Journal of Cardiovascular Development and Disease

Hypertriglyceridemia has been identified as a risk factor for cardiovascular disease and acute pancreatitis. To date, there are only few drug classes targeting triglyceride levels such as fibrates and ω-3 fatty acids. These agents are at times insufficient to address very high triglycerides and the residual cardiovascular risk in patients with mixed dyslipidemia. To address this unmet clinical need, novel triglyceride-lowering agents have been in different phases of early clinical development. In this review, the latest and experimental therapies for the management of hypertriglyceridemia are presented. Specifically, ongoing trials evaluating novel apolipoprotein C-III inhibitors, ω-3 fatty acids, as well as fibroblast growth 21 analogues are discussed. Full article

(1) Background: In cardiomyopathies, identification of genetic variants is important for the correct diagnosis and impacts family cascade screening. A classification system was published by the American College of Medical Genetics and Genomics (ACMG) in 2015 to standardize variants’ classification. The aim of the study was to determine the rate of reclassification of previously identified variants in patients with childhood-onset cardiomyopathies. (2) Methods: Medical records of patients and their relatives were screened for clinical and genetic information at the Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich. Patients without an identified genetic variant were excluded from further analyses. Previously reported variants were reevaluated by the ACMG criteria in November 2021. (3) Results: Data from 167 patients or relatives of patients with childhood-onset cardiomyopathy from 137 families were analyzed. In total, 45 different genetic variants were identified in 71 individuals. Classification changed in 29% (13/45) with the greatest shift in “variants of unknown significance” to “(likely) benign” (9/13). (4) Conclusions: In patients with childhood-onset cardiomyopathies, nearly a third of reported genetic variants change mostly to more benign classes upon reclassification. Given the impact on patient management and cascade screening, this finding underlines the importance of continuous genetic counseling and variant. Full article

Our study aimed to evaluate the potential of prognostic nutritional index (PNI) and Brain natriuretic peptide (BNP) in predicting the prognosis of heart transplantation (HTx). We retrospectively investigated 489 patients undergoing HTx between 2015 and 2020 in our center. The relationship between preoperative index and prognosis was analyzed respectively, the optimal cut-off values for preoperative PNI and BNP level were evaluated with receiver operating curve analysis. Uni-variate analysis and multivariate analysis were used to compare baseline data (sex, age, diagnosis, etc.) of groups divided by the level of PNI and BNP. Propensity score matching (PSM) was applied to eliminate bias. We calculated the C-index from the prediction efficiency of PNI and BNP. During the period, 489 recipients undergoing HTx in our center were included according to the inclusion criteria; 383 (78.3%) males and 106 (21.7%) females were included in this study, with a median age of 47.57 years old. The ROC curve showed that the optimal cut-off values of each indicator were verified as 49.345 for PNI, and 4397.500 for BNP. The multivariate analyses indicated that PNI (p = 0.047), BNP (p = 0.024), age (p = 0.0023), and waiting time (p = 0.012) were risk factors for all-cause death after HTx. Propensity score matching generated 116 pairs based on PNI level and 126 pairs based on BNP level, and the results showed that OS (overall survival) was significantly correlated with PNI (n = 232, p = 0.0113) and BNP (n = 252, p = 0.0146). Our study implied that higher PNI and lower BNP level had direct correlation with better survival after HTx. Combining PNI and BNP together would be a potential clinical preoperative instrument to predict the survival of patients after HTx, especially in short-term survival. Full article

Major advances in pediatric cardiology in recent decades, especially surgical techniques, have resulted in an increasing number of patients with congenital heart disease (CHD) surviving to adulthood. This has generated new challenges, particularly with regards to the late onset of complex arrhythmias. Abnormal anatomy, surgical scarring, chronic hypoxemia, hemodynamic compromise, neuro-hormonal abnormalities, and genetic factors can all contribute to creating a unique substrate for arrhythmia development. This review attempts to synthesize the current state of knowledge spanning the spectrum from underlying mechanisms of arrhythmias in patients with congenital heart disease to current ablative strategies. We discuss existing knowledge gaps and highlight important areas for future research. Full article

Post-transplant lymphoproliferative diseases (PTLD) are potentially fatal complications after cardiac transplantation. Most cases are Epstein–Barr virus (EBV)-related B-cell tumors, and reduction of immunosuppression treatment as well as the use of rituximab in combination with other chemotherapy are effective. However, patients with T/NK-cell PTLD post-cardiac transplantation are rarely reported. We had a patient with a fever that lasted for three weeks, with lung infiltrations and hepatosplenomegaly, who had EBV-associated hemophagocytosis 7 years after heart transplantation and was eventually diagnosed with T/NK-cell PTLD by autopsy. Although rare diseases, regular monitoring of EBV-DNA levels might be crucial for early diagnosis and treatment of PTLD. Full article

