Idiopathic Dilated Cardiomyopathy Research Articles

Expression of m6A Regulator Genes can Facilitate the Diagnosis of Chronic Heart Failure.

RNA N6-methyladenosine (m6A) is the most common type of modification in eukaryotic mRNA. The relationship between m6A modification and disease has been studied extensively, but there have been few studies on chronic heart failure (CHF). This study investigated a possible role for m6A in the diagnosis of CHF. Seven candidate m6A regulators (writers: WTAP and ZC3H13; readers: YTHDF3, FMR1, IGFBP1, and ELAVL1; eraser: FTO) were identified using a random forest (RF) model and the GSE5406 dataset from the Gene Expression Omnibus database. A nomogram model was developed to predict the risk of CHF, while consensus clustering methodology assigned CHF samples into two m6A patterns (cluster A and cluster B) according to the 7 candidate m6A regulators. Principal component analysis was used to calculate an m6A score for each sample and to quantify m6A patterns. Decision curve analysis and the nomogram model were used to obtain predictions that may be of clinical use. Patients in cluster B had higher m6A scores than patients in cluster A. Cluster B patients also had higher expression levels (ELs) of IL-4, IL-5, IL-10 and IL-13 than patients in cluster A, whereas cluster A patients had a higher EL for IL-33. The m6A cluster B pattern likely represents the ischemic heart failure (HF) disease group. m6A regulators are important in the pathogenesis of CHF associated with ischemic and idiopathic dilated cardiomyopathy, and may prove useful for the diagnosis and treatment of CHF.

Use of microaxial flow pumps in adolescents.

The Impella 5.5 has been successfully used in the adult population; however, safety and efficacy data in patients aged less than 18 years are limited. Six pediatric patients, aged 13 to 16years and weighing 45 to 113kg, underwent axillary artery graft placement and attempted placement of the Impella 5.5 device at our institution between August 2020 and March 2023. Indications for implantation were heart failure secondary to myocarditis (2), rejection of prior orthotopic heart transplant, idiopathic dilated cardiomyopathy (2), and heart failure after transposition of the great arteries repair. Placement was unsuccessful in a 13.8-year-old female patient due to prohibitively acute angulation of the right subclavian artery, and venoarterial extracorporeal membrane oxygenation cannulation was performed via the axillary graft. In 5 patients with successful Impella 5.5 placement, median duration of support was 13.5days (range, 7-42days). One experienced cardiac arrest secondary to coagulation-associated device failure, requiring temporary HeartMate3 implantation. Four patients were bridged to transplant; 3 patients received a transplant directly from Impella 5.5, and 1 patient received a transplant after HeartMate3. The final patient received the HeartMate3 on Impella day 42 and is awaiting transplant. Although exact size cutoffs and anatomy are still being determined, our experience provides a framework for use of the Impella 5.5 in adolescents.

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

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

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

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

Clinical profile and outcomes of young patients treated with implantable cardioverter defibrillators at a South African tertiary hospital: a review of two decades of implantable cardioverter defibrillator implantation and follow up.

In young patients without atherosclerotic coronary artery disease, the aetiology of sudden cardiac death (SCD) has been described in Europe and North America. However, there are important regional variations and there are limited data on the aetiology and outcome of SCD in South Africa. The objective of this study was to determine the profile and outcomes of young patients treated with implantable cardioverter defibrillators (ICDs) at a South African tertiary hospital. This study was designed as a retrospective review of patients aged 35 years or younger implanted with ICDs at Groote Schuur Hospital. During the study period, 38 patients younger than 35 years were implanted with ICDs. The mean (standard deviation) age at ICD implantation was 25.1 (7.6) years and 63.2% were male. A secondary-prevention ICD was implanted in 57.9% of the patient population, and primary prevention in the remaining 42.1%. Patients with secondary-prevention ICDs presented with ventricular tachycardia (59.1%), ventricular fibrillation (31.8%) and receipt of cardiopulmonary resuscitation but no recorded electrocardiograms (9.1%). Arrhythmogenic right ventricular cardiomyopathy (ARVC) was the leading cause of SCD in the secondary-prevention patient population (36.4%). Idiopathic dilated cardiomyopathy accounted for 50% of the primary-prevention patient population. After a median (interquartile range) follow up 32 (14-90) months, 7.9% died and 5.2% received a heart transplant; 42.1% of the study population received appropriate ICD shock therapies and 18.4% received inappropriate shock therapies. In this single-centre study from South Africa, ARVC and repaired congenital heart disease were the leading causes of SCD in patients younger than 35 years treated with secondary-prevention ICDs. Primary-prevention ICDs were frequently implanted for idiopathic dilated cardiomyopathy.

