Health-Related Quality of Life After Single Ventricle Palliation or Tetralogy of Fallot Repair.

Single ventricle (SV) cardiac lesions and tetralogy of Fallot (TOF) are both common forms of cyanotic congenital heart disease. With advances in perioperative care and longitudinal follow-up, survival of these patients has dramatically improved and the majority survive to adulthood. This study compares health-related quality of life (HRQoL) of adult SV and TOF patients to each other and the general population. HRQoL of all surviving, non-transplanted SV and TOF patients 21 years of age and older at our institution was assessed with the SF-36 questionnaire via phone. Additional data including demographic parameters and information related to comorbidities and healthcare utilization were also analyzed. Among 81 eligible SV patients and 207 TOF patients, 33 (41%) and 75 (36%) completed the SF-36 phone survey, respectively. The mean age of SV patients was 32 vs. 38 years in the TOF group (p=0.01). SV patients reported more hepatic, pulmonary, and renal comorbidities. TOF patients were more likely to complete advanced degrees and more likely to have children (p=0.03). SV physical functioning scores were worse compared to TOF. In other domains of the SF-36 questionnaire, SV and TOF scores were similar. Compared to the general population, both groups reported worse bodily pain and mental health, but other aspects of psychosocial and general health were comparable. Overall HRQoL is good for both SV and TOF patients through early and mid-adulthood. Some QoL metrics were modestly worse in the SV patients. While these patients may have some physical limitations, psychosocial wellbeing appears preserved.

The potential of genetically engineered pig heart transplantation in infants with complex congenital heart disease.

Despite advances in surgical and medical techniques, complex congenital heart disease in neonates and infants continues to be associated with significant mortality and morbidity. More than 500 infants in the USA are placed on the cardiac transplantation wait-list annually. However, there remains a critical shortage of deceased human donor organs for transplantation with a median wait-time of 4 months. Hence, infant mortality on the heart transplant wait-list in the USA is higher than for any other solid organ transplant group. Orthotopic transplantation of a pig heart as a bridge to allotransplantation might offer the best prospect of long-term survival of these patients. In recent years, there have been several advances in genetic engineering of pigs to mitigate the vigorous antibody-mediated rejection of a pig heart transplanted into a nonhuman primate. In this review, we briefly highlight (i) the history of clinical heart xenotransplantation, (ii) current advances and techniques of genetically engineering pigs, (iii) the current status of pig orthotopic cardiac graft survival in nonhuman primates, and (iv) progress toward pursuing clinical trials of cardiac xenotransplantation. Ultimately, we argue that pig heart xenotransplantation should initially be used as a bridge to cardiac allotransplantation in neonates and infants.

A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation.

There is a critical shortage of deceased human donor organs for transplantation. The need is perhaps most acute in neonates and infants with life-threatening congenital heart disease, in whom mechanical support devices are largely unsuccessful. If orthotopic (life-supporting) heart transplantation (OHTx) were consistently successful in the genetically engineered pig-to-nonhuman primate (NHP) model, a clinical trial of bridging with a pig heart in such patients might be justified. However, the results of pig OHTx in NHPs have been mixed and largely poor. We hypothesise that a factor is the detrimental effects of the inflammatory response that is known to develop (a) during any surgical procedure that requires cardiopulmonary bypass, and (b) immediately after an NHP recipient is exposed to a pig xenograft. We suggest that the combination of these two inflammatory responses has a direct detrimental effect on pig heart graft function, but also, and possibly of more importance, on recipient baboon pulmonary function, which further impacts survival of the pig heart graft. In addition, the inflammatory response almost certainly adversely impacts the immune response to the graft. If our hypothesis is correct, the potential steps that could be taken to reduce the inflammatory response or its effects (with varying degrees of efficacy) include (a) white blood cell filtration, (b) complement depletion or inactivation, (c) immunosuppressive therapy, (d) high-dose corticosteroid therapy, (e) cytokine/chemokine-targeted therapy, (f) ultrafiltration or CytoSorb hemoperfusion, (g) reduction in the levels of endogenous catecholamines, (h) triiodothyronine therapy and (i) genetic engineering of the organ-source pig. Prevention of the inflammatory response, or attenuation of its effects, by judicious anti-inflammatory therapy may contribute not only to early survival of the recipient of a genetically engineered pig OHTx, but also to improved long-term pig heart graft survival. This would open the possibility of initiating a clinical trial of genetically engineered pig OHTx as a bridge to allotransplantation.

