Outcomes after SynCardia® temporary total artificial heart implantation: A 20-year single-center experience in 196 patients.

BACKGROUND: The SynCardia® temporary total artificial heart (TAH) serves as a mechanical circulatory support device for patients suffering from irreversible biventricular failure. METHODS: This retrospective study analyzed 196 consecutive patients who underwent TAH implantation at our center from 2001 to 2021. We assessed survival rates and all-cause mortality during TAH support, including survival post-heart transplantation. RESULTS: The median age of patients was 55 years, with 88% being male. The primary diagnoses included cardiomyopathy (43.9%), acute myocardial infarction (26.5%), and postcardiotomy heart failure (15.5%). At implantation, 87.2% of patients were classified as INTERMACS Profile 1. The median duration of support was 96 days (IQR: 23-227). Survival rates at 1, 6, and 12 months were 72%, 41%, and 34%, respectively. Postoperative rethoracotomy was necessary in 44.4% of patients; 39.3% experienced neurological events and 24.6% developed gastrointestinal bleeding. Overall, 64.8% of patients died while on support, primarily due to multiple organ failure (55.9%). Factors such as older age, higher bilirubin levels, postcardiotomy and specific underlying diagnoses were independent predictors of mortality during TAH support. On a positive note, 35.2% of patients underwent successful heart transplants, with 1-, 5-, and 10-year posttransplant survival rates of 65%, 58%, and 51%, respectively. CONCLUSIONS: While high mortality rates persist among patients with biventricular failure, the SynCardia® TAH offers a viable interim solution for critically ill patients, particularly those who can be successfully bridged to heart transplantation.

The Efficacy and Safety of a Low-Dose Tranexamic Acid Bolus-Only Protocol Compared with the Moderate-Dose Protocol in Valvular Heart Surgery.

In 873 propensity score-matched pairs of patients undergoing valvular heart surgery, we compared a "moderate dose" of tranexamic acid (TXA) protocol (group 1; median TXA dose: 24 mg/kg body weight) with a 1.5-g "bolus-only" protocol (group 2; median TXA dose: 19 mg/kg body weight). The number of transfused patients was higher in group 2 than in group 1 (74.5 vs 66.0%, p < 0.001), as was the number of transfused red blood cell concentrates (p = 0.001). The risks of re-exploration and convulsive seizures were similar between groups (p > 0.50). Data indicate an impaired efficacy following the "bolus-only" protocol, without a significant safety improvement.

Early and Late Results after Surgical Mitral Valve Repair: A High-Volume Center Experience.

BACKGROUND: Surgical mitral valve repair is the gold standard treatment of severe primary mitral regurgitation (MR). In the light of rapidly evolving percutaneous technologies, current surgical outcome data are essential to support heart-team-based decision-making. METHODS: This retrospective, high-volume, single-center study analyzed in 1779 patients with primary MR early morbidity and mortality, postoperative valve function, and long-term survival after mitral valve (MV) repair. Surgeries were performed between 2009 and 2022. Surgical approaches included full sternotomy (FS) and right-sided minithoracotomy (minimally invasive cardiac [MIC] surgery). RESULTS: Of the surgeries (mean age: 59.9 [standard deviation:11.4] years; 71.5% males), 85.6% (n = 1,527) were minithoracotomies. Concomitant procedures were performed in 849 patients (47.7%), including tricuspid valve and/or atrial septal defect repair, cryoablation, and atrial appendage closure. The majority of patients did not need erythrocyte concentrates. Mediastinitis and rethoracotomy for bleeding rates were 0.1 and 4.3%, respectively. Reoperation before discharge for failed repair was necessary in 12 patients (0.7%). Freedom from more than moderate MR was > 99%. Thirty-day mortality was 0.2% and did not differ significantly between groups (p = 0.37). Median follow-up was 48.2 months with a completeness of 95.9%. Long-term survival was similar between groups (p = 0.21). In the FS and MIC groups, 1-, 5-, and 10-year survival rates were 98.8 and 98.8%, 92.9 and 94.4%, and 87.4 and 83.1%, respectively. CONCLUSION: MV surgery, both minimally invasive and via sternotomy, is associated with high repair rates, excellent perioperative outcomes, and long-term survival. Data underscore the effectiveness of surgical repair in managing MR, even in the era of advancing interventional techniques.

