Remodeling In Dilated Cardiomyopathy Research Articles

Endoplasmic reticulum stress-related gene expression causes the progression of dilated cardiomyopathy by inducing apoptosis.

Background: Previous studies have shown that endoplasmic reticulum stress (ERS) -induced apoptosis is involved in the pathogenesis of dilated cardiomyopathy (DCM). However, the molecular mechanism involved has not been fully characterized. Results: In total, eight genes were obtained at the intersection of 1,068 differentially expressed genes (DEGs) from differential expression analysis between DCM and healthy control (HC) samples, 320 module genes from weighted gene co-expression network analysis (WGCNA), and 2,009 endoplasmic reticulum stress (ERGs). These eight genes were found to be associated with immunity and angiogenesis. Four of these genes were related to apoptosis. The upregulation of MX1 may represent an autocompensatory response to DCM caused by a virus that inhibits viral RNA and DNA synthesis, while acting as an autoimmune antigen and inducing apoptosis. The upregulation of TESPA1 would lead to the dysfunction of calcium release from the endoplasmic reticulum. The upregulation of THBS4 would affect macrophage differentiation and apoptosis, consistent with inflammation and fibrosis of cardiomyocytes in DCM. The downregulation of MYH6 would lead to dysfunction of the sarcomere, further explaining cardiac remodeling in DCM. Moreover, the expression of genes affecting the immune micro-environment was significantly altered, including TGF-β family member. Analysis of the co-expression and competitive endogenous RNA (ceRNA) network identified XIST, which competitively binds seven target microRNAs (miRNAs) and regulates MX1 and THBS4 expression. Finally, bisphenol A and valproic acid were found to target MX1, MYH6, and THBS4. Conclusion: We have identified four ERS-related genes (MX1, MYH6, TESPA1, and THBS4) that are dysregulated in DCM and related to apoptosis. This finding should help deepen understanding of the role of endoplasmic reticulum stress-induced apoptosis in the development of DCM.

The predictive value of coronary microvascular dysfunction for left ventricular reverse remodelling in dilated cardiomyopathy.

To evaluate the degree of coronary microvascular dysfunction (CMD) in dilated cardiomyopathy (DCM) patients by cardiac magnetic resonance (CMR) first-pass perfusion parameters and to examine the correlation between myocardial perfusion and left ventricle reverse remodelling (LVRR). In this study, 94 DCM patients and 35 healthy controls matched for age and sex were included. Myocardial perfusion parameters, including upslope, time to maximum signal intensity (Timemax), maximum signal intensity (SImax), baseline signal intensity (SIbaseline), and the difference between maximum and baseline signal intensity (SImax-baseline) were measured. Additionally, left ventricular (LV) structure, function parameters, and late gadolinium enhancement (LGE) were also recorded. The parameters were compared between healthy controls and DCM patients. Univariable and multivariable logistic regression analyses were used to determine the predictors of LVRR. With a median follow-up period of 12 months [interquartile range (IQR), 8-13], 41 DCM patients (44%) achieved LVRR. Compared with healthy controls, DCM patients presented CMD with reduced upslope, SIbaseline, and increased Timemax (all p < 0.01). Timemax, SImax, and SImax-baseline were further decreased in LVRR than non-LVRR group (Timemax: 60.35 [IQR, 51.46-74.71] vs. 72.41 [IQR, 59.68-97.70], p = 0.017; SImax: 723.52 [IQR, 209.76-909.27] vs. 810.92 [IQR, 581.30-996.89], p = 0.049; SImax-baseline: 462.99 [IQR, 152.25-580.43] vs. 551.13 [IQR, 402.57-675.36], p = 0.038). In the analysis of multivariate logistic regression, Timemax [odds ratio (OR) 0.98; 95% confidence interval (CI) 0.95-1.00; p = 0.032)], heart rate (OR 1.04; 95% CI 1.01-1.08; p = 0.029), LV remodelling index (OR 1.73; 95% CI 1.06-3.00; p = 0.038) and LGE extent (OR 0.85; 95% CI 0.73-0.96; p = 0.021) were independent predictors of LVRR. CMD could be found in DCM patients and was more impaired in patients with non-LVRR than LVRR patients. Timemax at baseline was an independent predictor of LVRR in DCM.

