DCM Group Research Articles

Worse outcomes in patients with cardiac sarcoidosis and involvement of the right ventricle in cardiac magnetic resonance

Abstract Background Cardiac sarcoidosis (CS) can manifest with variety of unspecific symptoms. It can mimic all types of cardiomyopathies but most often it resembles dilated cardiomyopathy. Involvement of right ventricle (RV) is rare and may lead to a false diagnosis of arrhythmogenic right ventricular cardiomyopathy and delay of the immunosuppressive therapy. Purpose The aim of this research was to study the characteristics and the outcomes of this peculiar subtype of patients. Methods We analyzed 112 patients diagnosed with CS after elaborate work-up with cardiac magnetic resonance (CMR), FDG PET and endomyocardial biopsy (EMB). All patients underwent follow-up for occurrence of combined endpoint of death, LV assist device implantation or heart transplantation. Patients with evidence of late gadolinium enhancement (LGE) involving RV (RV group) were identified and compared to the rest (DCM group) for baseline clinical characteristics, arhythmic outcomes and combined endpoint. Results Involvement of the RV in CMR was observed in 19 (17%) patients. Patients in the RV group were more frequently male: 84% vs. 57%, P = 0.032. EMB confirmed CS in 63% vs. 19.4% in the DCM group; P= 0.0001. LV ejection fraction in the RV group was comparable to the DCM group: 42±14% vs. 45±14%; P = 0.3. Furthermore, in the RV group the rates of sustained ventricular tachycardia were significantly higher than the DCM: 68% vs. 34%; P = 0.009. Long-term immunosuppressive therapy was started in 74% in RV and in 70% of the DCM group; P=0.77. Despite this, during follow-up, the rate of death, LVAD implantation or heart transplantation was significantly higher in the RV than in the DCM group; 26.3% vs. 7.5%; P = 0.03. In binary logistic analysis, the OR for the combined endpoint was 4.4; 95% CI 1.2-15.7. Conclusions Patients with CS and RV involvement in CMR have worse outcomes as compared to patients presenting as DCM, despite the comparable LV EF and immunosuppressive therapy.

Single-cell insights: pioneering an integrated atlas of chromatin accessibility and transcriptomic landscapes in diabetic cardiomyopathy

BackgroundDiabetic cardiomyopathy (DCM) poses a growing health threat, elevating heart failure risk in diabetic individuals. Understanding DCM is crucial, with fibroblasts and endothelial cells playing pivotal roles in driving myocardial fibrosis and contributing to cardiac dysfunction. Advances in Multimodal single-cell profiling, such as scRNA-seq and scATAC-seq, provide deeper insights into DCM’s unique cell states and molecular landscape for targeted therapeutic interventions.MethodsSingle-cell RNA and ATAC data from 10x Multiome libraries were processed using Cell Ranger ARC v2.0.1. Gene expression and ATAC data underwent Seurat and Signac filtration. Differential gene expression and accessible chromatin regions were identified. Transcription factor activity was estimated with chromVAR, and Cis-coaccessibility networks were calculated using Cicero. Coaccessibility connections were compared to the GeneHancer database. Gene Ontology analysis, biological process scoring, cell-cell communication analysis, and gene-motif correlation was performed to reveal intricate molecular changes. Immunofluorescent staining utilized various antibodies on paraffin-embedded tissues to verify the findings.ResultsThis study integrated scRNA-seq and scATAC-seq data obtained from hearts of WT and DCM mice, elucidating molecular changes at the single-cell level throughout the diabetic cardiomyopathy progression. Robust and accurate clustering analysis of the integrated data revealed altered cell proportions, showcasing decreased endothelial cells and macrophages, coupled with increased fibroblasts and myocardial cells in the DCM group, indicating enhanced fibrosis and endothelial damage. Chromatin accessibility analysis unveiled unique patterns in cell types, with heightened transcriptional activity in myocardial cells. Subpopulation analysis highlighted distinct changes in cardiomyocytes and fibroblasts, emphasizing pathways related to fatty acid metabolism and cardiac contraction. Fibroblast-centered communication analysis identified interactions with endothelial cells, implicating VEGF receptors. Endothelial cell subpopulations exhibited altered gene expressions, emphasizing contraction and growth-related pathways. Candidate regulators, including Tcf21, Arnt, Stat5a, and Stat5b, were identified, suggesting their pivotal roles in DCM development. Immunofluorescence staining validated marker genes of cell subpopulations, confirming PDK4, PPARγ and Tpm1 as markers for metabolic pattern-altered cardiomyocytes, activated fibroblasts and endothelial cells with compromised proliferation.ConclusionOur integrated scRNA-seq and scATAC-seq analysis unveils intricate cell states and molecular alterations in diabetic cardiomyopathy. Identified cell type-specific changes, transcription factors, and marker genes offer valuable insights. The study sheds light on potential therapeutic targets for DCM.

Benefit of Catheter Ablation for Atrial Fibrillation in Heart Failure Patients with Different Etiologies.

