J. Cardiovasc. Dev. Dis., Volume 9, Issue 2 (February 2022) – 34 articles

During embryonic development, changes in the cardiovascular microstructure and material properties are essential for an integrated biomechanical understanding. This knowledge also enables realistic predictive computational tools, specifically targeting the formation of congenital heart defects. Material characterization of cardiovascular embryonic tissue at consequent embryonic stages is critical to understand growth, remodeling, and hemodynamic functions. Two biomechanical loading modes, which are wall shear stress and blood pressure, are associated with distinct molecular pathways and govern vascular morphology through microstructural remodeling. Dynamic embryonic tissues have complex signaling networks integrated with mechanical factors such as stress, strain, and stiffness. While the multiscale interplay between the mechanical loading modes and microstructural changes has been studied in animal models, mechanical characterization of early embryonic cardiovascular tissue is challenging due to the miniature sample sizes and active/passive vascular components. Accordingly, this comparative review focuses on the embryonic material characterization of developing cardiovascular systems and attempts to classify it for different species and embryonic timepoints. Key cardiovascular components including the great vessels, ventricles, heart valves, and the umbilical cord arteries are covered. A state-of-the-art review of experimental techniques for embryonic material characterization is provided along with the two novel methods developed to measure the residual and von Mises stress distributions in avian embryonic vessels noninvasively, for the first time in the literature. As attempted in this review, the compilation of embryonic mechanical properties will also contribute to our understanding of the mature cardiovascular system and possibly lead to new microstructural and genetic interventions to correct abnormal development. Full article

Innate and adaptive leukocytes rapidly mobilize to ischemic tissues after myocardial infarction in response to damage signals released from necrotic cells. Leukocytes play important roles in cardiac repair and regeneration such as inflammation initiation and resolution; the removal of dead cells and debris; the deposition of the extracellular matrix and granulation tissue; supporting angiogenesis and cardiomyocyte proliferation; and fibrotic scar generation and resolution. By organizing and comparing the present knowledge of leukocyte recruitment and function after cardiac injury in non-regenerative to regenerative systems, we propose that the leukocyte response to cardiac injury differs in non-regenerative adult mammals such as humans and mice in comparison to cardiac regenerative models such as neonatal mice and adult zebrafish. Specifically, extensive neutrophil, macrophage, and T-cell persistence contributes to a lengthy inflammatory period in non-regenerative systems for adverse cardiac remodeling and heart failure development, whereas their quick removal supports inflammation resolution in regenerative systems for new contractile tissue formation and coronary revascularization. Surprisingly, other leukocytes have not been examined in regenerative model systems. With this review, we aim to encourage the development of improved immune cell markers and tools in cardiac regenerative models for the identification of new immune targets in non-regenerative systems to develop new therapies. Full article

Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape. Full article

Mitral valve prolapse (MVP) is a common cause of valvular heart disease. Although many patients with MVP have a benign course, there is increasing recognition of an arrhythmic phenotype associated with ventricular arrhythmias and sudden cardiac death (SCD). Pathophysiologic mechanisms associated with arrhythmias include cardiac fibrosis, mechanical stress induced changes in ventricular refractory periods, as well as electrophysiologic changes in Purkinje fibers. Clinically, a variety of risk factors including demographic, electrocardiographic, and imaging characteristics help to identify patients with MVP at the highest at risk of SCD and arrhythmias. Once identified, recent advances in treatment including device therapy, catheter ablation, and surgical interventions show promising outcomes. In this review, we will summarize the incidence of ventricular arrhythmias and SCD in patients with MVP, the association with mitral annular disjunction, mechanisms of arrhythmogenesis, methods for arrhythmic and SCD risk stratification including findings with multimodality imaging, and treatments for the primary and secondary prevention of SCD. Full article

