Dilated Cardiomyopathy Patients Research Articles

A-007 Cardiomyocyte-monocyte Cross-talk Exploits Cellular Stress Pathways Leading to Myocyte Apoptosis in Dilated Cardiomyopathy of Idiopathic Origin

Abstract Background Dilated cardiomyopathy (DCM) is the most prevalent form of cardiovascular diseases (CVDs) results in dilation and disruption of pumping mechanism of heart. Most strikingly, about 50% DCM cases do not have any identified aetiology, hence known as idiopathic DCM (IDCM). The aim of this study is to investigate major inflammatory markers and cellular stress pathways in the circulating leukocytes and cardiomyocytes to find out the cross-talk between these cell types in vitro condition by mimicking the in vivo inflammatory milieu. Methods The study is divided into two parts, first part comprising patient study and the second part is the in vitro cell culture based mechanistic study. 50 IDCM patients and 30 age and sex matched control subjects were recruited from our in-house Ramakrishna Mission Seva Pratishthan (RKMSP) hospital based on their NYHA discomfort criteria followed by intra thoracic echocardiography. Exclusively the IDCM subjects were selected for this study. Blood was collected from the patients for biochemical and inflammatory parameters and to isolate PBMCs. mRNA and protein expressions were studied by real time PCR and immunoblotting respectively. H9C2 cardiomyocyte cells alone or with LPS-activated THP-1 monocyte/macrophage line were co-cultured in presence of the major inflammatory cytokines in the same in vivo concentration as found in the IDCM patients in presence or absence of ER stress agonist or antagonists. Immunofluorescence, RT-PCR and immunoblotting were done for markers specific to myocyte stress, inflammation and apoptosis. Results Inflammatory and cardiac blood biomarkers NLR, hs-CRP, IL-6, pro-BNP and troponin-I were found to be significantly high (P < 0.05) in IDCM. Subsequently, the mRNA expressions of pro-inflammatory genes TNF-α (2.6 fold), IFN-γ (10.2 fold), IL-1β (8.5 fold) and NF-κβ (2.427 fold) were all significantly increased (P < 0.05). Looking into the cellular stress pathways, we further found upregulations of antioxidant genes SOD (2.59 fold) and catalase (2.17 fold) and ER stress markers Grp78 (2.794 fold), CHOP (3.407 fold), IRE1-α (2.104 fold) and ATF-6 (40.618 fold) mRNA expression in the PBMCs. When we stimulated the H9C2 cardiomyocytes with IL-1B and TNF-α at comparable conc. as found in the IDCM patients, the ER stress and inflammation were observed. Further, when we co-cultured these H9C2 with LPS stimulated THP-1 macrophages an exaggerated inflammation and myocyte stress was observed that led to apoptosis of the cells. Interestingly using ER stress inhibitor TUDCA, remarkably blocked the apoptosis and promotes cell survival. Conclusion Our results showed that a systemic inflammation caused by stressed PBMCs leads to cardiac deterioration and dilation in the unknown DCM cases. So far we have established that an exaggerated inflammation induce the circulating PBMCs to migrate and infiltrate the cardiac musculature where they induce oxidative stress and ER stress to the cardiomyocytes leading to apoptosis of the later. In long run these unknown forms of dilated cardiomyopathy patients suffer from a dilated heart due to a decline in the myocyte population. Our findings may warrant for a treatment strategy that alleviate the intracellular stress of the circulating leukocytes and cardiomyocytes to minimize the inflammatory changes of the heart.

