Idiopathic Dilated Cardiomyopathy Research Articles

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy.

BackgroundPediatric dilated cardiomyopathy (DCM) is a well‐known clinical entity; however, phenotype–genotype correlations are inadequately described. Our objective was to provide genotype associations with life‐threatening cardiac outcomes in pediatric DCM probands.Methods and ResultsWe performed a retrospective review of children with DCM at a large pediatric referral center (2007–2016), excluding syndromic, chemotherapy‐induced, and congenital heart disease causes. Genetic variants were adjudicated by an expert panel and an independent clinical laboratory. In a cohort of 109 pediatric DCM cases with a mean age at diagnosis of 4.2 years (SD 5.9), life‐threatening cardiac outcomes occurred in 47% (42% heart transplant, 5% death). One or more pathogenic/likely pathogenic variants were present in 40/109 (37%), and 36/44 (82%) of pathogenic/likely pathogenic variants occurred in sarcomeric genes. The frequency of pathogenic/likely pathogenic variants was not different in patients with familial cardiomyopathy (15/33 with family history versus 25/76 with no family history, P=0.21). TTN truncating variants occurred in a higher percentage of children diagnosed as teenagers (26% teenagers versus 6% younger children, P=0.01), but life‐threatening cardiac outcomes occurred in both infants and teenagers with these TTN variants. DCM with left ventricular noncompaction features occurred in 6/6 patients with MYH7 variants between amino acids 1 and 600.ConclusionsSarcomeric variants were common in pediatric DCM. We demonstrated genotype‐specific associations with age of diagnosis and cardiac outcomes. In particular, MYH7 had domain‐specific association with DCM with left ventricular noncompaction features. Family history did not predict pathogenic/likely pathogenic variants, reinforcing that genetic testing should be considered in all children with idiopathic DCM.

Idiopathic dilated cardiomyopathy as cor bovinum in infancy: “A foggy road in winter”

Dilated cardiomyopathy, when diagnosed in infancy, poses an array of difficulties from reaching an etiological diagnosis to prognosticating the long-term outcome. Here, we report a case of idiopathic dilated cardiomyopathy in a 6-month-old child who responded well to beta-blocker (Carvedilol) in optimum dosage and revealed favorable cardiac remodeling over 6 months with substantial improvement in ejection fraction (EF) (EF of 22–44%) with significant amelioration of child’s symptoms. Our case has a unique message that while treating idiopathic dilated cardiomyopathy (DCM) in infancy, optimized use of the beta-blockers is most often the only way to clear the foggy road of idiopathic DCM and obtain a favorable outcome.

Altered Aortic Hemodynamics and Relative Pressure in Patients with Dilated Cardiomyopathy

Ventricular-vascular interaction is central in the adaptation to cardiovascular disease. However, cardiomyopathy patients are predominantly monitored using cardiac biomarkers. The aim of this study is therefore to explore aortic function in dilated cardiomyopathy (DCM). Fourteen idiopathic DCM patients and 16 controls underwent cardiac magnetic resonance imaging, with aortic relative pressure derived using physics-based image processing and a virtual cohort utilized to assess the impact of cardiovascular properties on aortic behaviour. Subjects with reduced left ventricular systolic function had significantly reduced aortic relative pressure, increased aortic stiffness, and significantly delayed time-to-pressure peak duration. From the virtual cohort, aortic stiffness and aortic volumetric size were identified as key determinants of aortic relative pressure. As such, this study shows how advanced flow imaging and aortic hemodynamic evaluation could provide novel insights into the manifestation of DCM, with signs of both altered aortic structure and function derived in DCM using our proposed imaging protocol.Graphic r

157 Efficacy and tolerability of sacubitril/valsartan in patients with chronic heart failure and reduced ejection fraction