(1) Background: A plethora of studies have elucidated the safety and efficacy of catheter ablation (CA) for patients afflicted with atrial fibrillation (AF) and concomitant reduction in left ventricular ejection fraction (LVEF). Nevertheless, the literature on the benefits of CA in the specific etiological context of heart failure (HF) remains limited. This study delineates a comparative assessment of outcomes for patients with AF and reduced LVEF across the primary etiologies. (2) Methods: Our inquiry encompassed 216 patients diagnosed with congestive heart failure and an LVEF of less than 50 percent who were referred to our institution for circumferential pulmonary vein isolation (CPVI) between the years 2016 and 2020. The selection criteria included a detailed medical history while excluding those suffering from valvular disease, congenital heart disease, and hypertrophic cardiomyopathy. In an effort to scrutinize varying etiologies, patients were stratified into three categories: dilated cardiomyopathy (DCM, n = 56, 30.6%), ischemic cardiomyopathy (ICM, n = 68, 37.2%), and tachycardia-induced cardiomyopathy (TIC, n = 59, 32.2%). (3) Results: Following an average (±SD) duration of 36 ± 3 months, the prevalence of sinus rhythm was 52.1% in the DCM group, 50.0% in the ICM group, and 68.14% in the TIC group (p = 0.014). This study revealed a significant disparity between the DCM and TIC groups (p = 0.021) and the ICM and TIC groups (p = 0.007), yet no significant distinction was discerned between the TIC and ICM groups (p = 0.769). Importantly, there were no significant variations in the application of antiarrhythmic drugs or recurrence of procedures among the three groups. The mortality rates were 14.29% for the DCM group and 14.71% for the ICM group, which were higher than the 3.39% observed in the TIC group (DCM vs. TIC p = 0.035 (HR = 4.50 (95%CI 1.38-14.67)), ICM vs. TIC p = 0.021 (HR = 5.00 (95%CI 1.61-15.50))). A noteworthy enhancement in heart function was evidenced in the TIC group in comparison to the DCM and ICM groups, including a higher LVEF (p < 0.001), diminution of LV end-diastolic diameter (p < 0.001), and an enhanced New York Heart Association classification (p = 0.005). Hospitalization rates for heart failure were discernibly lower in TIC patients (0.98 (0,2) times) relative to those with DCM (1.74 (0,3) times, p < 0.01) and TIC (1.78 (0,4) times, p < 0.001). Patients with paroxysmal atrial fibrillation and brief episodes were found to achieve superior clinical outcomes through a catheter ablation strategy. (4) Conclusion: Patients diagnosed with TIC demonstrated a more pronounced benefit from catheter ablation compared to those with DCM and ICM. This encompassed an augmented improvement in cardiac function, an enhanced maintenance of sinus rhythm, and a reduced mortality rate.

Cerebrospinal fluid biomarkers of white matter injury and astrogliosis are associated with the severity and surgical outcome of degenerative cervical spondylotic myelopathy

BACKGROUND CONTEXTDegenerative cervical spondylotic myelopathy (DCM) is the commonest form of spinal cord injury in adults. However, a limited number of clinical reports have assessed the role of biomarkers in DCM. PURPOSEWe evaluated cerebrospinal fluid (CSF) biomarkers in patients scheduled for DCM surgery and hypothesized that CSF biomarkers levels (1) would reflect the severity of preoperative neurological status; and (2) correlate with radiological appearance; and (3) correlate with clinical outcome. STUDY DESIGN/SETTINGProspective clinical and laboratory study. PATIENT SAMPLETwenty-three DCM patients, aged 66.4±12.8 years and seven controls aged 45.4±5.3 years were included. OUTCOME MEASURESThe American Spinal Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire and EuroQol 5-dimensions were assessed preoperatively and at 3 months post-surgery. METHODSWe measured preoperative biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], phosphorylated neurofilament-H [pNF-H] and Ubiquitin C-terminal hydrolase L1) in CSF samples collected from patients with progressive clinical DCM who underwent surgical treatment. Biomarker concentrations in DCM patients were compared with those of cervical radiculopathy controls. RESULTSThe median symptom duration was 10 (interquartile range 6) months. The levels of GFAP, NFL, pNF-H, Ubiquitin C-terminal hydrolase L1 were significantly higher in the DCM group compared to controls (p=.044, p=.002, p=.016, and p=.006, respectively). Higher pNF-H levels were found in patients with low signal on T1 Magnetic Resonance Imaging sequence compared to those without (p=.022, area under the receiver operating characteristic curve [AUC] 0.780, 95% Confidence Interval: 0.59–0.98). Clinical improvement following surgery correlated mainly with NFL and GFAP levels (p<.05). CONCLUSIONSOur results suggest that CSF biomarkers of white matter injury and astrogliosis may be a useful tool to assess myelopathy severity and predict outcome after surgery, while providing valuable information on the underlying pathophysiology.

