Dilated Cardiomyopathy Patients Research Articles

Feasibility and reproducibility of cardiovascular magnetic resonance-feature tracking for quantitative right atrial function in dilated cardiomyopathy patients.

The importance of right heart assessment in dilated cardiomyopathy (DCM) is increasingly recognized. The development of cardiovascular magnetic resonance-feature tracking (CMR-FT) has provided a novel approach to quantify myocardial deformation and evaluate cardiac function. In this study, we aimed to evaluate the feasibility and reproducibility of CMR-FT for the quantitative derivation of right atrial (RA) strain and strain rate (SR) in patients with DCM. A total of 68 DCM patients (84% male; aged 50.6±13.2 years) and 58 healthy controls (81% male; aged 48.4±11.2 years) were retrospectively enrolled from September 2018 to August 2022 at the First Affiliated Hospital of Zhejiang Chinese Medical University and Shenzhen Clinical Medical College of Guangzhou University of Chinese Medicine. RA reservoir, conduit, and booster strain (εs, εe, and εa) and peak positive, peak early negative, and peak late negative SR (SRs, SRe, and SRa) were measured using CMR-FT and compared between 2 groups using Student's t-test. Intra- and inter-observer reproducibility was evaluated using intraclass correlation coefficients (ICC) and Bland-Altman plots. Compared to healthy controls, DCM patients showed significantly lower RA strain (εs: 19.7%±9.0% vs. 44.4%±9.7%; εe: 7.9%±5.3% vs. 25.8%±8.6%; εa: 11.8%±6.2% vs. 18.6%±5.1%, all P<0.001) and SR (SRs: 1.17±0.48 vs. 1.92±0.62 s-1; SRe: -0.85±0.56 vs. -1.94±0.63 s-1; SRa: -1.39±0.71 vs. -2.01±0.65 s-1, all P<0.001). There was no significant difference in RA maximum volume index between the 2 groups. Simple linear regression analysis demonstrated a significant correlation between N-terminal B-type natriuretic peptide (NT-proBNP), RA emptying fraction passive (RAEF passive), and RA εe [(NT-proBNP and εe): r=-0.48, P<0.001, 95% confidence interval (CI): -0.64 to -0.26; and (RAEF passive and εe): r=0.41, P=0.001, 95% CI: 0.22 to 0.56, respectively] in DCM patients. Intra- and inter-observer reproducibility was excellent (all ICCs >0.85) for RA deformation measurements. CMR-FT is a promising, noninvasive approach for the quantitative assessment of RA phasic function in patients with DCM. DCM patients exhibit impaired RA reservoir, conduit, and booster pump function prior to visible RA enlargement.

Embarazo en mujeres portadoras de variantes genéticas de miocardiopatía dilatada

Introduction and objectivesLimited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. MethodsWe studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. ResultsA total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. ConclusionsCardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Sarcoplasmic reticulum (SR)-mitochondria tethering is lost in human heart failure