Abstract Aims The PARADIGM-HF study has shown, as is well known, that the association of sacubitril/valsartan (SV) was superior in terms of efficacy compared to enalapril in patients suffering from heart failure chronic cardiac (SC) and reduced systolic function (HFrEF). We have analysed the use of SV in patients with symptomatic HF and HFrEF, andits effect on humoural and functional parameters of easy evaluation. Methods and results From March 2018 to December 2019 we have introduced the SV in 158 patients 135 M and 23 F mean age 40–80 years with fraction of ejection <35% with idiopathic dilated cardiomyopathy (six patients) or post-ischaemic (150 patients), in NYHA III class. Patients were declared eligible according to the ESC 2016 criteria (EF 40%, NT-proBNP> 400 ng/l, target dose of ACE inhibitors/receptor antagonists angiotensin, GFR> 30 ml/min/1.73 m2, serum S-potassium <5.2 mmol/l, treatment with beta-blockers and antialdosteronics). Initially the administration of SV was a cp of 49/51 mg bid up to maximum tolerated dose (one tablet of 97/103 mg bid). All the patients had stopped taking ACE-I or sartans 48 h before and were evaluated at 4-week intervals for two years. In all patients we evaluated: ejection fraction (FE), filtered glomerular, systolic blood pressure, body weight, side effects, hospitalization and mortality. Of the 156 patients, 17 achieved the optimal dose of SV (97/103 mg), 113 achieved SV 49/51 mg bid. In all patients did not experience side effects or alterations of the electrolyte picture and renal function. The SV has determined an improvement NYHA class of at least 1; the echocardiogram showed a significant increase in FE: at follow-up 89 patients reached FE 45%, 44 patients FE 40–44%, and 6 patients about 50%; besides it is an improvement in indexed end-diastolic volume in moles was noted above patients (from 118.4 ± 38.4 to 110.9 ± 30 ml/m2). No case of re-hospitalization. Conclusions Our experience shows that the use of SV is well tolerated, improves functional capacity and ventricular remodelling and that does not modify the parameters of renal function and electrolytic of the patients.

Long‐chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy

Barth syndrome (BTHS) is an X-linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age- and sex-matched patients with idiopathic dilated cardiomyopathy (DCM) and nonfailing controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso-) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long-chain fatty acid oxidation enzymes and the tissue acyl-CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta-oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids, and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy.

Machine-learning–based exploration to identify remodeling patterns associated with death or heart-transplant in pediatric-dilated cardiomyopathy

We investigated left ventricular (LV) remodeling, mechanics, systolic and diastolic function, combined with clinical characteristics and heart-failure treatment in association to death or heart-transplant (DoT) in pediatric idiopathic, genetic or familial dilated cardiomyopathy (DCM), using interpretable machine-learning. Echocardiographic and clinical data from pediatric DCM and healthy controls were retrospectively analyzed. Machine-learning included whole cardiac-cycle regional longitudinal strain, aortic, mitral and pulmonary vein Doppler velocity traces, age and body surface area. We used unsupervised multiple kernel learning for data dimensionality reduction, positioning patients based on complex conglomerate information similarity. Subsequently, k-means identified groups with similar phenotypes. The proportion experiencing DoT was evaluated. Pheno-grouping identified 5 clinically distinct groups that were associated with differing proportions of DoT. All healthy controls clustered in groups 1 to 2, while all, but one, DCM subjects, clustered in groups 3 to 5; internally validating the algorithm. Cluster-5 comprised the oldest, most medicated patients, with combined systolic and diastolic heart-failure and highest proportion of DoT. Cluster-4 included the youngest patients characterized by severe LV remodeling and systolic dysfunction, but mild diastolic dysfunction and the second-highest proportion of DoT. Cluster-3 comprised young patients with moderate remodeling and systolic dysfunction, preserved apical strain, pronounced diastolic dysfunction and lowest proportion of DoT. Interpretable machine-learning, using full cardiac-cycle systolic and diastolic data, mechanics and clinical parameters, can potentially identify pediatric DCM patients at high-risk for DoT, and delineate mechanisms associated with risk. This may facilitate more precise prognostication and treatment of pediatric DCM.

Distinct Microbial Communities in Dilated Cardiomyopathy Explanted Hearts Are Associated With Different Myocardial Rejection Outcomes.