The potential predictive value of cardiac mechanics for left ventricular reverse remodelling in dilated cardiomyopathy.

Left ventricular reverse remodelling (LVRR) is an important objective of optimal medical management for dilated cardiomyopathy (DCM) patients, as it is associated with favourable long-term outcomes. Cardiac magnetic resonance (CMR) can comprehensively assess cardiac structure and function. We aimed to assess the CMR parameters at baseline and investigate independent variables to predict LVRR in DCM patients. Nighty-eight initially diagnosed DCM patients who underwent CMR and echocardiography examinations at baseline were included. CMR parameters and feature tracking (FT) based left ventricular (LV) global strain (nStrain) and nStrain indexed to LV cardiac mass index (rStrain) were measured. The predictors of LVRR were determined by multivariate logistic regression analyses. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of CMR parameters and were compared by the DeLong test. At a median follow-up time of 9 [interquartile range, 7-12] months, 35 DCM patients (36%) achieved LVRR. The patients with LVRR had lower LV volume, mass, LGE extent and stroke volume index (LVSVi) and higher left ventricular remodelling index (LVRI), nStrains, rStrains, and peak systolic strain rate (PSSR) in the longitudinal direction and rStrains in the circumferential direction at baseline (all P<0.05). In the multivariate logistic regression analyses, LVRI [per SD, odds ratio (OR) 1.79; 95% confidence interval (CI) 1.08-2.98; P=0.024] and the ratio of global longitudinal peak strain (rGLPS) (per SD, OR 1.88; 95% CI 1.18-3.01; P=0.008) were independent predictors of LVRR. The combination of LVSVi, LVRI, and rGLPS had a greater area under the curve (AUC) than the combination of LVSVi and LVRI (0.75 vs. 0.68), but not significantly (P=0.09). Patients with LVRR had a lower LV volume index, lower LVSV index, lower LGE extent, higher LVRI, and preserved myocardial deformation in the longitudinal direction at baseline. LVRI and rGLPS at baseline were independent determinants of LVRR.

Prevalence of early and late left ventricular reverse remodeling in dilated cardiomyopathy under optimal medical therapy

Prevalence of early and late left ventricular reverse remodeling in dilated cardiomyopathy under optimal medical therapy

Left ventricular shape predicts arrhythmic risk in fibrotic dilated cardiomyopathy.

AimsRemodelling of the left ventricular (LV) shape is one of the hallmarks of non-ischaemic dilated cardiomyopathy (DCM) and may contribute to ventricular arrhythmias and sudden cardiac death. We sought to investigate a novel three dimensional (3D) shape analysis approach to quantify LV remodelling for arrhythmia prediction in DCM.Methods and resultsWe created 3D LV shape models from end-diastolic cardiac magnetic resonance images of 156 patients with DCM and late gadolinium enhancement (LGE). Using the shape models, principle component analysis, and Cox-Lasso regression, we derived a prognostic LV arrhythmic shape (LVAS) score which identified patients who reached a composite arrhythmic endpoint of sudden cardiac death, aborted sudden cardiac death, and sustained ventricular tachycardia. We also extracted geometrical metrics to look for potential prognostic markers. During a follow-up period of up to 16 years (median 7.7, interquartile range: 3.9), 25 patients met the arrhythmic endpoint. The optimally prognostic LV shape for predicting the time-to arrhythmic event was a paraboloidal longitudinal profile, with a relatively wide base. The corresponding LVAS was associated with arrhythmic events in univariate Cox regression (hazard ratio = 2.0 per quartile; 95% confidence interval: 1.3–2.9), in univariate Cox regression with propensity score adjustment, and in three multivariate models; with LV ejection fraction, New York Heart Association Class III/IV (Model 1), implantable cardioverter-defibrillator receipt (Model 2), and cardiac resynchronization therapy (Model 3).ConclusionBiomarkers of LV shape remodelling in DCM can help to identify the patients at greatest risk of lethal ventricular arrhythmias.

