Recent-onset Dilated Cardiomyopathy Research Articles

Reverse remodeling of mitral leaflets after medical treatment in recent-onset dilated cardiomyopathy.

The growth of mitral leaflets (MLs) adaptive to left ventricluar (LV) remodeling has been observed. However, the elasticity of MLs upon mechanical stimuli would be supposed if it shrinks with LV reverse remodeling (LVRR). Patients with idiopathic recent-onset dilated cardiomyopathy (RODCM) (n = 82) and 50 matched normal controls (NC) were prospectively enrolled. Echocardiography was performed at baseline and 6 months of follow-up for the anterior and posterior mitral leaflet (AML and PML) length, mitral annular dimension (MAD), and tenting height (TH). LVRR was measured as a ≥ 15% reduction in LV end-diastolic volume (LVEDV). After 6 months, LVRR was achieved in 69.5% of patients. The AML (28 ± 3 vs. 26 ± 3 mm, p = 0.004) and PML (19 ± 4 vs. 17 ± 3 mm, p < 0.001) decreased in length, as well as the MAD (31 ± 5 vs. 28 ± 5 mm, p = 0.001) and TH (10 ± 3 vs. 8 ± 2 mm, p < 0.001). Compared with the NC group, the AML and PML of the RODCM group were 16.7% and 35.7% longer at baseline and remained 8.3% and 21.2% longer at follow-up, respectively. The change in AML or PML correlated moderately with that in LVEDV (r = 0.487, p < 0.001; r = 0.516, p < 0.001, respectively). The AML and PML length decreased in the LVRR (+) subgroup (AML, 28 ± 3 vs. 26 ± 3 mm, p = 0.001; PML, 20 ± 4 vs. 16 ± 3 mm, p < 0.001), but remained the same in the LVRR (-) subgroup (27 ± 4 vs. 28 ± 4 mm, p = 0.318; 17 ± 3 vs. 17 ± 3 mm, p = 0.790). Enlarged MLs could reverse accompanied by LV reverse remodeling. This study provided the other facet of ML plasticity adaptive to mechanical stretching.

Mitral leaflet retraction and left ventricular reverse remodeling in patients with treated dilated cardiomyopathy

Abstract Background Enlargement of the mitral leaflets (MLs) adaptive to mechanical stress caused by dilated left ventricle (LV) was recognized, but their changes after the stimuli withdrawn remained unexplored. Aims To observe morphological changes in the MLs along with LV reverse remodeling (LVRR) occurred after standard care. Methods Patients with recent-onset dilated cardiomyopathy (RODCM) were prospectively enrolled (n=82), as well as a group of age, sex and body surface area matched normal controls (NC) (n=50). Two-dimensional transthoracic echocardiography was performed at baseline and 6-month follow-up with special interests in the length of anterior and posterior mitral leaflet (AML and PML), mitral annular dimension (MAD) and tenting height (TH). LVRR was measured as a reduction in the LV end-diastolic volume (LVEDV) of ≥15%. Results At the 6-month follow-up, LVRR was achieved in 69.5% patients and there were 26.9% patients who reported ≥1 grade reduction in secondary mitral regurgitation that related to LVRR. The AML (28±3 vs. 26±3mm, p=0.004) and PML (19±4 vs. 17±3mm, p&amp;lt;0.001) were decreased, as well as the MAD (31±5 vs. 28±5mm, p=0.001) and TH (10±3 vs. 8±2mm, p&amp;lt;0.001), but all remained larger than that of the NC group (all p&amp;lt;0.05). When compared with the control group, the AML and PML of the RODCM group was 16.7% and 35.7% longer at baseline, which remained 8.3% and 21.2% longer at the follow-up, respectively. The change in the AML (△AML) or PML (△PML) correlated moderately to the change in the LVEDV (△LVEDV) (r=0.487, p&amp;lt;0.001; r=0.516, p &amp;lt;0.001, respectively) (Figure 1). When compared between the subgroups stratified by LVRR, both the AML and PML decreased in the patients who had LVRR (+) (AML, 28±3 vs. 26±3, p=0.001; PML, 20±4 vs. 16±3, p&amp;lt;0.001), but remained the same length in those with LVRR (-) (AML, 27±4 vs. 28±4, p=0.318; PML, 17±3 vs. 17±3, p=0.790). The comparison in the △AML and △PML between the two subgroups is shown in Figure 2. Conclusion The enlarged MLs could retract with different behavior in the AML and PML, accompanied by LV reverse remodeling. This study conducted in patients with RODCM who received standard therapy provided the other facet of mitral leaflet plasticity adaptive to mechanical stretch.correlation between △MLs and △LVEDVCompare △MLs between LVRR subgroups

Myocardial Recovery in Recent Onset Dilated Cardiomyopathy: Role of CDCP1 and Cardiac Fibrosis.

Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Abstract 12664: Comprehensive Histological Analysis of Endomyocardial Biopsy and T1 Mapping for Predicting Left Ventricular Reverse Remodeling in Patients with Recent-Onset Dilated Cardiomyopathy

Background: Cardiomyocyte injury is a key pathological pathway in the progression of heart failure that predicts a poor prognosis; therefore, combined assessment of myocardial fibrosis and cardiomyocyte DNA damage from endomyocardial biopsy (EMB) samples may be of great importance. Meanwhile, cardiovascular magnetic resonance (CMR) native T1 reflects a composite of both intra- and extracellular compartments in the whole myocardium. We sought to assess the performance of native T1 mapping and EMB results to predict left ventricular reverse remodeling (LVRR) in recent-onset dilated cardiomyopathy (DCM). Methods: A total of 29 patients with DCM underwent cine CMR and triple-slice T1 mapping using the MOLLI sequence at 3T, and EMB before receiving guideline-directed medical therapy. Poly ADP-ribose (PAR) nuclear and sirius-red staining were used for quantification of DNA damage and collagen volume fraction (CVF), respectively. LVRR was defined as an increase in LV ejection fraction of ≥10% to the final value of &gt;35%, accompanied by a decrease in LV end-diastolic volume ≥10% at the follow-up CMR. Results: Fifteen patients (52%) achieved LVRR. The mean native T1, histological CVF, and proportion of PAR-positive nuclei were 1376 ± 55 ms, 0.13 ± 0.05, 25 ± 15%, respectively. Native T1 correlated well with CVF (p=0.004) and trended to be higher in DCM patients with increased DNA damage (p=0.17). There was no significant association between CVF and %PAR-positive nuclei. Native T1 &lt;1400 ms provided 86% sensitivity and 67% specificity, with the C-statistic of 0.82 (95% CI 0.67-0.98) for predicting LVRR. By contrast, C-statistic of %PAR nuclei, CVF, and combined assessment of %PAR nuclei and CVF were 0.59, 0.61 and 0.66, respectively. Conclusion: CMR T1 mapping may be a promising strategy for noninvasive biopsy of the whole heart and provide a better prediction of LVRR in recent-onset DCM than comprehensive histological analysis of EMB.

Abstract 13730: Genotype-Phenotype Correlates in Recent-Onset Dilated Cardiomyopathy and Their Prognostic Implications

Introduction: Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous etiology and diverse clinical outcomes. Hypothesis: We hypothesized that the genotype of RODCM might correlate with left ventricular reverse remodeling (LVRR) and long-term clinical outcomes. Methods: A total of 386 RODCM patients (pts) [age 44±12 years, 277 males (72%), familial in 98 pts (25%)] with a history of symptoms less than six months underwent whole-exome sequencing (WES) where likely-pathogenic and pathogenic (class 4-5) disease-causing variants were identified. LVRR was defined as an improvement in left ventricular ejection fraction to &gt;50% or ≥10% absolute increase, with left ventricular end-diastolic diameter ≤33 mm/m2 or ≥10% relative decrease. In this prospective study, the primary outcome was the first event of all-cause death, heart transplantation or ventricular assist device. The secondary outcome included sudden cardiac death, resuscitated cardiac arrest or treated ventricular tachyarrhythmias. Results: WES detected class 4-5 titin truncated variants ( TTNtv ) in 69 pts (19%), class 4-5 non-titin variants (non- TTN ) (Figure) in 56 pts (14%), variants of unknown significance only in 103 pts (27%) and a negative result in 158 pts (40%). At 12 months, LVRR was assessed in 359 pts and was present in 171 pts (48%). Carriers of class 4-5 non- TTN variants developed LVRR less frequently than subjects with other genetic testing results (28% vs. 51%, p˂0.01). During a median follow-up of 55 months, the primary and secondary outcomes occurred in 79 pts (20%) and 50 pts (13%), respectively. Carriers of class 4-5 non- TTN variants had an increased risk of both primary [HR 2.36 (95% CI 1.32-4.20), p˂0.01] and secondary [HR 3.08 (95% CI 1.42-6.67), p˂0.01] outcomes as compared with genotype-negative pts. In multivariable models, genotype remained a strong predictor of both types of outcome. Conclusions: Among RODCM patients, carriers of class 4-5 non- TTN variants have an increased risk of death and progressive heart failure, and a higher long-term burden of life-threatening ventricular arrhythmias compared to genotype-negative subjects. Funding: Supported by the research grant of the Ministry of Health, Czech Republic: [NV19-08-00122] and IPO 00023001.