BackgroundIdiopathic dilated cardiomyopathy (IDCM) myocardial inflammation may be associated with external triggering factors such as infectious agents. Here, we searched if moderate/severe heart transplantation rejection is related to the presence of myocardial inflammation in IDCM explanted hearts, associated with microbial communities.MethodReceptor myocardial samples from 18 explanted hearts were separated into groups according to post-transplant outcome: persistent moderate rejection (PMR; n = 6), moderate rejection (MR; n = 7) that regressed after pulse therapy, and no rejection (NR; n = 5)/light intensity rejection. Inflammation was quantified through immunohistochemistry (IHC), and infectious agents were evaluated by IHC, molecular biology, in situ hybridization technique, and transmission electron microscopy (TEM).ResultsNR presented lower numbers of macrophages, as well as B cells (p = 0.0001), and higher HLA class II expression (p ≤ 0.0001). PMR and MR showed higher levels of Mycoplasma pneumoniae (p = 0.003) and hepatitis B core (p = 0.0009) antigens. NR presented higher levels of parvovirus B19 (PVB19) and human herpes virus 6 (HHV6) and a positive correlation between Borrelia burgdorferi (Bb) and enterovirus genes. Molecular biology demonstrated the presence of M. pneumoniae, Bb, HHV6, and PVB19 genes in all studied groups. TEM revealed structures compatible with the cited microorganisms.ConclusionsThis initial study investigating on infectious agents and inflammation in the IDCM explanted hearts showed that the association between M. pneumoniae and hepatitis B core was associated with a worse outcome after HT, represented by MR and PMR, suggesting that different IDCM microbial communities may be contributing to post-transplant myocardial rejection.

Abstract 12851: Prognostic Value Of Late Gadolinium Enhancement In Patients With Idiopathic Dilated Cardiomyopathy

Introduction: The aim of this study was to investigate the association between the extent and pattern of late gadolinium enhancement (LGE) and outcomes in a large idiopathic dilated cardiomyopathy (DCM) cohort Hypothesis: LGE is associated with worse outcomes in patient with idiopathic dilated cardiomyopathy Methods: In this study, we retrospectively identified all patients with idiopathic DCM who underwent cardiac MRI (CMR) from 2015 to 2020 at a single large academic center. The association between the pattern of LGE and event free survival from transplantation and mechanical circulatory support was analyzed using Kaplan Meier analysis and the log-rank test. Results: Of a total of 286 patients (64% male, 62% Caucasian) with idiopathic DCM who underwent CMR, LGE was detected in 59 (21%) patients. Of the patients with LGE, 7 (3%) patients had free-wall LGE, 40 (14%) had septal LGE and 12 (4%) had both septal and free wall LGE. All patients had linear mid-wall LGE and two patients had both linear-mid wall and sub-epicardial involvement. The presence of septal LGE was associated with older age (58 ± 12 vs 47 ± 16 years, p<0.001), a lower LV ejection fraction (EF) (30% ± 12 vs 37% ± 12, p<0.001), higher LV end-diastolic volume index (146 ± 47 vs 126 ± 36 ml/m 2 , p<0.001), lower right ventricular EF (37% ± 13 vs 42% ± 13, p=0.013), higher LV mass index (82 ± 25 vs 73 ± 24 g/m 2 , p=0.013), higher incidence of LBBB (29% ± 16 vs 16% ± 29) and atrial fibrillation (31% vs 17%, p=0.021). Over a mean follow-up time of 26 ± 19 months, patients with septal LGE were less likely to experience event free survival from heart transplant or durable mechanical circulatory support (Figure 1, p=0.009). Conclusions: The presence of septal LGE in this large idiopathic DCM cohort is associated with worse outcomes. Additional research is needed to determine whether these findings will aid clinical management of these patients.