TCAP gene is not a common cause of cardiomyopathy in Iranian patients

BackgroundHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most frequent cardiomyopathies that cause acute heart failure and sudden cardiac death. Previous genetic reports have shown that pathogenic variants of genes encoding Z-disc components such as telethonin protein (TCAP) are the primary cause of DCM and HCM.MethodsThis study was the first investigation on the TCAP gene among the Iranian cardiomyopathies population wherein the TCAP gene was analyzed in 40 unrelated patients (17 females and 23 males) who were clinically diagnosed with HCM and DCM. In addition, we conducted a thorough review of all published articles and the databases that were the first to report novel pathogenic or likely pathogenic variants the in TCAP gene.ResultsIn the cohort of this study, we identified only one intronic variant c.111-42G > A in one of the HCM patients that were predicted as polymorphism by in-silico analysis. Moreover, a total of 44 variants were reported for the TCAP gene in the literature where a majority of mutations were found to be missense. Pathogenic mutations in TCAP may cause diseases including limb-girdle muscular dystrophy 2G (LGMD-2G), DCM, HCM, intestinal pseudo-obstruction, and telethonin deficiency. However, a large number of affected patients were clinically diagnosed with limb-girdle 2G compared to other presenting phenotypes.DiscussionThese findings suggest that the TCAP gene pathogenic mutations might not be a common cause of cardiomyopathies among Iranian patients. These gene disease-causing mutations may cause various manifestations, but it has a high prevalence among LGMD-2G, HCM, and DCM patients.

Echocardiography-based machine learning algorithm for distinguishing ischemic cardiomyopathy from dilated cardiomyopathy

BackgroundMachine learning (ML) can identify and integrate connections among data and has the potential to predict events. Heart failure is primarily caused by cardiomyopathy, and different etiologies require different treatments. The present study examined the diagnostic value of a ML algorithm that combines echocardiographic data to automatically differentiate ischemic cardiomyopathy (ICM) from dilated cardiomyopathy (DCM).MethodsWe retrospectively collected the echocardiographic data of 200 DCM patients and 199 ICM patients treated in the First Affiliated Hospital of Guangxi Medical University between July 2016 and March 2022. All patients underwent invasive coronary angiography for diagnosis of ICM or DCM. The data were randomly divided into a training set and a test set via 10-fold cross-validation. Four ML algorithms (random forest, logistic regression, neural network, and XGBoost [ML algorithm under gradient boosting framework]) were used to generate a training model for the optimal subset, and the parameters were optimized. Finally, model performance was independently evaluated on the test set, and external validation was performed on 79 patients from another center.ResultsCompared with the logistic regression model (area under the curve [AUC] = 0.925), neural network model (AUC = 0.893), and random forest model (AUC = 0.900), the XGBoost model had the best identification rate, with an average sensitivity of 72% and average specificity of 78%. The average accuracy was 75%, and the AUC of the optimal subset was 0.934. External validation produced an AUC of 0.804, accuracy of 78%, sensitivity of 64% and specificity of 93%.ConclusionsWe demonstrate that utilizing advanced ML algorithms can help to differentiate ICM from DCM and provide appreciable precision for etiological diagnosis and individualized treatment of heart failure patients.

GLUT1 Mediates the Metabolic Reprogramming and Inflammation of CCR2$^+$ Monocytes/Macrophages from Patients with DCM.

Macrophages expressing CC chemokine receptor 2 (CCR2) possess characteristics and performance akin to M1 polarized macrophages, which promote inflammation. Advanced heart failure (HF) patients with higher abundance of CCR2+ macrophages are more likely to experience adverse remodeling. The precise mechanism of CCR2+ macrophages in how they affect the progression of dilated cardiomyopathy remains unknown. Cardiac biopsy samples from dilated cardiomyopathy patients (DCM) were used for immunohistochemistry and immunofluorescence staining. PCR is employed to identify the IL-1β, IL-6, TNF-α, TGF-β, MMP2, MMP9, PKM1, PKM1, GLUT1, GLUT2, GLUT3, GLUT4, PDK1, PFKFB3, PFK1 and HK2 mRNA expression of CCR2+ monocytes/macrophages from the peripheral blood of DCM patients. Seahorse was used to evaluate the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of CCR2+ monocytes/macrophages. 2-DG was used to simulate a lack of glucose. Lentivirus containing GLUT1 inhibitory sequence was used to knockdown GLUT1 gene expression of CCR2+ monocytes/macrophages. Western Blot and immunofluorescence staining was used to evaluate the expression of NLRP3. Immunostaining results of cardiac biopsy tissue from dilated cardiomyopathy (DCM) patients demonstrated that the progression to HF was associated with an increase in the number of CCR2+ macrophages. PCR results demonstrated that CCR2 monocytes and macrophages derived from the blood of DCM patients expressed elevated levels of inflammatory factors and up regulation of glycolysis related genes. In addition, OCR and glucose uptake experiments confirmed that increased glucose uptake of these cells was associated with greater inflammation and correlated with a worsening of cardiac function. limiting the glucose supply to CCR2+ monocytes and macrophages, or suppressing the activity of glucose transporter 1 (GLUT1) could reduce inflammation levels. These results suggest that CCR2+ monocytes and macrophages rely on metabolic reprogramming to trigger inflammatory response and contribute to myocardial injury and the progression of DCM.