NAV3 is a genetic determinant of myocardial recovery in dilated cardiomyopathy and attenuates cardiac fibrosis

Abstract Background A genome-wide association study (GWAS) assessing change in left ventricular ejection fraction (LVEF) in dilated cardiomyopathy (DCM), a surrogate marker of morbidity and mortality in heart failure (HF), had not been performed previously and could provide insight into novel biological pathways that could lead to the development of new drugs that might target myocardial recovery. The presence and extent of cardiac fibrosis in DCM is independently associated with myocardial recovery and cardiovascular mortality. Purpose To identify the biological relevance of genetic targets that are associated with change in LVEF in patients with DCM. Methods A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in LVEF at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used as an in vitro model to study the functional and biological relevance of the gene target identified in the GWAS. Specifically, HCFs were transfected with siRNA by using the Lipofectamine™ RNAiMAX Transfection Reagent for gene knockdown (KD). RNA-seq was performed using the Illumina TruSeq protocol with expression analysis conducted with the EdgeR package. Ingenuity Pathway Analysis was used. Results A single-nucleotide polymorphism, rs11105445(G&amp;gt;A), mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74±0.53) was associated with improvement in LVEF. We performed a phenome-wide association study using data from the UK Biobank and demonstrated that genetic variation in NAV3 was significantly associated with HF mortality (p=3.2E-28), highlighting the potential importance of this gene in HF. Using GTEx data we demonstrated that in LV tissue the minor allele A was associated with ↓NAV3 expression (p=0.03) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. We demonstrated that NAV3 KD significantly ↓TGF-β1 mediated HCF transdifferentiation into myofibroblasts, ↓α-smooth muscle actin (ACTA2) and ↓collagen I (COL1A1), therefore NAV3 KD was anti-fibrotic (see Figure 1), 1a. HCFs treated by vehicle/TGF-β1 after KD of NAV3/ctrl, and ACTA2 and COL1A1 were analyzed by qPCR; 1b. Representative immunofluorescence staining for α-SMA (in green), RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating cell cycle related proteins (Figure 2), 2a. Volcano plot shows significant differentially expressed genes identified by RNA-seq analysis (down-regulated in blue, up-regulated in red); 2b. NAV3 KD significantly increased expression of cell cycle related proteins, which was validated by Western blot. Conclusions Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its anti-fibrotic effect via direct regulation of cell cycle proteins. The role of NAV3 as a novel therapeutic target in DCM needs to be explored. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mayo Clinic Center for Individualized MedicineMayo Clinic Department of Cardiovascular Medicine

Myeloid differentiation factor-2 activates monocytes in patients with dilated cardiomyopathy.

Plasma levels of myeloid differentiation factor-2 (MD-2), a co-receptor of toll-like-receptor 4 (TLR4), independently predict mortality in patients with dilated cardiomyopathy (DCM). We tested whether monocyte activation by MD-2 contributes to immune activation and inflammatory status in DCM patients. We found increased MD-2 plasma levels in 25 patients with recent-onset DCM (1250 ± 80.7ng/ml) compared to 25 age- and gender-matched healthy controls (793.4 ± 52.0ng/ml; p < 0.001). Monocytes isolated from DCM patients showed a higher expression (141.7 ± 12.4%; p=0.006 vs. controls) of the MD-2 encoding gene, LY96 and an increased NF-κB-activation. Further, the TLR4-activator lipopolysaccharide (LPS) caused a higher increase in interleukin (IL)-6 in monocytes from DCM patients compared to controls (mean fluorescence intensity: 938.7 ± 151.0 vs. 466.9 ± 51.1; p=0.005). MD-2 increased IL-6 secretion in a TLR4/NF-κB-dependent manner in monocyte-like THP-1-cells as demonstrated by TLR4-siRNA and NF-κB-inhibition. Since endothelial cells (ECs) are responsible for recruiting monocytes to the site of inflammation, ECs were treated with MD-2 leading to an activation of Akt and increased secretion of monocyte-chemoattractant-protein-1 (MCP-1). Activation of ECs by MD-2 was accompanied by an increased expression of the adhesion molecules CD54, CD106 and CD62E, resulting in an increased monocyte recruitment, which was attenuated by CD54 inhibition. In addition, in murine WT but not LY96-KO bone marrow-derived macrophages LPS increased the amount of CD54 and CD49d/CD29. MD-2 facilitates a pro-inflammatory status of monocytes and EC-mediated monocyte recruitment via TLR4/NF-κB. Elevated MD-2 plasma levels are possibly involved in monocyte-related inflammation-promoting disease progression in DCM. Our results suggest that MD-2 contributes to increasing monocytic inflammatory activity and triggers the recruitment of monocytes to ECs in DCM.