Association between low-density lipoprotein cholesterol level and all-cause mortality in idiopathic dilated cardiomyopathy patients: a single-institutional study

Aims To determine the association between all-cause mortality and low-density lipoprotein cholesterol (LDL-C) in patients with idiopathic cardiomyopathy (iDCM). Background LDL-C had long been considered as a dangerous predictor of cardiovascular diseases; however, the correlation between them was not fully clarified. Methods A total of 1058 patients who met the World Health Organization criteria for iDCM in West China Hospital (2009–2016) were enrolled in this retrospective study. Baseline demographic characteristics and correlations between variables were calculated and analyzed, and potential predictors were explored using univariate and multivariate regressions. Cox proportional hazards models were used to determine correlation on a continuous scale. Results LDL-C is an independent prognostic factor and higher LDL-C levels are associated with better prognosis in iDCM patients according to cox regression analysis. Compared with individuals which LDL > 2.28 mmol/L (75th–100th percentile), the multivariable-adjusted hazard ratio for all-cause mortality was 1.52 (95%CI: 1.03–2.26) in patients with LDL-C < 1.78 mmol/L (0–25th percentile). In patients with New York Heart Association function III and IV, LDL-C levels have a hazard ratio of 0.83 (confidence interval 0.73–0.95). Conclusions In patients with iDCM, lower LDL-C level was associated with an increased risk of all-cause mortality. The correlation between mortality and LDL-C level was stronger in patients with worse heart function. LDL-C levels have a potential predictive value in iDCM patients.

Assessment of Cardiac Functions in Children Suffering from Celiac Disease

Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed individuals. Among the complications of celiac disease, idiopathic dilated cardiomyopathy and autoimmune myocarditis are popular causes of considerable mortality and morbidity. The objective of this study is to evaluate the heart functioning in CD children.&#x0D; Methods: This cross-sectional study was conducted out on 40 children (twenty Patients diagnosed as having celiac disease and twenty healthy, age and sex matched children send as control group). All participants underwent basic laboratory investigations. Every child had an echocardiogram, which comprised both traditional echocardiography and tissue Doppler imaging.&#x0D; Results: The conventional echocardiographic assessment parameters (LVEED, LVESD, septal thickness, EF% FS%, E/A and TAPSE) were insignificantly different between both groups. There was no statistically substantial variation in mitral anulus velocity (S) and E/A among both groups. According to mean value of myocardial performance index (MPI) it was statistically significant greater in celiac disease of the affected group contrasted to the control group (P value 0.002).&#x0D; Conclusions: The tissue doppler echocardiogram can identify subclinical early stage of cardiac involvement in CD patients.

