Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

The Physiology of Continuous-Flow Left Ventricular Assist Devices.

The use of left ventricular assist devices (LVADs) has increased significantly over the past few years, in part because heart transplant activity has plateaued, but also because of the improving clinical outcomes with contemporary continuous-flow LVAD. As such, there is now a growing population of patients with continuous-flow LVADs. Management of these patients is complicated by the altered circulatory physiology, because continuous-flow LVADs provide a parallel circulation from the heart to the aorta, which interacts with the native left heart (systemic) circulation with consequent effects on the right heart circulation. In addition, the displayed pump parameters can mislead the unwary clinician. An understanding of LVAD physiology can guide clinicians in the management of patients with LVADs. This review describes the basic design of axial and centrifugal continuous-flow LVADs, the functional anatomy and physiology of continuous-flow LVADs, and the interaction between the heart and the LVAD. leading to a discussion about the interpretation of the pump parameters in clinical practice.

Extracorporeal Life Support: Physiological Concepts and Clinical Outcomes.

Extracorporeal life support (ECLS) describes a system that involves drainage from the venous circulation and return via an oxygenator into the arterial circulation (veno-arterial extracorporeal membrane oxygenation). ECLS provides effective cardiopulmonary support, but the parallel circulation has complex effects on the systemic and pulmonary circulatory physiology. An understanding of the physiological changes is fundamental to the management of ECLS. In this review, the key physiological concepts and the implications on the clinical management of ECLS are discussed. In addition, the clinical outcomes associated with ECLS in cardiogenic shock are systematically reviewed. The paucity of clinical trials on ECLS highlights the need for randomized trials to guide the selection of patients.

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.

AIM: Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. METHODS: Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. RESULTS: Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12-0.44), the median atrial concentration was 6.02 mg kg⁻¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg kg⁻¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1-27.1), ventricular : plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84). CONCLUSIONS: This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.

Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) trial.

BACKGROUND: Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery. METHODS AND RESULTS: Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5' adenosine monophosphate-activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked ß-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands. CONCLUSIONS: Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis.

Titin isoform expression in aortic stenosis.

Titin is a giant sarcomeric protein that plays a major role in determining passive myocardial stiffness. The shorter N2B isoform results in a higher passive myocardial stiffness than the longer N2BA isoform. We hypothesised that the expression of the short N2B isoform would be increased in patients with aortic stenosis compared with healthy controls in response to pressure overload, in order to act as a modulator for the increased demand placed on the left ventricle during the early stages of the hypertrophic response. Myocardial biopsies were obtained from the left ventricle of 19 patients undergoing aortic valve replacement for aortic stenosis who had no significant co-existing coronary artery disease. Left ventricular biopsies were also obtained from 13 donor hearts for comparison. SDS-agarose gels revealed small N2B and large N2BA cardiac titin isoforms, with a mean N2BA/N2B ratio that was significantly decreased in the 19 aortic stenotic patients compared with the 13 controls (0.66+/-0.04 in the normal donor hearts compared with 0.48+/-0.03 in patients with aortic stenosis; P=0.02). However, total titin remained unchanged (0.28+/-0.02 compared with 0.24+/-0.02 respectively; P=0.29). In conclusion, the expression of less N2BA and more N2B titin in response to pressure overload may result in the generation of higher passive tension upon stretch to a given sarcomere length and this might affect cardiac performance.

Arteriovenous fistula creation in a patient without a pulse: Vascular access in patients with left ventricular assist devices.

Left ventricular assist devices are used in heart failure patients as bridge to transplantation or increasingly as a destination therapy. These patients frequently have renal dysfunction and many reach end-stage renal failure. If haemodialysis is required, minimization of infection risk is essential. Arteriovenous grafts have been recommended for these patients due to hypothetical concerns regarding fistula maturation due to continuous flow. A case is described where a brachiocephalic arteriovenous fistula was successfully formed and used for dialysis without issue. This is one case of a small number in the literature where arteriovenous fistulas have been used in left ventricular assist device patients and it appears that concerns are unfounded and good outcomes have been reported. It would appear from this experience that approaches to vascular access for dialysis in patients with continuous-flow left ventricular assist devices are in accordance with vascular access guidelines and standard practice.

MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants.

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease. We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS.

mtDNA mutations and common neurodegenerative disorders.

The incidence and prevalence of Alzheimer's disease (AD) and Parkinson's disease (PD) are increasing as the population ages. Both disorders have been associated with oxidative stress and mitochondrial dysfunction, and it has been proposed that mutations in the mitochondrial genome have a key role in neurodegeneration in AD and PD patients. Two recent publications propose that heteroplasmic mtDNA mutations are involved in AD and PD. However, when these new studies are considered in relation to the sum of previous evidence, the role of mtDNA mutations in the development of either AD or PD still remains to be established.

Mild renal dysfunction predicts in-hospital mortality and post-discharge survival following cardiac surgery.