Longitudinal Arrhythmic Risk Assessment Based on Ejection Fraction in Patients with Recent-Onset Nonischemic Dilated Cardiomyopathy

Practice guidelines suggest the use of implantable cardioverter-defibrillators in patients with left ventricular ejection fractions (LVEF)≤35% despite 3 to 6months of guideline-directed medical therapy (GDMT). It remains unclear whether this strategy is appropriate for patients with dilated cardiomyopathy (DCM), who can experience reverse ventricular remodeling for up to 24months after the initiation of GDMT. The aim of this study was to assess the longitudinal dynamic relationship between LVEF ≤ 35% and arrhythmic risk in patients with recent-onset nonischemic DCM on GDMT. A retrospective analysis was conducted among patients with recent-onset DCM (≤6months) and recent initiation of GDMT (≤3months) consecutively enrolled in a longitudinal registry. Risk for major ventricular arrhythmic events or sudden cardiac death was assessed in relationship to LVEF ≤ 35% at enrollment and 6 and 24months after initiation of GDMT. Five hundred forty-four patients met the inclusion criteria. LVEF ≤ 35% identified patients with increased risk for major ventricular arrhythmic events or sudden cardiac death starting from 24months after initiation of GDMT (hazard ratio, 2.126; 95% CI, 1.065-4.245; P=.03). However, LVEF ≤ 35% at presentation or 6months after enrollment did not have prognostic significance. Sixty-seven percent of 131 patients with LVEF ≤ 35% at 6months after initiation of GDMT had improved LVEFs (to >35%) by 24months. This late LVEF improvement correlated with lower arrhythmic risk (P=.012) and was preceded by a reduction of LV dimensions in the first 6months of GDMT. In patients with DCM, the present findings suggest that risk stratification for major ventricular arrhythmic events or sudden cardiac death on the basis of LVEF ≤ 35% is effective after 2years of GDMT, but not after 6months. In selected patients with DCM, it would be appropriate to wait 24months before primary prevention ICD implantation.

303 Longitudinal arrhythmic risk assessment based on ejection fraction in patients with recent-onset non-ischaemic dilated cardiomyopathy

Abstract Aims Practice guidelines suggest implantable cardioverter defibrillators (ICD) in patients with left ventricular ejection fraction (LVEF) ≤35% despite 3–6 months of guideline-directed medical therapy (GDMT). It remains unclear whether this strategy is appropriate for patients with dilated cardiomyopathy (DCM), who can experience reverse ventricular remodelling for up to 24 months after initiation of GDMT. We sought to assess the longitudinal dynamic relationship between LVEF ≤35% and arrhythmic risk in patients with recent onset non-ischaemic DCM under GDMT. Methods and results We performed a competitive risk analysis on patients with recent onset DCM (≤6 months) and recent initiation of GDMT (≤3 months), consecutively enrolled in a longitudinal registry. We assessed risk of major ventricular arrhythmic events or sudden cardiac death (MVAs/SCD) in relationship to LVEF ≤35% at enrollment, 6-months and 24-months post initiation of GDMT. 544 patients met inclusion criteria. LVEF ≤35% identified patients with increased risk of MVAs/SCD starting from 24-months after initiation of GDMT (hazards ratio: 2.126, 95% confidence interval: 1.065–4.245, P = 0.03). However, LVEF ≤35% at presentation or at 6 months post enrollment did not have prognostic significance. 67% of patients with LVEF ≤35% at 6 months after initiation of GDMT improved their LVEF to &amp;gt; 35% by 24 months. This late LVEF improvement correlated with a lower arrhythmic risk (P = 0.012) and was preceded by a reduction of LV dimensions in the first 6 months of GDMT. Conclusions In patients with DCM, risk stratification based on LVEF ≤35% is effective after 2 years of GDMT, but not after 6 months.

Late gadolinium enhancement for re-worsening left ventricular ejection fraction in patients with dilated cardiomyopathy.