84 Left atrial reverse remodelling in dilated cardiomyopathy

Abstract Aims Left atrial (LA) dilation is associated a with worse prognosis in several cardiovascular settings but therapies can promote LA reverse remodelling. Characterizing and defining the prognostic implications of LA volume (LAVI) reduction in dilated cardiomyopathy (DCM). Methods and results Consecutive DCM patients from two tertiary care centres, with available echocardiography at baseline and at 1 year follow-up, were analysed. LA dilation was defined as LAVI &amp;gt;34 ml/m2, Delta (Δ)LAVI was defined as the 1 year relative LAVI reduction. The outcome was a composite of death/heart transplantation/heart failure hospitalization (D/HTx/HFH). Five hundred sixty patients were included [age 52 ± 13 years; left ventricular ejection fraction (LVEF) 31 ± 10%, LAVI 45 ± 18 ml/m2]. Baseline LAVI had a non-linear association with the risk of D/HTx/HFH, independently from LVEF (P &amp;lt; 0.001). At 1 year follow-up, LAVI decreased in 374 patients (67%, median ΔLAVI 24%, interquartile range 37% 11%). Factors independently associated with ΔLAVI were higher baseline LAVI and lower baseline LVEF. After adjustment for confounders, ΔLAVI showed a linear association with the risk of D/HTx/HHF (HR: 0.92, 95% CI: 0.86 0.99 per 5% decrease, P &amp;lt; 0.001). At 1 year Follow-up, patients with a ≥ 15% reduction in ΔLAVI or LAVI normalization (i.e. Follow-up LAVI ≤34ml/m2) (42% of the cohort) were at lower risk of D/HTx/HFH (HR: 0.49, 95% CI: 0.33 0.74, P &amp;lt; 0.001). Conclusions In a large cohort of DCM, 1 year reduction in LAVI is observed in the majority of patients. The association between reduction in LAVI and D/HTx/HHF candidates LA reverse remodelling as complementary early therapeutic goal in DCM.

Cytokine-Mediated Alterations of Human Cardiac Fibroblast's Secretome.

Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast’s secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli.

Highlighting the latest research: September 2021

British Journal of Cardiac NursingVol. 16, No. 9 Research RoundupHighlighting the latest research: September 2021Sarah Jane PalmerSarah Jane PalmerCorrespondence to: Sarah Jane Palmer; E-mail Address: [email protected]Department of Work and Pensions, Maximus Management Training Institute, London, UKSearch for more papers by this authorSarah Jane PalmerPublished Online:28 Sep 2021https://doi.org/10.12968/bjca.2021.0098AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Chiavaroli L, Lee D, Ahmed A et al. Effect of low glycaemic index or load dietary patterns on glycaemic control and cardiometabolic risk factors in diabetes: systematic review and meta-analysis of randomised controlled trials. BMJ. 2021;374:n1651. https://doi.org/10.1136/bmj.n1651 Crossref, Google ScholarMahmood A, Ray M, Dobalian A et al. Insomnia symptoms and incident heart failure: a population-based cohort study. Eur Heart J. 2021;ehab500. https://doi.org/10.1093/eurheartj/ehab500 Crossref, Google ScholarMorseth B, Geelhoed B, Linneberg A et al. Age-specific atrial fibrillation incidence, attributable risk factors and risk of stroke and mortality: results from the MORGAM consortium. Open Heart. 2021;8:e001624. https://doi.org/10.1136/openhrt-2021-001624 Crossref, Google ScholarDecarlo C, Latz C, Boitano L et al. Prognostication of asymptomatic penetrating aortic ulcers: a modern approach. Circulation. 2021. https://doi.org/10.1161/CIRCULATIONAHA.121.054710circulation Crossref, Google ScholarTayal U, Gregson J, Buchan R et al. Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy. Heart. 2021. https://doi.org/10.1136/heartjnl-2021-319418 Crossref, Google Scholar FiguresReferencesRelatedDetails 2 September 2021Volume 16Issue 9ISSN (online): 2052-2207 Metrics History Published online 28 September 2021 Published in print 2 September 2021 Information© MA Healthcare LimitedPDF download

Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage

The present research was designed to examine the effects of disintegrin metalloproteinases 10 (ADAM10) on the doxorubicin (DOX)-induced dilated cardiomyopathy (DCM) and the mechanisms involved, with a focus on ADAM10-dependent cleavage of N-cadherin. The present study constructed recombinant lentiviral vectors expressing short hairpin RNA (shRNA) targeting the ADAM10 gene. H9C2 cells were treated with the recombinant lentivirus or GI254023 (an ADAM10 inhibitor). The expression level of N-cadherin and its C-terminal fragment1 (CTF1) was tested by western blotting and flow cytometry. The adhesion ability was analyzed using a plate adhesion model. Cardiac function and morphology were assessed in control and lentivirus-transfected rats with or without DOX treatment. The inhibition of ADAM10 activity significantly increased the expression of full-length N-cadherin on the cellular surface and reduced CTF1 generation in vivo and in vitro. The adhesion ability was also increased in ADAM10-knockdown H9C2 cells. Furthermore, DOX-induced myocardial dysfunction was ameliorated in rats transfected with ADAM10-shRNA lentivirus. These findings demonstrated that ADAM10 specifically cleaves N-cadherin in cardiomyocytes. ADAM10-induced N-cadherin cleavage results in changes in the adhesive behavior of cells. Therefore, ADAM10 may serve as a therapeutic target to reverse cardiac remodeling in DCM.

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy

ObjectiveThe effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help...

MAGGIC Risk Model Predicts Adverse Events and Left Ventricular Remodeling in Non-Ischemic Dilated Cardiomyopathy.

PurposeWe aimed to study the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk model’s prognostic value and relationship with left ventricular remodeling in dilated cardiomyopathy.Patients and MethodsDilated cardiomyopathy patients were prospectively recruited and underwent clinical assessments. MAGGIC risk score was calculated. Patients were followed up for adverse events and echocardiography. Primary endpoints were all-cause mortality and first rehospitalization due to heart failure. Secondary endpoint was left ventricular remodeling defined as a decline in left ventricular ejection fraction >10% or an increase in left ventricular end-diastolic diameter >10%. Survival status was examined using Cox regression analysis. The model’s ability to discriminate adverse events and left ventricular remodeling was calculated using a receiver operating characteristics curve.ResultsIn total, 114 patients were included (median follow-up time = 31 months). The risk score was independently related to adverse events (2-year all-cause mortality: hazard ratio [HR] = 1.122; 95% confidence interval [CI], 1.043–1.208; 1-year first rehospitalization due to heart failure: HR = 1.094; 95% CI, 1.032–1.158; 2-year first rehospitalization due to heart failure: HR = 1.088; 95% CI, 1.033–1.147, all P < 0.05). One-year change in left ventricular end-diastolic diameter was correlated with the risk score (r = 0.305, P = 0.002). The model demonstrated modest ability in discriminating adverse events and left ventricular remodeling (all areas under the curve were 0.6–0.7).ConclusionThe MAGGIC risk score was related to adverse events and left ventricular remodeling in dilated cardiomyopathy.