OBJECTIVES: To assess the impact of preoperative renal dysfunction on in-hospital mortality and late survival outcome following adult cardiac surgery. METHODS: Prospectively collected data were analysed on 7621 consecutive patients not requiring preoperative renal-replacement therapy, who underwent CABG, valve surgery or combined procedures from 1/1/98 to 1/12/06. Preoperative estimated glomerular filtration rate was calculated using Cockcroft-Gault formula. Patients were classified in the four chronic kidney disease (CKD) stage classes defined by the National Kidney Foundation Disease Outcome Quality Initiative Advisory Board. Late survival data were obtained from the UK Central Cardiac Audit Database. RESULTS: There were 243 in-hospital deaths (3.2%). There was a stepwise increase in operative mortality with each CKD class independent of the type of surgery. Multivariate analysis confirmed CKD class to be an independent predictor of in-hospital mortality (class 2 OR 1.45, 95% CI 1.1-2.35, p=0.001; class 3 OR 2.8, 95% CI 1.68-4.46, p=0.0001; class 4 OR 7.5, 95% CI 3.76-15.2, p=0.0001). The median follow-up after surgery was 42 months (IQR 18-74) and there were 728 late deaths. Survival analysis using a Cox regression model confirmed CKD class to be an independent predictor of late survival (class 2 HR 1.2, 95% CI 1.1-1.6, p=0.0001; class 3 HR 1.95, 95% CI 1.6-2.4, p=0.0001; and class 4 HR 3.2, 95% CI 2.2-4.6, p=0.0001). Ninety-eight percent (7517/7621) of patients had a preoperative creatinine <200 micromol/l, which is not included as a risk factor in most risk stratification systems. CONCLUSIONS: Mild renal dysfunction is an important independent predictor of in-hospital and late mortality in adult patients undergoing cardiac surgery.

Cardiogenic Shock Due to End-Stage Heart Failure and Acute Myocardial Infarction: Characteristics and Outcome of Temporary Mechanical Circulatory Support.

BACKGROUND: Mechanical circulatory support (MCS) is increasingly used in cardiogenic shock, but outcomes may differ between patients with acute myocardial infarction (AMI) or end-stage heart failure (ESHF). This study aimed to describe the characteristics of patients with cardiogenic shock due to AMI and ESHF. METHODS: Single-center study of consecutive patients with cardiogenic shock due to AMI (n = 26) and ESHF (n = 42) who underwent MCS (extracorporeal life support, Impella or temporary ventricular assist devices). Arterial and venous O2 content and CO2 tension (PCO2), O2-hemoglobin affinity (P50) were measured. Veno-arterial difference in PCO2/arterio-venous difference in O2 content ratio was derived. Acid-base balance was characterized by the Gilfix method. MCS-related complications that required intervention or surgery were collected. RESULTS: Patients with ESHF had lower ejection fraction, higher right and left-sided filling pressures, pulmonary artery pressure and vascular resistance, lower oxygen delivery (DO2) compared with AMI, which was not fully compensated by the increased hemoglobin P50. As a result, patients with ESHF had higher veno-arterial difference in PCO2 relative to arterio-venous difference in O2 content. Despite greater anerobic metabolism, patients with ESHF had less severe metabolic acidosis and base deficit compared with AMI, predominantly due to differences in strong ions. CONCLUSION: The cardiogenic shock phenotype in ESHF was distinct from AMI, characterized by higher filling and pulmonary artery pressures, lower DO2, greater anaerobic metabolism but less severe metabolic acidosis.

The interval between brainstem death and cardiac assessment influences the retrieval of hearts for transplantation.

OBJECTIVES: The optimum time after brainstem death (BSD) at which to assess the function of donor hearts is unknown. We hypothesized that a longer interval may be associated with a higher transplantation rate due to improved function. METHODS: Data were obtained from the UK Transplant Registry for the period between April 2010 and March 2015. The time when fixed dilated pupils were first noted in the donor was considered as the time of BSD. Retrieval was defined as the time when the abdominal organs were surgically perfused. RESULTS: BSD to retrieval duration was available for 1947 donors, of which 458 (24%) donated their heart. In the univariable analysis (not adjusting other donor risk factors), evidence was available to suggest that the BSD to cardiac assessment duration had a non-linear association with heart utilization (P < 0.0001). Adjusting for donor risk factors, the relationship remained with longer intervals being associated with increased transplantation (P = 0.0056). The modelled probability of heart utilization had a similar pattern to the observed rate of heart utilization. However, the probability of heart donation began to plateau after approximately 48 h. The analysis of the subset of donors attended by a cardiothoracic retrieval team showed a similar pattern. CONCLUSIONS: These data suggest that time interval from BSD to organ retrieval influences the heart retrieval rate. When the sole reason for declining a donor heart is poor function, a period of further observation and optimization up to 2 days should be considered.

Assigning pathogenicity to mitochondrial tRNA mutations: when "definitely maybe" is not good enough.

Some mutations in mitochondrial tRNA (mt-tRNA) genes cause devastating disease, whereas others have no clinical consequences. We understand little of the factors determining the pathogenicity of specific mt-tRNA mutations, making prediction of clinical outcome extremely difficult. Using extensive sequence databases, we compared the characteristics of neutral variations with those of pathogenic mutations. We recommend that the location of the proposed mutation within the secondary structure of the mt-tRNA molecule and the disruption it causes to Watson-Crick base pairing should be considered when assessing the pathological significance of a novel mt-tRNA mutation.