AimsThis study aimed to evaluate the clinical parameters including late gadolinium enhancement (LGE) of cardiovascular magnetic resonance to predict re‐worsening of left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy (DCM).Methods and resultsWe included 138 patients with recent‐onset DCM who had an LVEF <45% and underwent LGE of cardiovascular magnetic resonance imaging at diagnosis and echocardiography at the yearly follow‐up [median 6 (4–8.3) years]. Initial LVEF recovery was defined as LVEF increase >10% from baseline, resulting in LVEF ≧45% after treatment. The patients were divided into three groups: (i) improved (n = 83, 60%), defined as those with sustained LVEF ≧45%; (ii) re‐worsening (n = 39, 28%), those with >5% decrease and LVEF <45% after the initial LVEF recovery; and (iii) not‐improved (n = 16, 12%), those without initial LVEF recovery. The primary endpoint was a composite of hospitalization for heart failure or sudden cardiac death. In baseline, LGE was observed in 70 patients. The LGE area was significantly larger in the re‐worsening and not‐improved groups than that in the improved group (P < 0.001). Loess curves of long‐term LVEF trajectories showed that LVEF in the re‐worsening group increased in the first 2 years and slowly declined thereafter. Multivariate logistic regression analysis demonstrated that LGE area [odds ratio (OR) 1.09, 95% confidence interval (CI) 1.03–1.16, P = 0.004], B‐type natriuretic peptide (OR 1.49, 95% CI 1.05–2.21, P = 0.030) level at the initial recovery, and LVEF (OR 0.91, 95% CI 0.86–0.97, P = 0.004) at the initial LVEF recovery were independent predictors of re‐worsening of LVEF. During a median follow‐up of 2273 (interquartile range: 1634–3191) days, the primary endpoint was observed in 31 (22%) patients. Univariate Cox proportional hazards analysis demonstrated that the risk of experiencing the primary event in the re‐worsening group was significantly higher (hazard ratio: 4.30, 95% CI 1.63–11.31, P = 0.003) than that in the improved group and was lower than that in the not‐improved group (hazard ratio: 0.33, 95% CI 0.15–0.72, P = 0.006).ConclusionsRe‐worsening of LVEF was observed in 28% of patients with recent‐onset DCM who showed an initial improvement in LVEF. High LGE burden, higher B‐type natriuretic peptide level, and lower LVEF at the initial LVEF recovery were independent predictors of re‐worsening of LVEF in patients with DCM. Careful observation is recommended for patients with a high risk for re‐worsening of LVEF, even in those with an initial LVEF recovery.

Prognostic implications of late gadolinium enhancement for re-worsening left ventricular ejection fraction in patients with dilated cardiomyopathy: a longitudinal study of left ventricular function

Abstract Background Re-worsening left ventricular ejection fraction (LVEF) after initial recovery occurs in some patients with dilated cardiomyopathy (DCM). However, prevalence and predictors of re-worsening LVEF in longitudinal follow-up are unclear. Late gadolinium enhancement of cardiovascular magnetic resonance (LGE-CMR) can evaluate the damage of myocardial tissue. Purpose This study sought to evaluate the clinical parameters including LGE-CMR to predict re-worsening LVEF in patients with recent-onset DCM. Methods We included patients with recent-onset DCM who had an LVEF &amp;lt;45% and underwent LGE-CMR at diagnosis. We performed yearly echocardiographc follow-up [median 6 [4–8.3] years]. Initial LVEF recovery defined as patients increased in &amp;gt;5% LVEF from baseline and had an LVEF≥45% after medical therapy. Patients were divided into three groups: (1) Improved: defined as those with sustained LVEF ≥45% after initial LVEF recovery; (2) Re-worse: those with decreased &amp;gt;5% and had an LVEF &amp;lt;45% after initial LVEF recovery. and (3) Not-improved: those with no initial LVEF recovery during follow-up. To evaluate the prognostic factors for Re-worsening LVEF after initial LVEF recovery, multivariate logistic regression analysis performed between the Improved group and the Re-worse group. Cardiac events defined as hospitalization due to heart failure and sudden death. Results Of 138 patents, 82 patients (59%) were the Improved group, 42 patients (30%) were the Re-worse group, and 14 (10%) were the Not-improved group. Loess curves of long-term LVEF trajectories showed that LVEF in the Re-worse group increased first 2 years and declined slowly thereafter (Fig. 1A). Re-worsening LVEF occurred 4.5±2.2 years after initial LVEF recovery. Multivariate logistic regression analysis demonstrated that LGE area at baseline (Odds ratio: 1.09, 95% confidence interval (CI) 1.02–1.18, p=0.014) and Log brain natriuretic peptide (BNP) at initial LVEF recovery (Odds ratio: 1.53, 95% confidence interval (CI) 1.01–2.31, p=0.042) were independent predictors for Re-worsening LVEF. Kaplan Meier analysis demonstrated that the risk of cardiac events in the Re-worse group was significantly higher (hazard ratio: 3.93, 95% CI 1.49–10.36, p=0.006) than in the Improved group and lower risk than in the Not-improved group (hazard ratio: 0.28, 95% CI 0.12–0.62, p=0.002) (Fig. 1B). Conclusion Re-worsening LVEF occurred in 30% of patients in patients with recent-onset DCM. LGE area and BNP at initial LVEF recovery were independently associated with re-worsening LVEF after initial LVEF recovery. Figure 1 Funding Acknowledgement Type of funding source: None