Racial differences in attitudes to clinical pig organ Xenotransplantation.

INTRODUCTION: In addition to an organ donor shortage, racial disparities exist at different stages of the transplantation process. Xenotransplantation (XTx) could alleviate these issues. This study describes racial differences in attitudes to XTx among populations who may need a transplant or are transplant recipients. METHODS: A Likert-scale survey was distributed at outpatient clinics to parents of children with congenital heart disease (CHD) and kidney patients on their attitudes to pig organ XTx. Data from these two groups were stratified by race and compared. RESULTS: Ninety-seven parents of children with CHD (74.2% White and 25.8% Black) and 148 kidney patients (50% White and 50% Black) responded to our survey. Black kidney patients' acceptance of XTx although high (70%) was lower than White kidney patients (91%; P .003). White kidney patients were more likely to accept XTx if results are similar to allotransplantation (OR 4.14; 95% CI 4.51-11.41), and less likely to be concerned with psychosocial changes when compared to Black kidney patients (receiving a pig organ would change your personality OR 0.08; 95% CI 0.01-0.67 and would change social interaction OR 0.24; 95% CI 0.07-0.78). There were no racial differences in attitudes to XTx among parents of children with CHD. CONCLUSION: There are differences in attitudes to XTx particularly among Black kidney patients. Because kidneys may be the first organ for clinical trials of XTx, future studies that decrease scientific mistrust and XTx concerns among the Black community are needed to prevent disparities in uptake of possible future organ transplant alternatives.

Attitudes toward xenotransplantation: A survey of parents and pediatric cardiac providers.

BACKGROUND: Scientific advancements are occurring in cardiac xenotransplantation (XTx). However, there have been religious and social concerns surrounding this allotransplantation alternative. The purpose of this study was to explore the acceptance of XTx among stakeholders of the congenital heart disease (CHD) community. METHODS: A Likert-scale anonymous survey was distributed to physicians and nurses who care for children with CHD and parents of children with CHD. Psychosocial and clinical attitudes were compared across all groups to identify differences, and regression analysis was performed to identify factors associated with XTx acceptance. RESULTS: A total of 297 responded to the survey: 134 physicians, 62 nurses, and 101 parents. Potential acceptance of XTx if outcomes were similar to allotransplantation was high overall (75.3%), but different between the groups (physicians 86%; nurses 71%, parents 64%; P < .0001). Regression analysis showed respondents who reported religion would influence medical decision making (OR 0.48; 95%CI 0.24-0.97) and those who would not use a pig heart transplant as a bridge until a human heart became available were less likely to accept XTx (OR 0.09; 95%CI 0.04-0.21). Psychosocial concerns to XTx were minimal but were also associated with XTx acceptance particularly among parents (OR 0.17; 95%CI 0.03-0.80). CONCLUSIONS: Potential acceptance of XTx is high, assuming results are similar to allotransplantation. Religious beliefs and attitudes toward the use of XTx as a bridge to allotransplant may present barriers to XTx acceptance. Future research is needed to assess potential attitude differences in light of ethical, psychosocial, and religious objections to XTx.