Abstract 9479: Novel Predictors of Left Ventricular Reverse Remodeling in Patients With Recent-onset Dilated Cardiomyopathy Using T1 and T2 Mapping on Cardiac Magnetic Resonance

Introduction: The prognosis of patients with idiopathic dilated cardiomyopathy (DCM) has improved in recent decades with guideline-directed medical therapy. There is an essential need for better biomarkers to predict left ventricular reverse remodeling (LVRR) in DCM. Native T1, T2 and left ventricular (LV) global strain by cardiac magnetic resonance (CMR) without contrast agents provides a novel quantitative method for myocardial tissue characterization. Hypothesis: CMR parameters predict LVRR in patients with DCM. Methods: A total 34 patients ( 58 ± 13 years, 25 male) with DCM underwent baseline CMR imaging (3T Philips), including cine, late gadolinium enhancement (LGE) CMR, and triple-slice T1 and T2 mapping (short modified look locker inversion recovery ShMOLLI sequence). The 6SD-LGE (% area), global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), global radial strain (GRS), LV mass index (LVMI), LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) were calculated from multiple short-axis views. Echocardiography was conducted before and > 1 year after after optimal medical therapy. Results: The patients were divided into two groups, LVRR with LVEF increase of >10% and the final value of ≥40% for those without. There were no significant differences in LV mass index, LVEDV, LVESV, and LVEF between the two groups (80 ± 20 g/m 2 vs 78 ± 19 g/m 2 ; 174 ± 54 ml vs 165 ± 48 ml; 134 ± 51 ml vs 122 ± 46 ml; 24 ± 9% vs 28 ± 9%, respectively). The any LV global strain showed no significant difference between the two groups. The 6SD-LGE, native T1, and T2 values were significantly lower in LVRR+ group than in LVRR-group (15.3 ± 15.5 % vs 5.9 ± 6.8%;1376 ± 59 ms vs 1301 ± 42 ms;55 ± 3.5 ms vs 50 ± 2.5 ms,respectively). The LGE-6SD < 13%. native T1 value < 1330 ms and T2 values < 53ms were the best threshold values for predicting LVRR (The LGE-6SD: sensitivity, 82%; specificity, 41%; AUC 0.72, T1:sensitivity, 82%; specificity, 71%; AUC 0.87, and T2: sensitivity, 82%; specificity, 63%; AUC 0.88). Conclusions: Native T1 and T2 mapping values may be useful for assessing of the LVRR in patients with DCM even without contrast.

Abstract 13550: Genotype-Phenotype Mismatch of Val122Ile Transthyretin Mutation in Dilated Cardiomyopathy

Introduction: An estimated 3.4% of African Americans carry the Valine 122 Isoleucine (Val122Ile) mutation associated with hereditary transthyretin (TTR) amyloidosis cardiomyopathy (hATTR-CM). Val122Ile is inherited in an autosomal dominant pattern, but penetrance of the clinical disease is variable and incompletely understood. Asymptomatic carriers therefore require screening for phenotypic manifestations of hATTR-CM before initiation of TTR-targeted therapies. Case Description: A 57-year-old African American male with non-ischemic dilated cardiomyopathy (DCM) presented in cardiogenic shock for advanced therapy evaluation. DCM was diagnosed 20 years prior, and family history was pertinent for cardiomyopathy in both parents. Echocardiography on admission revealed severely reduced left ventricular systolic function (EF 10%) with moderate cavitary dilation but no evidence of concentric or septal hypertrophy (LVeDd 6.1 cm, IVSd 0.9 cm, LVPWd 1.0 cm & LVMI 103 g/m 2 ). His family history prompted genetic testing to evaluate hereditary etiologies of DCM. However, his genetic test only revealed a heterozygous Val122Ile mutation. He underwent left ventricular assist device (LVAD) implantation, after which LV apical core biopsy was negative for Congo red staining. Discussion: This case illustrates a clear genotype (Val122Ile) - phenotype (DCM) mismatch. Although positive for the Val122Ile mutation, the lack of Congo red staining on his LV core biopsy rules out cardiac infiltration of mutated TTR amyloid fibrils and instead suggests an entirely independent, idiopathic DCM. The increasing ease and availability of genetic testing, combined with the known high prevalence of the Val122Ile mutation in the African American population will inevitably lead to more cases of genotype-phenotype mismatch. The variable penetrance of this pathogenic mutation (Val122Ile) may lead to inappropriate treatment with TTR-targeted therapies in patients without clear disease, potentially increasing patient and healthcare costs unnecessarily. Further research is needed to understand the variable penetrance of Val122Ile and factors that may predict development of clinical disease in the future.