Characteristics of the right ventricle in left ventricular noncompaction with reduced ejection fraction in the light of dilated cardiomyopathy.

Reports of left ventricular noncompaction (LVNC) rarely include descriptions of the right ventricle (RV). This study aimed to describe the characteristics of the RV in LVNC patients with reduced LV function (LVNC-R) compared with patients with dilated cardiomyopathy (DCM) and subjects with LVNC with normal left ventricular ejection fraction (LV-EF) (LVNC-N). Forty-four LVNC-R patients, 44 LVNC-N participants, and 31 DCM patients were included in this retrospective study (LV-EF: LVNC-R: 33.4±10.2%; LVNC-N: 65.0±5.9%; DCM: 34.6±7.9%). Each group was divided into two subgroups by the amount of RV trabeculation. There was no difference in the RV-EF between the groups, and the RV trabecular mass correlated positively with the RV volume and negatively with the RV-EF in all the groups. All the measured parameters were comparable between the groups with decreased LV function. The hypertrabeculated RV subgroups showed significantly higher RV volumes and lower RV-EF only in the decreased-LV-function groups. The correlation of LV and RV trabeculation was observed only in the LVNC-N group, while LV trabeculation correlated with RV volumes in both noncompacted groups. Both decreased-LV-function groups had worse RV strain values than the LVNC-N group; however, RV strain values correlated with RV trabeculation predominantly in the LVNC-R group. The presence and characteristics of RV hypertrabeculation and the correlations between LV trabeculation and RV parameters raise the possibility of RV involvement in noncompaction; moreover, RV strain values might be helpful in the early detection of RV function deterioration.

Predictive value for mortality of left ventricular wall thickness in dilated cardiomyopathy.

The purpose of this study was to explore the predictive value of wall thickness measured by cardiac magnetic resonance (CMR) for all-cause mortality in dilated cardiomyopathy (DCM) patients. DCM patients who underwent CMR and completed the regular follow-up were included in this study. The left ventricular end-diastolic diameter (LVDd), left ventricular end-diastolic volume (LVEDV), left ventricular posterior wall thickness (PWT), interventricular septum thickness (IVST), left ventricular ejection fraction, and left ventricular mass (LVM) were measured by CMR. The presence and extent of late gadolinium enhancement (LGE) were also assessed. The relative posterior wall thickness (RWTPW ) and relative interventricular septum wall thickness (RWTIVS ) were defined by the following equations: RWTPW =(2×PWT)/LVDd, and RWTIVS =(2×IVST)/LVDd. All patients received regular telephone and outpatient follow-up. The primary endpoint was all-cause mortality. A total of 161 patients were enrolled in this study, including 126 (78.3%) males. The mean age was 52.3±13.6years. During the median follow-up of 47months (interquartile range 32-57months), 41 (24.8%) patients died. Compared with the non-death group, LVDd (75.2±11.9 vs. 70.5±8.8mm; P=0.025) was greater in the death group, while PWT [5.2mm (3.7-6.8) vs. 6.9mm (5.3-8.6); P<0.001], IVST [8.2mm (6.5-9.5) vs. 9.3mm (7.4-10.5); P=0.005], RWTPW [0.15 (0.11-0.19) vs. 0.20 (0.15-0.25); P<0.001], RWTIVS [0.22 (0.17-0.26) vs. 0.26 (0.22-0.31); P<0.001], and LVM/LVEDV ratio (0.5±0.2 vs. 0.7±0.2g/mL; P<0.001) were lower. The presence of LGE [LGE(+)] was more frequent in the death group (75.6% vs. 58.3%; P=0.048). However, the LGE extent was not significantly different between the two groups [4 (1-7) vs. 2 (0-6); P=0.096]. Multivariate Cox regression analysis showed that PWT [hazard ratio (HR) 0.086, 95% confidence interval (CI) 0.665-0.976; P<0.05] and RWTPW (HR 0.001, 95% CI 0.000-0.502; P<0.05) were independent predictors of all-cause death. In contrast, IVST, RWTIVS , and the presence of LGE were not clearly associated with death. PWT measured by CMR is an independent predictor of all-cause mortality in DCM patients. However, there was no significant correlation between septum wall thickness and mortality.