Tachyarrhythmia as a possible symptom of coronavirus in a neonate diagnosed with transposition of the great arteries.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic poses broad challenges to healthcare systems and providers. The manifestations of this disease are still being described in a variety of different contexts and patient populations. RESULTS: We report the case of a neonate who demonstrated COVID-19 after surgical correction of transposition of the great arteries. In addition, the patient demonstrated an evolving and persistent tachyarrhythmia consistent with neither the most likely postoperative complications nor typical COVID-19. DISCUSSION: The patient had negative preoperative testing for the virus and presented with profound oxygen desaturation and respiratory failure several days postoperatively. This raised concern for a complication of his arterial switch operation. It was found that one of the patient's caregivers was an asymptomatic carrier of COVID-19, and imaging ruled out intracardiac shunting. After initiating treatment for COVID-19, the patient's oxygen requirements and need for anti-arrhythmic agents improved. CONCLUSION: We propose that, despite negative preoperative testing, coronavirus infection may present as refractory tachyarrhythmia, and may be considered along with surgical complications as a cause for unexplained hypoxemia postoperatively.

An approach to induction of tolerance to pig cardiac xenografts in neonates.

There is a continuing need for donor hearts for infants with complex congenital heart defects. The transplantation of hearts from neonatal pigs would be an alternative to human organs, particularly if donor-specific immunological tolerance could be achieved. The great majority of infant humans do not make natural (preformed) antibodies against triple-knockout (TKO) pigs (that do not express any of the three known pig antigens against which humans have natural anti-pig antibodies). The transplantation of a heart from a TKO pig into an infant would therefore minimize any risk of early antibody-mediated rejection, and, with adequate immunosuppressive therapy, prolonged graft survival may well be achieved. Total host thymectomy (commonly carried out at the time of orthotopic heart transplantation in this age group) ± residual T-cell depletion and donor-specific pig thymus tissue transplantation might induce T-cell tolerance and allow immunosuppressive therapy to be discontinued (if there is in vitro evidence of T-cell and B-cell nonresponsiveness to donor-specific pig cells). Even if tolerance were not achieved, with continuing immunosuppressive therapy, the graft would likely "bridge" the patient until a suitable allograft became available or be associated with prolonged xenograft function.

Furosemide Response Predicts Acute Kidney Injury After Cardiac Surgery in Infants and Neonates.

OBJECTIVE: Cardiac surgery-induced acute kidney injury occurs frequently in neonates and infants and is associated with postoperative morbidity/mortality; early identification of cardiac surgery-induced acute kidney injury may be crucial to mitigate postoperative morbidity. We sought to determine if hourly or 6-hour cumulative urine output after furosemide in the first 24 hours after cardiopulmonary bypass could predict development of cardiac surgery-induced acute kidney injury and other deleterious outcomes. DESIGN: Retrospective chart review. SETTING: Pediatric cardiac ICU. PATIENTS: All infants younger than 90 days old admitted to the cardiac ICU from October 2012 to December 2015 who received at least one dose of furosemide in the first 24 hours after cardiopulmonary bypass surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-nine patients met inclusion and exclusion criteria. In total, 45.5% developed cardiac surgery-induced acute kidney injury. Median time between cardiopulmonary bypass and furosemide was 7.7 hours (interquartile range, 4.4-9.5). Six-hour cumulative urine output was 33% lower (p = 0.031) in patients with cardiac surgery-induced acute kidney injury. Area under the curve for prediction of cardiac surgery-induced acute kidney injury was 0.69 (p = 0.002). Other models demonstrated urine output response to furosemide had significant area under the curves for prediction of peak fluid over load greater than 15% (0.68; p = 0.047), prolonged peritoneal dialysis (area under the curve, 0.79; p = 0.007), prolonged mechanical ventilation (area under the curve, 0.79; p < 0.001), prolonged hospitalization (area under the curve, 0.62; p = 0.069) and mortality (area under the curve, 0.72; p = 0.05). CONCLUSIONS: Urine output response to furosemide within 24 hours of cardiopulmonary bypass predicts cardiac surgery-induced acute kidney injury development and other important morbidity in children younger than 90 days old; prospective validation is warranted.

Correction to: Routine Sildenafil Does Not Improve Clinical Outcomes After Fontan Operation.

