. Pearson correlation was used to evaluate the relationship between LV strain and remodelling. Cardiac specimens were obtained at 6, 10, and 16 months after modelling to observe the myocardial ultrastructural and microstructure at different courses of diabetes. RESULTS: Twelve pigs developed diabetes. The 80% diastolic volume recovery rate (DVR) at 6 months after modelling was significantly higher than that before modelling (0.78 ± 0.08vs. 0.67 ± 0.15). The LV global longitudinal peak strain (GLPS) (- 10.21 ± 3.15 vs. - 9.74 ± 2.78 vs. - 9.38 ± 3.71 vs. - 8.71 ± 2.68 vs. - 6.59 ± 2.90%) altered gradually from the baseline data to 2, 6, 10 and 16 months after modelling. After 16 months of modelling, the LV remodelling index (LVRI) of pigs increased compared with that before modelling (2.19 ± 0.97 vs. 1.36 ± 0.45 g/ml). The LVRI and myocardial peak strain were correlated in diabetic pigs (r= - 0.40 to - 0.54), with GLPS being the most significant. Electron microscopy and Masson staining showed that myocardial damage and fibrosis gradually increased with the progression of the disease. CONCLUSION: Intravenous injection of STZ can induce a porcine diabetic cardiomyopathy model, mainly characterized by decreased LV diastolic function and strain changes accompanied by myocardial remodelling. The changes in CMR biomarkers could reflect the early myocardial injury of diabetic cardiomyopathy.

Dual roles of myocardial mitochondrial AKT on diabetic cardiomyopathy and whole body metabolism.

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 cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.

Speckle-tracking echocardiography provides sensitive measurements of subtle early alterations associated with cardiac dysfunction in T2DM rats.

BACKGROUND: Diabetic cardiomyopathy results in cardiac structural and functional abnormalities. Previous studies have demonstrated that inhibiting the RhoA/ROCK signalling pathway increases the injury resistance of cardiomyocytes. The early detection of cardiac structural and functional alterations may facilitate an improved understanding of the pathophysiologic progress and guide therapy. This study aimed to identify the optimal diagnostic measures for the subtle early alterations of cardiac dysfunction in type 2 diabetes mellitus (T2DM) rats. METHODS: Twenty-four rat models were divided into four groups and received treatments for 4 weeks: the CON group (control rats), the DM group (T2DM rats), the DMF group (T2DM rats receiving fasudil) and the CONF group (control rats receiving fasudil) group. Left ventricular (LV) structure was quantified by histological staining and transmission electron microscopy. LV function and myocardial deformation were assessed by high-frequency echocardiography. RESULTS: Treatment with fasudil, a ROCK inhibitor, significantly protected against diabetes-induced myocardial hypertrophy, fibrosis and mitochondrial dysfunction. Impaired LV performance was found in T2DM rats, as evidenced by significant reductions in the ejection fraction (EF), fractional shortening (FS) and the mitral valve (MV) E/A ratio (which decreased 26%, 34% and 20%, respectively). Fasudil failed to improve the conventional ultrasonic parameters in T2DM rats, but the myocardial deformation measured by speckle-tracking echocardiography (STE) were significantly improved (global circumferential strain, GCS: P = 0.003; GCS rate, GCSR: P = 0.021). When receiver operating characteristic (ROC) curves were used in combination with linear regression analysis, STE parameters were found to be characterized by both optimal prediction of cardiac damage [AUC (95% CI): fractional area change, FAC: 0.927 (0.744, 0.993); GCS: 0.819 (0.610, 0.945); GCSR: 0.899 (0.707, 0.984)] and stronger correlations with cardiac fibrosis (FAC: r = -0.825; GCS: r = 0.772; GCSR: r = 0.829) than conventional parameters. CONCLUSION: The results suggest that STE parameters are more sensitive and specific than conventional parameters in predicting the subtle cardiac functional changes that occur in the early stage, providing new insight into the management of diabetic cardiomyopathy.

Metabolic and Molecular Imaging of the Diabetic Cardiomyopathy.