Sarcoplasmic reticulum (SR)-mitochondria (SR-mito) tethering facilitates communication between these organelles and regulates many physiological processes critical for cardiomyocyte function. Recent evidence suggests that alterations in SR-mito tethering impacts cardiac metabolism and calcium handling which contributes to cardiovascular pathologies, such as heart failure (HF). To characterize SR-mito apposition in cardiac disease we obtained electron microscopy (EM) images of individual cardiomyocytes freshly isolated from failing hearts explanted from ischemic (ICM), ischemic-dilated (ICM-DCM) and dilated cardiomyopathy (DCM) patients undergoing transplantation and nonfailing control hearts. Topographical EM analysis revealed a significant increase in the mean SR-Mito distance, as well as an increase in the minimum SR-mito distance (closest approximation of any single mitochondrion to SR) in ICM, ICM-DCM and DCM cardiomyocytes, compared to nonfailing controls. Results from the EM analysis also revealed that in DCM there was a decrease in mean mitochondrion perimeter in contact with the SR, as well as a decrease in SR in approximation with mitochondria at a distance &lt;50-nm. In agreement, nonfailing hearts had a greater length of outer mitochondrial membrane in close contact (&lt;20-nM) with the SR, as compared to failing cardiomyocytes. ICM and DCM cardiomyocytes displayed an overall reduction in mitochondrion perimeter and circularity, suggesting smaller and more fragmented mitochondria. Surprisingly, failing cardiomyocytes exhibited an overall increase in mitochondrial area compared to nonfailing controls. To define the molecular changes that may underlie loss of SR-mito tethering, we evaluated the expression of several proposed linkers. qPCR analysis of left ventricular samples revealed that mRNA expression of mitofusin 2 is significantly decreased in both hypertrophic cardiomyopathy (HCM) and DCM. Further, other proposed tethering components including FUNDC1, BAP31, DJ-1 and VAPB demonstrated decreased mRNA expression in HCM, DCM and ischemic HF samples, compared to nonfailing controls. IP3R1 displayed increased mRNA expression in HCM and DCM human HF samples, whereas IP3R2 and VDAC1 displayed increases in expression in HCM and ICM. These results highlight that transcriptional remodeling of the components mediating SR-mito tethering and communication may contribute to the observed structural changes in inter-organelle approximation in cardiomyocytes. These studies provide rationale for causal interrogation of the structural mechanisms regulating SR-mito communication in the context of HF progression. Fellowship in Biomedical Sciences, Lewis Katz School of Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dynamic LVEF Decline and Serum NT-proBNP and Uric Acid Levels before Heart Transplantation are Independent Predictors of Adverse Outcomes in Young Adult Patients with Dilated Cardiomyopathy.

The present study investigated the predictors of adverse outcomes in young adult patients with dilated cardiomyopathy (DCM) who underwent heart transplantation (HTx). Twenty-four young adult patients (aged 18-45 years) with DCM who underwent HTx in our hospital from January 2012 to December 2022 were included in this retrospective analysis. Pre- and post-HTx data were collected for echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP), and uric acid (UA). Data collected at the time of DCM diagnosis were designated as baseline data. Post-HTx assessments were conducted at 1 week and 3, 6, 12, and 36 months post-HTx. The primary endpoint was defined as any adverse event, including left ventricular ejection fraction (LVEF) 50% (n = 3), 50% increase in right or left ventricular diameter (n = 12), or death (n = 2). Patients were categorized into a non-adverse-event group (n = 12) or an adverse-event group (n = 12). Baseline NT-proBNP (p = 0.014) and UA (p = 0.012) were significantly higher in the adverse-event group than in the non-adverse-event group. Baseline NT-proBNP 7390 pg/mL (relative risk (RR) = 7.412, p = 0.046), UA 542 µmol/L (RR = 8.838, 95% confidence interval (95% CI) = 1.541-50.694, p = 0.014), and sustained reduction in LVEF ( 3%) over a 2-year pharmacological treatment prior to HTx (RR = 3.252, p = 0.046) were significantly associated with an increased risk of adverse events post-HTx. In young adult DCM patients post-HTx, heightened baseline levels of NT-proBNP and UA levels and a sustained reduction in LVEF over time prior to undergoing an HTx are significantly associated with an increased risk of adverse events post-HTx. Future studies are needed to observe whether individualized monitoring strategies could reduce the incidence of adverse events following HTx in these patients.

Analysis of long-term prognosis and risk factors in patients with dilated cardiomyopathy