Abstract 11041: Time Course of Recovery from Left Ventricular Systolic Dysfunction in Patients with Arrhythmia and Newly Diagnosed Heart Failure

Background: Newly diagnosed heart failure and concomitant persistent arrhythmia often is a challenging situation for clinicians, especially if left ventricular systolic dysfunction (LVSD) is otherwise not explainable. The time to recovery of arrhythmia-induced cardiomyopathy (AIC) is not well known and the prevalence of this disease is likely underestimated. Purpose: As AIC only can be diagnosed after rhythm control (RC) and thereafter recovery from LVSD (diagnosis ex juvantibus), we aimed to characterize the time course of recovery and describe the prevalence in such a specific cohort. Method and Results: We prospectively screened 95 patients hospitalized for newly diagnosed and otherwise unexplainable LVSD (left ventricular ejection fraction (LVEF) <50%) and coexisting tachyarrhythmia (atrial fibrillation/flutter + heart rate (HR) >100/min) in three cardiological centers. Coronary angiography and cardiac magnetic resonance imaging were performed to exclude other causes for LVSD. RC was achieved by electrocardioversion, ablation, pharmacologically or a combination of those. 50 of 68 included patients (age 69±11y, 63% male, LVEF 35.6±8%, mean±SD) were free from recurrent arrhythmia after 6 months and analyzed: AIC was diagnosed by any increase of ≥15% in absolute LVEF or an LVEF ≥50% with an improvement of ≥10% 6 months after RC; all others were diagnosed idiopathic DCM. LVEF was assessed by echocardiography at presentation and at follow-up visits 2, 4, and 6 months after RC. 9 patients did not meet the AIC-criteria, resulting in a prevalence of 82% for AIC. At presentation, AIC vs. DCM had smaller left ventricles (LVEDD 53.6±7.5 vs. 59.7±3.1mm, P<0.05; LVESD 44.4±6.6 vs. 51.6±5.1mm, P<0.01), biomarkers did not differ: NT-proBNP 4525±4535 vs. 4793±4076pg/mL, P=n.s., Troponin T-hs: 46.8±108.8 vs. 22.9±15.7ng/L, P=n.s.. 2 and 4 months after RC, 58% and 73% of patients fulfilled AIC criteria. Conclusion: The prevalence of AIC in patients in this specific collective with newly diagnosed and otherwise unexplainable LVSD with concomitant persistent tachycardia is surprisingly high and the time course of recovery suggests that the final diagnosis cannot be established before 6 months after rhythm restoration.

Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients.

Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients’ myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.

Left Atrial Function Predicts Outcome in Dilated Cardiomyopathy: Fast Long-Axis Strain Analysis Derived from MRI.

Background There is increasing recognition that left atrial (LA) function is prognostically important in cardiovascular disease. LA strain is a sensitive parameter to describe complex LA phasic function. However, the prognostic value of LA strain in participants with idiopathic dilated cardiomyopathy (DCM) remains unclear. Purpose To evaluate the prognostic value of LA strain derived from cardiac MRI in study participants with idiopathic DCM. Materials and Methods Participants with idiopathic DCM who underwent cardiac MRI between June 2012 and November 2018 were prospectively enrolled. The fast long-axis strain MRI method was performed to assess LA strain. The primary end point was all-cause mortality and heart transplant, and the secondary end point was a combination of primary end point, heart failure readmission, and aborted sudden cardiac death. Cox regression analyses and Kaplan-Meier survival analysis were performed to identify the association between variables and outcomes. Results There were 497 participants (mean age, 47 years ± 14 [standard deviation]; 357 men) evaluated. During a median follow-up of 36 months (interquartile range, 26-54 months), 113 participants reached primary end points and 203 participants reached secondary end points. LA reservoir, conduit and booster strain, and strain rate were lower in participants with primary end points (P < .001). In multivariable Cox regression analysis, LA reservoir strain and conduit strain were independent predictors for primary end point (hazard ratio [HR] per 1% increase, 0.95 [95% CI: 0.91, 0.99; P = .008] and 0.92 [95% CI: 0.87, 0.98; P = .010], respectively) and secondary end points (HR per 1% increase, 0.95 [95% CI: 0.93, 0.97; P < .001] and 0.93 [95% CI: 0.89, 0.97; P < .001], respectively). In addition, LA reservoir strain and conduit strain added incremental prognostic value to clinical risk factors and late gadolinium enhancement presence (all, P < .05). Conclusion Left atrial reservoir and conduit strain, derived from cardiac MRI by using the fast long-axis method, were independent predictors of adverse clinical outcomes in idiopathic dilated cardiomyopathy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh in this issue.