Vitamin D Deficiency and its Correlation with the Severity of Heart Disease in Dilated Cardiomyopathy Patients

Background: Cardiomyopathy is primarily a disorder of the cardiac muscle that causes myocardial dysfunction and is not the result of disease or dysfunction of other cardiac structures, systemic arterial hypertension and valvular stenosis or regurgitation. Aim: The present study aimed to determine the prevalence of vitamin D deficiency and its correlation with the severity of heart disease in patients with dilated cardiomyopathy (DCMP). Method: 70 ECHO-proven DCMP cases were enrolled from the medicine/ cardiology department of LHMC &amp; associated hospitals and ABVIMS &amp; Dr. RML Hospital, New Delhi from November 2019 to October 2021. DCMP patients with ages more than 18 years who were willing to give consent and does not meet any of the exclusion criteria were enrolled in this study. Results: Mean age of idiopathic DCMP patients was 48.3 ± 15.2. There were more males 48 (69%) than females 22 (31%). The mean ejection fraction was 26.6 ± 7.3, while the mean fractional shortening was 17.6 ± 3.1. Vitamin D deficiency was observed in 90% of patients, among which 68.5% were having moderate vitamin D deficiency and 10% were having severe vitamin D deficiency. Conclusion: In our study, vitamin D levels were inversely correlated with the severity of heart disease in DCMP patients.

Ventricular-atrial coupling in subjects with normal, preserved, and reduced left ventricular ejection fraction: insights from cardiac magnetic resonance imaging.

To assess the correlation between LA and LV strain measurements in different clinical scenarios and evaluate to what extent LA deformation contributes to the prognosis of patients. A total of 297 consecutive participants including 75 healthy individuals, 75 hypertrophic cardiomyopathy (HCM) patients, 74 idiopathic dilated cardiomyopathy (DCM), and 73 chronic myocardial infarction (MI) patients were retrospectively enrolled in this study. The associations of LA-LV coupling with clinical status were statistically analyzed by correlation, multiple linear regression, and logistic regression. Survival estimates were calculated by receiver operating characteristic analyses and Cox regression analyses. Overall, moderate correlations were found between LA and LV strain in every phase of the cardiac cycle (r: -0.598 to -0.580, all p < 0.001). The slope of the regression line of the individual strain-strain curve had a significant difference among 4 groups (-1.4 ± 0.3 in controls, -1.1 ± 0.6 in HCM, -1.8 ± 0.8 in idiopathic DCM, -2.4 ± 1.1 in chronic MI, all p < 0.05). During a median follow-up of 4.7 years, the total LA emptying fraction was independently associated with primary (hazard ratio: 0.968, 95% CI: 0.951-0.985) and secondary endpoints (hazard ratio: 0.957, 95% CI: 0.930-0.985) with an area under the curve (AUC) of 0.720 respectively, 0.806, which was significantly higher than the AUC of LV parameters. The coupled correlations between the left atria and ventricle in every phase and the individual strain-strain curve vary with etiology. LA deformation in late diastole provides prior and incremental information on cardiac dysfunction based on LV metrics. The total LA emptying fraction was an independent indicator for clinical outcome superior to that of LV typical predictors. Left ventricular-atrial coupling is not only valuable for comprehending the pathophysiological mechanisms of cardiovascular diseases caused by different etiologies but also holds significant importance for the prevention of adverse cardiovascular events and targeted treatment. • In HCM patients with preserved LVEF, LA deformation is a sensitive indicator for cardiac dysfunction prior to LV parameters with a reduced LA/LV strain ratio. • In patients with reduced LVEF, LV deformation impairment is more consequential than that of the LA with an increased LA/LV strain ratio. Furthermore, impaired LA active strain indicates potential atrial myopathy. • Among LA and LV parameters, the total LA emptying fraction is the best predictor for guiding clinical management and follow-up in patients with different statuses of LVEF.

CCND1 Overexpression in Idiopathic Dilated Cardiomyopathy: A Promising Biomarker?