STAT4 regulates cardiomyocyte apoptosis in rat models of diabetic cardiomyopathy

ObjectiveThis study aimed to investigate the protective role of the signal transducer and activator of transcription 4 (STAT4) in diabetic cardiomyopathy. Materials and methodsMale Sprague-Dawley (SD) rats (6–8 weeks old) were purchased from the Experimental Animal Center of Zhengzhou University. The rats were randomly divided into the control and diabetic cardiomyopathy groups. Rat models of diabetic cardiomyopathy were established by a high-sugar and high-fat diet combined with a peritoneal injection of streptozocin. Pathological changes in the heart were visualized using Hematoxylin-eosin (HE) staining and Masson’s staining. Moreover, cell apoptosis was detected using terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) staining and Annexin V apoptosis detection kit. Furthermore, H9C2 cells were transfected with lentivirus overexpressing STAT4 and treated with high glucose. The CCK-8 assay was performed to determine cell viability. Finally, Western blotting was used to determine the expression of STAT4, Bax, and Bcl-2. ResultsThe myocardial tissue of the diabetic cardiomyopathy models showed hypertrophy, myocardial fibrosis and collagen deposition. Furthermore, TUNEL staining showed increased apoptosis and decreased expression of STAT4 in the myocardial cells. Moreover, the myocardial tissues of the DCM models showed increased expression of Bax/Bcl-2 and a high percentage of Annexin V positive cells. The H9C2 cells showed decreased expression of STAT4 following high glucose treatment. However, the H9C2 cells overexpressing STAT4 showed decreased expression of Bax/Bcl-2 and reduced percentage of Annexin V positive cells. ConclusionThe DCM group had decreased myocardial expression of STAT4. Furthermore, overexpression of STAT4 was shown to reduce high glucose-induced apoptosis.

Soluble ST2 Receptor: Biomarker of Left Ventricular Impairment and Functional Status in Patients with Inflammatory Cardiomyopathy.

Introduction: Inflammatory cardiomyopathy (ICM) frequently leads to myocardial fibrosis, resulting in permanent deterioration of the left ventricular function and an unfavorable outcome. Soluble suppression of tumorigenicity 2 receptor (sST2) is a novel marker of inflammation and fibrosis in cardiovascular tissues. sST2 was found to be helpful in predicting adverse outcomes in heart failure patients with reduced ejection fraction. The aim of this study was to determine the association of sST2 plasma levels with cardiac magnetic resonance (CMR) and echocardiography imaging features of left ventricular impairment in ICM patients, as well as to evaluate the applicability of sST2 as a prognosticator of the clinical status in patients suffering from ICM. Methods: We used plasma samples of 89 patients presenting to the Heart Center Leipzig with clinically suspected myocardial inflammation. According to immunohistochemical findings in endomyocardial biopsies (EMB) conducted in the context of patients’ diagnostic work-up, inflammatory cardiomyopathy was diagnosed in 60 patients (ICM group), and dilated cardiomyopathy in 29 patients (DCM group). All patients underwent cardiac catheterization for exclusion of coronary artery disease and CMR imaging on 1.5 or 3 Tesla. sST2 plasma concentration was determined using ELISA. Results: Mean plasma concentration of sST2 in the whole patient cohort was 45.8 ± 26.4 ng/mL (IQR 27.5 ng/mL). In both study groups, patients within the highest quartile of sST2 plasma concentration had a significantly lower left ventricular ejection fraction (LV-EF) compared to patients within the lowest sST2 plasma concentration quartile (26 ± 11% vs. 40 ± 13%, p = 0.05 for ICM and 24 ± 13% vs. 51 ± 10%, p = 0.004 for DCM). sST2 predicted New York Heart Association (NYHA) class III/IV at 12 months follow-up more efficiently in ICM compared to DCM patients (AUC 0.85 vs. 0.61, p = 0.02) and was in these terms superior to NT-proBNP and cardiac troponin T. ICM patients with sST2 plasma concentration higher than 44 ng/mL at baseline had a significantly higher probability of being assigned to NYHA class III/IV at 12 months follow-up (hazard ratio 2.8, 95% confidence interval 1.01–7.6, log rank p = 0.05). Conclusion: Plasma sST2 levels in ICM patients reflect the degree of LV functional impairment at hospital admission and predict functional NYHA class at mid-term follow-up. Hence, ST2 may be helpful in the evaluation of disease severity and in the prediction of the clinical status in ICM patients.

Effects of Dietary Pork Fat Cooked Using Different Methods on Glucose and Lipid Metabolism, Liver Inflammation and Gut Microbiota in Rats.

Cooking may affect the nutritional value of pork fat, and, nowadays, people have been paying an increasing amount of attention to the method of cooking. In this study, the effects of dietary pork fat cooked using different methods on body metabolism and intestinal microbes were studied in rats. Fat was extracted from pork belly meat cooked using three methods: braising (braising cooking method, BCM), stewing (SCM) and deep fat frying (DCM). The three types of pork fat were added to animal feed, and the effects of each on body weight, glucose and lipid metabolism, liver inflammation and intestinal microbes in rats were compared with the effects of soybean oil-treated feed (SO) and a blank control (BC). Rats in all three groups fed with cooked pork fat exhibited significant increases in body weight compared with the controls across the experimental feeding period. Furthermore, all three types of pork fat led to significant changes in the serum concentrations of triglycerides (TG) and total cholesterol (TC) relative to the controls, with the greatest increases in TG and TC in the BCM and DCM groups, respectively. All three types of pork fat led to significant decreases in serum high-density lipoprotein cholesterol concentrations relative to the controls, with the lowest concentration in the SCM group. All three types of pork fat also led to significant increases in low-density lipoprotein cholesterol concentrations relative to the controls, with the smallest increase in the DCM group. Rats in the SCM group had the highest level of liver fat deposition, followed by those in the BCM, DCM, SO and BC groups. Compared with the controls, the three groups fed with different types of cooked pork fat had significantly lower hepatic expression of nuclear transcription factor kappa B (NF-κB). The expression levels of NF-κB in the DCM and SO groups were significantly lower than those in the other groups. The abundance of Proteobacteria species in the intestines of rats was significantly lower in the BC group than in the other groups fed with cooked pork fat, and the abundance of Bacteroidetes species was significantly lower in the BCM, SCM and DCM groups than in the BC and SO groups. From the changes in the abundance of Firmicutes and Bacteroides, pork fat in the three cooking methods has a certain potential to promote the production of body obesity.