Frontal QRS/T angle can predict mortality in COVID-19 patients

Abstract Aims fQRS-T angle was investigated from general population including healthy people to patients who has hearth failure. It can predict mortality of myocarditis, ischemic cardiomyopathy, non-ischemic cardiomyopathy, idiopathic dilated cardiomyopathy and chronic heart failure in general population. There is no study in the literature that has been investigated for COVID-19 patients. The purpose of this retrospective multi-center study is to evaluate fQRS angle of COVID-19 patients for in-hospital mortality and need mechanical ventilation. Methods and results ECG was enrolled in 327 COVID-19 patients during admission and the fQRS angle calculated. Mechanical ventilation was needed for 119 patients and 110 of them died in hospital. Patients were divided into two groups according to their fQRS angle as fQRs&amp;gt;90° and fQRS≤90°. Percentages of mortality and need of MV according to fQRS angle were found 67.8% and 66.1% respectively in fQRs&amp;gt;90° group and 26.1%, 29.9% in fQRS≤90°group. Heart rate, SO2, fQRS, eGFR and CRP only were predictors for mortality in multivariable analysis. Mortality risk was increased 2.9-fold in univariate analysis and 1.6-fold in multivariate analysis for fQRS&amp;gt;90 patient group in respect to fQRS≤90 group. Conclusion In conclusion, a wide fQRS angle (&amp;gt;90°) was found as a predictor for mortality in-hospital and associated with the need for mechanical ventilation in COVID-19 patients. Funding Acknowledgement Type of funding sources: None. Mortality, need mechanical ventilationUnivariable and multivariable predictors

Prevalence and time course of arrhythmia-induced cardiomyopathy in patients with newly diagnosed heart failure and concomitant tachyarrhythmia – the TACHY-HF pilot trial

BackgroundArrhythmias may often be a result of heart failure, but they can also cause left-ventricular systolic dysfunction (LVSD), thereby presenting as arrhythmia-induced cardiomyopathy (AIC). AIC-diagnosis is established retrospectively when LVSD normalizes or improves significantly over time following rhythm restoration. However, the prevalence and most importantly the time course of this relevant disease remain unclear and hence merit investigation to enable the correct diagnosis.PurposeTherefore, our aim was to evaluate a) the occurrence of AIC in this clinical relevant cohort of patients with newly diagnosed and otherwise unexplainable LVSD and concomitant tachycardia and b) the time needed to fulfill the diagnostic criteria of AIC in order to facilitate a diagnostic algorithm.MethodWe prospectively screened patients hospitalized for newly diagnosed and otherwise unexplainable LVSD (i.e. left ventricular ejection fraction (LVEF) <50%) and coexisting tachyarrhythmia (atrial fibrillation/flutter + heart rate (HR) >100/min) in 3 cardiological centers. Coronary angiography and cardiac magnetic resonance imaging were performed to exclude other causes for LVSD. Patients underwent a rhythm control strategy in accordance to the local clinical pathways. LVEF was assessed by echocardiography at presentation and at follow-up (FU) visits after 2, 4, and 6 months. Patients who lost sinus rhythm (SR) during FU were excluded. Patients with any increase of ≥15% in absolute EF or an EF ≥50% with an improvement of ≥10% after 6 months of FU were assigned to the AIC-group, which is a common definition of AIC. All others were assigned to an idiopathic DCM-group as final comparator.Results68 patients were eligible, 18 of them were excluded: 1 lost to follow-up, 1 PCI, 2 COVID-19, 1 diagnosed cancer, 1 withdraw consent and 12 lost SR. Thus, our sample consists of a total of 50 patients. At presentation, mean±SD HR was 121±17/min. After rhythm therapy, HR normalized (67±10/min) and LVEF increased in both groups, see fig. 1. Surprisingly, only 9 patients did not fulfill the AIC-criteria in this specific collective resulting in a prevalence of 82% (95%-CI: 68% – 92%). This high prevalence of AIC underlines the importance of the disease. 2 and 4 months after rhythm intervention, 58% and 73% of patients fulfilled AIC-criteria (fig. 2). The sensitivity for detection of AIC by echocardiographic LVEF-measurement at months 2 and 4 of FU was 65% and 86% with a specificity of 100%, emphasizing that a FU of 6 months is necessary to certainly distinguish between AIC and idiopathic DCM.ConclusionThe prevalence of AIC in patients with newly diagnosed and otherwise unexplainable LVSD with concomitant tachycardia is 82%. Analysis of the time course of AIC clearly suggests that the final diagnosis cannot be established before 6 months after successful rhythm restoration. These results may help to improve diagnosis of AIC in daily clinical practice.Funding AcknowledgementType of funding sources: None.