Choroid plexus cysts (CPCs) are often transient and benign findings observed in pregnancy screenings. This study aimed to examine the association between the frequency of congenital heart diseases and the detection of CPCs. In this prospective case-control study, pregnant mothers with no predisposing risk factors for the development of fetal cardiac abnormalities were eligible for entry. Based on the presence or absence of CPCs on ultrasound, the enrolled fetuses were divided into two groups. All patients (n = 100) underwent two-dimensional and color Doppler echocardiography to identify potential cardiac anomalies. Overall, CPCs were detected in 53 enrolled fetuses, and the remainder were enrolled as controls (n = 47). Pathological findings, such as echogenic intracardiac focus (EIF), ductal spasm, atrial septal defect (ASD), pericardial effusion, cardiomyopathy, and congenital heart disease were found in neither group. In the CPC group, two mild and six trivial cases of tricuspid regurgitation (TR) were detected. In the controls, five cases of trivial TR were identified. In conclusion, the presence of CPCs was not associated with significant functional or structural fetal cardiac abnormalities, which may be due to altered developmental mechanisms. Full article

Background: SARS-CoV-2 can lead to several systemic complications, including myocardial injuries; these might be worsened by heavy physical activity. The optimal approach to cardiac risk stratification following SARS-CoV-2 infection in athletes for a safe return to play (RTP) still needs defining. The aim of this study was to assess the prevalence of abnormal RTP test results, according to the protocol of Italian Federation of Sport Medicine (FMSI), which was endorsed by the Italian Ministry of Health, potentially representing COVID-19-associated cardiac injuries. Methods: This was a prospective, multicenter, observational study. All consecutive competitive athletes who underwent COVID-19 RTP testing protocol from 1 May to 31 July 2021, across 60 Italian Centers of Sports Medicine, were enrolled in the study. Athletes were tested at least 30 days after negativization of the nasopharyngeal swab (or immediately after negativization in professional athletes or Probable Olympians). A 12-lead electrocardiography at rest and during maximal incremental exercise test with continuous O₂ saturation monitoring and an echocardiographic examination were part of the protocol. In athletes with “moderate” disease (NHI classification), 24 h ECG monitoring (to be performed on a training day) and Magnetic Resonance Imaging (MRI) were also performed. Results: A total of 4143 athletes (67.8% males and 32.2% females) (53% > 18 years, 20% 18–35 years and 16% > 35 years), from more than 40 different sport disciplines, were included in the study. The mean age was 22.5 ± 13.3 years, with ages ranging from 8 to 80 years. Of these athletes, 52.3% were asymptomatic, 46.4% manifested mild symptoms, 1.1% and 0.14% had moderate or severe symptoms, respectively, while critical illness was evident in one athlete. Abnormal echocardiographic findings were detected in 80 cases (1.9%), and pericarditis in 7 cases (0.2%); all were from mildly symptomatic athletes. Arrhythmic events were recorded in 239 athletes, with 224 (5.4%) in the exercise test and 15 (0.4%) during 24 h ECG monitoring. Ventricular arrhythmias were observed in 101 (2.4%) athletes from the total population (mostly isolated or couples of premature ventricular beats): 91 in the exercise test and 10 during 24 h ECG monitoring. Cardiac magnetic resonance was performed in 34 athletes; the presence of myocarditis was confirmed in 5 athletes (0.12% of the total population, 14.7% of athletes in which MRI was performed). Conclusions: According to our results, cardiac complications from SARS-CoV-2 in asymptomatic or mildly symptomatic competitive athletes are rare, and an RTP assessment based on symptoms and ECG-monitored exercise test would ensure a safe RTP in these athletes. Full article

(1) Background: ST-elevation myocardial infarction (STEMI) is an inflammatory disease in which neutrophils, macrophages, and lymphocytes accumulate in the ischemic myocardium and have important functions. Nucleolar-organizing regions (NORs) are the site of the ribosomal genes composed of ribosomal DNA and proteins. We aimed to evaluate AgNOR proteins, which have never been studied in patients with STEMI in the literature. (2) Methods: A total of 140 participants (75 with STEMI and 65 volunteers without any diagnosis of acute coronary syndrome) were included in this study. Echocardiography was carried out, and mean AgNOR number and total AgNOR area/total nuclear area (TAA/TNA) were evaluated for all individuals. (3) Results: The mean AgNOR number and TAA/TNA ratio were significantly higher in the STEMI group than the control (p < 0.001). Statistically significant relations between both TAA/TNA ratio and mean AgNOR number and interventricular septal thickness, fasting blood sugar, creatinine, HDL, hemoglobin (g/dL), WBC (µL/mL), monocytes, neutrophils, and neutrophil/lymphocyte ratio were detected (p < 0.05). Moreover, a statistically significant relation between LDL (mg/dL) and mean AgNOR number (p = 0.005) was detected. (4) Conclusion: Both AgNOR protein amounts increase depending on the hypoxia that occurs in STEMI. The AgNOR proteins may thus be promising markers in STEMI. Full article