Objective: To investigate the risk factors and long-term prognosis of major adverse cardiovascular events(MACEs) in patients with dilated cardiomyopathy (DCM). Methods: This study was a single-center retrospective cohort study. Clinical information from 300 patients with DCM hospitalized in Peking Union Medical College Hospital from April 2013 to April 2023 was collected. Based on echocardiography results, the patients were divided into two groups: isolated DCM and DCM with left ventricular non-compaction cardiomyopathy (LVNC). The MACEs, including major heart failure events, severe ventricular arrhythmias, and cardiovascular death, were recorded by outpatient or telephone follow-up. Univariate and multivariate Cox proportional hazard regression models were used to analyze the risk factors affecting the prognosis of patients with DCM. Kaplan-Meier curve and log-rank were used for survival analysis to compare the difference in the incidence of cardiovascular events between the two groups. Results: The included 300 DCM patients were (47.8±16.8) years old, with 197 males (65.7%), of which 237 (79.0%) were isolated DCM and 63 (21.0%) were DCM with LVNC. The follow-up time was 4.0 (1.9, 6.2) years. A total of 142 (47.3%) MACEs occurred, including 117 (39.0%) major heart failure events, 20 (6.7%) severe ventricular arrhythmia events, and 53 (17.7%) cardiovascular death events. Multivariate Cox proportional hazard regression analysis showed that increased left ventricular end-diastolic diameter (HR=1.21, 95%CI: 1.01-1.44, P=0.042), moderate or severe mitral regurgitation (HR=1.71, 95%CI: 1.19-2.47, P=0.004), increased ln (N-terminal pro-B-type natriuretic peptide) (HR=1.30, 95%CI: 1.10-1.54, P=0.002) were independent risk factors for dverse cardiovascular events in DCM patients, and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI) treatment (HR=0.45, 95%CI: 0.26-0.78, P=0.004) was independent protective factor. Kaplan-Meier survival analysis found no significant difference in the risk of MACEs between isolated DCM and DCM with LVNC (P=0.22). Similarly, there were no significant differences in the incidence of major heart failure, severe ventricular arrhythmia, and cardiovascular death between the two groups (all P>0.05). Conclusion: An increase in left ventricular end-diastolic diameter, moderate or severe mitral regurgitation, elevated N-terminal pro-B-type natriuretic peptide, and non use of ACEI/ARB/ARNI are independent predictors of cardiovascular events in DCM patients. There was no significant risk of MACEs in patients with isolated DCM and DCM with LVNC, and suggested that LVNC may be a unique phenotype and should be accurately managed in combination with genetic background.

Prognosis value of galectin-3 in patients with dilated cardiomyopathy: a meta-analysis.

Accurate prediction and assessment of myocardial fibrosis (MF) and adverse cardiovascular events (MACEs) are crucial in patients with dilated cardiomyopathy (DCM). Several studies indicate that galectin-3 (gal-3) as a promising prognostic predictor in patients with DCM. A comprehensive search was conducted in PubMed, EMBASE, the Cochrane Library, and Web of Science for relevant studies up to August 2023. The hazard ratios (HRs) of gal-3 for MACEs in DCM patients, and for MACEs in LGE(+) versus LGE(-) groups, were evaluated. Statistical analysis was performed using STATA SE 14.0 software. Seven studies, encompassing 945 patients, met the eligibility criteria. In DCM patients, abnormally elevated gal-3 levels were indicative of an increased MACEs risk (HR = 1.10, 95% CI [1.00-1.21], I2 = 65.7%, p=0.008). Compared with the LGE(-) group, the level of gal-3 in LGE(+) group was higher (HR = 1.12, 95% CI [1.05-1.19], I2 = 31.4%, p=0.233), and the combination of gal-3 and LGE significantly improved the prediction of MACEs. Sensitivity analysis confirmed the robustness of all results. This study's findings suggest that elevated gal-3 levels significantly correlate with increased MACE risk in DCM, highlighting its potential as a biomarker. However, significant heterogeneity among studies necessitates further research to ascertain gal-3's predictive and diagnostic value in DCM prognosis, particularly in conjunction with LGE. CRD42023471199.

Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localise to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52-53, localised to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four and half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in maintenance and/or regulation of sarcomeric organisation and function.