The role of inflammation in recent-onset dilated cardiomyopathy

Abstract Background The aetiology of recent-onset dilated cardiomyopathy (RODCM) includes inflammatory, genetic, toxic and metabolic causes. Delineating the role of inflammation on the genetic background could improve risk stratification. Purpose We aimed to ascertain the role of inflammation evaluated by serum CRP immunohistochemical and PCR analysis of endomyocardial biopsy (EMB) in conjunction with genetic testing in left ventricular reverse remodelling (LVRR) in 12-month follow-up. Methods 83 RODCM patients enrolled in this prospective observational study underwent 12-month echocardiographic follow up whole-exome sequencing, and EMB. Presence of cardiotropic viruses was determined by PCR analysis of the EMB samples. Inflammation was defined according to TIMIC immunohistochemical criteria as the presence of &amp;gt;7 CD3+ lymphocytes/mm2 and/or &amp;gt;14 infiltrating leukocytes (LCA+ cells/mm2). LVRR was defined as an absolute increase in LV ejection fraction &amp;gt; +10% and a relative decrease of LV end-diastolic diameter &amp;gt;−10% at 12 months. Results LVRR occurred in 28 (34%) of all cases. PCR analysis uncovered cardiotropic viruses in 55 (66%) patients, with highest prevalence of parvovirus B19 (47%). (Figure 1) EMB analysis detected inflammation in 28 (34%) cases and inflammation significantly positively predicted LVRR (P=0.019). Sequencing identified disease-related gene variants (ACMG class 3–5) in 45 (54%) patients. Carriers of non-titin gene variants showed a lowest probability of 12-month LVRR (19%) P=0.041. Combination of genetic findings and inflammation did not improve the prediction of LVRR in 12 months. (Table 1) Conclusion Both myocardial inflammation and disease-causing variants can be identified in a large proportion of RODCM cases. Prognostic value of CRP and virus detection is low. Non-titin disease-related variants carriers of are less likely to reach LVRR. In contrast, myocardial inflammation detected by EMB predicts favourable remodelling in 12 months. Figure 1 Funding Acknowledgement Type of funding source: None

Intravenous immunoglobulin for presumed viral myocarditis in children and adults.

Intravenous immunoglobulin for presumed viral myocarditis in children and adults.

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.

P1570 Evaluation of The Echocardiographic Parameters of Patients Enrolled to The CZECH-ICIT Study

Abstract Background Dilated cardiomyopathy (DCM) is a serious disease leading to heart failure (HF) often in young people. One of the most common causes of DCM is myocarditis. Aim of the study To compare the changes of the echocardiographic (ECHO) parameters of patients enrolled to the CZCEH-ICIT study (randomized study comparing the immunosuppression regiment with conventional heart failure therapy in patients with biopsy proven inflammatory cardiomyopathy). The primary outcome was the change of LVEF in 12 months after randomization. Obtained ECHO parameters were analysed at the baseline and in 12 months during the study . Study population We enrolled 20 patients (17 men and 2 women), age from 18 to 65 years , with diagnosis of recent onset dilated cardiomyopathy. EF LV &amp;lt; 40% and NYHA class II or worse who underwent EMB with confirmation of inflammatory cells in myocardium (&amp;gt; 14 LCA+ and/or &amp;gt; 7 CD3+ cells/mm2). All patients had negative PCR of infectious cardiotropic agents and were randomized in to two groups – IT – (prednison and azathioprin given on the top of standard HF therapy) and conventional HF therapy (CHT). Results Mean value of EF at the baseline clustered by groups were for IT group 22.3% with SD = 4.7 and for CHT group 21.7% with SD = 4. There were no statistically significant differences between two groups at the baseline p = 0.757. The mean value clustered for groups in 12 months were significant different, we found mean EF = 33.7% for IT group with SD = 9.5 and mean EF = 41.3 with SD = 13 for CHT group. The p-value based on t-test in 12 months was p = 0.175 due to huge variability. The results obtained on the basis of linear mixed models show that there is a trend that needs to be considered. At the baseline there is slightly lower level of EF in the group CHT (estimate of difference is -0.63, p = 0.879) the trend is changing in the time in 12 month - there is higher level of EF in CHT (estimate of difference is 11.37, p = 0.008). Total p-value difference based on the F test adjusted obtained for group is p = 0.065, for time p &amp;lt; 0.0001 and for time*group p = 0.537. Conclusion In our small study population we haven´t found positive effect of the immunosuppressive therapy on the development of the ECHO parameters.