Regression of Electrocardiographic Left Ventricular Hypertrophy and Strain Pattern Using Pharmacotherapy in a Patient With Dilated Cardiomyopathy

Summary A patient with dilated cardiomyopathy (DCM) was hospitalized for acute decompensated heart failure. His electrocardiogram (ECG) showed left ventricular hypertrophy (LVH) and strain pattern. As heart failure drugs were up-titrated, he experienced LV reverse remodeling. Serial ECG demonstrated regression of LVH and strain pattern. ECG-LVH and its regression can predictor and monitor reverse remodeling in DCM.

Abstract 16880: Exosomes From Dilated Cardiomyocytes Activate Fibrosis

In dilated cardiomyopathy (DCM), exaggerated fibrosis reduces tissue compliance and accelerates the progression to heart failure. However, the mechanisms for fibrotic remodeling in DCM are not well understood. Exosomes are small extracellular vesicles that function as intercellular messengers. Our hypothesis is that exosomes from hypertrophic stimulated DCM cardiomyocytes activate fibrosis in the heart. We utilized iPSCs reprogrammed from DCM patients and healthy control individuals (CTL) to differentiate them into cardiomyocytes (iCMs). iCMs were stimulated by Angiotensin II, and conditioned media were collected to isolate exosomes thereafter. Fibroblasts were treated with CTL-exosomes and DCM-exosomes respectively in vitro. Meanwhile, we injected exosomes into the mouse hearts in vivo. Fibrotic markers and protein expression were examined by western blot and histology. Additionally, we also analyzed the microRNA profiles in the DCM-exosomes and CTL-exosomes by small RNA sequencing. The microRNAs expressions in exosomes were also confirmed by RT-PCR. We found DCM exosomes treatment significantly upregulated extracellular matrix proteins expressions in fibroblasts. Collagen I, collagen III, and CTGF were significantly upregulated in DCM exosomes treatment group compared to CTL exosomes treatment group. Intramyocardial injection of DCM exosomes into wild type mice (CD-1) caused impaired ejection fraction after 7 days compared to CTL exosomes injection (DCM = 51.5 ± 6.21%*, CTL =64.6 ± 3.99%; * = P &lt; 0.05). Picro sirius red staining for extracellular matrix showed significant increase of fibrosis in DCM exosome injection group, compared to CTL exosomes and PBS group (DCM = 3.08 ± 0.24%*, CTL = 0.087 ± 0.02%, PBS = 0.053 ± 0.01%; * = P &lt; 0.05). Next-generation sequencing of these exosomes exhibited upregulation of a group microRNAs in the DCM exosomes. microRNA-103a upregulation was confirmed in DCM exosomes. Overexpression microRNA-103a resulted in fibroblast activation and upregulation of Col I, Col III, and CTGF expression in vitro. Our findings uncovered a critical role for exosomal microRNA (microRNA-103a) mediating pathological fibrotic remodeling in DCM.

Analysis of DCM associated protein alterations of human right and left ventricles

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and impaired myocardial function. Endomyocardial biopsies (EMB) enable immunohistochemical and molecular characterization of this disease. However, knowledge about specific molecular patterns and their relation to cardiac function in both ventricles is rare. Therefore, we performed a mass spectrometric analysis of 28 paired EMBs of left (LV) and right ventricles (RV) of patients with DCM or suspected myocarditis allowing quantitative profiling of 743 proteins. We analysed associations between protein abundance of LV and RV as well as the echocardiographic parameters LVEF, TAPSE, LVEDDI, and RVEDDI by linear regression models.Overall, more LV than RV proteins were associated with LV parameters or with RVEDDI. Most LV and RV proteins increasing in level with impairing of LVEF were annotated to structural components of cardiac tissue. Additionally, a high proportion of LV proteins with metabolic functions decreased in level with decreasing LVEF. Results were validated with LV heart sections of a genetic murine heart failure model.The study shows, that remodelling and systolic dysfunction in DCM is mirrored by distinct alterations in protein composition of both ventricles. Loss of LV systolic function is reflected predominantly by alterations in proteins assigned to metabolic functions in the LV whereas structural remodelling was more obvious in the RV. Alterations related to intermediate filaments were seen in both ventricles and highlight such proteins as early indicators of LV loss of function. SignificanceThe present study report protein sets in the RV and the LV being associated with ventricular function and remodelling in DCM. Protein abundances in the LV and the RV emphasize and expand current knowledge on pathophysiological changes in heart failure and DCM. While RV and LV EMBs do not differ concerning diagnostic assessment of inflammatory status and virus persistence, additional information reflecting disease severity associated protein alterations can be gained by EMB protein profiling. RV and LV protein data provided complementary information. The protein pattern of the LV reflects metabolic changes and an impaired energy production, which is associated with the degree of LV systolic dysfunction and remodelling and may yield important information about the disease status in DCM. On the other hand, at this disease stage of DCM with still preserved RV function, RV alterations in structural proteins may reflect myocardial compensatory protective mechanisms for maintenance of structure and cellular function.The study highlight particular proteins being of interest as heart failure biomarkers in both ventricles which seem to reflect the severity of the disease. Further comparative studies between different HF aetiologies have to evaluate those proteins as markers specific for DCM.