Pregnancy in women with dilated cardiomyopathy genetic variants

Introduction and objectivesLimited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. MethodsWe studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. ResultsA total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. ConclusionsCardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Frequency Of Left Ventricular Thrombi In Dilated Cardiomyopathy Patients Presenting In Tertiary Care Hospital Of Punjab

Objective: This study has been carried out to determine the frequency of left ventricular thrombi in dilated cardiomyopathy patients presenting in tertiary care hospitals in Punjab. Methods: This descriptive case series was carried out at Arif Memorial Teaching Hospital Lahore. This study involved 150 children of both genders aged between 4-12 years diagnosed with dilated cardiomyopathy. These children underwent echocardiographic screening for left ventricular thrombi (mass filling the ventricular cavity and distinct from normal endocardium). The frequency of left ventricular thrombi was noted and compared across various subgroups of children based on age, gender and BMI. Written informed consent was obtained from parents of every child. Results: The mean age of the children was 8.5±2.4 years. There were 98 (65.3%) boys and 52 (34.7%) girls with a male-to-female ratio of 1.9:1. The mean BMI of these children was 26.9±3.0 Kg/m2 and 29 (19.3%) children were obese. 63 (42.0%) children had left ventricular thrombi. There was no statistically significant difference in the frequency of left ventricular thrombi across various subgroups of children based on age (p-value=0.979), gender (p-value=0.956), and BMI (p-value=0.731). Conclusion: In the present study, a substantial proportion of children with dilated cardiomyopathy had left ventricular thrombi which due to the associated risk of thromboembolism and CVA warrant routine echocardiographic screening of such children so that timely identification and anticipated management may improve the outcome of children with dilated cardiomyopathy in future pediatric practice. Keywords: Dilated cardiomyopathy, Left ventricular thrombus, echocardiography

Temporal progression of replacement and interstitial fibrosis in optimally managed dilated cardiomyopathy patients: A prospective study

Background: To prospectively examine the dynamic evolution of fibrotic processes within a one-year in patients with dilated cardiomyopathy (DCM). Methods: Between May 2019 and September 2020, 102 DCM patients (mean age 45.2 ± 11.8 years, EF 29.9 ± 11.6%) underwent cardiac magnetic resonance (CMR-1). After 13.9 ± 2.9 months, 92 of these patients underwent a follow-up CMR (CMR-2). Replacement fibrosis was assessed via late gadolinium enhancement (LGE), quantified in terms of LGE mass and extent. Interstitial fibrosis was evaluated via T1-mapping and expressed as extracellular volume fraction (ECV). This data, along with left ventricular (LV) mass, facilitated the calculation of LV matrix and cellular volumes. Results: At CMR-1, LGE was present in 45 patients (48.9%), whereas at CMR-2 LGE was detected in 46 (50%) (p = 0.88). Although LGE mass remained stable, LGE extent increased from 2.18 ± 4.1% to 2.7 ± 4.6% (p < 0.01). Conversely, ECV remained unchanged [27.7% (25.5–31.3) vs. 26.7% (24.5–29.9); p = 0.19]; however, LV matrix and cell volumes exhibited a noteworthy regression. During a subsequent follow-up of 19.2 ± 9 months (spanning from CMR-2 to April 30th, 2023), the composite primary outcome (all-cause mortality, HTX, LVAD or heart failure worsening) was evident in 18 patients. Only the LV matrix volume index at follow-up was an independent predictor of outcome (OR 1.094; 95%CI 1.004–1.192; p < 0.05). Conclusions: In optimally managed DCM patients, both replacement and interstitial fibrosis remained stable over the course of one year. In contrast, LV matrix and cell volumes displayed significant regression. LV matrix volume index at 12-month follow-up was found to be an independent predictor of outcome in DCM.