The original version of this article unfortunately contained a mistake. The presentation of Table 2 was incorrect .The corrected table is given below.

Central Venous to Arterial CO2 Difference After Cardiac Surgery in Infants and Neonates.

OBJECTIVES: Venous to arterial CO2 difference correlates with cardiac output in critically ill adults, but its utility in pediatric patients is unclear. We sought to correlate venous to arterial CO2 difference with other cardiac output surrogates (arteriovenous oxygen saturation difference, central venous oxygen saturation, and lactate) and investigate its capacity to predict poor outcomes associated with low cardiac output (low cardiac output syndrome) in infants after cardiac surgery with cardiopulmonary bypass. DESIGN: Retrospective chart review. Poor outcome was defined as any inotrope score greater than 15; death, cardiac arrest, extracorporeal membrane oxygenation; and unplanned surgical reintervention. SETTING: Pediatric cardiovascular ICU. PATIENTS: One hundred thirty-nine infants less than 90 days who underwent cardiopulmonary bypass, from October 2012 to May 2015. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Two hundred ninety-six arterial and venous blood gas pairs from admission (n = 139), 6 (n = 62), 12 (n = 73), and 24 hours (n = 22) were included in analysis. For all pairs, venous to arterial CO2 difference was moderately correlated with arteriovenous oxygen saturation difference (R = 0.53; p < 0.01) and central venous oxygen saturation (R = -0.43; p < 0.01), but not lactate. At admission, venous to arterial CO2 difference was also moderately correlated with central venous oxygen saturation (R = -0.40; p < 0.01) and arteriovenous oxygen saturation difference (R = 0.55; p < 0.01), but not lactate. Thirty-four of 139 neonates (24.5%) had poor outcome. Median admission venous to arterial CO2 difference was 5.9 mm Hg (3.8-9.2 mm Hg). Patients with poor outcome had median admission venous to arterial CO2 difference 8.3 (5.6-14.9) versus 5.4 mm Hg (3.0-8.4 mm Hg) in those without poor outcome. Venous to arterial CO2 difference (area under the curve = 0.69; p < 0.01), serum lactate (area under the curve = 0.64; p = 0.02), and central venous oxygen saturation (area under the curve = 0.74; p < 0.01) were predictive of poor outcome. After controlling for covariates, admission venous to arterial CO2 difference remained significantly associated with poor outcome (odds ratio, 1.3; 95% CI, 1.1-1.45), including independent association with mortality (odds ratio, 1.2; 95% CI, 1.07-1.31). CONCLUSIONS: Venous to arterial CO2 difference is correlated with important surrogates of cardiac output, and is associated with poor outcome and mortality related to low cardiac output syndrome after cardiac surgery in infants. Prospective validation of these findings, including confirmation that venous to arterial CO2 difference can identify low cardiac output syndrome in real time, is warranted.

Routine Sildenafil Does Not Improve Clinical Outcomes After Fontan Operation.

Fontan operation can be complicated by persistent chest tube output (CTO) leading to prolonged hospital length of stay (LOS). Postoperative sildenafil administration has been shown to improve clinical outcomes in selected patients after Fontan. We initiated a practice change utilizing intravenous (IV) sildenafil in early postoperative period in all patients undergoing Fontan operation with aim to decrease LOS and CTO. Nineteen patients (February 2014-May 2016) received 0.35 mg/kg sildenafil IV (three doses) followed by enteral, 1 mg/kg every eight hours until hospital discharge. Clinical outcomes were compared to 84 pre-protocol controls. Vital signs were recorded after second sildenafil dose. Demographics were similar between groups. Sildenafil group had longer median LOS [9 (7, 11) vs. 13 (8, 25) days, p = 0.016]. CTO days were longer [6 (5, 8) vs. 8 (6, 13) days, p = 0.011]. Sildenafil group had longer mechanical ventilation [6.9 (3.5, 11.1) vs. 4 (2, 7) h, p = 0.045] and longer oxygen therapy [99 (52, 225) vs. 14.5 (14, 56) h, p = 0.001]. There was a trend towards more albumin 5% resuscitation in first 24 h [17 (1, 30) vs. 21 (10, 40) ml/kg, p = 0.069]. There was no difference in inotrope score at 24 h, maximum lactate, or fluid balance. Readmission rates were similar. There was no mortality. IV sildenafil was well tolerated, and no doses were held. Routine early administration of sildenafil after Fontan operation is not associated with an improvement in any measured clinical outcome, including postoperative CTO, LOS, colloid administration, or duration of mechanical ventilation.