Moderate Dose of Tranexamic Acid and Complications after Valvular Heart Surgery.

BACKGROUND: In valvular open-heart surgery, data regarding the effect of a moderate dose of tranexamic acid (TXA) on clinical outcomes are limited. METHODS: Out of a cohort of 13,293 patients, we performed a propensity-score-matched analysis in 6,106 patients and assessed the risk of convulsive seizures (CS, primary endpoint), stroke, renal replacement therapy, and mortality (secondary endpoints). In the entire study cohort of 13,293 patients, we also assessed the multivariable-adjusted association of CS with postoperative outcomes. RESULTS: The risk of CS was significantly higher in the TXA group (2.4%; n = 72) than in the non-TXA group (1.0%; n = 32), with a relative risk ratio (RR) of 2.28 (95% confidence interval [CI]: 1.50-3.47; p < 0.001). The risk of CS was also higher in patients receiving TXA doses ≥25 mg/kg body weight (3.7%; n = 40) than in patients receiving <25 mg/kg body weight (1.6%; n = 32; p < 0.001). Perioperative secondary clinical endpoints and 1-year mortality did not differ significantly between study groups (p-value > 0.05). Compared with non-CS patients (n = 13,000), patients with nonhemorrhagic, nonembolic CS (n = 253) revealed higher multivariable-adjusted in-hospital risks of stroke (RR: 3.82 [95% CI: 2.44-5.60; p < 0.001]) and mortality (RR: 2.07 [95% CI: 1.23-3.48; p = 0.006]), and a higher 1-year mortality risk (RR: 1.85 [95% CI: 1.42-2.41; p < 0.001]). CONCLUSION: A moderate TXA dose was associated with a significantly higher risk of seizure, but not with other clinical complications such as stroke, renal replacement therapy, and mortality. However, in the small group of patients experiencing a seizure, the risks of stroke and short- and mid-term mortality were substantially higher than in patients not experiencing a seizure, indicating that the use of a low-dose TXA protocol (<25 mg/kg body weight) should be considered.

Stroke after transcatheter aortic valve replacement: A severe complication with low predictability.

OBJECTIVES: We aimed to describe stroke and transient ischemic attacks (TIAs) after transcatheter aortic valve replacement (TAVR) and to identify associated risk factors. BACKGROUND: Stroke/TIA after TAVR is a major complication. METHODS: A total of 1919 concomitant patients underwent TAVR in a single center from 2007 to 2017. Pre-, intra-, and postprocedural data were collected prospectively in a database and analyzed retrospectively. Stroke and TIA were documented according to the Valve Academic Research Consortium-II criteria. Logistic regression was used to determine risk factors for stroke after TAVR. RESULTS: Mean age was 79.5 ± 6.8 years, mean logistic EuroScore was 17.6% ± 12.8%, and 51.8% (n = 994) of the patients were female. Stroke/TIA occurred in 76 patients (3.9%), 1.9% were disabling, and 1.6% nondisabling. The predominant type of stroke were territorial ischemic lesions (82.4%), with primary bleeding in 4.4% and border zone infarctions in 4.4%. Left-sided lesions were more common (45.6% left sided vs. 25% right sided) and 13.2% of the lesions were bilateral (4.4% no finding and 11.8% missing data). In multivariate logistic regression, prior stroke (odds ratio [OR] = 1.83, p = 0.046) and initial experience (first 300 TAVR implanted at our center) were identified as independent risk factors for stroke/TIA during the first 30 days (OR = 1.95, p = 0.045). Overall, the occurrence of stroke had a highly significant impact on a 30-day mortality (13.2% vs. 4.9% in patients without stroke (p = 0.005). CONCLUSION: Stroke within the first 30 days after TAVR severely impairs 30-day survival. We identified prior stroke and initial experience as significant independent risk factors for the occurrence of stroke after TAVR.