Clinical characteristics, treatment, trajectories and outcome of patients with dilated cardiomyopathy in a national heart failure registry

BackgroundAvailable data on the clinical characteristics and prognosis of patients with heart failure (HF) due to dilated cardiomyopathy (DCM) derive mainly from tertiary care centres for cardiomyopathies or from drug trial sub-studies, which may entail a referral bias. MethodsFrom 2008 to 2021, we enrolled in a nationwide HF Registry 1886 DCM patients and 3899 with ischemic heart disease (IHD). ResultsPatients with DCM were younger, more often female, had more commonly recent onset HF, left bundle branch block, and showed higher LV end-diastolic volume and lower LVEF than IHD. With respect to IHD, DCM patients received more often mineralocorticoid receptor antagonists, renin angiotensin system inhibitors and betablockers, the latter more commonly at doses ≥50% of target, and triple guideline-directed medical therapy (GDMT) (adjusted OR 1.411, 95% CI 1.247-1.595, p < .0001). During one-year follow-up, 819 patients (14.2%) died or were hospitalized for HF [187 (9.9%) DCM, 632 (16.2%) IHD]; DCM was associated with lower risk of the combined end-point (adjusted HR 0.745, 95% CI 0.625- 0.888, p = .0011). Among the 1954 patients with 1-year echocardiograms available, 1483 had LVEF≤40% at baseline; of these,166 (30.6%) DCM and 165 (17.5%) IHD improved their LVEF to >40% (p < .0001). DCM aetiology was associated with higher likelihood of LVEF improvement (adjusted OR 1.722, 95% CI 1.328 -2.233, p < .0001). ConclusionsDCM patients have a different clinical profile, greater uptake of GDMT and better outcomes than IHD subjects. A comprehensive management approach is needed to further address the risk of unfavorable outcomes in DCM.

A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a significant cause of heart failure that requires heart transplantation. Fibroblasts play a central role in the fibro-inflammatory microenvironment of DCM. However, their cellular heterogeneity and interaction with immune cells have not been well identified. An integrative analysis was conducted on single-cell RNA sequencing (ScRNA-Seq) data from human left ventricle tissues, which comprised 4 hearts from healthy donors and 6 hearts with DCM. The specific antigen-presenting fibroblast (apFB) was explored as a subtype of fibroblasts characterized by expressing MHCII genes, the existence of which was confirmed by immunofluorescence staining of 3 cardiac tissues from DCM patients with severe heart failure. apFB highly expressed the genes that response to IFN-γ, and it also have a high activity of the JAK-STAT pathway and the transcription factor RFX5. In addition, the analysis of intercellular communication between apFBs and CD4+T cells revealed that the anti-inflammatory ligand-receptor pairs TGFB-TGFR, CLEC2B-KLRB1, and CD46-JAG1 were upregulated in DCM. The apFB signature exhibited a positive correlation with immunosuppression and demonstrated diagnostic and prognostic value when evaluated using a bulk RNA dataset comprising 166 donors and 166 DCM samples. In conclusion, the present study identified a novel subpopulation of fibroblasts that specifically expresses MHCII-encoding genes. This specific apFBs can suppress the inflammation occurring in DCM. Our findings further elucidate the composition of the fibro-inflammatory microenvironment in DCM, and provide a novel therapeutic target.

Diverse distribution patterns of segmental longitudinal strain are associated with different clinical features and outcomes in dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) presents with diverse clinical courses, hardly predictable solely by the left ventricular (LV) ejection fraction (EF). Longitudinal strain (LS) offers distinct information from LVEF and exhibits various distribution patterns. This study aimed to evaluate the clinical significance of LS distribution patterns in DCM. We studied 139 patients with DCM (LVEF ≤ 35%) who were admitted for heart failure (HF). LS distribution was assessed using a bull's eye map and the relative apical LS index (RapLSI), calculated by dividing apical LS by the sum of basal and mid-LS values. We evaluated the associations of LS distribution with cardiac events (cardiac death, LV assist device implantation, or HF hospitalization) and LV reverse remodeling (LVRR), as indicated by subsequent LVEF changes. Twenty six (19%) and 29 (21%) patients exhibited a pattern of relatively apical impaired or preserved LS (defined by RapLSI < 0.25 or > 0.75, signifying a 50% decrease or increase in apical LS compared to other segments), and the remaining patients exhibited a scattered/homogeneously impaired LS pattern. The proportion of new-onset heart failure and LVEF differed between the three groups. During the median 595-day follow-up, patients with relatively-impaired apical LS had a higher rate of cardiac events (both log-rank p < 0.05) and a lower incidence of LVRR (both p < 0.01) compared to patients with other patterns. RapLSI was significantly associated with cardiac event rates after adjusting for age, sex, and new-onset HF or global LS. DCM patients with reduced EF and distinct distribution patterns of impaired LS experienced different outcomes.