Twin-twin transfusion syndrome (TTTS) is a rare but serious cause of fetal cardiomyopathy with poorly understood pathophysiology and challenging prognostication. This study sought a nonbiased, comprehensive assessment of amniotic fluid (AF) microRNAs from TTTS pregnancies and associations of these miRNAs with clinical characteristics. For the discovery cohort, AF from ten fetuses with severe TTTS cardiomyopathy were selected and compared to ten normal singleton AF. Array panels assessing 384 microRNAs were performed on the discovery cohort and controls. Using a stringent q < 0.0025, arrays identified 32 miRNAs with differential expression. Top three microRNAs were miR-99b, miR-370 and miR-375. Forty distinct TTTS subjects were selected for a validation cohort. RT-PCR targeted six differentially-expressed microRNAs in the discovery and validation cohorts. Expression differences by array were confirmed by RT-PCR with high fidelity. The ability of these miRNAs to predict clinical differences, such as cardiac findings and later demise, was evaluated on TTTS subjects. Down-regulation of miRNA-127-3p, miRNA-375-3p and miRNA-886 were associated with demise. Our results indicate AF microRNAs have potential as a diagnostic and prognostic biomarker in TTTS. The top microRNAs have previously demonstrated roles in angiogenesis, cardiomyocyte stress response and hypertrophy. Further studies of the mechanism of actions and potential targets is warranted. Full article

Subaortic stenosis (SAS) is a rare heart disease in adults with an unclear etiology and variable clinical presentation. In some cases, SAS appears as hypertrophic cardiomyopathy with obstruction due to the accompanying systolic anterior motion of the mitral valve. A 46-year-old male with dizziness for several months presented in the outpatient department. Two-dimensional transthoracic echocardiography demonstrated a slightly hypertrophic left ventricle with normal systolic function without wall-motion abnormalities. Just below the aortic valve, a linear structure protruding from the septum side and the left-ventricular outflow tract (LVOT) side of the mitral valve was confirmed, which was causing a significant pressure gradient (mean and maximum of 91 mmHg and 138 mmHg, respectively). A diagnosis of SAS with subaortic membrane was made, and surgical myomectomy and subaortic membrane removal surgery were performed. Postoperative transthoracic echocardiography did not show flow acceleration through the LVOT, nor a significant pressure gradient across the aortic valve. This case report highlights the clinical significance of SAS with subaortic membrane, which can be confused with aortic stenosis of other etiology. Full article

Background. Measures of adverse cardiac remodeling, left ventricular global longitudinal strain (LVGLS) and left atrial (LA) phasic function, are predictive of cardiac events in patients with severe aortic stenosis (AS). How these parameters of cardiac function change following TAVR requires further investigation. Methods. A number of 109 consecutive patients with symptomatic severe AS who were seen in the heart valve clinic between 2014 and 2019 for TAVR were included. All patients underwent echocardiographic assessment prior to and 30 days following TAVR, with LVGLS and LA phasic function evaluation using 2D speckle-tracking echocardiography. Heart failure hospitalization, and death were assessed at 12 months. Results. The mean age of the study cohort was 81 ± 7.3 years. Following TAVR, there was a significant reduction in NYHA class III/IV symptoms [89 (82%) vs. 12 (11%), p < 0.01], and median mean aortic valve gradient [44 mmHg (16) vs. 9 mmHg (7), p < 0.01]. There was no significant change in the median LVEF [62% (13) vs. 62% (6.0), p = 0.2]; however, the LVGLS significantly increased following TAVR [15 ± 3.5% vs. 18 ± 3.3%, p < 0.01]. The median LA reservoir, conduit and contractile function significantly improved following TAVR [22.0% (14.0) vs. 18.0% (14.0) p < 0.01, 8.9% (5.4) vs. 7.8% (4.8) p < 0.01, 12% (11.0) vs. 9.6% (11.0) p < 0.01, respectively]. The incidence of death or heart failure hospitalization at 12 months was low, and occurred in eight patients (7.3%). Conclusions. TAVR results in significant short-term reverse LV and LA remodeling, as shown by improvement in LV GLS and all three components of LA phasic function, despite no change in the LVEF. The findings indicate the possible utility of strain imaging for the assessment of global LV and LA function following TAVR. Full article