Grip Strength as a Screening Index for Severe Degenerative Cervical Myelopathy in Primary Care: Development of Cutoff Values Using Receiver Operating Curve Analysis.

PurposeEarly diagnosis of degenerative cervical spondylosis (DCM) is desirable because late treatment can lead to irreversible sequelae. No screening method has yet been established. Grip strength is commonly used in primary care settings to evaluate disease activity and diagnose sarcopenia. This single-center, cross-sectional study aimed to determine the diagnostic accuracy of grip strength for cervical myelopathy (DCM) and cutoff values for primary care DCM screening using area under the curve (AUC) and sensitivity values.Patients and MethodsThe DCM group comprised 249 consecutive participants (165 males, 84 females; mean age, 65.1 years) with DCM who had undergone surgery at the affiliated hospital. The control group comprised 735 (280 males, 455 females; mean age, 65.8 years) participants undertaking a local government health checkup. Stratifying by age and sex, receiver operating characteristic (ROC) analyses were constructed for each group using minimum grip strength values for both hands. Based on ROC analysis, cut-off values were established so that the screening sensitivity would be 90% for either sex or age group, respectively.ResultsAccording to age group and sex (males/females [M/F]), AUC values for a diagnosis of DCM in M/F were as follows: 40–59 years, 0.92/0.87; 60–69 years, 0.94/0.89; 70–79 years, 0.89/0.91; and 80–89 years, 0.97/0.97. Calculated M/F cutoff values were 41/24.5, 27/16, 27/15, and 20/10 kg, which were similar to cutoff scores for sarcopenia in M/F patients aged 60–69 and 70–79 years. M/F sensitivities in each age groups were 0.94/0.91, 0.92/0.90, 0.95/0.96, and 0.92/0.93. M/F specificities were 0.62/0.59, 0.84/0.83, 0.61/0.71, and 0.83/0.88.ConclusionGrip strength had moderate-to-high diagnostic accuracy for DCM between participants in the control and DCM groups. We developed easily applicable cutoff values for primary care DCM screening with ≥90% sensitivity. In patients with sarcopenia, DCM should be differentially diagnosed in primary care.

Diagnostic value of FNDC5 in patients with subclinical diabetic cardiomyopathy

Objective: To estimate the diagnostic value of fibronectin type Ⅲ-domain containing protein 5 (FNDC5) in subclinical diabetic cardiomyopathy. Methods: A total of 94 patients with type 2 diabetes (T2DM), who were hospitalized from April 2018 to June 2019 in the Third Affiliated Hospital of Soochow University, were enrolled in this study. Patients were divided into T2DM with cardiac dysfunction (subclinical DCM) group (n=47) and T2DM without cardiac dysfunction (non-DCM) group (n=47) according to echocardiography and gated myocardial perfusion imaging results. Basic clinical data and serum FNDC5 level were compared between the two groups. Logistic regression analysis was used to establish predicting models and the diagnostic efficiency of established models was compared by ROC curve analysis. Results: Compared to non-DCM group, patients in subclinical DCM group were older, with longer duration of diabetes, and had higher levels of glycosylated hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) (all P<0.05). Serum FNDC5 level was significantly lower in subclinical DCM group than in non-DCM group (P<0.001). FNDC5 level was positively correlated with ventricular septal e'(r=0.451,P=0.005), mitral valve e'(r=0.291,P<0.001), the ratio of peak early diastolic trans-mitral flow velocity (E) to peak late diastolic trans-mitral flow velocity (A)(r=0.490,P=0.002), while negatively correlated with A(r=-0.399,P<0.001), the average ratio of E/e'(r=-0.490,P<0.001), tricuspid regurgitation velocity(r=-0.567,P<0.001), left atrial volume index(r=-0.491,P<0.001). Univariate ROC analysis showed that the diagnostic efficacy of FNDC5(AUC=0.940,95%CI 0.897-0.982)was superior to age(AUC=0.639,95%CI 0.523-0.752), diabetic duration(AUC=0.663,95%CI 0.555-0.772), HbA1c(AUC=0.740,95%CI 0.638-0.839), TG(AUC=0.661,95%CI 0.547-0.776), TC(AUC=0.675,95%CI 0.563-0.788)and LDL-C(AUC=0.644,95%CI 0.532-0.756). Model 1 was established with subclinical DCM as dependent variable, age, diabetic duration, TG, TC, LDL-C and HbA1c as independent variables. Model 2 was established by adding FNDC5 as independent variable on the basis of model 1. Diagnostic efficacy for subclinical DCM was compared between the two models by ROC analysis. The diagnostic efficiency was better with model 2 (AUC=0.980) than with model 1 (AUC=0.879, P<0.001). When sensitivity was set at 0.617, the specificity of model 2 was higher than that of model 1(0.979 vs. 0.936). When sensitivity was set at 0.532, the sensitivity of model 2 was higher than that of model 1 (1.000 vs. 0.915). Conclusions: Our findings suggest that serum FNDC5 could be used as a novel biomarker for the diagnosis of subclinical DCM.