The term diabetic cardiomyopathy is defined as the presence of abnormalities in myocardial structure and function that occur in the absence of, or in addition to, well-established cardiovascular risk factors. A key contributor to this abnormal structural-functional relation is the complex interplay of myocardial metabolic remodeling, defined as the loss the flexibility in myocardial substrate metabolism and its downstream detrimental effects, such as mitochondrial dysfunction, inflammation, and fibrosis. In parallel with the growth in understanding of these biological underpinnings has been developmental advances in imaging tools such as positron emission tomography and magnetic resonance imaging and spectroscopy that permit the detection and in many cases quantification, of the processes that typifies the myocardial metabolic remodeling in diabetic cardiomyopathy. The imaging readouts can be obtained in both preclinical models of diabetes mellitus and patients with diabetes mellitus facilitating the bi-directional movement of information between bench and bedside. Moreover, imaging biomarkers provided by these tools are now being used to enhance discovery and development of therapies designed to reduce the myocardial effects of diabetes mellitus through metabolic modulation. In this review, the use of these imaging tools in the patient with diabetes mellitus from a mechanistic, therapeutic effect, and clinical management perspective will be discussed.

Multiparametric CMR imaging of myocardial structure and function changes in diabetic mini-pigs with preserved LV function: a preliminary study.

BACKGROUND: The purpose of this study is to dynamically monitor the myocardial structure and function changes in diabetic mini-pigs by 1.5 T cardiac magnetic resonance. METHODS: Three male mini-pigs underwent cardiac magnet resonance (CMR) imaging, and histologic examination. T1-mapping was acquired at basal, mid and apical segments. CMR feature-tracking (CMR-FT) is used to quantify left ventricle global longitudinal (LVGLS), circumferential (LVGCS) and radial strain (LVGRS). Epicardial adipose tissue (EAT) was evaluated using a commercially available software. RESULTS: Left ventricular mass (LVM), myocardial native T1 value, extracellular volume (ECV) value and EAT were increased gradually after 6 months of modeling, while LVGLS decreased gradually after 6 months of modeling (LVM: 24.5 (23.4, 26.7) vs. 42.7 (41.4, 44.6) g/m2, p < 0.001; Native T1: 1005.5 (992.6, 1010.7) vs. 1028.7 (1015.5, 1035.6) ms, p = 0.041; EAT: 16.1 (14.5, 18.2) vs. 24.6 (20.8, 26.9) mL, p = 0.020; ECV: 21.4 (20.2, 23.9) vs. 28.9 (26.7, 30.3) %, p = 0.011; LVGLS: - 22.8 (- 21.4, - 23.9) vs. - 17.4 (- 17.2, - 19.2)%, p = 0.008). The diffuse myocardial interstitial fibrosis was found in histology samples. CONCLUSION: The progressive impairments in LV structure and myocardial deformation occurs in diabetic mini-pigs. T1 mapping and CMR-FT technology are promising to monitor abnormal changes of diabetic myocardium in the early stage of diabetic cardiomyopathy.

Echocardiographic study of myocardial work in patients with type 2 diabetes mellitus.

BACKGROUND: A noninvasive left ventricular (LV) pressure-strain loop (PSL) provides a new method to quantify myocardial work (MW) by combining global longitudinal strain (GLS) and LV pressure, which exerts potential advantages over traditional GLS. We studied the LV PSL and MW in patients with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 201 subjects (54 healthy controls and 147 T2DM patients) who underwent complete two-dimensional echocardiography (2DE), including 2D speckle-tracking echocardiography (STE), as well as brachial artery pulse pressure measurement. The PSL was used to determine the global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) of all study participants. The association between T2DM and LV function was evaluated according to these MW indices. RESULTS: The GLS was significantly lower in the T2DM group than in the control group (P < 0.001), indicating that the LV myocardium had been damaged, although the LV ejection fraction (LVEF) was still normal. The GWI and GWE were decreased (P = 0.022) and the GWW was increased (P < 0.001) in diabetic patients compared with controls, but the GCW was comparable in the two groups (P = 0.160). In all diabetic patients, age, body mass index, systolic blood pressure, smoking history, and LVEF were correlated with GWI, GWW and GWE. CONCLUSIONS: The use of LV PSL is a novel noninvasive technique that could help to depict the relationship between LV myocardial damage and MW in patients with T2DM.