Cardiomyopathy, a disorder of electrical or heart muscle function, represents a type of cardiac muscle failure and culminates in severe heart conditions. The prevalence of dilated cardiomyopathy (DCM) is higher than that of other types (hypertrophic cardiomyopathy and restrictive cardiomyopathy) and causes many deaths. Idiopathic dilated cardiomyopathy (IDCM) is a type of DCM with an unknown underlying cause. This study aims to analyze the gene network of IDCM patients to identify disease biomarkers. Data were first extracted from the Gene Expression Omnibus (GEO) dataset and normalized based on the RMA algorithm (Bioconductor package), and differentially expressed genes were identified. The gene network was mapped on the STRING website, and the data were transferred to Cytoscape software to determine the top 100 genes. In the following, several genes, including VEGFA, IGF1, APP, STAT1, CCND1, MYH10, and MYH11, were selected for clinical studies. Peripheral blood samples were taken from 14 identified IDCM patients and 14 controls. The RT-PCR results revealed no significant differences in the expression of the genes APP, MYH10, and MYH11 between the two groups. By contrast, the STAT1, IGF1, CCND1, and VEGFA genes were overexpressed in patients more than in controls. The highest expression was found for VEGFA, followed by CCND1 (p < 0.001). Overexpression of these genes may contribute to disease progression in patients with IDCM. However, more patients and genes need to be analyzed in order to achieve more robust results.

PEDS12: Use of Impella 5.5 in the Pediatric Population – Safety and Outcomes

Background: Transvalvular micro-axial flow pumps for mechanical circulatory support have continued to advance, with the latest devices providing up to 5.5L/min of flow. These devices have been successfully utilized in the adult population, however safety and efficacy data in the pediatric patient is limited. Here, we present our institutional experience with Impella 5.5 placement in pediatric patients. Methods: Five pediatric patients underwent right axillary artery graft placement and attempted placement of the Impella 5.5 device between August 2020 and January 2023 at our institution. Most patients received pre-operative imaging to evaluate axillary artery anatomy, and all undergo post-operative monitoring for hemolysis and device positioning. Results: Five pediatric patients received Impella 5.5 placement: three male and two female patients, ages 13.2, 13.7, 13.8, 16.8, and 16.9 years (Table). Indications for device implantation were heart failure secondary to myocarditis (2), allograft rejection of prior orthotopic heart transplant, idiopathic dilated cardiomyopathy, and heart failure after transposition of the great arteries repair. Impella 5.5 placement was unsuccessful in a 13.8-year-old female patient due to prohibitively acute right subclavian anatomy, and VA-ECMO cannulation was performed instead via the axillary graft. In the four patients with successful Impella 5.5 placements, median duration of support was 13.5 days (range 7-42 days). One patient experienced cardiac arrest secondary to coagulation-associated device failure, requiring temporary left ventricular assist device implantation (Figure). Three patients were bridged to transplant, two of whom received transplant directly from Impella 5.5, while one received transplant after HeartMate III. The final patient had a HeartMate III placed on Impella day 42 and is currently awaiting transplant. Conclusion: The Impella 5.5 is a minimally invasive mechanical circulatory support device which can be used to bridge pediatric patients to cardiac transplantation. Although exact size cutoff and anatomy are still being determined, our experience gives a framework for which smaller patients are still appropriate for device placement. Careful patient selection and post-placement monitoring are required to achieve optimal outcomes as a bridge to recovery, durable device, or transplant.Figure 1. Operative image demonstrating clot at Impella 5.5 outflow tract associated with cardiac arrest and device failure.