Adropin Alleviates Myocardial Fibrosis in Diabetic Cardiomyopathy Rats: A Preliminary Study.

Aim: Adropin (ADR) is a novel regulatory polypeptide and has important effects on energy metabolism in the heart. However, it is still unclear whether ADR can relieve ventricular remodeling in DCM. Therefore, this study was conducted to assess the effect of ADR on myocardial fibrosis in DCM rats.Materials and Methods: Twenty Wistar rats were randomly assigned into four groups: healthy control group (CON), DCM model group (DCM), DCM model treated with ADR group (ADR) and DCM model treated with perindopril group (PER). Collagen volume fraction (CVF) and perivascular collagen area (PVCA) were calculated. Diastolic function was assessed by echocardiography. The mitochondrial membrane potential assay was conducted by Rhodamine 123 staining. The protein expression levels of Col I, Col III, Mitofusin-1, Mitofusin-2 and Drp1 were evaluated using western blot.Results: Compared to CON group, CVF, PVCA and the relative protein expression of Col I, Col III and Drp1 increased in DCM group. And the relative expression of Mitofusin-1 and Mitofusin-2 proteins decreased. During our investigations, CVF, PVCA and the relative protein expression of Col I, Col III and Drp1 decreased in ADR treated rats compared to DCM group. The diastolic function was elevated in ADR group. The fluorescence of Rhodamine 123 and the expression of Mitofusin-1 and Mitofusin-2 also increased in ADR group.Conclusion: Our study demonstrated that ADR could alleviate myocardial fibrosis and improve diastolic function in DCM rats. ADR may be a putative candidate for the treatment of DCM.

Subannular repair for functional mitral regurgitation type IIIb in patients with ischaemic versus dilated cardiomyopathy.

Functional mitral regurgitation (FMR) is a sequel of left ventricular (LV) remodelling in heart failure patients. Relocation of both papillary muscles aims to specifically address mitral leaflet tethering to improve long-term durability of modern FMR repair. Nevertheless, the prognostic impact of the underlying cardiomyopathy on the outcome after FMR repair is unknown. We analysed 84 consecutive heart failure patients with severe FMR, LV ejection fraction <40%, LV end-diastolic diameter ≥55 mm and tenting height >10 mm, who underwent ring annuloplasty and simultaneous bilateral papillary muscles relocation between June 2016 and March 2019. One-year outcome of 54 patients with ischaemic cardiomyopathy ('ICM group') was prospectively compared to the remaining 30 patients with dilated cardiomyopathy ('DCM group'). One-year survival was similar in both groups (96% in the 'ICM group' vs 97% in the 'DCM group'; P = 0.93). Furthermore, primary composite outcome (i.e. freedom from death or mitral regurgitation ≥ 2) at 1-year postoperatively was comparable between the study groups (94%in the 'ICM group' vs 87% in the 'DCM group'; P = 0.10). LV end-diastolic diameter 1-year after surgery was significantly reduced, as compared to preoperative values, in the 'DCM group' (P = 0.018), but not in the 'ICM group' (P = 0.058). Improvement of New York Heart Association functional class and reduction of serum levels of N-terminal pro-B natriuretic peptide at 1 year was comparable in both study groups. Standardized relocation of both papillary muscles to correct FMR resulted in very satisfactory in-hospital and 1-year outcomes, in both ICM and DCM. DCM patients showed similar improvement in heart failure symptoms and LV re-remodelling compared to ICM patients. Subannular repair is developing towards a valid therapeutic option in heart failure patients presenting with severe FMR.

The role of circumferential strain in the differential diagnosis of cardiomyopathies with left ventricular hypertrabeculation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by the ÚNKP-19-3-II New National Excellence Program of the Ministry for Innovation and Technology Dilated (DCM), hypertrophic (HCM) and noncompaction cardiomyopathy (NCMP) are genetically and morphologically overlapping diseases, however they differ in clinical manifestation, treatment and prognosis. Cardiac MRI feature-tracking might help to differentiate between these cardiomyopathies with left ventricular (LV) hypertrabeculation. We aimed to describe the differences in the functional and strain parameters of NCMP patients with good LV ejection fraction (EF, NCMP-G) compared with patients with HCM, and NCMP patients with reduced EF (NCMP-R) compared with patients with DCM . We included 62 NCMP patients from which 31 had good LV function and 31 had decreased LV-EF. The NCMP-G group was compared with an HCM population (n = 31) and the NCMP-R group was compared with a DCM group (n = 31) matching in age and sex (age, EF; NCMP-G 46.0 ± 13.0 years, 65.5 ± 5.3% vs. HCM 47.2 ± 14.4 years, 74.8 ± 6.3%; NCMP-R 54.5 ± 12.1 years, 32.8 ± 10.1% vs. DCM 50.8 ± 16.7 years, 34.0 ± 8.2%). 1.5 T Philips Achieva and Siemens Aera MRI machines were used for the scans, Medis Suite program was used for analysis and MedCalc software for statistics, p &amp;lt; 0.05 was considered statistically significant. Significant differences were found between the functional parameters of HCM and NCMP-G patients, while the DCM and NCMP-R groups differed only in the trabecular mass values (LV-trab, NCMP-G vs. HCM: 26.2 ± 7.5 vs. 30.7 ± 7.0 g/m2, NCMP-R vs. DCM: 48.2 ± 13.2 vs. 42.1 ± 10.1 g/m2, p &amp;lt; 0.05). The global longitudinal strain values of the studied populations were not significantly different, however the global circumferential strain (GCS) values were significantly better in patients with HCM and DCM compared with the NCMP groups (GCS, NCMP-G vs. HCM: -31.2 ± 4.9 vs. -43.0 ± 8.4%, NCMP-R vs. DCM: -11.7 ± 7.3 vs. -16.9 ± 6.1%). The average circumferential strain values of the LV basal, mid and apical parts were significantly better in the HCM and DCM groups compared with the NCMP groups (NCMP-G vs. HCM: -35.7 ± 9.5 vs. -50.5 ± 14.1%, NCMP-R vs. DCM: -29.5 ± 13.2 vs. -15.6 ± 6,7%). We assessed the cut-off point of the average LV apical circumferential strain to differentiate the studied populations (HCM vs. NCMP-G cut-off: -47.3% sens.: 83.9%, spec.: 67.7%, AUC: 0.81; DCM vs. NCMP-R cut-off: -19.3% sens.: 83.9%, spec.: 83.9%, AUC: 0.86). The diverse circumferential strain values of the hypertrabeculated LV apical third could help the differential diagnosis of NCMP, DCM and HCM.