Aggravation of functional mitral regurgitation on left ventricle stiffness in type 2 diabetes mellitus patients evaluated by CMR tissue tracking.

BACKGROUND: Functional mitral regurgitation (FMR) is one of the most common heart valve diseases in diabetes and may increase left ventricular (LV) preload and aggravate myocardial stiffness. This study aimed to investigate the aggravation of FMR on the deterioration of LV strain in type 2 diabetes mellitus (T2DM) patients and explore the independent indicators of LV peak strain (PS). MATERIALS AND METHODS: In total, 157 T2DM patients (59 patients with and 98 without FMR) and 52 age- and sex-matched healthy control volunteers were included and underwent cardiac magnetic resonance examination. T2DM with FMR patients were divided into T2DM patients with mild (n = 21), moderate (n = 19) and severe (n = 19) regurgitation. LV function and global strain parameters were compared among groups. Multivariate analysis was used to identify the independent indicators of LV PS. RESULTS: The T2DM with FMR had lower LV strain parameters in radial, circumferential and longitudinal direction than both the normal and the T2DM without FMR (all P < 0.05). The mild had mainly decreased peak diastolic strain rate (PDSR) compared to the normal. The moderate had decreased peak systolic strain rate (PSSR) compared to the normal and PDSR compared to the mild and the normal. The severe FMR group had decreased PDSR and PSSR compared to the mild and the normal (all P < 0.05). Multiple linear regression showed that the regurgitation degree was independent associated with radial (ß = - 0.272), circumferential (ß = - 0.412) and longitudinal (ß = - 0.347) PS; the months with diabetes was independently associated with radial (ß = - 0.299) and longitudinal (ß = - 0.347) PS in T2DM with FMR. CONCLUSION: FMR may aggravate the deterioration of LV stiffness in T2DM patients, resulting in decline of LV strain and function. The regurgitation degree and months with diabetes were independently correlated with LV global PS in T2DM with FMR.

Diabetes induces remodeling of the left atrial appendage independently of atrial fibrillation in a rodent model of type-2 diabetes.

BACKGROUND: Diabetic patients have an increased predisposition to thromboembolic events, in most cases originating from thrombi in the left atrial appendage (LAA). Remodeling of the LAA, which predisposes to thrombi formation, has been previously described in diabetic patients with atrial fibrillation, but whether remodeling of the LAA occurs in diabetics also in the absence of atrial fibrillation is unknown. To investigate the contribution of diabetes, as opposed to atrial fibrillation, to remodeling of the LAA, we went from humans to the animal model. METHODS: We studied by echocardiography the structure and function of the heart over multiple time points during the evolution of diabetes in the Cohen diabetic sensitive rat (CDs/y) provided diabetogenic diet over a period of 4 months; CDs/y provided regular diet and the Cohen diabetic resistant (CDr/y), which do not develop diabetes, served as controls. All animals were in sinus rhythm throughout the study period. RESULTS: Compared to controls, CDs/y developed during the evolution of diabetes a greater heart mass, larger left atrial diameter, wider LAA orifice, increased LAA depth, greater end-diastolic and end-systolic diameter, and lower E/A ratio-all indicative of remodeling of the LAA and left atrium (LA), as well as the development of left ventricular diastolic dysfunction. To investigate the pathophysiology involved, we studied the histology of the hearts at the end of the study. We found in diabetic CDs/y, but not in any of the other groups, abundance of glycogen granules in the atrial appendages , atria  and ventricles, which may be of significance as glycogen granules have previously been associated with cell and organ dysfunction in the diabetic heart. CONCLUSIONS: We conclude that our rodent model of diabetes, which was in sinus rhythm, reproduced structural and functional alterations previously observed in hearts of human diabetics with atrial fibrillation. Remodeling of the LAA and of the LA in our model was unrelated to atrial fibrillation and associated with accumulation of glycogen granules. We suggest that myocardial accumulation of glycogen granules is related to the development of diabetes and may play a pathophysiological role in remodeling of the LAA and LA, which predisposes to atrial fibrillation, thromboembolic events and left ventricular diastolic dysfunction in the diabetic heart.

Association of left ventricular longitudinal myocardial function with subclinical right ventricular dysfunction in type 2 diabetes mellitus.