Prognosis and Clinical Results after Coronary Artery Bypass Operation in Young Patients Aged <45 Years: Chances and Limitations of a New Therapy Option.

Coronary artery bypass grafting (CABG) is the recommended type of revascularization procedure in patients with left main or three-vessel disease and is considered an alternative when percutaneous coronary intervention is not feasible. We evaluated registry data to obtain long-term outcome data.All patients ≤45 years in whom CABG was performed between 2009 and 2019 were selected from the Heart and Diabetes Center NRW, Germany. Cox regression analysis was applied to estimate the incidence risk of events after surgery.A total of 209 patients (81.8% male) were included. Mean (standard deviation) follow-up duration was 5.8 (3.1) years. The combined outcome of death, stroke, myocardial infarction, or repeated revascularization occurred in 31 patients (14.8%). Estimated mean time to event was 8.5 (standard error: 0.22) years. By the end of the follow-up period, 8 patients (3.8%) had died, among whom 2 (1.0%) died within 1 month after surgery, 1 (0.5%) within 1 year, 1 (0.5%) within 2 years, and 4 (1.9%) after 2 years.Risk factors independently associated with postsurgery events were angina pectoris CCS (Canadian Cardiovascular Society) class IV (adjusted hazard ratio [HR]: 4.954; 95% confidence interval [CI]: 1.322-18.563; p = 0.018) and STS (Society of Thoracic Surgeons) score (adjusted HR: 1.152 per scoring point; 95% CI: 1.040-1.276; p = 0.007).After performing CABG in patients ≤45 years, event-free long-term outcomes were observed in the majority of patients. Presence of angina pectoris CCS class IV and higher STS scores were independently associated with adverse postsurgery events.

Tranexamic Acid and the Risk of Delirium after Off-Pump Surgery.

We investigated whether in patients undergoing off-pump coronary artery bypass grafting surgery a single bolus of 1 g tranexamic acid (TXA) impacts the risk of postoperative delirium using the propensity score matching approach. In 2,757 pairs, the risk of delirium was 4.2% (TXA group) and 5.0% (non-TXA group), with a relative risk in the TXA versus the non-TXA group of 0.83 (95% confidence interval: 0.65-1.07; p = 0.16). There was no significant interaction between TXA administration and renal function on the risk of delirium (p = 0.12). Data indicate that a single bolus of 1 g TXA does not increase the risk of delirium in patients undergoing off-pump surgery.

Secondary aortic valve replacement in continuous flow left ventricular assist device therapy.

The purpose of the study was to investigate the outcome of secondary surgical aortic valve replacement (sSAVR) in patients with severe aortic regurgitation (AR) in the context of ventricular assist device (VAD) therapy. From 2009 to 2020, 792 patients underwent cf-LVAD implantation [HVAD (Medtronic, USA), n = 585, and HM 3 (Abbott, USA), n = 207]. All cf-LVAD patients with severe AR requiring secondary AVR were enrolled in this study. A total of six patients (median, 40 years, IQR; 34-61 years, 50% male) underwent secondary surgical aortic valve replacement (sSAVR) after cf-LVAD implantation. Median time of previous LVAD support was 26 months (IQR: 21-29 months). Two patients required additional tricuspid valve repair (TVR) and one patient underwent SAVR after failed TAVR. Four patients needed temporary right ventricular assist device (RVAD) with a median of 30 days (IQR; 29-33 days). Three patients were bridged to urgent heart transplantation due to persevering right heart failure, whereas two destination therapy (DT) candidates survived without any associated complications. An additional DT patient died of pneumonia 1 month after sSAVR. Secondary surgical aortic valve replacement in ongoing LVAD patients is an advanced procedure for a complex cohort. In our series, sSAVR was safely performed and effective, but involved a high-risk for subsequent right heart failure, requiring urgent heart transplantation. In LVAD patients with severe AR requiring treatment where TAVR is not feasible, sSAVR can be evaluated as salvage option for bridge to transplant patients or selected destination therapy candidates.