Effects of PPARγ agonist pioglitazone on cardiac fibrosis in diabetic mice by regulating PTEN/AKT/FAK pathway.

The aim of this study was to explore the role of pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, in cardiac fibrosis of diabetic mice. A total of 60 adult male C57/B6 mice were divided into 3 groups using a random number table, namely, control group (Sham group, n=20), diabetic cardiomyopathy group (DCM group, n=20), DCM + PIO group (n=20). Streptozocin (STZ) was injected into mice at a dose of 125 mg/Kg to induce the model of diabetes in vivo. After successful induction, mice in DCM + PIO group were intragastrically given PIO at 10 mg/kg/d once a day for 6 weeks. Meanwhile, those in Sham group and DCM group were given the same volume of normal saline. After 6 weeks, ejection fraction % (EF%), fraction shortening % (FS%) and heart rate of mice in each group were examined via echocardiography. Picrosirius red (PSR) staining assay was conducted to detect collagen deposition in myocardial tissues of mice in each group. The protein expression level of PPARγ in mouse myocardial tissues in each group was measured through Western blotting and immunohistochemical staining assays. Hematoxylin-eosin (H&E) staining assay was carried out to evaluate the myocardial hypertrophy of mice in each group. The protein expression level of transforming growth factor-β (TGF-β) in mouse myocardial tissues in each group was measured through immunohistochemical staining assay. In addition, Western blotting was employed to detect the expression of proteins related to the phosphate and tension homology deleted on chromsome ten (PTEN)/protein kinase B (AKT)/focal adhesion kinase (FAK) signaling pathway in myocardial tissues of mice in each group. The messenger ribonucleic acid (mRNA) and protein expression levels of PPARγ in mouse myocardial tissues were significantly lower in DCM group than those in Sham group (p<0.05). PPARγ agonist PIO could significantly increase the protein expression of PPARγ in myocardial tissues of DCM mice. The results of cardiac Doppler ultrasound revealed that PIO significantly upregulated EF% and FS% in DCM mice (p<0.05). Besides, PIO remarkably reduced collagen deposition and TGF-β protein expression in myocardial tissues in DCM mice (p<0.05). H&E staining results showed that PIO notably attenuated myocardial hypertrophy in DCM mice (p<0.05). Furthermore, it was discovered that PIO markedly elevated PTEN protein in myocardial tissues of DCM mice and inhibited the phosphorylation of AKT and FAK proteins (p<0.05). The protective effect of PIO against cardiac fibrosis in diabetic mice may be related to its regulation on the PTEN/AKT/FAK signaling pathway. Our findings suggest that PIO is expected to become a targeted drug for the treatment of DCM in clinical practice.

Quantitative determination of circulating L-cartinine and its derivates contributes to Heart failure diagnosis, etiology discrimination and clinical prognosis prediction