BACKGROUND: Left ventricular (LV) involvement in diabetic cardiomyopathy has been reported; however, only limited data exist on right ventricular (RV) involvement. Therefore, our purpose was to investigate RV systolic dysfunction and its association with LV longitudinal myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM) and preserved LV ejection fraction (LVEF). METHODS: We studied 177 T2DM patients with preserved LVEF and 79 age-, sex-, and LVEF-matched healthy volunteers. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), and RV systolic function was assessed as RV free-wall strain, and predefined cutoff values for subclinical dysfunction were set at GLS < 18% and RV free-wall strain < 20%, respectively. RESULTS: RV free-wall strain in T2DM patients was significantly lower than that in normal controls (19.3% ± 4.8% vs. 24.4% ± 5.1%; P < 0.0001). RV free-wall strain in T2DM patients and LV longitudinal dysfunction was similar compared to that in T2DM patients without (19.0 ± 4.5% vs. 19.6 ± 5.0%, P = 0.40). Furthermore, multivariate logistic regression analyses showed that GLS was independently associated with RV systolic dysfunction as well as mitral inflow E and mitral e' annular velocities ratio (odds ratio, 1.16; 95% confidence interval: 1.03-1.31; P < 0.05). Sequential logistic models evaluating the association of RV systolic dysfunction in T2DM patients showed an improvement in clinical variables (χ2 = 6.2) with the addition of conventional echocardiographic parameters (χ2 = 13.4, P < 0.001) and a further improvement with the addition of GLS (χ2 = 20.8, P < 0.001). CONCLUSION: RV subclinical systolic dysfunction was observed in T2DM patients with preserved LVEF and was associated with LV longitudinal myocardial dysfunction. Our findings may provide additional findings for the management of T2DM patients.

Impact of myocardial scars on left ventricular deformation in type 2 diabetes mellitus after myocardial infarction by contrast-enhanced cardiac magnetic resonance.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease and myocardial infarction (MI). The interaction of diabetic cardiomyopathy and MI scars on myocardial deformation in T2DM patients is unclear. Therefore, we aimed to evaluate myocardial deformation using cardiac magnetic resonance (CMR) in T2DM patients with previous MI and investigated the influence of myocardial scar on left ventricular (LV) deformation. METHODS: Overall, 202 T2DM patients, including 46 with MI (T2DM(MI+)) and 156 without MI (T2DM(MI-)), and 59 normal controls who underwent CMR scans were included. Myocardial scars were assessed by late gadolinium enhancement. LV function and deformation, including LV global function index, LV global peak strain (PS), peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR), were compared among these groups. Correlation and multivariate linear regression analyses were used to investigate the relationship between myocardial scars and LV deformation. RESULTS: Decreases were observed in LV function and LV global PS, PSSR, and PDSR in the T2DM(MI+) group compared with those of the other groups. Reduced LV deformation (p < 0.017) was observed in the T2DM(MI+) group with anterior wall infarction. The increased total LV infarct extent and infarct mass of LV were related to decreased LV global PS (radial, circumferential, and longitudinal directions; p < 0.01) and LV global PSSR (radial and circumferential directions, p < 0.02). Multivariate analysis demonstrated that NYHA functional class and total LV infarct extent were independently associated with LV global radial PS (ß = - 0.400 and ß = - 0.446, respectively, all p < 0.01; model R2 = 0.37) and circumferential PS (ß = 0.339 and ß = 0.530, respectively, all p < 0.01; model R2 = 0.41), LV anterior wall infarction was independently associated with LV global longitudinal PS (ß = 0.398, p = 0.006). CONCLUSIONS: The myocardial scarring size in T2DM patients after MI is negatively correlated with LV global PS and PSSR, particularly in the circumferential direction. Additionally, different MI regions have different effects on the reduction of LV deformation, and relevant clinical evaluations should be strengthened.

Assessment of subclinical diabetic cardiomyopathy by speckle-tracking imaging.