The aim of this qualitative systematic review is to summarize and analyze the different modalities of exercise training and its potential effects in patients on extracorporeal membrane oxygenation (ECMO) support. ECMO is an outbreaking, life-saving technology of the last decades which is being used as a gold standard treatment in patients with severe cardiac, respiratory or combined cardiorespiratory failure. Critically ill patients on ECMO very often present intensive care unit-acquired weakness (ICU-AW); thus, leading to decreased exercise capacity and increased mortality rates. Early mobilization and physical therapy have been proven to be safe and feasible in critically ill patients on ECMO, either as a bridge to lung/heart transplantation or as a bridge to recovery. Rehabilitation has beneficial effects from the early stages in the ICU, resulting in the prevention of ICU-AW, and a decrease in episodes of delirium, the duration of mechanical ventilation, ICU and hospital length of stay, and mortality rates. It also improves functional ability, exercise capacity, and quality of life. Rehabilitation requires a very careful, multi-disciplinary approach from a highly specialized team from different specialties. Initial risk assessment and screening, with appropriate physical therapy planning and exercise monitoring in patients receiving ECMO therapy are crucial factors for achieving treatment goals. However, more randomized controlled trials are required in order to establish more appropriate individualized exercise training protocols. Full article

Background: Pediatric patients with cardiomyopathies are at risk of malignant arrhythmias and sudden cardiac death (SCD). An ICD may prevent SCD. The aim of this study was to evaluate ICD implantation outcomes, and to compare transvenous and subcutaneous ICDs (S-ICDs) implanted in pediatric patients with cardiomyopathies. Methods: The study is single center and retrospective, and includes pediatric patients with cardiomyopathies who required ICD implantation (2010–2021). Outcomes were recorded for appropriate/inappropriate ICD therapy and surgical complications. Transvenous ICD and S-ICD were compared. Data are presented as median values (25th–75th centiles). Results: Forty-four patients with cardiomyopathies (hypertrophic 39%, arrhythmogenic 32%, dilated 27%, and restrictive 2%) underwent transvenous (52%) and S-ICD (48%) implantation at 14 (12–17) years of age, mostly for primary prevention (73%). The follow-up period was 29 (14–60) months. Appropriate ICD therapies were delivered in 25% of patients, without defibrillation failures. Lower age at implantation and secondary prevention were significant risk factors for malignant ventricular arrhythmias that required appropriate ICD therapies. ICD-related complications were surgical complications (18%) and inappropriate shocks (7%). No significant differences in outcomes were recorded, either when comparing transvenous and S-ICD or comparing the different cardiomyopathies. Conclusions: In pediatric patients with cardiomyopathy, ICD therapy is effective, with a low rate of inappropriate shocks. Neither ICD type (transvenous and S-ICDs) nor the cardiomyopathies subgroup revealed divergent outcomes. Full article

Background: Previous animal studies reported an association of non-steroidal anti-inflammatory drugs (NSAIDs) with adverse outcomes in acute myocarditis, which is why these drugs are currently not recommended in affected patients. In this retrospective case-control study, we sought to investigate the effects of NSAID treatment in patients with acute myocarditis and myopericarditis to complement the available evidence. Method: A total of 114 patients with acute myocarditis were retrospectively enrolled. Demographical, clinical and laboratory data were extracted from hospital records. Patients who received NSAIDs (n = 39, 34.2%) were compared to controls. Follow-up on all-cause mortality was acquired for two years. Propensity score matching was additionally conducted to account for covariate imbalances between groups. Results: Treatment with NSAIDs was neither associated with a worse outcome (p = 0.115) nor with significant differences in left ventricular systolic function (p = 0.228) or in-hospital complications (p = 0.507). Conclusion: Treatment with NSAIDs was not associated with adverse outcomes in our study cohort. Together with the findings of previous studies, our results indicate that these drugs could be safely administered in patients with myocarditis and myopericarditis. Full article