Remote dielectric sensing (ReDS^TM) is a novel technology that noninvasively quantifies lung fluid levels. Trends in ReDS values following hemodialysis remain uninvestigated. In a 64-year-old man with clinically stable hemodynamics, 2.7 L of fluid was drained during hemodialysis whereas the ReDS value remained almost unchanged (from 32 to 30%). In a 60-year-old woman with unstable hemodynamics, only 1.8 L of fluid was drained during hemodialysis, whereas ReDS value decreased considerably from 37 to 27%. Given our initial experience measuring ReDS values during hemodialysis, the ratio of fluid removal by hemodialysis between systemic plasma and lung fluid might vary in each patient. ReDS value might be a promising marker to determine the degree of fluid removal in addition to the conventional multidisciplinary index, particularly for those with unstable hemodynamics. The implications of ReDS-guided hemodialysis remain a future concern. Full article

(1) Background: Patients with acute myocardial infarction (AMI) still experience many major adverse cardiovascular events (MACEs), including myocardial infarction, heart failure, kidney failure, coronary events, cerebrovascular events, and death. This retrospective study aims to assess the prognostic value of machine learning (ML) for the prediction of MACEs. (2) Methods: Five-hundred patients diagnosed with AMI and who had undergone successful percutaneous coronary intervention were included in the study. Logistic regression (LR) analysis was used to assess the relevance of MACEs and 24 selected clinical variables. Six ML models were developed with five-fold cross-validation in the training dataset and their ability to predict MACEs was compared to LR with the testing dataset. (3) Results: The MACE rate was calculated as 30.6% after a mean follow-up of 1.42 years. Killip classification (Killip IV vs. I class, odds ratio 4.386, 95% confidence interval 1.943–9.904), drug compliance (irregular vs. regular compliance, 3.06, 1.721–5.438), age (per year, 1.025, 1.006–1.044), and creatinine (1 µmol/L, 1.007, 1.002–1.012) and cholesterol levels (1 mmol/L, 0.708, 0.556–0.903) were independent predictors of MACEs. In the training dataset, the best performing model was the random forest (RDF) model with an area under the curve of (0.749, 0.644–0.853) and accuracy of (0.734, 0.647–0.820). In the testing dataset, the RDF showed the most significant survival difference (log-rank p = 0.017) in distinguishing patients with and without MACEs. (4) Conclusions: The RDF model has been identified as superior to other models for MACE prediction in this study. ML methods can be promising for improving optimal predictor selection and clinical outcomes in patients with AMI. Full article

Cardiovascular disease, especially coronary heart disease and cerebrovascular disease, is a leading cause of mortality and morbidity in women globally. The development of cardiometabolic conditions in pregnancy, such as gestational diabetes mellitus and hypertensive disorders of pregnancy, portend an increased risk of future cardiovascular disease in women. Pregnancy therefore represents a unique opportunity to detect and manage risk factors, prior to the development of cardiovascular sequelae. Risk prediction models for gestational diabetes mellitus and hypertensive disorders of pregnancy can help identify at-risk women in early pregnancy, allowing timely intervention to mitigate both short- and long-term adverse outcomes. In this narrative review, we outline the shared pathophysiological pathways for gestational diabetes mellitus and hypertensive disorders of pregnancy, summarise contemporary risk prediction models and candidate predictors for these conditions, and discuss the utility of these models in clinical application. Full article