BACKGROUND: Diastolic dysfunction is traditionally believed to be the first subclinical manifestation of diabetic cardiomyopathy (DCM), leading to systolic dysfunction and then overt heart failure. However, in the last few years, several studies suggested that systolic subclinical dysfunction measured by speckle-tracking echocardiography (STE) may appear ahead of diastolic dysfunction. In this review, the main endpoint is to show whether subclinical myocardial systolic dysfunction appears ahead of diastolic dysfunction and the implication this may have on the evolution and management of DCM. MATERIALS AND METHODS: We performed a search in PubMed for all relevant publications on the assessment of DCM by STE from 1 June 2015 to 1 June 2020. RESULTS AND CONCLUSIONS: The results illustrate that subclinical systolic dysfunction assessed by STE is present in early DCM stages, with or without the association of diastolic dysfunction. This could be a promising perspective for the early management of patients with DCM leading to the prevention of the overt form of disease.

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes.

OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.

miR-34a attenuates myocardial fibrosis in diabetic cardiomyopathy mice via targeting Pin-1.

Diabetic cardiomyopathy (DCM) is characterized by myocardial hypertrophy and fibrosis. This study aimed to investigate the effects of microRNA (miR)-34a on myocardial fibrosis in DCM and its potential mechanism of targeting Pin-1 signaling. Vimentin and Pin-1 proteins in mouse cardiac tissues were detected by immunohistochemical staining. Locked nucleic acid in situ hybridization was used to measure miR-34a expression in cardiac tissues. Primary mouse cardiac fibroblasts (CFs) were transfected with a mimics control/miR-34a mimics or Pin-1 plasmid and cultured in high-glucose (HG) Dulbecco's modified Eagle's medium. The miR-34a levels were measured by quantitative polymerase chain reaction. The apoptosis and viability of transfected cells were detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling and Cell Counting Kit-8 assays respectively. A cell migration experiment and dual-luciferase reporter assay were also performed. The body weight and fasting blood glucose of DCM mice were significantly higher than those in the control (CTL) group. In addition, DCM mice had decreased serum insulin levels and impaired cardiac function. The number of CFs in the DCM group was higher than in the CTL group and Pin-1 expression was upregulated. The expression level of miR-34a in the cardiac tissue of mice in the DCM group was obviously downregulated compared with the CTL group. The HG stimulation of CFs for 48 h significantly downregulated the expression level of miR-34a and was associated with increased Type I collagen expression, cell viability, and migration and decreased apoptosis. However, these effects could be reversed by overexpressing miR-34a in HG-induced CFs. Furthermore, we found that Pin-1 was a direct target of miR-34a. Our results suggest that miR-34a can attenuate myocardial fibrosis in DCM by reducing Type I collagen production, cell viability, and migration and increasing the apoptosis of CFs by targeting Pin-1 signaling.

Left atrial dysfunction and stiffness in pediatric and adult patients with Type 1 diabetes mellitus assessed with speckle tracking echocardiography.

BACKGROUND: Subclinical diastolic dysfunction in patients with Type 1 diabetes mellitus (T1DM) caused by myocardial injury due to diabetic cardiomyopathy leads to a high risk of death and heart failure. This myocardial injury extends not only to the left ventricle (LV) but also to the left atrium (LA). However, LA function in children and young adults with T1DM has not been extensively studied. OBJECTIVE: Therefore, the aim of this study was to assess LA dysfunction in pediatric and adult patients with T1DM using LA strain analysis with echocardiography. SUBJECTS: Fifty-three patients (median age: 23 [range: 5-41] years) with T1DM. METHODS: We divided the patients into three age groups (D1: 5-14 years, D2: 15-24 years, D3: 25-41 years); 53 age- and sex-matched controls were divided into three corresponding groups (C1, C2, and C3). LA and LV functions were evaluated using echocardiography. RESULTS: LA reservoir strain was lower in the D2 and D3 groups than in the C2 and C3 groups (P = 0.001, P = 0.004, respectively). LA conduit strain was lower in the D2 group than in the C2 group (P = 0.002). LA stiffness was significantly greater in the D3 group than in the C3 group (P < 0.001). CONCLUSIONS: In patients with T1DM, LA phasic function decreased in adolescents and young adults, and LA stiffness increased in adult patients aged >30 years. LA phasic function and LA stiffness can be potentially used as early markers for diastolic dysfunction.