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients.

Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria. This study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23-316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator. Panel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.

Quality of life and societal costs in patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a major cause of heart failure impairing patient wellbeing and imposing a substantial economic burden on society, but respective data are missing. This study aims to measure the quality of life (QoL) and societal costs of DCM patients. A cross-sectional evaluation of QoL and societal costs of DCM patients was performed through the 5-level EuroQol and the Medical Consumption Questionnaire and Productivity Cost Questionnaire, respectively. QoL was translated into numerical values (i.e. utilities). Costs were measured from a Dutch societal perspective. Final costs were extrapolated to 1 year, reported in 2022 Euros, and compared between DCM severity according to NYHA classes. A total of 550 DCM patients from the Maastricht cardiomyopathy registry were included. Mean age was 61 years, and 34% were women. Overall utility was slightly lower for DCM patients than the population mean (0.840vs. 0.869, P=0.225). Among EQ-5D dimensions, DCM patients scored lowest in 'usual activities'. Total societal DCM costs were €14 843 per patient per year. Cost drivers were productivity losses (€7037) and medical costs (€4621). Patients with more symptomatic DCM (i.e. NYHA class III or IV) had significantly higher average DCM costs per year compared to less symptomatic DCM (€31 099vs. €11 446, P< 0.001) and significantly lower utilities (0.631vs. 0.883, P< 0.001). DCM is associated with high societal costs and reduced QoL, in particular with high DCM severity.

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.

Circulating and Cardiac Tissue miRNAs in Children with Dilated Cardiomyopathy.

microRNAs (miRs) are small non-coding single-stranded RNAs that regulate gene expression. We previously evaluated expression of miRs in the cardiac tissue of children with dilated cardiomyopathy (DCM) using miRNA-seq. However, a comparative analysis of serum and cardiac miRs has not been performed in this population. The current study aimed to evaluate miR levels in the serum of pediatric DCM patients compared to healthy non-failing (NF) donor controls and investigate the association between miR levels in tissue and sera from the same pediatric DCM patients. Defining the relationship between serum and tissue miRs may allow the use of circulating miRs as surrogate markers of cardiac miRs. miR levels were investigated through miR-array in sera [n = 10 NF, n = 12 DCM] and miR-seq in tissue (n = 10 NF, n = 12 DCM). Pathway analysis was investigated using the miR enrichment analysis and annotation tool (miEAA) for the five miRs commonly dysregulated in the sera and tissue of pediatric DCM patients. Functional analysis of miRs commonly dysregulated in the sera and tissue of pediatric DCM patients suggests altered pathways related to cell growth, differentiation and proliferation, inflammation, mitochondrial function, and metabolism. These findings suggest that circulating miRs could reflect altered levels of cardiac tissue miRs.

β1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues.

A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the β1-adrenergic receptor (β1AR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). Β1AR-Aabs have agonist effects inducing desensitization of β1AR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. Β1AR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including β1AR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of β1AR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with β1AR-AAb better responded to β-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of β1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.