Familial Dilated Cardiomyopathy: A Novel MED9 Short Isoform Identification.

Familial dilated cardiomyopathy (DCM) is among the leading indications for heart transplantation. DCM alters the transcriptomic profile. The alteration or activation/silencing of physiologically operating transcripts may explain the onset and progression of this pathological state. The mediator complex (MED) plays a fundamental role in the transcription process. The aim of this study is to investigate the MED subunits, which are altered in DCM, to identify target crossroads genes. RNA sequencing allowed us to identify specific MED subunits that are altered during familial DCM, transforming into human myocardial samples. N = 13 MED subunits were upregulated and n = 7 downregulated. MED9 alone was significantly reduced in patients compared to healthy subjects (HS) (FC = -1.257; p < 0.05). Interestingly, we found a short MED9 isoform (MED9s) (ENSG00000141026.6), which was upregulated when compared to the full-transcript isoform (MED9f). Motif identification analysis yielded several significant matches (p < 0.05), such as GATA4, which is downregulated in CHD. Moreover, although the protein-protein interaction network showed FOG2/ZFPM2, FOS and ID2 proteins to be the key interacting partners of GATA4, only FOG2/ZFPM2 overexpression showed an interaction score of "high confidence" ≥ 0.84. A significant change in the MED was observed during HF. For the first time, the MED9 subunit was significantly reduced between familial DCM and HS (p < 0.05), showing an increased MED9s isoform in DCM patients with respect to its full-length transcript. MED9 and GATA4 shared the same sequence motif and were involved in a network with FOG2/ZFPM2, FOS, and ID2, proteins already implicated in cardiac development.

Cardiac atrial pathology in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by fibrofatty replacement of muscle. This has been documented in the ventricular myocardium of DMD patients, but there is limited description of atrial involvement. The purpose of this study is to examine the arrhythmia and ectopy burden in patients with DMD and non-DMD dilated cardiomyopathy (DCM) and to characterize the cardiac histopathologic changes in DMD patients across the disease spectrum. This was a retrospective analysis of age-matched patients with DMD and non-DMD DCM who received a Holter monitor and cardiac imaging within 100 days of each other between 2010 and 2020. Twenty-four-hour Holter monitors were classified based on the most recent left ventricular ejection fraction at the time of monitoring. Cardiac histopathologic specimens from whole-heart examinations at the time of autopsy from three DMD patients and one DCM patient were reviewed. A total of 367 patients with 1299 Holter monitor recordings were included over the study period, with 94% representing DMD patients and 6% non-DMD DCM. Patients with DMD had more atrial ectopy across the cardiac function spectrum (p < 0.05). There was no difference in ventricular ectopy. Four DMD patients developed symptomatic atrial arrhythmias. Autopsy specimens from DMD patients demonstrated fibrofatty infiltration of both atrial and ventricular myocardium. The atrial myocardium in patients with DMD is unique. Autopsy specimens reveal fibofatty replacement of the atrial myocardium, which may be a nidus for both ectopy and arrhythmias in DMD patients.

The Added Value of Advanced Echocardiography for the Morpho-Functional and Prognostic Evaluation of the Right Heart in Dilated Cardiomyopathy: Do Not Forget about the Right Atrium.