July 2020 at a glance: focus on imaging and cardiomyopathies

Data on epidemiology of cardiomyopathies are limited.1-3 Merlo et al.4 showed a reduction in mortality, heart transplantation, left ventricular (LV) assist device implantation and sudden cardiac death in the last decade, compared with the previous ones, in patients with non-ischaemic dilated cardiomyopathy (DCM). Outcomes were also dependent on specific phenotypes with the poorest in patients with chemotherapy-induced DCM and the best in those with tachycardia-induced DCM. An analysis of the Swedish Heart Failure (HF) Register of the young patients with HF, compared with the others, showed that patients aged <55 years were more likely to have DCM, obesity, congenital heart disease, and a low LV ejection fraction (LVEF). Patients aged <55 years had a five times higher mortality risk compared with control subjects with the highest risk in the youngest ones, 18-34 years old.5 Diabetes is a known risk factor for cardiovascular death in patients with a recent myocardial infarction.6 Shin et al.7 showed the independent prognostic value for HF hospitalizations or cardiovascular death of glycated haemoglobin (A1C) levels (adjusted hazard ratio 1.11, 95% confidence interval 1.01–1.21 per 1% higher A1C) and LVEF in patients with type 2 diabetes and a recent acute coronary syndrome. Cardiac magnetic resonance (CMR) has a major role in the detection and quantification of myocardial fibrosis and adipose tissue, two major determinants of the phenotype and outcomes of patients with HF and preserved ejection fraction (HFpEF).8, 9 Quarta et al.10 review the role of CMR in the management of HFpEF patients. Tayal et al.11 used CMR to evaluate LV reverse remodelling in DCM. Absolute LV contractile reserve by dobutamine stress CMR and female gender predicted LVEF increase over 12 months. Nauta et al.12 retrospectively evaluated the association between LV geometry, clinical and biomarker phenotypes, and therapeutic response in patients with chronic HF. Compared to patients with an eccentric hypertrophy pattern, those with a concentric one had a different clinical and biomarker phenotype and did not benefit from the up-titration of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Left ventricular ejection time (LVET) was an independent predictor of HF in a community-based cohort studied by echocardiography.13 Patel et al.14 explored its prognostic role in 545 HF outpatients stratified by LVEF. LVET was shorter in HF patients with reduced ejection fraction (HFrEF) vs. those with HFpEF and its longer duration was independently associated with better 1-year outcomes in HFrEF but not in HFpEF patients. Left atrial (LA) structure and function are major determinants of outcomes in patients with HF and atrial fibrillation.15, 16 LA diameter predicted 4-year mortality also in HF patients with mitral regurgitation treated by percutaneous repair.17 Impaired LA strain may contribute to reduced exercise capacity.18 Sugimoto et al.19 showed that a blunted LA strain is associated with lower stroke volume and cardiac output response to exercise and worse outcomes in HF patients. Pulmonary hypertension and right ventricular dysfunction are major prognostic markers in HF and valve disease.20-23 Santiago-Vacas et al.24 assessed the long-term trajectories of systolic pulmonary artery pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE) and TAPSE/SPAP ratio in 1557 HF patients. These parameters were independent determinants of outcomes and increasing SPAP and declining TAPSE and TAPSE/SPAP ratio in the preceding period were associated with higher mortality. Sodium–glucose co-transporter type 2 inhibitors were found to reduce HF events25, 26 and are studied in major clinical trials in HF patients.27-30 A pre-specified analysis from the Dapagliflozin And Prevention of Adverse-outcomes in HF (DAPA-HF) study showed the lack of interaction between LVEF and the beneficial effect of dapagliflozin on outcomes in HFrEF patients.31 Breast cancer therapies can lead to late-onset HF.32 A pro-inflammatory state, detected by biomarker measurements, can cause cardiac dysfunction even 10 years after treatment in breast cancer survivors.33 Heart rate is a major prognostic marker, especially in patients in sinus rhythm.34, 35 Anker et al.36 identified elevated resting heart rate as associated with increased levels of HF biomarkers and poor outcomes in treatment-naïve cancer patients.