Early Postoperative Albumin Administration Contributes to Morbidity After the Fontan Operation.

The Fontan operation has low mortality, but is associated with significant postoperative morbidity, including prolonged chest tube output (PCTO), which is associated with prolonged hospital length of stay (PLOS). We sought to identify variables present early in the clinical course that could predict patients at high risk for PCTO and PLOS. Retrospective data were collected on 84 Fontan (extracardiac conduit) operations from 1/2008 to 12/2013 at a single institution. PCTO was defined as ≥8 days (>75th percentile); PLOS was defined as ≥12 days postoperatively (>75th percentile). Multivariate regression was used to determine covariates associated with PCTO and PLOS. Median age was 3.5 years (IQR 3-5); weight was 14.5 kg (IQR 13-17). There was no mortality. LOS was 9 days (IQR 3-11), and duration of chest tube drainage 6 days (IQR 5-8) at 15 ml/kg/day (IQR 9-20). In univariate analysis, only systemic right ventricle, 24-h 5 % albumin administration, 24-h fluid balance, and 12-h inotrope score were associated with PCTO. In multivariate analysis, only 5 % albumin administration in first 24 h (p < 0.001) and PCTO were independently associated with PLOS. ROC curve analysis showed patients receiving >25 ml/kg of 5 % albumin in first 24-h predicted PLOS (94 % specificity, 93 % sensitivity, AUC = 0.95, p < 0.001). Increased colloid in the first 24-h post-CPB strongly predicts PCTO and PLOS after Fontan operation, potentially providing an early identification of a cohort with unfavorable Fontan physiology. A better understanding of the role of colloid resuscitation after Fontan is necessary, and efforts to reduce perioperative colloid administration could decrease hospital morbidity.

Postoperative Hydrocortisone Infusion Reduces the Prevalence of Low Cardiac Output Syndrome After Neonatal Cardiopulmonary Bypass.

OBJECTIVE: Neonatal cardiac surgery with cardiopulmonary bypass is often complicated by morbidity associated with inflammation and low cardiac output syndrome. Hydrocortisone "stress dosing" is reported to provide hemodynamic benefits in some patients with refractory shock. Development of cardiopulmonary bypass-induced adrenal insufficiency may provide further rationale for postoperative hydrocortisone administration. We sought to determine whether prophylactic, postoperative hydrocortisone infusion could decrease prevalence of low cardiac output syndrome after neonatal cardiac surgery with cardiopulmonary bypass. DESIGN: Double-blind, randomized control trial. SETTING: Pediatric cardiac ICU and operating room in tertiary care center. PATIENTS: Forty neonates undergoing cardiac surgery with cardiopulmonary bypass were randomized (19 hydrocortisone and 21 placebo). Demographics and known risk factors were similar between groups. INTERVENTIONS: After cardiopulmonary bypass separation, bolus hydrocortisone (50 mg/m²) or placebo was administered, followed by continuous hydrocortisone infusion (50 mg/m²/d) or placebo tapered over 5 days. Adrenocorticotropic hormone stimulation testing (1 µg) was performed before and after cardiopulmonary bypass, prior to steroid administration. Blood was collected for cytokine analysis before and after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Subjects receiving hydrocortisone were less likely to develop low cardiac output syndrome (5/19, 26% vs 12/21, 57%; p = 0.049). Hydrocortisone group had more negative net fluid balance at 48 hours (-114 vs -64 mL/kg; p = 0.01) and greater urine output at 0-24 hours (2.7 vs 1.2 mL/kg/hr; p = 0.03). Hydrocortisone group weaned off catecholamines and vasopressin sooner than placebo, with a difference in inotrope-free subjects apparent after 48 hours (p = 0.033). Five placebo subjects (24%) compared with no hydrocortisone subjects required rescue steroids (p = 0.02). Thirteen (32.5%) had adrenal insufficiency after cardiopulmonary bypass. Patients with adrenal insufficiency randomized to receive hydrocortisone had lower prevalence of low cardiac output syndrome compared with patients with adrenal insufficiency randomized to placebo (1/6 vs 6/7, respectively; p = 0.02). Hydrocortisone significantly reduced proinflammatory cytokines. Ventilator-free days, hospital length of stay, and kidney injury were similar. CONCLUSIONS: Prophylactic, postoperative hydrocortisone reduces low cardiac output syndrome, improves fluid balance and urine output, and attenuates inflammation after neonatal cardiopulmonary bypass surgery. Further studies are necessary to show if these benefits lead to improvements in more important clinical outcomes.