Nanoscale Organisation of Ryanodine Receptors and Junctophilin-2 in the Failing Human Heart.

The disrupted organisation of the ryanodine receptors (RyR) and junctophilin (JPH) is thought to underpin the transverse tubule (t-tubule) remodelling in a failing heart. Here, we assessed the nanoscale organisation of these two key proteins in the failing human heart. Recently, an advanced feature of the t-tubule remodelling identified large flattened t-tubules called t-sheets, that were several microns wide. Previously, we reported that in the failing heart, the dilated t-tubules up to ~1 μm wide had increased collagen, and we hypothesised that the t-sheets would also be associated with collagen deposits. Direct stochastic optical reconstruction microscopy (dSTORM), confocal microscopy, and western blotting were used to evaluate the cellular distribution of excitation-contraction structures in the cardiac myocytes from patients with idiopathic dilated cardiomyopathy (IDCM) compared to myocytes from the non-failing (NF) human heart. The dSTORM imaging of RyR and JPH found no difference in the colocalisation between IDCM and NF myocytes, but there was a higher colocalisation at the t-tubule and sarcolemma compared to the corbular regions. Western blots revealed no change in the JPH expression but did identify a ~50% downregulation of RyR (p = 0.02). The dSTORM imaging revealed a trend for the smaller t-tubular RyR clusters (~24%) and reduced the t-tubular RyR cluster density (~35%) that resulted in a 50% reduction of t-tubular RyR tetramers in the IDCM myocytes (p < 0.01). Confocal microscopy identified the t-sheets in all the IDCM hearts examined and found that they are associated with the reticular collagen fibres within the lumen. However, the size and density of the RyR clusters were similar in the myocyte regions associated with t-sheets and t-tubules. T-tubule remodelling is associated with a reduced RyR expression that may contribute to the reduced excitation-contraction coupling in the failing human heart.

Cardiac Magnetic Resonance Imaging and Ventricular Tachycardias Involving the Sinuses of Valsalva in Patients With Nonischemic Cardiomyopathy

The goal of this study was to investigate the relationship between cardiac scar on late gadolinium enhancement cardiac resonance imaging (LGE-CMR) and the presence of ventricular tachycardia (VT) ablation target sites within the sinuses of Valsalva (SV). Patients with idiopathic dilated cardiomyopathy (IDCM) often have scarring involving the basal myocardium, including the SV, allowing targeting of VTs from within the SV. Forty-three consecutive patients with IDCM underwent a VT ablation procedure with pre-procedure LGE-CMR. Retrospectively, scar characteristics were compared between patients with and without VT target sites in the SV. The ratio between SV-related scarring and the total cardiac scarring was defined as the SV scar index: SV-related scarring/total cardiac scarring. VT target sites were identified in the SV in 22 (51%) of 43 patients. LGE-CMR identified peri-aortic scarring involving the SV in 34 patients (79%). Scarring extended to the septum in 26 patients, involved the lateral basal wall in 4, and both areas in 13 patients. Scar volume within the SV was larger in patients with SV-VT targets (1.7 ± 0.9cm3 vs. 0.7 ± 0.6cm3; p<0.0001) compared with other patients. A cutoff scar volume identifying SV-VT targets was 1.23cm3 in the short-axis view (area under the curve 0.82; sensitivity 0.64; specificity 0.91). The SV scar index was significantly greater in patients who had SV-VT target sites (0.33 ± 0.2 vs. 0.09 ± 0.09; p<0.0001). Patients with IDCM undergoing ablation of VT often have peri-aortic scarring visualized on LGE-CMR. Both the presence and the extent of scarring adjacent to the aortic annulus are associated with the presence of VT target sites within the SV.