P1815The impact of PVB19 presence in myocardium in recent onset dilated cardiomyopathy

Abstract Introduction The most common virus in myocardium of patients with recent onset dilated cardiomyopathy (RODCM) is PVB19. Opinions on its pathogenicity are different. According to some, viral load has to be evaluated and if it is low, the PVB19 has no potential to induce inflammation. Others recommend assessment of viral replication, while “innocent” are those cases where replication activity is low. Purpose To compare the development of echocardiographic parameters in patients with RODCM with isolated presence of PVB19 in low viral load (below 500 copies per μg nucleic acid) against a group in which no virus was detected in the myocardium. Patient and methods 243 patients with RODCM, in 151 cases (62%), the virus was detected in the myocardium (PCR+ group), in 92 cases the finding was negative (PCR−; ie 38%). In the PCR+ group, PVB19 was captured in 135 cases (89% of all PCR+), in 121 cases of them was PVB19 the only one isolated virus (PCRPVB19+; 80% of all PCR+). The viral presence was assessed by real time PCR. Results In the PCR− group, the left ventricular ejection fraction (LVEF) was 23.5±7.2%, in the PCRPVB19+ group 24.6±7.1% (p=0.26). Left ventricle end-diastolic diameter (LVEDD) in PCR− was 66.4±8.9mm vs 65.5±7.9mm in PCRPVB19+ (p=0.42), right ventricle diameter (RV) 33.1±5.7mm vs. 33.4±5.2mm (p=0.69), TAPSE 19.5±4.1mm vs 18.9±4.0mm (p=0.28) and E/é 14.0±5.7 vs. 14.9±7.0 (p=0.32). In the 12-month control, LVEF in the PCR− was 35.5±12.3% (p&lt;0.001 for comparison with baseline), in PCRPVB19+ 35.3±12.3% (p&lt;0.001 for comparison with baseline; p=0.92 for difference between groups); LVEDD in PCR− was 62.0±9.3mm vs 62.1±9.3mm in PCRPVB19+ (both p&lt;0.001 for comparison with baseline, p=0.91 for difference between groups), RV 31.6±5.5mm vs. 31.6±5.4mm (p=0.033, resp. p=0.003 for comparison with baseline; p=0.98 for difference between groups), TAPSE 20.7±4.3mm vs. 20.7±4.4mm (p=0.026, resp. p&lt;0.001 for comparison with baseline; p=0.98 for difference between groups), and E/e' 10.3±4.1 vs. 10.4±4.1 (both p&lt;0.001 for comparison with baseline; p=0.93 for difference between groups). Conclusion PVB19 presence in myocardium had no effect on the development of echocardiographic parameters in RODCM patients in one-year follow-up. Acknowledgement/Funding Supported by Ministry of Health of Czech Republic AZV Grant 16-30537A

P6451Genetics of recent-onset dilated cardiomyopathy as a predictor of left ventricular reverse remodelling

Abstract Background Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous aetiology including genetic, inflammatory, toxic and metabolic causes. Recognition of the genetic component could improve diagnostic management and risk stratification. Left ventricular reverse remodelling (LVRR) has been identified as a marker of favourable prognosis in RODCM. Purpose In this pilot study, we are first to assess the genetic background of RODCM in the Czech Republic by whole-exome sequencing and correlate genotype with LV reverse remodelling. Methods In this multi-centre prospective observational study, we enrolled 83 patients with RODCM and a history of symptoms of less than 6 months, for whole-exome sequencing. All patients underwent 12-month clinical and echocardiographic follow-up. LVRR was defined as an absolute increase in left ventricular ejec-tion fraction &gt;10% accompanied by a relative decrease of left ventricular end-diastolic diameter &gt;10% at 12 months. Results Whole-exome sequencing identified at least one disease-related variant in 45 patients (54%). As expected, the gene spectrum of identified variants in RODCM was quite wide comprising a total of 28 different genes, with the majority of truncating variants in titin gene which was found in 10 (12%) patients. LVRR occurred in 28 patients (34%), most often in carriers of isolated titin truncating variants, followed by individuals with a negative, or inconclusive results and carriers of other disease-related variants (56% vs. 42% vs. 19%, P 0.041). Genotype and LVRR Exom negative or non conclusive Isolated titin truncating variant Other variant or combination P-value (n=38) (n=9) (n=36) 12 months ΔLVEF absolute (%) 16 (6–23) 15 (9–34) 6 (3–15) 0.036* 12 months ΔLVEF &gt;10% (n=44; 53%) 24 (63%) 7 (78%) 13 (36%) 0.019* 12 months ΔLVEDD &lt;−10% (n=34; 41%) 18 (47%) 6 (67%) 10 (28%) 0.058 LVRR – 12 months, ΔLVEF &gt;10% and ΔLVEDD &lt;−10% (n=28; 34%) 16 (42%) 5 (56%) 7 (19%) 0.041* n, number; ΔLVEF, change of left ventricular ejection fraction; ΔLVEDD, change of left ventricular end-diastolic diameter; LVRR, left ventricular reverse remodelling. *Statistically significant result. Gene distribution in RODCM Conclusion A substantial proportion of RODCM cases has genetic background. Carriers of titin truncating variants are more likely to reach LVRR at 12 months, which could be seen as a positive prognostic marker of disease development. Genetic testing could contribute to better prognosis prediction and individualised treatment of patients with RODCM. Acknowledgement/Funding This study was supported by the research grant of the Ministry of Health, Czech Republic: MZ 15-27682A. All rights reserved.