Identification of characteristics, risk factors, and predictors of recurrent LVAD thrombosis: conditions in HeartWare devices.

BACKGROUND: Redictors of repetitive left-ventricular assist device (LVAD)-thrombosis have not been studied yet. METHODS: We identified predictors of recurrent LVAD thrombosis in HeartWare (HVAD) patients in a long-term study from 2010 until 2020. We included all patients with two or more thrombolysis treatments for repetitive HVAD thrombosis and effectiveness of thrombolytic therapy was defined as freedom from stroke, death, another HVAD thrombosis, or surgical device exchange within 30 days after the event. Study endpoints also include all-cause mortality and heart transplantation. RESULTS: A total of 534 HVAD implantations have been screened, and 73 patients (13.7%) developed first HVAD thrombosis after a median of 10 months (IQR; 6-21 months). 46 of these patients had effective thrombolysis in 71.7% (n = 33/46). After a median of 14 months (IQR 4-32 months) follow-up, 17 patients (51.5%) had developed a second HVAD thrombosis and all were treated with t-PA therapy again, resulting in effectiveness in 76.5% (n = 13/17). The four patients with ineffective t-PA therapy underwent subsequent surgical HVAD exchange. Multiple Cox regression model analysis revealed time interval between HVAD implantation and first thrombosis as an independent risk factor of recurrent thrombosis (HR, 0.93, 95% CI 0.87-0.99, p = 0.031). Kaplan-Meier analysis at 3 year follow-up showed no significant difference in overall survival for recurrent vs non-recurrent thrombosis groups (log-rank test, p = 0.959). CONCLUSION: Recurrent HVAD thrombosis mostly appears within 12 months after first thrombosis. Systemic t-PA therapy for recurrent pump thrombosis seems safe, achieving comparable effectiveness rates to initial t-PA therapy. Survival does not differ between patients with or without recurrent HVAD thrombosis.

Associations of preoperative stroke and tranexamic acid administration with convulsive seizures in valvular open-heart surgery.

In cardiac surgery, use of the antifibrinolytic agent tranexamic acid (TXA) and acute perioperative stroke are both associated with convulsive seizures. We hypothesized that an older (preoperative) stroke increases the risk of TXA-associated seizures as well. To test this hypothesis, we retrospectively analyzed data from 16,110 patients who had undergone open-heart valvular surgery at our institution between 2009 and 2020. The dosing of TXA was moderate. Use of TXA and a history of stroke were both independently associated with convulsive seizure with an adjusted odds ratio (OR) of 2.40 (95%CI: 1.71-3.37) and 1.79 (95%CI: 1.27-2.54), respectively. Compared to patients without TXA administration, the adjusted OR of experiencing a seizure in TXA patients without a history of stroke was 2.44 (95%CI: 1.71-3.46) and in patients receiving TXA with a history of stroke 4.30 (95%CI: 2.65-6.99). However, there was no significant interaction between TXA use and preoperative stroke on convulsive seizures (P = 0.77). Compared to patients without seizure, for patients with seizure, the inverse probability-weighted ORs of in-hospital mortality and 30-day mortality were 3.58 (95%CI: 2.20-5.83) and 4.04 (95%CI: 2.34-6.98), respectively. We conclude that, in patients undergoing open-heart surgery, a history of stroke is independently associated with convulsive seizures but is not a contraindication for TXA use.

A homozygous DSC2 deletion associated with arrhythmogenic cardiomyopathy is caused by uniparental isodisomy.