Background: Complex aortic anatomy needs careful preoperative planning in which a patient-tailored approach with novel immersive techniques could serve as a valuable addition to current preoperative imaging. This pilot study aimed to investigate the technical feasibility of virtual reality (VR) as an additional imaging tool for preoperative planning in ascending aortic surgery. Methods: Ten cardiothoracic surgeons were presented with six patients who had each undergone a recent repair of the ascending aorta. Two-dimensional computed tomography images of each patient were assessed prior to the VR session. After three-dimensional (3D) VR rendering and 3D segmentation of the ascending aorta and aortic arch, the reconstructions were analyzed by each surgeon in VR via a head-mounted display. Each cardiothoracic surgeon completed a questionnaire after each planning procedure. The results of their assessments were compared to the performed operations. The primary endpoint of the present study was a change of surgical approach from open to clamped distal anastomosis, and vice versa. Results: Compared with conventional imaging, 80% of surgeons found that VR prepared them better for surgery. In 33% of cases (two out of six), the preoperative decision was adjusted due to the 3D VR-based evaluation of the anatomy. Surgeons rated CardioVR usefulness, user-friendliness, and satisfaction with median scores of 3.8 (IQR: 3.5–4.1), 4.2 (IQR: 3.8–4.6,) and 4.1 (IQR: 3.8–4.7) on a five-point Likert scale, respectively. Conclusions: Three-dimensional VR imaging was associated with improved anatomical understanding among surgeons and could be helpful in the future preoperative planning of ascending aortic surgery. Full article

Acute myocardial infarction (AMI), one of the most severe and fatal cardiovascular diseases, remains the main cause of mortality and morbidity worldwide. The objective of this study is to investigate the potential biomarkers for AMI based on bioinformatics analysis. A total of 2102 differentially expressed genes (DEGs) were screened out from the data obtained from the gene expression omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) explored the co-expression network of DEGs and determined the key module. The brown module was selected as the key one correlated with AMI. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that genes in the brown module were mainly enriched in ‘ribosomal subunit’ and ‘Ribosome’. Gene Set Enrichment Analysis revealed that ‘TNFA_SIGNALING_VIA_NFKB’ was remarkably enriched in AMI. Based on the protein–protein interaction network, ribosomal protein L9 (RPL9) and ribosomal protein L26 (RPL26) were identified as the hub genes. Additionally, the polymerase chain reaction (PCR) results indicated that the expression levels of RPL9 and RPL26 were both downregulated in AMI patients compared with controls, in accordance with the bioinformatics analysis. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of AMI. Full article

Point-of-care ultrasonography (POCUS) refers to limited bedside ultrasound used to evaluate patients for conditions specific to the scope of their practice. Given the benefits of its application, interest in its use is increasing. We aimed to review the literature and assess the potential feasibility of using POCUS of the heart and lungs in the field of obstetrics. We aim to describe its relevance and value as an adjunctive tool for critically ill obstetric patients on labor and delivery wards. Full article

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (I_Na, I_to, I_CaL, I_Kur, I_Kr, I_Ks, I_K1, I_NCX and I_NaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of I_CaL and I_NCX resulted in AP shortening, while the inhibition of I_Kur, I_Kr, I_Ks, I_K1 and I_NaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of I_Kr and I_Ks only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of I_Kr and I_Ks significantly prolonged APD and vice versa. Additionally, a 50% reduction of I_to density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable I_K1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca²⁺ concentration, promoting a repolarization failure in I_CaL upregulation above 150% and facilitating reentrant spiral waves stabilization by I_CaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of I_Kr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model’s accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims. Full article

Background: Thrombosis with cardiovascular involvement is a crucial complication in COVID-19 infection. COVID-19 infects the host by the angiotensin converting enzyme-2 receptor (ACE2r), which is expressed in endothelial cells too. Thus, COVID-related thrombotic events might be due to endothelial dysfunction. IL-6 is one of the main cytokines involved in the COVID-19 inflammatory storm. Some evidence indicates that Vitamin D (VitD) has a protective role in COVID-19 patients, but the molecular mechanisms involved are still debated. Thus, we investigated the effect of VitD on Tissue Factor and adhesion molecules (CAMs) in IL-6-stimulated endothelial cells (HUVEC). Moreover, we evaluated levels of the ACE2r gene and proteins. Finally, we studied the modulation of NF-kB and STAT3 pathways. Methods: HUVEC cultivated in VitD-enriched medium were stimulated with IL-6 (0.5 ng/mL). The TF gene (RT-PCR), protein (Western blot), surface expression (FACS) and procoagulant activity (FXa generation assay) were measured. Similarly, CAMs soluble values (ELISA) and ACE2r (RT-PCR and Western blot) levels were assessed. NF-kB and STAT3 modulation (Western blot) were also investigated. Results: VitD significantly reduced TF expression at both gene and protein levels as well as TF-procoagulant activity in IL-6-treated HUVEC. Similar effects were observed for CAMs and ACE2r expression. IL-6 modulates these effects by regulating NF-κB and STAT3 pathways. Conclusions: IL-6 induces endothelial dysfunction with TF and CAMs expression via upregulation of ACE2r. VitD prevented these IL-6 deleterious effects. Thus, it might be speculated that this is one of the hypothetical mechanism(s) by which VitD exerts its beneficial effects in COVID-19 infection. Full article