(1) Introduction and Aims: Right ventricular (RV) remodeling significantly impacts the prognosis of dilated cardiomyopathy (DCM) patients, and right atrial (RA) size and function are still often neglected in DCM patients. Accordingly, our aims were to (i) evaluate right heart subclinical changes and (ii) the prognostic value of RA compared to left atrial (LA) size and function in patients with DCM by advanced echocardiography. (2) Materials and Methods: Sixty-eight patients with DCM (with a mean age of 60 years; 35 men) were evaluated by comprehensive transthoracic echocardiography, compared to 62 age- and sex-matched healthy controls (with a mean age of 61 years; 32 men), and followed up for 12.4 ± 5 months. (3) Results: DCM patients have RV and RA global longitudinal dysfunction by 2DSTE, higher RA minimum volumes and tricuspid annulus areas despite having normal RV volumes, ejection fractions, and RA maximum volumes by 3DE compared to the controls. The RA strain and RV strain are correlated with each other. The RA reservoir strain (with an AUC = 0.769) has an increased value for outcome prediction compared to that of the LA strain. (4) Conclusion: Patients with DCM have RV longitudinal dysfunction and decreased RA function, in the absence of clinical RV involvement or atrial arrhythmias, and the RA strain is associated with an increased risk of hospitalization and cardiac death.

Imagenetics for Precision Medicine in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as DSP (desmoplakin) or FLNC (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.

The Prognostic Value of Serum Calcium Levels in Elderly Dilated Cardiomyopathy Patients.

It is unclear whether serum calcium on admission is associated with clinical outcomes in dilated cardiomyopathy (DCM). In this study, we conducted a retrospective study spanning a decade to investigate the prognostic value of baseline calcium in elderly patients with DCM. A total of 1,089 consecutive elderly patients (age ≥60 years) diagnosed with DCM were retrospectively enrolled from January 2010 to December 2019. Univariate and multivariate analyses were performed to investigate the association of serum calcium with their clinical outcomes. In this study, the average age of the subjects was 68.36 ± 6.31 years. Receiver operating characteristic (ROC) curve analysis showed that serum calcium level had a great sensitivity and specificity for predicting in-hospital death, with an AUC of 0.732. Kaplan-Meier survival analysis showed that patients with a serum calcium >8.62 mg/dL had a better prognosis than those with a serum calcium ≤8.62 mg/dL (log-rank χ2 40.84, p < 0.001). After adjusting for several common risk factors, a serum calcium ≤8.62 mg/dL was related to a higher risk of long-term mortality (HR: 1.449; 95% CI: 1.115~1.882; p = 0.005). Serum calcium level could be served as a simple and affordable tool to evaluate patients' prognosis in DCM.

Compliance with Guideline-Directed Medical Therapy and Early Implantable Cardioverter-Defibrillator Activation in Heart Failure: A Retrospective Study.

This study was conducted to evaluate compliance with guideline-directed optimal medical therapy (OMT) and its association with early implantable cardioverter-defibrillator (ICD) activation in patients with heart failure and reduced ejection fraction (HFrEF). Retrospective data from 307 patients who underwent ICD implantation for primary prevention from 2011 to 2017 were collected and analyzed. Among the study participants, only 23.8% received the maximum tolerated dose of OMT prior to ICD implantation, with 59.0% receiving all three OMT medication groups. No significant difference in OMT compliance was found between patients with ischemic cardiomyopathy (ICM) and those with non-ischemic dilated cardiomyopathy (DCM). However, DCM patients received ICDs more frequently at the time of diagnosis than ICM patients (13.8% vs. 0.7%). Early ICD activation (within 3 months) occurred in only one patient who had not received appropriate OMT, representing 0.7% of all ICM patients. Furthermore, early activation was also infrequent in patients who received OMT (2.9% of ICM patients and 2.6% of DCM patients). Echocardiography follow-up data revealed that 20.4% of ICM patients and 29.8% of DCM patients who did not receive OMT before ICD implantation showed improvement in the left ventricular ejection fraction (EF) to 35% or more. This study found suboptimal compliance with OMT prior to ICD implantation in HFrEF patients. The results showed that early ICD activation was rare in all patient groups, especially those who did not receive the prescribed 3 months of OMT. More research is needed to investigate longer waiting periods for the evaluation of potential EF improvement, and to better evaluate the eligibility of HFrEF patients for ICD. The current findings have potential implications for clinical practice and patient outcomes.

Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF]<35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.