Cardiogenic Shock in Idiopathic Dilated Cardiomyopathy Patients: Red Flag for Myocardial Decline

Idiopathic dilated cardiomyopathy (IDCM) is one of the most common forms of nonischemic cardiomyopathy worldwide, possibly leading to cardiogenic shock (CS). Despite this heavy burden, the outcomes of CS in IDCM are poorly reported. Based on a large registry of unselected CS, our aim was to shed light on the 1-year outcomes after CS in patients with and without IDCM. FRENSHOCK was a prospective registry including 772 patients with CS from 49 centers. The 1-year outcomes (rehospitalizations, mortality, heart transplantation [HTx], ventricular assist devices [VAD]) were analyzed and adjusted on independent predictive factors. Within 772 CS included, 78 occurred in IDCM (10.1%). Patients with IDCM had more frequent history of chronic kidney failure and implantable cardioverter-defibrillator implantation. No difference was found in 1-month all-cause mortality between groups (28.2 vs 25.8%for IDCM and others, respectively; adjusted hazard ratio 1.14 [0.73 to 1.77], p=0.57). Patients without IDCM were more frequently treated with noninvasive ventilation and intra-aortic balloon pump. At 1 year, IDCM led to higher rates of death or cardiovascular rehospitalizations (adjusted odds ratio 4.77 [95% confidence interval 1.13 to 20.1], p=0.03) and higher rates of HTx or VAD for patients aged <65 years (adjusted odds ratio 2.68 [1.21 to 5.91], p=0.02). In conclusion, CS in IDCM is a very common scenario and is associated with a higher rate of 1-year death or cardiovascular rehospitalizations and a more frequent recourse to HTx or VAD for patients aged <65 years, encouraging the consideration of it as a red flag for myocardial decline and urging for a closer follow-up and earlier evaluation for advanced heart failure therapies.

Coronary Angiography in Dilated Cardiomyopathy Patients Presenting to Cardiac Hospital at Lumbini Province Nepal

INTRODUCTION Dilated cardiomyopathy is one of the common cause of patients presenting with symptoms of heart failure. It is often treated as respiratory disease in the absence of specific evaluation. We wanted to evaluate the presence of coronary artery disease in dilated cardiomyopathy patients. MATERIAL AND METHODS It was a prospective observational study conducted at Gautam Buddha Community Heart Hospital. One hundred sixty patients with the diagnosis of dilated cardiomyopathy were evaluated with coronary angiography. RESULTS Distribution of patients was males 68.1% and females 31.9%. Most patients (61.2%) were in the age group 45 to 65 years. Dyspnea (80.6%), fatigue (25%), cough (20%), chest discomfort (16.9%), edema (15%) and palpitation (11.9%) were common symptoms. Majority of patients were smoker 41.9%. Coronary artery disease was found in 44.4% with significant stenosis in36.3%. Among the patients with significant coronary artery stenosis two vessel disease was present in 54%, one vessel disease in 32% and three vessel disease in 14%. CONCLUSION Coronary artery disease was frequently present in dilated cardiomyopathy patients. Optimization of management becomes easier with thorough evaluation of DCM patients including coronary angiography.

Right ventricular systolic function and mechanical dyssynchrony in ischemic or non-ischemic dilated cardiomyopathy: A speckle-tracking study.

This study assessed RV dyssynchrony (irrespective to QRS duration) and RV systolic function in non-ischemic dilated cardiomyopathy (NIDCM) versus ischemic dilated cardiomyopathy (IDCM) patients by using different echo-Doppler modalities. Eighty-five cases (48 patients with DCM [whether ischemic or non-ischemic] and 37 age-matched healthy controls) were studied. Conventional echo-Doppler study, tissue Doppler (TDI), and speckle tracking (STE) were carried out to measure LV and RV systolic function. Time-to-peak negative longitudinal strain at the four RV sites were assessed by TDI derived strain and 2D speckle tracking. Patients with DCM (whether ischemic or non-ischemic) had significantly lower fractional area change, RV tricuspid annular systolic velocity (p<.001 for both), tricuspid annular plane systolic excursion (p=.01), RV-GLS whether TDI or 2D derived (p<.001). Twenty-nine patients (60%) showed right intraventricular delay (RV4SD>60ms). The RV-dyssynchrony index was negatively correlated to %FAC (r=-.362, p=.01), RV Sm (r=-.312, p=.04), and 2D-RV GLS (r=-.305, p=.05). Insignificant higher RV-dysynchrony index was detected in NIDCM compared to IDCM group; however, the basal septal segment was significantly delayed in dilated group. More impaired RV systolic function was detected in ischemic group. 2D STE and TDI showed a significant correlation in the assessment of the right-intraventricular delay (p=.001). Right-intraventricular dyssynchrony are detectable in patients with dilated cardiomyopathy (whether ischemic or non-ischemic) with a higher statistically insignificant value in non-ischemic group by using tissue Doppler imaging and 2D speckle tracking. More impairment of the RV systolic function was noticed in the ischemic group. Impaired RV systolic function was associated with right intraventricular delay.