Relations between circulating and myocardial fibrosis-linked microRNAs with left ventricular reverse remodeling in dilated cardiomyopathy.

Left ventricular reverse remodeling (LVRR) determines clinical status and outcomes in dilated cardiomyopathy (DCM). The extent of myocardial fibrosis is connected to the systolic function of the heart. The recent discovery of the contribution of microRNAs (miRs) to the regulation of cardiac remodeling, LVRR and fibrosis warrants exploration. The aim of the study was to examine the predictive value of circulating and myocardial miR expression for LVRR in DCM. Seventy consecutive DCM patients (age 48 ±12.1 years, 90% male, ejection fraction (EF) 24.4% ±7.4%) were included in the study. At baseline, all patients underwent clinical assessment, echocardiography, venous blood sampling, and right ventricular endomyocardial biopsy. Circulating and myocardial miRs (miR-21, -26, -29, -30, -133a, and -423) were measured with quantitative real-time polymerase chain reaction (qRT-PCR). LVRR was defined as an increase in EF ≥ 10%, accompanied by a decrease in left ventricle end-diastolic diameter (LVEDd) ≥10% or LVEDd ≤ 33 mm/m2 between baseline and 3-month follow-up. At the 3-month follow-up, 4 patients had died and 3 patients had incomplete data. The remaining patients were divided according to the presence of LVRR into LVRR-present (n = 32, 51%) and LVRR-absent (n = 31, 49%) groups. Out of all the circulating and tissue miRs under study, only myocardial expression of miR-133a significantly differed between the LVRR-present and LVRR-absent group (1.22 (0.47-1.90) vs 0.61 (0.25-0.99) ΔCq, respectively, p < 0.01). miR-133a was found to be a significant LVRR predictor in unadjusted (odds ratio (OR) = 2.81 (1.23-6.40), p < 0.05) and adjusted for duration of disease, left ventricle end-diastolic (LVED) volume (LVEDvol), hs-troponin-T, and NT-proBNP (OR = 5.20 (1.13-24.050, p < 0.05) models. From all of the circulating and tissue miRs, only myocardial miR-133a showed increased expression in LVRR-present patients and was found an independent LVRR predictor. This indicates a link between miR-133 and cardiac remodeling in DCM.

Predictors of left ventricular remodelling in patients with dilated cardiomyopathy - a cardiovascular magnetic resonance study.

There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling. Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P=0.02). Baseline myocardial strain (P=0.39 global longitudinal strain), interstitial myocardial fibrosis (P=0.41), replacement myocardial fibrosis (P=0.25), and right ventricular contractile reserve (P=0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r=-0.22, P=0.23) or baseline LVEF (r=0.07, P=0.62). Men were more likely to experience adverse LV remodelling (P=0.01) but age (P=0.88) and disease-modifying heart failure medication (beta-blocker, P=0.28; angiotensin-converting enzyme inhibitor, P=0.92) did not predict follow-up LVEF. Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

Relationships between left ventricular geometry and remodeling in dilated cardiomyopathy.