A Novel Model for Xenograft Right Ventricle to Pulmonary Artery Conduit.

The last 40 years have shown dramatic improvement in outcomes for neonatal cardiac surgery for a spectrum of congenital heart disease diagnoses. With more patients surviving into adulthood, the long-term impact of initial management strategies of these patients has come into focus. This is particularly true for patients with pediatric heart valve disease. Many patients born with right ventricular to pulmonary artery (RVPA) discontinuity require placement of a valved conduit in the neonatal period. Valved conduit options are limited in this patient population due to patient size and inability to respond to somatic growth. Genetically engineered porcine (GEP) donors may offer a xenograft conduit alternative that can grow with the patient. We have developed a model utilizing GEP donor RVPA conduits placed in infantile nonhuman primate (NHP) recipients. Our recipient is maintained on single-drug immunosuppression and demonstrates no evidence of pulmonary valve insufficiency or stenosis during short-term follow-up. Further studies and long-term outcomes are necessary to determine the utility of this technology in human application.

Pigs in Transplantation Research and Their Potential as Sources of Organs in Clinical Xenotransplantation.

The pig has long been used as a research animal and has now gained importance as a potential source of organs for clinical xenotransplantation. When an organ from a wild-type (i. e., genetically unmodified) pig is transplanted into an immunosuppressed nonhuman primate, a vigorous host immune response causes hyperacute rejection (within minutes or hours). This response has been largely overcome by 1) extensive gene editing of the organ-source pig and 2) the administration to the recipient of novel immunosuppressive therapy based on blockade of the CD40/CD154 T cell costimulation pathway. Gene editing has consisted of 1) deletion of expression of the 3 known carbohydrate xenoantigens against which humans have natural (preformed) antibodies and 2) the introduction of human 'protective' genes. The combination of gene editing and novel immunosuppressive therapy has extended life-supporting pig kidney graft survival to greater than 1 y and of pig heart survival to up to 9 mo. This review briefly describes the techniques of gene editing, the potential risks of transfer of porcine endogenous retroviruses with the organ, and the need for breeding and housing of donor pigs under biosecure conditions.

The potential of cardiac xenotransplantation for management of infants with complex congenital heart disease.