Patients with repaired Tetralogy of Fallot (rToF) typically report having preserved subjective exercise tolerance. Chronic pulmonary regurgitation (PR) with varying degrees of right ventricular (RV) dilation as assessed by cardiac magnetic resonance imaging (MRI) is prevalent in rToF and may contribute to clinical compromise. Cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capacity, and the International Physical Activity Questionnaire (IPAQ) can provide additional data on physical activity (PA) achieved. Our aim was to assess the association between CPET values, IPAQ measures, and MRI parameters. All rToF patients who had both an MRI and CPET performed within one year between March 2019 and June 2021 were selected. Clinical data were extracted from electronic records (including demographic, surgical history, New York Heart Association (NYHA) functional class, QRS duration, arrhythmia, MRI parameters, and CPET data). PA level, based on the IPAQ, was assessed at the time of CPET. Eighty-four patients (22.8 ± 8.4 years) showed a reduction in exercise capacity (median peak VO₂ 30 mL/kg/min (range 25–33); median percent predicted peak VO₂ 68% (range 61–78)). Peak VO₂, correlated with biventricular stroke volumes (RVSV: β = 6.11 (95%CI, 2.38 to 9.85), p = 0.002; LVSV: β = 15.69 (95% CI 10.16 to 21.21), p < 0.0001) and LVEDVi (β = 8.74 (95%CI, 0.66 to 16.83), p = 0.04) on multivariate analysis adjusted for age, gender, and PA level. Other parameters which correlated with stroke volumes included oxygen uptake efficiency slope (OUES) (RVSV: β = 6.88 (95%CI, 1.93 to 11.84), p = 0.008; LVSV: β = 17.86 (95% CI 10.31 to 25.42), p < 0.0001) and peak O₂ pulse (RVSV: β = 0.03 (95%CI, 0.01 to 0.05), p = 0.007; LVSV: β = 0.08 (95% CI 0.05 to 0.11), p < 0.0001). On multivariate analysis adjusted for age and gender, PA level correlated significantly with peak VO₂/kg (β = 0.02, 95% CI 0.003 to 0.04; p = 0.019). We observed a reduction in objective exercise tolerance in rToF patients. Biventricular stroke volumes and LVEDVi were associated with peak VO₂ irrespective of RV size. OUES and peak O₂ pulse were also associated with biventricular stroke volumes. While PA level was associated with peak VO₂, the incremental value of this parameter should be the focus of future studies. Full article

(1) Background: Patients with schizophrenia have higher mortality, with cardiovascular diseases being the first cause of mortality. This study aims to estimate the excess risk of hospital admission for cardiovascular events in schizophrenic patients, adjusting for comorbidity and risk factors. (2) Methods: The APNA study is a dynamic prospective cohort of all residents in Navarra, Spain. A total of 505,889 people over 18 years old were followed for five years. The endpoint was hospital admissions for a cardiovascular event. Direct Acyclic Graphs (DAG) and Cox regression were used. (3) Results: Schizophrenic patients had a Hazard Ratio (HR) of 1.414 (95% CI 1.031–1.938) of hospital admission for a cardiovascular event after adjusting for age, sex, hypertension, type 2 diabetes, dyslipidemia, smoking, low income, obesity, antecedents of cardiovascular disease, and smoking. In non-adherent to antipsychotic treatment schizophrenia patients, the HR was 2.232 (95% CI 1.267–3.933). (4) Conclusions: Patients with schizophrenia have a higher risk of hospital admission for cardiovascular events than persons with the same risk factors without schizophrenia. Primary care nursing interventions should monitor these patients and reduce cardiovascular risk factors. Full article

Endomyocardial biopsy (EMB) is a well-known diagnostic tool for the investigation and treatment of myocardial diseases and remains the gold standard for the diagnosis of myocarditis. Due to its invasiveness, with a complication rate ranging from 1 to 15%, its role in the diagnostic work-up of pediatric heart failure is not well established. The aim of this review is to define the role of EMB as diagnostic technique in the work up of children presenting with severe left ventricular dysfunction with the support of our center experience. Full article