AIMS: We aimed to unravel the genetic, molecular and cellular pathomechanisms of DSC2 truncation variants leading to arrhythmogenic cardiomyopathy (ACM). METHODS AND RESULTS: We report a homozygous 4-bp DSC2 deletion variant c.1913_1916delAGAA, p.Q638LfsX647hom causing a frameshift carried by an ACM patient. Whole exome sequencing and comparative genomic hybridization analysis support a loss of heterozygosity in a large segment of chromosome 18 indicating segmental interstitial uniparental isodisomy (UPD). Ultrastructural analysis of the explanted myocardium from a mutation carrier using transmission electron microscopy revealed a partially widening of the intercalated disc. Using qRT-PCR we demonstrated that DSC2 mRNA expression was substantially decreased in the explanted myocardial tissue of the homozygous carrier compared to controls. Western blot analysis revealed absence of both full-length desmocollin-2 isoforms. Only a weak expression of the truncated form of desmocollin-2 was detectable. Immunohistochemistry showed that the truncated form of desmocollin-2 did not localize at the intercalated discs. In vitro, transfection experiments using induced pluripotent stem cell derived cardiomyocytes and HT-1080 cells demonstrated an obvious absence of the mutant truncated desmocollin-2 at the plasma membrane. Immunoprecipitation in combination with fluorescence measurements and Western blot analyses revealed an abnormal secretion of the truncated desmocollin-2. CONCLUSION: In summary, we unraveled segmental UPD as the likely genetic reason for a small homozygous DSC2 deletion. We conclude that a combination of nonsense mediated mRNA decay and extracellular secretion is involved in DSC2 related ACM.

Impact of a Two-Filter Cerebral Embolic Protection Device on the Complexity and Risk of Transcatheter Aortic Valve Replacement.

BACKGROUND: There is a growing use of cerebral protection devices in patients undergoing transcatheter aortic valve replacement (TAVR). We aimed to analyze if the use of these devices itself has an impact on the complexity and the risk of TAVR. METHODS: Between February 2016 and July 2017, 391 patients underwent transfemoral TAVR with Medtronic CoreValve Evolut R (n = 196) or Edwards Sapien 3 (n = 195). In 39 patients, the Claret Sentinel™ embolic protection device (CS-EPD) was used. Prospectively collected data were retrospectively analyzed, comparing fluoroscopy/operation time, amount of contrast used, vascular events, and postprocedural renal function in TAVR patients with (n = 39) and without (n = 352) CS-EPD. RESULTS: The CS-EPD was placed through the right radial (n = 35) or brachial (n = 4) artery. Procedural success rate defined as correct deployment and retraction of both filters was 94.9%. No device-related vascular complications occurred. TAVR patients with CS-EPD showed a significantly higher total operation time, total fluoroscopy time, and amount of used contrast (85.4 ± 39.3 vs. 64 ± 29.8 minutes, p = 0.002; 20.7 ± 9.3 vs. 13.7 ± 7 minutes, p ≤ 0.001; 133.7 ± 42.6 vs. 109.7 ± 44.5 mL, p = 0.001). Comparing the initial third of patients receiving a CS-EPD with the last third of CS-EPD cases, procedural time had decreased significantly (102.5 ± 34.9 vs. 67 ± 11.9; p = 0.002). There were no differences in postprocedural renal failure (p = 0.80). CONCLUSION: Our data add evidence that the application of the CS-EPD is not associated with an additional risk for the patient. Although procedural time and amount of contrast are still higher when using the CS-EPD, there were no device-related complications or increased incidence of renal failure.

TAVR in Patients on Hemodialysis: Outcome of A High-Risk Patient Group.