Association of galectin-3 with changes in left ventricular function in recent-onset dilated cardiomyopathy

Background: The course of newly diagnosed dilated cardiomyopathy (DCM) varies from persistent reduction of left ventricular ejection fraction (LVEF) to recovery or even worsening. The aim of the present study was to examine the prognostic value of selected biomarkers with regard to changes in LVEF.Methods: Main inclusion criterion was LVEF ≤45% with exclusion of coronary artery or valvular heart disease. The primary endpoint was LVEF ≤35% in the follow-up echocardiogram. Galectin-3, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were related to the endpoint.Results: Data from 80 DCM patients (55 male, mean age 53 years) were analyzed. Median LVEF was 25% (IQR 25–30). The endpoint was met for 24 patients (30%). These had higher baseline levels of galectin-3 (median 20.3 ng/mL [IQR 14.3–26.9] vs. 14.7 ng/mL [IQR 10.9–17.7], p = 0.007) and NT-proBNP (3089 pg/mL [IQR 1731–6694] vs. 1498 pg/mL [IQR 775–3890]; p = 0.004) in univariate Cox regression analysis. ROC analysis revealed that CRP (median 0.4 mg/dL [IQR 0.2–1.2]) was also related to the endpoint (p = 0.043).Conclusion: Higher levels of galectin-3, NT-proBNP, and CRP were associated with LVEF ≤35% in our cohort. An approach utilizing a combination of biomarkers for patient management should be assessed in further studies.

Plasma osteopontin levels, but not its myocardial expression, reflect heart failure severity in recently diagnosed dilated cardiomyopathy.

Elevated levels of the extracellular matrix glycoprotein osteopontin (OPN) may be detected in both myocardium and plasma under various pathological conditions affecting the heart. Several studies demonstrated increased plasma OPN levels in patients with heart failure due to dilated cardiomyopathy (DCM), while other studies showed high OPN expression levels in the myocardium of such patients. However, very little is known about OPN levels in both plasma and myocardium of the same individual with DCM. Therefore, we aimed to compare plasma OPN levels and levels of myocardial OPN expression in patients with recent-onset DCM (Ro-DCM). We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain natriuretic peptide (BNP), and troponinI levels in 25patients with Ro-DCM. Furthermore, all subjects underwent transthoracic echocardiography, selective coronary angiography, and endomyocardial biopsy (EMB) for the assessment of myocardial OPN expression. No significant correlation between myocardial OPN expression and clinical, biochemical, or echocardiographic parameters was found. In log transformation analysis, plasma OPN levels correlated significantly with BNP levels (r = 0.46, p = 0.031), with CRP levels (r = 0.52, p = 0.015), and with early diastolic mitral annular velocity (r = -0.57, p = 0.009). There was aborderline association between the plasma OPN log value and New York Heart Association class (p = 0.053). Plasma OPN levels reflect heart failure severity in patients with Ro-DCM. Myocardial OPN expression is not associated with either plasma OPN levels or markers of heart failure in these individuals.

Genetic architecture of recent-onset dilated cardiomyopathy in Moravian region assessed by whole-exome sequencing and its clinical correlates.

Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous aetiology and clinical outcome. In this pilot study, we aimed to assess its genetic architecture and correlate genotype with left ventricular reverse remodelling (LVRR). In this multi-centre prospective observational study, we enrolled 83 Moravian patients with RODCM and a history of symptoms of less than 6 months, for whole-exome sequencing (WES). All patients underwent 12-month clinical and echocardiographic follow-up. LVRR was defined as an absolute increase in left ventricular ejection fraction > 10% accompanied by a relative decrease of left ventricular end-diastolic diameter > 10% at 12 months. WES identified at least one disease-related variant in 45 patients (54%). LVRR occurred in 28 patients (34%), most often in carriers of isolated titin truncated variants, followed by individuals with a negative, or inconclusive WES and carriers of other disease-related variants (56% vs. 42% vs. 19%, P=0.041). A substantial proportion of RODCM cases have a monogenic or oligogenic genetic background. Carriers of non-titin disease-related variants are less likely to reach LVRR at 12- months than other individuals. Genetic testing could contribute to better prognosis prediction and individualized treatment of RODCM.