Abstract Background Despite the latest progress in heart failure therapy, early diagnosis and clinical prognosis prediction are still critical issues nowadays. It has been proved that carnitines play an essential role in fatty acid metabolism. However, it is unclear about the changes and clinical effects of circulating carnitines in heart failure. Objectives This study was designed to clarify the alteration of serum carnitine and its derivates in heart failure patients, and to verify the impact of carnitines on heart failure etiology discrimination and mortality prediction. Methods A total of 161 heart failure patients (Dilated cardiomyopathy: DCM, n=98; ischemia cardiomyopathy: ICM, n=63) and control patients (n=48) were enrolled from Feb to Sep in 2017. Serum L-carnitines were quantitatively measured by liquid chromatography/ mass spectrometry. All patients underwent follow-up (mean 30.8 months). Multi-variable Cox survival was performed to verify the impact of carnitines on heart failure mortality prediction. Results A total of 27 different carnitine derivates were detected. Compared with control group, 26 types of carnitines were increased significantly in heart failure patients. Several circulating carnitines were independent biomarkers for heart failure even adjusted by multi-variable logistic analysis. We also found 7 carnitines were obviously increased in DCM group than those in ICM group. Isobutyryl-L-carnitine and stearoyl-L-carnitine were independently associated with higher probability of DCM than ICM. DCM prediction model established by adding carnitines (isobutyryl-L-carnitine and stearoyl-L-carnitine) to age, serum creatinine and left ventricular ejection fraction,had favorable discrimination (C-index = 0.832, P&amp;lt;0.01, Figure 1A and B) and calibration efficiency (Hosmer-Lemeshow χ2=7.376, P=0.497&amp;gt;0.05). Meanwhile, a total of 43 mortality event occurred, 18 death (31.6%) in ICM group and 25 (27.2%) in DCM group. Independent clinical risk factors for the occurrence of mortality were serum creatinine &amp;gt;2mg/dl, left atrial diameter 0.55mm and N-terminal pro-B-type natriuretic peptide &amp;gt;4000 pg/ml. Using multi-variable COX survival analysis simultaneously adjusted by serum creatinine, left atrial diameter, NT-pro-BNP and age, oleoyl L-carnitine &amp;gt;300nmo/L (HR=2.364, 95% CI: 1.122–4.976, P=0.024) and isovaleryl-L-carnitine &amp;lt;100nmol/L (HR=2.108, 95% CI: 1.091–4.074, P=0.026) were also independently associated with higher mortality. Conclusions As one of critical participants in fatty acid metabolism, L-carnitines alteration not only differentiates DCM patients from ICM ones, but also independently predicts the risk of long-term mortality in heart failure patients. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China, Grant of Shanghai Municipal Commission of Health and Family Planning

Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway

AimsDiabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular diseases. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM. Materials and methodsDCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine. Key findingsCompared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression. SignificanceTo our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.

Value of circulating miRNA-21 in the diagnosis of subclinical diabetic cardiomyopathy

BackgroundDiabetic cardiomyopathy (DCM) is a type of cardiac dysfunction that affects approximately 12% of diabetic patients, ultimately leading to heart failure or even death. However, there is currently no efficient or specific biomarker for DCM diagnosis. MethodsA total of 266 subjects with type II diabetes (T2DM) were enrolled in this study and were divided into the T2DM with cardiac dysfunction (DCM) group and T2DM without cardiac dysfunction (non-DCM) group. The diagnostic efficacy of miR-21 was determined and compared with that of serum hemoglobin A1c% (HbA1c%). Db/db mice and H9c2 cells stimulated with high glucose (HG)/high fatty acid (PA) were used as in vivo and in vitro models of DCM, respectively. ResultsThrough echocardiography and gated-myocardial perfusion imaging (gated-MPI), 49 patients were selected to be enrolled in the DCM group, with 49 matched controls in the non-DCM group. The circulating miR-21 levels were significantly decreased in the DCM group compared to the non-DCM group (P < 0.001). The diagnostic efficiency of miR-21 (area under the curve AUC = 0.899) was higher than that of other parameters, including HbA1c%. Moreover, when miR-21 was combined with the duration of diabetes, HbA1c%, and lipid profiles, the AUC was the highest (AUC = 0.939) and had the highest diagnostic efficiency. Furthermore, overexpression of miR-21 improved the impaired mitochondrial biogenesis and decreased the cardiomyocyte apoptosis induced by HG/PA, while inhibition of miR-21 exerted the opposite effects. ConclusionsOur findings identify circulating miR-21 as a novel biomarker in the diagnosis of DCM and provide an underlying mechanism for miRNA-based therapy for the treatment of DCM. Trial registrationThe study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University and has been registered in the Chinese Clinical Trial Registry (ChiCTR1900027080).

Outcomes of Left Ventricular Assist Device for Patients with Hypertrophic Cardiomyopathy

The treatment of end stage hypertrophic cardiomyopathy (HCM) is sometimes complicated because some cases of HCM are not suitable for LVAD. Scarce data exist on outcomes of continuous-flow (CF) LVAD support in these challenging patient cohorts. We evaluated the clinical outcomes of LVAD therapy for patients with HCM. Between 2005 and 2018, 191 consecutive patients underwent CF-LVAD implantation at Osaka University Hospital. Of these, we retrospectively compared the clinical outcomes between HCM (n=29) and idiopathic dilated cardiomyopathy (DCM, n=106) patients with CF-LVAD support. The primary outcome was all-cause mortality. Median follow-up time was 815 days (interquartile range [IQR]: 373-1172). There were no significant differences between the two groups about patient's baseline characteristics. HCM group had significant smaller left ventricle (LV) than DCM group. [LV end-diastolic diameter: 67 (IQR: 55-71) vs 72 (IQR: 62-82), p<0.05] In short-term outcome, there was no significant difference about in-hospital mortality. [HCM vs DCM; 2 (7%) vs 4 (4%), p=0.47] Regarding postoperative complication, HCM group required more frequent right ventricular assist device (RVAD) support than DCM group. [8 (28%) vs 4 (4%), p<0.01] In long-term outcome, the overall survival rate at 1 and 3 years was 89% and 74% in HCM group, 92% and 90% in DCM group, respectively (p=0.03). (Figure A) During the follow up period, HCM group had significantly more LVAD pump exchanges than DCM group. [hazard ratio, 4.10 95% confidence interval, 1.67 to 10.1; p=0.002] (Figure B) CONCLUSION: The long-term outcome of LVAD therapy for patients with HCM is still challenging. In particular, careful attention is required for right heart function.