Early research on neprilysin inhibition showed that sacubitril/valsartan, a combination of the valsartan and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF study in 2014. Therefore, for patients with HFrEF, worldwide recommendations have been reformed to include sacubitril/valsartan. In addition, sacubitril/valsartan has been investigated in other cardiovascular disease states, such as patients with heart failure and preserved ejection fraction (HFpEF) and following myocardial infarction (MI) events. In February 2021, the FDA expanded the indication use of sacubitril/valsartan to include the HFpEF patient population based on the results of the PARAGON-HF trial. However, randomized clinical trials post-MI did not show promising results. Sacubitril/valsartan is currently being investigated in many other cardiovascular and non-cardiovascular conditions. This review aims to shed light and summarize the ongoing sacubitril/valsartan registered studies on the United States National Library of Medicine clinical trials registry. Full article

Left bundle branch block (LBBB) is associated with specific septal-to-lateral wall activation patterns which are strongly influenced by the intrinsic left ventricular (LV) contractility and myocardial scar localization. The objective of this study was to propose a computational-model-based interpretation of the different patterns of LV contraction observed in the case of LBBB and preserved contractility or myocardial scarring. Two-dimensional transthoracic echocardiography was used to obtain LV volumes and deformation patterns in three patients with LBBB: (1) a patient with non-ischemic dilated cardiomyopathy, (2) a patient with antero-septal myocardial scar, and (3) a patient with lateral myocardial scar. Scar was confirmed by the distribution of late gadolinium enhancement with cardiac magnetic resonance imaging (cMRI). Model parameters were evaluated manually to reproduce patient-derived data such as strain curves obtained from echocardiographic apical views. The model was able to reproduce the specific strain patterns observed in patients. A typical septal flash with pre-ejection shortening, rebound stretch, and delayed lateral wall activation was observed in the case of non-ischemic cardiomyopathy. In the case of lateral scar, the contractility of the lateral wall was significantly impaired and septal flash was absent. In the case of septal scar, septal flash and rebound stretch were also present as previously described in the literature. Interestingly, the model was also able to simulate the specific contractile properties of the myocardium, providing an excellent localization of LV scar in ischemic patients. The model was able to simulate the electromechanical delay and specific contractility patterns observed in patients with LBBB of ischemic and non-ischemic etiology. With further improvement and validation, this technique might be a useful tool for the diagnosis and treatment planning of heart failure patients needing CRT. Full article

The in-depth epidemiology of hypertension has not been studied in Kazakhstan (KZ) yet. We aimed to investigate the crude; age and sex standardized prevalence, incidence, and all-cause mortality rate among hypertensive patients in Kazakhstan using a large-scale Unified National Electronic Health System (UNEHS) for the period 2014–2019. Hypertension was defined based on the ICD-10 codes (ICD-code: I10; I11; I12; I13). Of 1,908,419 patients, 1,186,706 (62.18%) were females and 721,713 (37.82%) were males. The majority of the patients (56.3%) were ethnic Kazakhs, 26.6% were Russians, and 16.2% were of other ethnicities. In 2014, the crude rates of prevalence, incidence, and mortality were 3661, 1396.1, and 33.1 per 100,000 population, respectively. The overall prevalence, incidence, and mortality rates among hypertension patients had a gradual increase over the period 2014–2019. The sex and age adjusted rates demonstrate the same trend throughout the entire period. We observed 71% higher risk of crude death in males comparing to females (Hazard ratio (HR): 1.71 [95%CI: 1.69–1.72]); Russian and other ethnicities had 1.56-fold (95%CI: 1.54–1.58 and 1.43-fold (95%CI: 1.41–1.45) higher risk of all-cause death compared to Kazakhs, and the elderly group had the highest risk of death (Hazard ratio (HR): 35.68 [95%CI: 28.11–45.31]) comparing to the younger generation, which remained significant after adjustment to age and sex. Overall, these findings show statistically significant lower survival probability in male patients compared to female, in older patients compared to younger ones, and in patients of Russian and other ethnicities compared to Kazakh. Full article

Approximately half of all women presenting to the emergency department with angina chest pain do not have obstructive coronary artery disease (CAD) on coronary angiography. This condition is termed non-obstructive coronary artery disease (NOCAD), and includes ischemia with no obstructive coronary artery disease (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA). Oxidative stress has been reported to be involved in the development and progression of CAD. However, a scarcity of studies has assessed a correlation between oxidative stress and NOCAD. Thus, a literature review was performed of available reports on the role of oxidative stress in NOCAD. Possible mechanisms involved in oxidative stress that may contribute to NOCAD were identified and evaluated. A key finding of this literature review was that oxidative stress caused vasoconstriction and endothelial damage, and this results in coronary microvascular dysfunction and vasospasm, which, in turn, lead to the pathogenesis of NOCAD. Full article