Since left ventricular reverse remodeling (LVRR) and sphericity index (SI) are correlated with DCM patients' survival, we attempted to establish the relationship between LVRR, SI and left ventricle (LV) dimensions. In 70 DCM patients, we measured EF, LV transverse (sLVd) and longitudinal (lLVd) diameters at hospital admission, then after 3 and 12 months. SI was assessed thus: SI=sLVd/lLVd. LVRR was present in 32 patients (52%). SI measurements were similar in LVRR-present and -absent groups at baseline (0.71 vs. 0.70) and differed after 3 and 12 months (0.61 vs. 0.72, P<0.005; 0.59 vs. 0.73, P<0.001; respectively). During 12 months, SI and sLVd decreased in the LVRR-present (0.71 vs. 0.61 vs. 0.59, P<0.05; 5.75 vs. 5.00 vs. 4.82 cm, P<0.001; respectively) and increased in the LVRR-absent cohort (0.70 vs. 0.72 vs. 0.73, P<0.001; 6.01 vs. 6.15 vs. 6.67, P<0.001; respectively). lLVd remained stable (8.23 vs. 8.16 vs. 8.38cm; 8.66 vs. 8.85 vs. 9.13 cm; respectively). SI was significantly correlated with sLVd but not with lLVd. At 3-month follow-up, SI (P<0.005, OR=14000 [95% CI: 5 - 3.9*107]) was found to be a significant LVRR predictor via univariate logistic regression. To summarize, changes in sLVd are crucial for changes in LV geometry, whereas lLVd has a negligible effect on this process. The presence of LVRR was not always associated with an improvement in SI and its absence with increase in SI. Since the assessment of SI is less complex than LVRR, SI as a significant LVRR predictor can be useful part of a regular echocardiography examination.

Identification of new biophysical markers for pathological ventricular remodelling in tachycardia-induced dilated cardiomyopathy.

Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia‐induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up‐regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60‐fold vs 1.61‐fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles – indicating structural changes in the tissue architecture – and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis.

Role of blocking ADAM10 hydrolysis site on N-cadherin by single-chain antibody in ventricular remodeling.

The present study aimed to investigate the roles of the hydrolytic process of N-cadherin by A disintegrin and metalloproteases 10 (ADAM10) in sustaining myocardial structure and integrity, and discuss the mechanisms of ventricular remodeling in dilated cardiomyopathy (DCM). Single chain variable fragment antibody (ScFv) with the ability to specifically block the ADAM10 hydrolysis site of N-cadherin was designed and constructed. Western blot analysis and flow cytometry were used to detect the expression of N-cadherin and its C-terminal fragment 1 (CTF1) on cardiomyocytes, and cells were also subjected to a cell adhesion assay. Furthermore, in a rat model of dilated cardiomyopathy (DCM), the effects of intracardiac injection of the recombinant adenovirus on cardiac structure and contractile function were observed by hematoxylin and eosin staining and color Doppler echocardiography. The recombinant ScFv-expressing adenoviral plasmid with the ability to block the ADAM10 hydrolysis site on N-cadherin was successfully constructed and efficiently transfected into H9C2 cells. After transfection, N-cadherin protein expression was significantly increased, CTF1 protein was significantly decreased and the adhesion capability of myocardial cells was significantly improved. In the in vivo experiment, N-cadherin expression was significantly increased in the treatment group compared with that in the model group, and the structure and function of the heart were significantly improved. In conclusion, blocking of the ADAM10 hydrolysis site on N-cadherin by ScFv increased N-cadherin expression and improved ventricular remodeling. The present study provided experimental evidence for a novel approach for the treatment and prevention of DCM.