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

P289 HEART FAILURE DUE TO HIGH OUTPUT ARTERIOVENOUS FISTULA IN A DIALYSIS PATIENT AFFECTED BY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Autosomal dominant polycystic kidney disease (ADPKD) can determine end stage renal disease (ESRD) which require haemodialysis. Surgical creation of arteriovenous fistula (AVF) has been associated with development of left ventricular (LV) dilatation and high output heart failure (HF) and right ventricle (RV) dysfunction at long term follow–up. Databases show an association between ADPKD and idiopathic dilated cardiomyopathy, suggesting that PKD mutations contribute to development of heart failure. 36 ys old female patient affected by ADPKD who required in 2018 bilateral nephrectomy, due to a relapse of severe urinary tract bleeding, and then put in thrice–weekly hemodialysis. Before the procedure in 2016 an echocardiogram showed normal biventricular function, with valvular defects. An AVF, between left humeral artery and the perforator vein of the elbow, was employed as vascular access. 6 months later she was referred to our center for atypical chest pain and palpitations. A transthoracic echocardiogram showed a diffuse hypokinesia with severe left ventricular dysfunction and dilation (EF 25%, VTDi 90ml/mq), a cardiac output of 6,5 l/min, moderate mitral insufficiency, hypokinetic RV, pulmonary artery systolic pressure (PASP) of 56mmHg, severe biatrial dilatation. No signs of congestion. She was admitted to our service. The coronary angiogram was normal, ruling out an underlying ischemic cardiomyopathy. Therapy with b–blocker and ACE–I was started. Doppler ultrasonography of the AVF was performed and showed an high output fistula. Two weeks later at Hospital discharge with medical therapy only, EF improved to 43%. Five months later, the AVF was ligated, after the creation of another more distal one. Echocardiographic re–evaluation one month after the intervention showed a normalization of left ventricular function and volumes ( EF 55%, VDTi 54ml/mq)and of PASP. In 2020 she underwent renaltransplant without complications. The patient is nowadays stable only on beta–blocker for some PVCs, with ongoing annual follow–up. Even if dilated cardiomyopathy and HF in patients affected by APDKD can be caused by genetic predisposition, in our case the main factor was a high output AVF, as showed by complete reversion of left ventricular dysfunction after its ligation.

P477 PIRCHE (PREDICTED INDIRECTLY RECOGNIZABLE HLA EPITOPES) ALGORITHM AS A POSSIBLE PREDICTOR OF AMR (ANTIBODY MEDIATED REJECTION) FOLLOWING HEART TRANSPLANT, FROM LAB EXPERIENCE TO CLINICAL PRACTICE: A CASE REPORT

Abstract PIRCHE–II is an algorithm used to estimate the risk for developing alloreactivity towards HLA mismatches. A 35–year–old man with idiopathic dilated cardiomyopathy with several previous hospitalizations for heart failure is admitted to our unit for a new episode in August 2021. After evaluation, the patient was placed on the waiting list for transplant. The following month the patient underwent heart transplant. The donor had a compatible CDC crossmatch and was negative for anti–HLA antibodies. After 46 days, the patient was discharged at home in stable conditions after 2 negative endomyocardial biopsies (EMB): ISHLT’04 0. In January 2021, the patient was newly admitted for dyspnea and oliguria. Imaging revealed bilateral severe pleural effusion, biventricular cardiac disfunction; EMB showed acute rejection (ISHLT’04 3R). Panel–reactive antibody (PRA) screening found 93 % of class I PRA, 3 % of class II PRA with IgM and IgG donor–specific antibodies (DSA), C1q–positive. After 2 months, the patient was placed again on the transplant waitlist for a persistent severe biventricular disfunction, massive tricuspid regurgitation and diffuse myocardial fibrosis; class I PRA was decreasing (41 % in March 2022, 31 % in April 2022). Unfortunately, the patient died of infection before re–transplantation. After the event, which was recognized as AMR caused by class I DSA, a form rarely described in literature, we employed the PIRCHE (Predicted Indirectly Recognizable HLA Epitopes) algorithm to predict indirect donor–recipient alloreactivity: PIRCHE–II was 54. Is a high PIRCHE–II score a reliable predictor of AMR following heart transplant? More data and deeper understanding is surely needed. A correct after–transplant serologic monitoring is definitely needed to search for de–novo DSA.