Background: Left atrial tachycardias (LAT) are a well-known outcome of pulmonary vein isolation (PVI). Few data are available on whether the catheter used to perform PVI influences the incidence, as well as the characteristics of post PVI LAT. We present data on LAT following PVI by the following three ablation technologies: (1) phased multi-electrode radiofrequency catheter (PVAC), (2) irrigated single-tip catheter (iRF), and (3) cryoballoon ablation. Methods: Using a prospectively designed single-center database, we analyzed 650 patients (300 iRF, 150 PVAC, and 200 cryoballoon) with paroxysmal (n = 401) and persistent atrial fibrillation (AF), who underwent their first PVI at our center. Results: The three populations were comparable in their baseline characteristics; however, the cryoballoon group comprised a higher percentage of patients with persistent AF (p = 0.05). The LAT rates were 3.7% in the iRF group (mean follow-up 22 ± 14 months), 0.7% in the PVAC group (mean follow-up 21 ± 14 months), and 4% in the cryoballoon group (mean follow-up 15 ± 8 months). The predominant mechanism of LAT was macro-reentrant tachycardia. Reconnection of at least one pulmonary vein was observed in 87% of the patients who underwent 3D mapping. No predictors for LAT occurrence were identified. Conclusion: The occurrence of LAT post PVI is rare; the predominant mechanism was macro-reentrant tachycardia. Reconnection of at least one pulmonary vein was observed in nearly all the LAT patients. In our retrospective analysis, the lowest rate of LAT was observed with the PVAC. No predictors for LAT occurrence were identified. Full article

Left ventricular noncompaction (LVNC) is a type of cardiomyopathy characterized anatomically by prominent ventricular trabeculation and deep intertrabecular recesses. The mortality associated with LVNC ranges from 5% to 47%. The etiology of LVNC is yet to be fully understood, although decades have passed since its recognition as a clinical entity globally. Furthermore, critical questions, i.e., whether LVNC represents an acquired pathology or has a congenital origin and whether the reduced contractile function in LVNC patients is a cause or consequence of noncompaction, remain to be addressed. In this study, to answer some of these questions, we analyzed the clinical features of LVNC patients. Out of 9582 subjects screened for abnormal cardiac functions, 45 exhibit the characteristics of LVNC, and 1 presents right ventricular noncompaction (RVNC). We found that 40 patients show valvular regurgitation, 39 manifest reduced systolic contractions, and 46 out of the 46 present different forms of arrhythmias that are not restricted to be caused by the noncompact myocardium. This retrospective examination of LVNC patients reveals some novel findings: LVNC is associated with regurgitation in most patients and arrhythmias in all patients. The thickness ratio of the trabecular layer to compact layer negatively correlates with fractional shortening, and reduced contractility might result from LVNC. This study adds evidence to support a congenital origin of LVNC that might benefit the diagnosis and subsequent characterization of LVNC patients. Full article

Background: The effect of PPM in mechanical prostheses on long-term survival is not well-established. Methods: Patients who received a 21 mm or smaller aortic valve between 2000 and 2011 were retrospectively analyzed (n = 416). Propensity matching was used in order to account for baseline differences in patient subgroups (PPM vs. no PPM; severe PPM vs. no severe PPM). Results: Five- and ten-year survival was 78 ± 3.52% and 64.51 ± 4.51% in patients with PPM, versus 83.3 ± 3.12% and 69.37 ± 4.36% in patients without (p = 0.28) when analyzed at 10.39 ± 5.25 years after the primary procedure. Independent risk factors for impaired survival, after matching, were age, serum creatinine, and severe pulmonary hypertension. Five- and ten-year survival in patients with severe PPM was 73.34 ± 6.01% and 61.76 ± 8.17%, respectively, versus 74.72 ± 5.68% and 67.50 ± 7.09% in those without (p = 0.49), at 8.82 ± 5.17 years after SAVR. Age was the only independent variable that influenced long-term survival when severe PPM was added to the model. Conclusions: PPM or severe PPM does not impact long-term survival up to 10 years in mechanical valve recipients when matching for preoperative variables. Full article