Biomarkers of Collagen Metabolism Are Associated with Left Ventricular Function and Prognosis in Dilated Cardiomyopathy: A Multi-Modal Study.

Collagen cross-linking is a fundamental process in dilated cardiomyopathy (DCM) and occurs when collagen deposition exceeds degradation, leading to impaired prognosis. This study investigated the associations of collagen-metabolism biomarkers with left ventricular function and prognosis in DCM. DCM patients who underwent endomyocardial biopsy, blood sampling, and cardiac MRI were included. The primary endpoint included death, heart failure hospitalization, or life-threatening arrhythmias, with a follow-up of 6 years (5-8). In total, 209 DCM patients were included (aged 54 ± 13 years, 65% male). No associations were observed between collagen volume fraction, circulating carboxy-terminal propeptide of procollagen type-I (PICP), or collagen type I carboxy-terminal telopeptide [CITP] and matrix metalloproteinase [MMP]-1 ratio and cardiac function parameters. However, CITP:MMP-1 was significantly correlated with global longitudinal strain (GLS) in the total study sample (R = -0.40, p < 0.0001; lower CITP:MMP-1 ratio was associated with impaired GLS), with even stronger correlations in patients with LVEF > 40% (R = -0.70, p < 0.0001). Forty-seven (22%) patients reached the primary endpoint. Higher MMP-1 levels were associated with a worse outcome, even after adjustment for clinical and imaging predictors (1.026, 95% CI 1.002-1.051, p = 0.037), but CITP and CITP:MMP-1 were not. Combining MMP-1 and PICP improved the goodness-of-fit (LHR36.67, p = 0.004). The degree of myocardial cross-linking (CITP:MMP-1) is associated with myocardial longitudinal contraction, and MMP-1 is an independent predictor of outcome in DCM patients.

The microtubule signature in cardiac disease: etiology, disease stage, and age dependency

Employing animal models to study heart failure (HF) has become indispensable to discover and test novel therapies, but their translatability remains challenging. Although cytoskeletal alterations are linked to HF, the tubulin signature of common experimental models has been incompletely defined. Here, we assessed the tubulin signature in a large set of human cardiac samples and myocardium of animal models with cardiac remodeling caused by pressure overload, myocardial infarction or a gene defect. We studied levels of total, acetylated, and detyrosinated α-tubulin and desmin in cardiac tissue from hypertrophic (HCM) and dilated cardiomyopathy (DCM) patients with an idiopathic (n = 7), ischemic (n = 7) or genetic origin (n = 59), and in a pressure-overload concentric hypertrophic pig model (n = 32), pigs with a myocardial infarction (n = 28), mature pigs (n = 6), and mice (n = 15) carrying the HCM-associated MYBPC32373insG mutation. In the human samples, detyrosinated α-tubulin was increased 4-fold in end-stage HCM and 14-fold in pediatric DCM patients. Acetylated α-tubulin was increased twofold in ischemic patients. Across different animal models, the tubulin signature remained mostly unaltered. Only mature pigs were characterized by a 0.5-fold decrease in levels of total, acetylated, and detyrosinated α-tubulin. Moreover, we showed increased desmin levels in biopsies from NYHA class II HCM patients (2.5-fold) and the pressure-overload pig model (0.2–0.3-fold). Together, our data suggest that desmin levels increase early on in concentric hypertrophy and that animal models only partially recapitulate the proliferated and modified tubulin signature observed clinically. Our data warrant careful consideration when studying maladaptive responses to changes in the tubulin content in animal models.Graphical

Anesthetic Management of Patients with Dilated Cardiomyopathy Undergoing Noncardiac Surgery.