Outcomes of Spironolactone Withdrawal in Dilated Cardiomyopathy With Improved Ejection Fraction.

Background: The feasibility of spironolactone withdrawal in dilated cardiomyopathy patients with improved ejection fraction remains unknown. This study sought to determine whether spironolactone can be withdrawn safely in this circumstance.Methods: Consecutive patients with idiopathic dilated cardiomyopathy and prescribed spironolactone at discharge were included in this prospective, observational cohort using the Risk Evaluation and Management in Heart Failure Trial (NCT02998788) database. Those patients who experienced an absolute left ventricular ejection fraction (LVEF) improvement ≥10% and a second measurement of LVEF >40% would choose whether to continue spironolactone therapy and be included in final analysis. The primary endpoint was dilated cardiomyopathy relapse within 12 months, defined as a more than 10% reduction in LVEF, a 15% or greater increase in LVESVi, a 2-fold rise in NT-proBNP, or clinical signs of heart failure.Results: Seventy patients achieved an ejection fraction improvement and were included in the final analysis, of whom 30 chose to continue spironolactone and 40 decided to withdraw. In primary endpoint analysis, 23 (58%) patients from the withdrawal group and 4 (13%) patients from the continuation group relapsed (relative risk for relapse: 4.31; 95% CI: 1.67–11.11; p < 0.001). Patients from the withdrawal group experienced more symptom aggravation than the continuation group. No secondary safety endpoint was recorded. Improvements in cardiac structure parameters were no longer observed after spironolactone withdrawal, while improvements persisted in continuation group.Conclusions: Most dilated cardiomyopathy patients with improved ejection fraction will relapse after spironolactone withdrawal. These results should be weighed before spironolactone withdrawal was attempted.

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing — involving genetics, imaging, or cardiovascular techniques — makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case–control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker.Key messagesThe limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM).The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies.Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters.We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

Characteristics and Outcomes of Patients with Inflammatory Cardiomyopathies Receiving Mechanical Circulatory Support: An STS–INTERMACS Registry Analysis

BackgroundDurable mechanical circulatory support (MCS) therapy improves survival in patients with advanced heart failure. Knowledge regarding the outcomes experienced by patients with inflammatory cardiomyopathy (CM) who receive durable MCS therapy is limited. Methods and ResultsWe compared patients with inflammatory CM with patients with idiopathic dilated CM enrolled in the STS–INTERMACS registry. Among 19,012 patients, 329 (1.7%) had inflammatory CM and 5978 had idiopathic dilated CM (31.4%). The patients with inflammatory CM were younger, more likely to be White, and women. These patients experienced more preoperative arrhythmias and higher use of temporary MCS. Patients with inflammatory CM had a higher rate of early adverse events (<3 months after device implant), including bleeding, arrhythmias, non–device-related infections, neurologic dysfunction, and respiratory failure. The rate of late adverse events (≥3 months) was similar in the 2 groups. Patients with inflammatory CM had a similar 1-year (80% vs 84%) and 2-year (72% vs 76%, P = .15) survival. Myocardial recovery resulting in device explant was more common among patients with inflammatory CM (5.5% vs 2.3%, P < .001). ConclusionsPatients with inflammatory CM who received durable MCS appear to have a similar survival compared with patients with idiopathic dilated CM despite a higher early adverse event burden. Our findings support the use of durable MCS in an inflammatory CM population.