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives’ recurrence risk calculation. The previous points represent a cornerstone in patients’ empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective “autophagy” process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions. Full article

Left atrial appendage thrombus (LAAT) is a surrogate of thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). We aimed to investigate the risk factors for LAAT formation before catheter ablation and cardioversion beside the CHA2DS2-VASc score. In this case-control study, patients with NVAF who underwent transesophageal echocardiography (TEE) were included. Demographic data, laboratory results, and echocardiographic measurements were retrospectively collected. Logistic regression analysis was performed to determine risk factors predicting LAAT. Of the 543 included patients, LAAT was identified in 50 patients (9.2%). Multivariable logistic regression analysis for the entire cohort showed that NT-proBNP (per 500 ng/L increase, OR (95% CI): 1.09 (1.00–1.19), p = 0.038) and LDL-C (per 1 mmol/L increase, OR (95% CI): 1.70 (1.05–2.77), p = 0.032) were independently correlated with the presence of LAAT after the adjustment for CHA2DS2-VASc score and anticoagulant therapy. The subgroup analysis of patients without anticoagulant therapy also yielded similar results. Regarding patients with CHA2DS2-VASc scores ≤ 1, a higher level of LDL-C (per 1 mmol/L increase, OR (95% CI): 6.31 (2.38–16.74), p < 0.001) independently correlated with the presence of LAAT. The present study suggests that beyond CHA2DS2-VASc score, raised NT-proBNP and LDL-C are additional predictors for LAAT in NVAF patients. Full article

(1) Background: Minimal invasive cardiac surgery via right anterolateral thoracotomy for heart valve surgery and other intracardiac procedures proven to have lower postoperative complications. We aim to compare the neurological complications and post-operative outcomes in two cohort groups as well as survival rates up to 5 years postoperatively; (2) Methodology: Retrospective observational study for patients who had minimally invasive cardiac valve surgery with retrograde femoral arterial perfusion between 2007 and 2021 (n = 596) and the categorized patients into two groups based on their age (≥70 years old and below 70). Propensity match analysis was conducted. The primary endpoint consisted of major postoperative complications and the secondary endpoint was the long-term survival rate. (3) Results: There was no difference between the two groups in terms of postoperative outcomes. Patients ≥ 70 years old had no increased risk for neurological complications (p = 0.75) compared with those below 70 years old. The mortality rate was also not significant between the two groups (p = 0.37) as well as the crude survival rates. (4) Conclusions: The use of retrograde femoral arterial perfusion in elderly patients is not associated with increased risk compared to the younger patients’ group for a spectrum of primary cardiac valve procedures. Hence, minimally invasive approaches could be offered to elderly patients who might benefit from it. Full article

Contractility of the adult heart relates to the architectural degree of sarcomeres in individual cardiomyocytes (CMs) and appears to be inversely correlated with the ability to regenerate. In this study we utilized multiple imaging techniques to follow the sequence of sarcomere disassembly during mitosis resulting in cellular or nuclear division in a source of proliferating human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We observed that both mono- and binuclear hiPSC-CMs give rise to mononuclear daughter cells or binuclear progeny. Within this source of highly proliferative hiPSC-CMs, treated with the CHIR99021 small molecule, we found that Wnt and Hippo signaling was more present when compared to metabolic matured non-proliferative hiPSC-CMs and adult human heart tissue. Furthermore, we found that CHIR99021 increased the efficiency of non-viral vector incorporation in high-proliferative hiPSC-CMs, in which fluorescent transgene expression became present after the chromosomal segregation (M phase). This study provides a tool for gene manipulation studies in hiPSC-CMs and engineered cardiac tissue. Moreover, our data illustrate that there is a complex biology behind the cellular and nuclear division of mono- and binuclear CMs, with a shared-phenomenon of sarcomere disassembly during mitosis. Full article

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