Acute kidney injury in patients with acute decompensated heart failure-cardiogenic shock: Prevalence, risk factors and outcome

BackgroundAcute Kidney Injury (AKI) represents a major complication of acute heart failure and cardiogenic shock (CS). There is a paucity of data on AKI complicating acutely decompensated heart failure patients presenting with CS (ADHF-CS). We aimed to investigate AKI prevalence, risk factors and outcomes in this subgroup of patients. MethodsRetrospective observational study on patients admitted for ADHF-CS to our 12-bed Intensive Care Unit (ICU), between January 2010 and December 2019. Demographic, clinical, and biochemical variables were collected at baseline and during hospital stay. ResultsEighty-eight patients were consecutively recruited. The predominant etiologies were idiopathic dilated cardiomyopathy (47%), followed by post-ischemic (24%). AKI was diagnosed in 70 (79.5%) of patients. Forty-three out of 70 patients met the criteria for AKI at ICU admission. On multivariate analysis, a central venous pressure (CVP) higher than 10 mmHg (OR 3.9; 95%CI 1.2–12.6; p = 0.025) and serum lactate higher than 3 mmol/L (OR 4.1; 95%CI 1.01–16.3; p = 0.048) were identified to be independently associated with AKI. Age and AKI stage were independent predictors of 90-day mortality. ConclusionAKI is a common and early complication of ADHF-CS. Venous congestion and severe hypoperfusion are risk factors for AKI development. Early detection and prevention of AKI could lead to better outcome in this clinical subgroup.

Coronary Artery Disease and Prognosis of Heart Failure with Reduced Ejection Fraction.

Our aim was to determine the prognostic impact of coronary artery disease (CAD) on heart failure with reduced ejection fraction (HFrEF) mortality and readmissions. From a prospective multicenter registry that included 1831 patients hospitalized due to heart failure, 583 had a left ventricular ejection fraction of <40%. In total, 266 patients (45.6%) had coronary artery disease as main etiology and 137 (23.5%) had idiopathic dilated cardiomyopathy (DCM), and they are the focus of this study. Significant differences were found in Charlson index (CAD 4.4 ± 2.8, idiopathic DCM 2.9 ± 2.4, p < 0.001), and in the number of previous hospitalizations (1.1 ± 1, 0.8 ± 1.2, respectively, p = 0.015). One-year mortality was similar in the two groups: idiopathic DCM (hazard ratio [HR] = 1), CAD (HR 1.50; 95% CI 0.83-2.70, p = 0.182). Mortality/readmissions were also comparable: CAD (HR 0.96; 95% CI 0.64-1.41, p = 0.81). Patients with idiopathic DCM had a higher probability of receiving a heart transplant than those with CAD (HR 4.6; 95% CI 1.4-13.4, p = 0.012). The prognosis of HFrEF is similar in patients with CAD etiology and in those with idiopathic DCM. Patients with idiopathic DCM were more prone to receive heart transplant.

Considering Diastolic Dyssynchrony as a Predictor of Favorable Response in LV-Only Fusion Pacing Cardiac Resynchronization Therapy

Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″ (respectively, A″) peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling (LV end-diastolic volume 193.7 ± 81 vs. 243.2 ± 82 mL at baseline, p < 0.0028) and lower LV filling pressures (E/E' 13.2 ± 4.6 vs. 11.4 ± 4.5, p = 0.0295). DD profile improved in 65% of R with a reduction in E/E' ratio (21 ± 9 vs. 14 ± 4 ms, p < 0.0001). Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up.

Long-term milrinone therapy in children with dilated cardiomyopathy.