BACKGROUND: Perioperative mortality is high and long-term survival is poor for patients on hemodialysis undergoing surgical aortic valve replacement (SAVR). Transcatheter aortic valve replacement (TAVR) offers a safe and effective therapy for high-risk patients suffering from aortic valve stenosis. However, in patients on hemodialysis only limited information is available on the outcome following TAVR. METHODS: Of the 2613 consecutive patients in our single-center TAVR registry, all hemodialysis patients, were identified. Demographics, procedural details, clinical outcomes, mortality, and complications were evaluated. RESULTS: Forty-two hemodialysis patients with a mean age of 75.2±8.2 years, a mean STS predicted risk of mortality of 11.1±9.5% and a mean logEuroScore of 27.9±18.8% underwent TAVR. Mean duration on hemodialysis prior to intervention was 62.8±49.6 months. A transfemoral access was chosen in 24 patients, a transapical in 16, and a transaxillary and a transaortic in one patient, respectively. Estimated survival at 30 days, one, three and five years was 83.3%, 68.3%, 37.7% and 18.9%, respectively. Estimated median survival was 1.8±0.4 years. VARC-2 defined perioperative complications included stroke in 7.1% (3/42), major bleeding in 16.7% (7/42), and vascular complications in 7.1% (3/42). In two patients, echocardiographic examination at three and four years, respectively, showed evidence for structural valve deterioration. CONCLUSION: A high number of patients with ESRD undergoing TAVR require a non-transfemoral access. Predominantly, bleeding events contribute to the perioperative morbidity. An estimated median survival of less than two years after TAVR allows only limited assessment of valve prosthesis durability. Cardiovascular and non-cardiovascular mortality contribute equally to the causes of death beyond the first year after TAVR.

Human Induced Pluripotent Stem-Cell-Derived Cardiomyocytes as Models for Genetic Cardiomyopathies.

In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original discovery that pluripotency can be artificially induced by the expression of different transcription factors, various patient-specific-induced pluripotent stem cell lines have been generated to model non-ischemic, genetic cardiomyopathies in vitro. In this review, we describe the genetic landscape of non-ischemic, genetic cardiomyopathies and give an overview about different human iPSC lines, which have been developed for the disease modeling of inherited cardiomyopathies. We summarize different methods and protocols for the general differentiation of human iPSCs into cardiomyocytes. In addition, we describe methods and technologies to investigate functionally human iPSC-derived cardiomyocytes. Furthermore, we summarize novel genome editing approaches for the genetic manipulation of human iPSCs. This review provides an overview about the genetic landscape of inherited cardiomyopathies with a focus on iPSC technology, which might be of interest for clinicians and basic scientists interested in genetic cardiomyopathies.

Quality of Life and Anxiety in Younger Patients after Biological versus Mechanical Aortic Valve Replacement.

Background Since biological valve recipients are likely to need a redo procedure in the future for valve deterioration, we hypothesized patients might be more fearful about the progression of their disease than patients after aortic valve replacement (AVR) with a mechanical valve. The aim of this study is to compare the quality of life (QOL) and anxiety in patients who have undergone biological versus mechanical AVR. Method A total of 56 patients after mechanical AVR (mean age: 64.4 ± 8.17 years) and 66 patients after biological AVR (mean age: 64.8 ± 11.05 years) received three questionnaires 5.66 (± 2.68) years after surgery, including: The short form-36 (SF-36) to assess QOL, the fear of progression questionnaire (FOP), and the cardiac anxiety questionnaire (CAQ) to assess general anxiety, anxiety related to cardiac symptoms, and anxiety about progression of heart disease and valve and anticoagulation-specific questions. Results No significant differences were found for all categories of the SF-36. The FOP showed significantly favorable values for the biological AVR group. The CAQ showed a tendency in the subscale "avoidance" (i.e., avoidance of pulse increase) and "attention" towards more favorable values for the biological AVR group. Conclusions In contrast to our hypothesis, patients after mechanical AVR show significantly higher anxiety values for the FOP, and a tendency toward higher values for "avoidance" (i.e., avoidance of pulse increase). Partnership concerns, especially in terms of sexuality can be explained by factors that are recognizable for the partner, such as valve sound. These data provide evidence that factors that are continuously present after mechanical AVR, such as valve sound or anticoagulation might affect wellbeing stronger than the certainty of reoperation in the future after biological AVR. We conclude that implantation of a biological prosthesis can be justified in younger patients with regards to QOL.

Live fluorescent RNA-based detection of pluripotency gene expression in embryonic and induced pluripotent stem cells of different species.