Dilated cardiomyopathy (DCM), a primary myocardial disease, is characterized by dilation of the left or both ventricles and systolic dysfunction with or without congestive heart failure. DCM per se is a well-recognized risk factor for sudden cardiac death and poor surgical outcomes following noncardiac surgery. Surgical trauma/stress represents unique challenges for DCM patient management. Unfortunately, there is a big knowledge gap in managing DCM patients undergoing non-cardiac surgery. Therefore, the aim of our review is to provide basic facts and current advances in DCM, as well as a practical guideline to perioperative care providers, for the management of surgical patients with DCM, who are quite rare compared with the general surgical population. This review summarizes recent advances in the medical management of DCM as well as perioperative assessment and management strategies for DCM patients undergoing noncardiac surgery. Optimal surgical outcomes depend on multiple-disciplinary care to minimize perioperative cardiovascular disturbances.

Clonal Hematopoiesis Has Prognostic Value in Dilated Cardiomyopathy Independent of Age and Clone Size

BackgroundClonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation and thereby impact the disease course in atherosclerosis and ischemic heart failure. CH of indeterminate potential refers to a variant allele frequency (VAF) (a marker for clone size) in blood of ≥2%. The impact of CH clones—including small clone sizes (VAF <0.5%)—in nonischemic dilated cardiomyopathy (DCM) remains largely undetermined. ObjectivesThe authors sought to establish the prognostic impact of CH in DCM including small clones. MethodsCH is determined using an ultrasensitive single-molecule molecular inversion probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were analyzed using receiver-operating characteristic curve–optimized VAF cutoff values. ResultsA total of 520 DCM patients have been included. A total of 109 patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 <0.5%. The median follow-up duration was 6.5 years (IQR: 4.7-9.7 years). DCM patients with CH have a higher risk of cardiac death (HR: 2.33 using a VAF cutoff of 0.36%, 95% CI: 1.24-4.40) and all-cause mortality (HR: 1.72 using a VAF cutoff of 0.06%, 95% CI: 1.10-2.69), independent of age, sex, left ventricular ejection fraction, and NYHA functional classification. ConclusionsCH predicts cardiac death and all-cause mortality in DCM patients with optimal thresholds for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant, independent of clone size in patients with DCM.

Nonspecific intraventricular conduction delay predicts the prognosis of dilated cardiomyopathy

PurposeLeft bundle branch block (LBBB) has been confirmed to be independently associated with adverse outcomes in dilated cardiomyopathy (DCM). However, prognostic data on nonspecific intraventricular conduction delay (NSIVCD) are still limited and conflicting. We aimed to evaluate the prognosis of DCM with NSIVCD.MethodsA total of 548 DCM patients who underwent cardiovascular magnetic resonance imaging (CMR) from January 2016 to December 2017 were consecutively enrolled. The cohort was divided into four groups: 87 with LBBB, 27 with RBBB, 61 with NSIVCD, and 373 without intraventricular conduction delay (IVCD). After a median follow-up of 58 months (interquartile range: 47–65), 123 patients reached the composite endpoints, which included cardiovascular death, heart transplantation, and malignant arrhythmias. The associations between different patterns of IVCD and the outcomes of DCM were analysed by Kaplan‒Meier analysis and Cox proportional hazards regression analysis.ResultsOf 548 DCM patients, there were 398 males (72.6%), and the average age was 46 ± 15 years, ranging from 18 to 76 years. In Kaplan‒Meier analysis, patients with NSIVCD and LBBB showed higher event rates than patients without IVCD, while RBBB patients did not. By multivariate Cox regression analysis, LBBB, NSIVCD, NYHA class, left ventricular ejection fraction (LVEF), indexed left ventricular end-diastolic diameter (LVEDDI), percentage of late gadolinium enhancement mass (LGE%), and global longitudinal strain (GLS) were found to be independently associated with the outcomes of DCM.ConclusionsIn addition to LBBB, NSIVCD was an unfavourable prognostic marker in patients with DCM, independent of LVEDDI, NYHA class, LVEF, LGE%, and GLS.

Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.

Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.