Comparative study between physiological remodeling of the athlete's heart and dilated cardiomyopathies with cardiac MRI

The differential diagnosis between physiological remodeling of the athlete's heart and cardiomyopathies responsible for sudden death is sometimes difficult. Describe the difference between physiological dilatation of cardiac cavities in athletes with pathological dilatation by comparing a group of high-level athletes (athlete group) to a subject group followed for dilated cardiomyopathy (DCM group). We conducted a prospective comparative study including 61 subjects. The group of athletes comprised 31 subjects. The DCM group consisted of 30 subjects. All subjects were paired to age and body surface and had cardiac MRI with late enhancement study. Left ventricular systolic function in MRI by left ventricular ejection fraction (LVEF) study, LV shortening fraction and MAPSE (Mitral annular plane systolic excursion) study were normal in the athlete group and impaired in the DCM group. Left and right ventricular dilatation in the athlete group was proportionate with a ratio of LV tele diastolic volume indexed to RV tele-diastolic volume (LV TDVi/RV TDVi) at 1.1 ± 0.1 versus disproportionate dilatation in the patient DCM group (LV TDVi/RV TDVi) at 2 ± 0.8). The ROC curve was used to identify the threshold value of the LV TDVi/RV TDVi ratio. This threshold value corresponds to 1.21 with a 90% sensitivity and a 90.3% specificity. The correlation between the LV TDVi/RV TDVi ratio and the LV ejection fraction (LVEF) was negative (correlation coefficient = −0.55, P < 0.0001). There is no late enhancement of the myocardium in the athlete group against 30% in the DCM group. Cardiac MRI is a major contributor to the Athlete Heart distinction from the DCM. LV TDVi/RV TDVi ratio represents a discriminating role between a normal proportional adaptation of the two ventricles and a pathological dilatation.

Metabolic stress and reproductive features in post-partum goats supplemented for a long period with detoxified castor meal as the source of dietary nitrogen

ABSTRACT This study evaluated the effect of detoxified castor meal on the reproductive performance, metabolic stress, milk production, and kid development in peripartum goats. The diet of the animals were with (DCM, n= 20) or without (WDCM, n= 21) detoxified castor meal during the entire gestation and until weaning, 60 days post-birth. No differences were observed in the gestation period, litter size, rate of multiple births, and mortality between the two groups. The postpartum plasma concentrations of progesterone remained below 1ng/mL in all animals, thus, confirming the absence of active corpora lutea. The thickness of sternum adipose tissue and loin area, levels of urea and cholesterol, milk production, and daily weight gain in the kids were low in the DCM group when compared to those in the WDCM group (P&lt; 0.05). To conclude, the use of detoxified castor meal in peripartum goats resulted in lower level of performance in the kids because of reductions in the amount of milk received from their mothers during lactation. In addition, the diet containing detoxified castor meals was not efficient in recovering from the loss of stored body reserves able to initiate the recovery of the cyclic activity of the goats.

Metabolic markers of myocardium insulin resistance in dogs with heart failure.

Background:Heart failure syndrome is an aspect of primary or secondary heart disease and is associated with decompensation, formation, and activation of pathological interactions between regulation systems. This results in myocardial energy metabolism alteration. This study was carried out to defy some metabolic aspects of myocardial tissue insulin resistance (IRM) development in canine heart failure.Aim:To investigate the myocardial tissue concentration of adenosine triphosphate (ATP), glucose transporters 1 and 4, pyruvate dehydrogenase (PDH), hexokinase 2, insulin receptor (InsR), and adropin (ADR) protein and to screen metabolic changes and IRM in canine myocardium with heart failure.Methods:We studied 28 dogs of different sexes, ages, and breeds. Groups were formed according to primary pathology: apparently healthy dogs (HD, n = 6); dogs with CDVD (CDVDD, n = 8); dogs with DCM (DCMD, n = 6); and dogs with doxorubicin chemotherapy and doxorubicin-induced cardiomyopathy (DoxCMD, n = 8). Animals in the study were diagnosed for primary disease by standard methods and algorithms. Animals were euthanized due to incurable neurological disease, refractory heart failure, or by owners will. The material was obtained immediately after death, fixed in liquid nitrogen, and stored in −80°C refrigerator. Studied proteins concentrations were analyzed in a specialized research laboratory, using ELISA kits, provided by Cloud-Clone Corp.Results:ATP, GLUT1, and GLUT4 concentrations in myocardial tissue from the valvular disease group did not differ from the HD group. In CDVD, we found depression of PDH, hexokinase II (HX2), and ADR concentrations in comparison to HD. InsR was significantly lower in the CDVD and DoxCMD groups in comparison to the HD group, but in the DCM group, it was twofold higher than in the HD group. In the DCMD and DoxCMD groups, all parameters were lower than in the HD group. ATP, HX2, ADR, GLUT1, and GLUT4 were higher in the CDVD group, than in the DCM and DoxCM groups. PDH in the CDVD and DoxCM groups did not differ. PDH was depleted in the DCM to CDVD and DoxCM groups. InsR did not differ between the CDVD and DoxCM groups, but was upregulated in the DCM to CDVD and DoxCM groups.Conclusion:Development of myocardial tissue IRM is a part of the structural, functional and metabolic remodeling in dogs with heart failure of different etiology. At the late stages, we found significant changes in energy supply availability and production in the myocardium.