The generation of induced pluripotent stem (iPS) cells has successfully been achieved in many species. However, the identification of truly reprogrammed iPS cells still remains laborious and the detection of pluripotency markers requires fixation of cells in most cases. Here, we report an approach with nanoparticles carrying Cy3-labeled sense oligonucleotide reporter strands coupled to gold-particles. These molecules are directly added to cultured cells without any manipulation and gene expression is evaluated microscopically after overnight incubation. To simultaneously detect gene expression in different species, probe sequences were chosen according to interspecies homology. With a common target-specific probe we could successfully demonstrate expression of the GAPDH house-keeping gene in somatic cells and expression of the pluripotency markers NANOG and GDF3 in embryonic stem cells and iPS cells of murine, human, and porcine origin. The population of target gene positive cells could be purified by fluorescence-activated cell sorting. After lentiviral transduction of murine tail-tip fibroblasts Nanog-specific probes identified truly reprogrammed murine iPS cells in situ during development based on their Cy3-fluorescence. The intensity of Nanog-specific fluorescence correlated positively with an increased capacity of individual clones to differentiate into cells of all three germ layers. Our approach offers a universal tool to detect intracellular gene expression directly in live cells of any desired origin without the need for manipulation, thus allowing conservation of the genetic background of the target cell. Furthermore, it represents an easy, scalable method for efficient screening of pluripotency which is highly desirable during high-throughput cell reprogramming and after genomic editing of pluripotent stem cells.

Essential and unexpected role of Yin Yang 1 to promote mesodermal cardiac differentiation.

RATIONALE: Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). OBJECTIVE: To identify novel regulators of mesodermal cardiac lineage commitment. METHODS AND RESULTS: We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs. CONCLUSIONS: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome - Complex Clinical Phenotypes Meet Complex Genetic Networks.

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Matched Comparison of Two Different Biological Prostheses for Complete Supra-annular Aortic Valve Replacement.

Objective The aim of this retrospective study was to evaluate the hemodynamic performance of the St. Jude Medical Trifecta (SJM Trifecta; St. Jude Medical, St Paul, Minnesota, United States) and the Carpentier-Edwards Perimount Magna Ease (CEPM Ease; Edwards Lifesciences, Irvine, California, United States) bioprostheses early postoperative and at 1 year. Methods From October 2007 to October 2008, a total of 61 consecutive patients underwent aortic valve replacement (AVR) with the CEPM Ease prosthesis. From a prospective cohort of 201 patients (March 2011 to January 2012) who received AVR with the SJM Trifecta valve, a matched group of 51 patients was selected. Matching was conducted 1:1 by ejection fraction, gender, age, and body surface area. A Hegar dilator was used to define the aortic tissue annulus diameter. Data were grouped on the basis of the patient's tissue annulus diameter (≤22 mm; 23-24 mm; ≥25 mm). Results Early postoperative and at 1 year mean pressure gradients (MPGs) in the various groups ranged from 7.2 ± 4.6 to 7.1 ± 2.4 mm Hg and from 10.0 ± 4.3 to 8.0 ± 2.8 mm Hg in the SJM Trifecta group and from 18.0 ± 5.0 to 12.1 ± 3.6 mm Hg and from 17.7 ± 4.5 to 11.8 ± 3.2 mm Hg in the CEPM Ease group, respectively. Likewise, effective orifice areas (EOAs) ranged from 1.7 ± 0.5 to 2.0 ± 0.5 cm(2) and from 1.5 ± 0.3 to 1.7 ± 0.4 cm(2) in the SJM Trifecta group and from 1.3 ± 0.5 to 1.9 ± 0.5 cm(2) and from 1.2 ± 0.3 to 1.8 ± 0.3 cm(2) in the CEPM Ease group, respectively. A marked left ventricular mass (LVM) regression across all annulus sizes was noted in both groups. Severe patient-prosthesis mismatch (PPM) was infrequent overall. Conclusion The SJM Trifecta valve showed lower MPGs early postoperative and at 1 year as well as higher EOA and effective orifice area index early postoperative. No significant differences were detected with regard to LVM regression and PPM.