The aim of this study was to assess the safety and efficacy of long-term milrinone therapy in children with acute decompensated heart failure due to dilated cardiomyopathy (DCM). A single-centre retrospective study of all children ≤18 years with acute decompensated heart failure and DCM who received continuous long-term (≥7 consecutive days) intravenous milrinone between January 2008 and January 2022. The 47 patients had a median age of 3.3 months [interquartile range (IQR) 1.0-18.1], weight of 5.7kg [IQR 4.3-10.1] and fractional shortening of 11.9% [±4.7]. Idiopathic DCM (n=19) and myocarditis (n=18) were the most common diagnoses. The median milrinone infusion duration was 27 days [IQR 10-50, range 7-290]. No adverse events necessitated milrinone termination. Nine patients required mechanical circulatory support. Median follow-up was 4.2 years [IQR 2.7-8.6]. On initial admission, four patients died, six were transplanted and 79% [37/47] were discharged home. The 18 readmissions resulted in five more deaths and four transplantations. Cardiac function recovered in 60% [28/47], as measured by normalised fractional shortening. Long-term intravenous milrinone is safe and effective in paediatric acute decompensated DCM. Combined with conventional heart failure therapies, it can act as a bridge to recovery and thereby potentially reduce the need for mechanical support or heart transplantation.

Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy

Synonymous variations have always been ignored while studying the underlying genetic mechanisms for most of the human diseases. However, recent studies have suggested that these silent changes in the genome can alter the protein expression and folding. CSRP3, which is a well-known candidate gene associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), was screened for 100 idiopathic DCM cases and 100 controls. Three synonymous variations were identified viz., c.96G > A, p.K32=; c.336G > A, p.A112=; c.354G > A, p.E118=. A comprehensive in silico analysis was performed using various web based widely accepted tools, Mfold, Codon Usage, HSF3.1 and RNA22. Mfold predicted structural changes in all the variants except c.96 G > A (p.K32=), however it predicted changes in the stability of mRNA due to all the synonymous variants. Codon bias was observed as evident by the Relative Synonymous Codon Usage and Log Ratio of Codon Usage Frequencies. The Human Splicing Finder also predicted remarkable changes in the regulatory elements in the variants c.336G > A and c.354 G > A. The miRNA target prediction using varied modes available in RNA22 revealed that 70.6% of the target sites of miRNAs in CSRP3 were altered due to variant c.336G > A while 29.41% sites were completely lost. Findings of the present study suggest that synonymous variants revealed striking deviations in the structural conformation of mRNA, stability of mRNA, relative synonymous codon usage, splicing and miRNA binding sites from the wild type suggesting their possible role in the pathogenesis of DCM, either by destabilizing the mRNA structure, or codon usage bias or else altering the cis-acting regulatory elements during splicing.

Association between MMP2 gene polymorphisms and dilated cardiomyopathy in a Chinese Han population.

Dilated cardiomyopathy (DCM) belongs to the common types of cardiomyopathies. The pathogenesis remains unclear despite the fact that various genes have been found associated with DCM. MMP2 is a zinc-dependent and calcium-containing secreted endoproteinases, which could cleave a broad spectrum of substrates including extracellular matrix components and cytokines. It has proved to play an important role in the cardiovascular diseases. This study aimed to investigate the potential role of MMP2 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population. A total of 600 idiopathic DCM patients and 700 healthy controls were enrolled. Patients with contact information were followed up for a median period of 28months. Three tagged single nucleotide polymorphisms (rs243865, rs2285052, and rs2285053) in the promoter of MMP2 gene were genotyped. A series of function analysis were conducted to illuminate the underlying mechanism. The frequency of rs243865-C allele was increased in DCM patients when compared with healthy controls (P=0.001). Genotypic frequencies of rs243865 were associated with the susceptibility of DCM in the codominant, dominant, and overdominant models (P<0.05). Besides, rs243865-C allele presented a correlation with the poor prognosis of DCM patients in both dominant (HR=2.0, 95% confidence interval [CI]=1.14-3.57, P=0.017) and additive (HR=1.85, 95% CI=1.09-3.13, P=0.02) model. The statistical significance remained after adjustment for sex, age, hypertension, diabetes, hyperlipidaemia, and smoking status. There were significant differences in left ventricular end-diastolic diameter and left ventricular ejection fraction between rs243865-CC and CT genotypes. Functional analysis indicated that rs243865-C allele increased luciferase activity and the mRNA expression level of MMP2 by facilitating ZNF354C binding. Our study suggested that MMP2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese Han population.