Gene editing of the porcine genome has enabled the production of pigs that do not express the three known carbohydrate antigens that are associated with hyperacute rejection of a pig organ xenotransplant. In addition, it is now possible to insert a variety of human transgenes to protect against the human immune response, e.g., to protect from complement and coagulation activation. As a result, cardiac xenotransplantation of the gene-edited porcine heart is progressing towards clinical application. Many hope that it will definitively address the disparity between organ supply and demand. The role of cardiac xenotransplantation in pediatric care remains controversial but we believe there is an infant patient population with complex congenital heart disease (CHD) (not optimally managed by conventional surgical approaches) that is ideally suited to initial clinical application of this new technology. The most efficacious start would be to initiate clinical use as a short-term bridge to allotransplantation, particularly in infants with single ventricle pathology and significant risk factors for first stage Norwood palliation. Infants with end-stage heart failure after first stage palliation would represent a second target population. Infants experience unacceptably high mortality and morbidity when placed on mechanical circulatory support as a bridge to allotransplant. Effectively bridging these vulnerable populations could promote acceptance of cardiac xenotransplantation, allowing indications and use to expand, e.g., by (I) bridging patients with failed second and third stage single ventricle disease, or (II) with complex biventricular CHD, or (III) those with a restrictive or dilated cardiomyopathy. Finally, there is a reasonable expectation that the immunologic privilege of infants will allow porcine heart xenotransplantation to be destination therapy for some patients. In summary, heart allotransplantation in infants offers superior outcomes when compared to three-stage single ventricle palliation, but there is a continual shortage of deceased human donor organs. We should pursue research towards the application of xenotransplantation in patients with single ventricle pathology, in whom the results of staged palliation are likely to be suboptimal. There are many remaining issues to be resolved before cardiac xenotransplantation enters regular pediatric clinical use, but experience in this field is progressing rapidly.

Comparative analysis of the cardiomyocyte differentiation potential of induced pluripotent stem cells reprogrammed from human atrial or ventricular fibroblasts.

Background: We had shown that cardiomyocytes (CMs) were more efficiently differentiated from human induced pluripotent stem cells (hiPSCs) when the hiPSCs were reprogrammed from cardiac fibroblasts rather than dermal fibroblasts or blood mononuclear cells. Here, we continued to investigate the relationship between somatic-cell lineage and hiPSC-CM production by comparing the yield and functional properties of CMs differentiated from iPSCs reprogrammed from human atrial or ventricular cardiac fibroblasts (AiPSC or ViPSC, respectively). Methods: Atrial and ventricular heart tissues were obtained from the same patient, reprogrammed into AiPSCs or ViPSCs, and then differentiated into CMs (AiPSC-CMs or ViPSC-CMs, respectively) via established protocols. Results: The time-course of expression for pluripotency genes (OCT4, NANOG, and SOX2), the early mesodermal marker Brachyury, the cardiac mesodermal markers MESP1 and Gata4, and the cardiovascular progenitor-cell transcription factor NKX2.5 were broadly similar in AiPSC-CMs and ViPSC-CMs during the differentiation protocol. Flow-cytometry analyses of cardiac troponin T expression also indicated that purity of the two differentiated hiPSC-CM populations (AiPSC-CMs: 88.23% ± 4.69%, ViPSC-CMs: 90.25% ± 4.99%) was equivalent. While the field-potential durations were significantly longer in ViPSC-CMs than in AiPSC-CMs, measurements of action potential duration, beat period, spike amplitude, conduction velocity, and peak calcium-transient amplitude did not differ significantly between the two hiPSC-CM populations. Yet, our cardiac-origin iPSC-CM showed higher ADP and conduction velocity than previously reported iPSC-CM derived from non-cardiac tissues. Transcriptomic data comparing iPSC and iPSC-CMs showed similar gene expression profiles between AiPSC-CMs and ViPSC-CMs with significant differences when compared to iPSC-CM derived from other tissues. This analysis also pointed to several genes involved in electrophysiology processes responsible for the physiological differences observed between cardiac and non-cardiac-derived cardiomyocytes. Conclusion: AiPSC and ViPSC were differentiated into CMs with equal efficiency. Detected differences in electrophysiological properties, calcium handling activity, and transcription profiles between cardiac and non-cardiac derived cardiomyocytes demonstrated that 1) tissue of origin matters to generate a better-featured iPSC-CMs, 2) the sublocation within the cardiac tissue has marginal effects on the differentiation process.