The effect of left ventricular assist device therapy in patients with heart failure and mixed pulmonary hypertension.

BACKGROUND: Diastolic pressure gradient (DPG) of ≥7 mmHg has been proposed to distinguish mixed pulmonary hypertension from isolated post-capillary pulmonary hypertension in heart failure (HF). We evaluated the changes in pulmonary hemodynamics with left ventricular assist devices (LVADs) in patients with DPG of ≥7 or <7 mmHg, and effects on peak oxygen uptake (VO2) in patients with advanced HF. METHODS: Pre- and post-LVAD implant pulmonary hemodynamics (including right atrial (RA) pressures, DPG, pulmonary vascular resistance (PVR), pulmonary capacitance (PCap) and cardiac output), echocardiography, cardiopulmonary exercise test were measured in 38 consecutive patients. RESULTS: Ten of 38 patients had baseline DPG ≥7 mmHg. There were no significant difference in baseline characteristics, peak VO2 and ventilation slope, but PVR were higher, and PCap lower in patients with DPG ≥7 mmHg. Pulmonary artery pressures improved in all patients, but PVR and DPG remained higher and PCap lower in patients with baseline DPG ≥7 mmHg after a median follow-up of 181 (IQR 153-193) days. Peak VO2 increased and ventilation slope reduced post-LVAD, and these improvements were comparable between groups. Only RA pressure reduction and exercise increase in heart rate were significant predictors of peak VO2 increase on multivariate analysis. CONCLUSIONS: Baseline DPG of ≥7 mmHg compared to DPG <7 mmHg have persistently lower PCap and higher PVR post-LVAD, but the increase in peak VO2 was comparable despite these residual pulmonary vascular abnormalities. The improvement in peak VO2 was related to reduction in right atrial pressure and exercise increase in heart rate.

MutPred mutational load analysis shows mildly deleterious mitochondrial DNA variants are not more prevalent in Alzheimer's patients, but may be under-represented in healthy older individuals.

Mitochondrial DNA (mtDNA) association studies have been conducted for over a decade using the haplogroup (lineage) association method, but this frequently produces conflicting results. Here we analyzed complete mtDNA sequence data of Alzheimer's disease (AD) patients and aged controls, from the United Kingdom (UK) and the United States (US), using a new "mutational load" method. We calculated a pathogenicity score for each of the non-synonymous substitutions of the mtDNA sequences to produce a "total mutational load" for each sequence, and compared the mutational loads of cases and controls. Using these mutational load measures, we found no evidence to support the cumulative role of mtDNA variants as a susceptibility factor in AD; that is, AD patients (UK and US cohorts) did not have higher "mutational loads" than controls. However, the US aged controls, who are significantly older than the UK ones, with many showing evidence of being healthy and having good cognition in old age, had significantly lower "mutational loads". This finding suggests that low mtDNA mutational load is more prevalent in healthy older people.

Mitochondrial DNA and survival after sepsis: a prospective study.

BACKGROUND: Human genome evolution has been shaped by infectious disease. Although most genetic studies have focused on the immune system, recovery after sepsis is directly related to physiological reserve that is critically dependent on mitochondrial function. We investigated whether haplogroup H, the most common type of mitochondrial DNA (mtDNA) in Europe, contributes to the subtle genetic variation in survival after sepsis. METHODS: In a prospective study, we included 150 individuals who were sequentially admitted to the intensive care unit in a hospital in Newcastle upon Tyne, UK. After clinical data were obtained, patients underwent mtDNA haplotyping by analysis with PCR and restriction fragment length polymorphism. As endpoints, we used death during the 6-month period or survival at 6 months. FINDINGS: Follow-up was complete for all study participants, although the haplotype of two patients could not be reliably determined. On admission to the intensive care unit, the frequency of mtDNA haplogroup H in study patients did not differ between study patients admitted with severe sepsis and 542 age-matched controls from the northeast of England. MtDNA haplogroup H was a strong independent predictor of outcome during severe sepsis, conferring a 2.12-fold (95% CI 1.02-4.43) increased chance of survival at 180 days compared with individuals without the haplogroup H. INTERPRETATION: Although haplogroup H is the most recent addition to the group of European mtDNA, paradoxically it is also the most common. Increased survival after sepsis provides one explanation for this observation. MtDNA haplotyping offers a new means of risk stratification of patients with severe infections, which suggests new avenues for therapeutic intervention.

Patient-prosthesis mismatch does not affect survival following aortic valve replacement.

OBJECTIVE: Patient-prosthesis mismatch (PPM) has been reported to increase perioperative mortality and reduce postoperative survival in patients undergoing aortic valve replacement (AVR). We analysed the effect of PPM at values predicting severe mismatch on survival following AVR in our unit. METHODS: Prospectively collected data on 1481 consecutive patients who had undergone AVR with or without coronary artery revascularisation between 1997 and 2005 were analysed. Projected in vitro valve effective orifice area (EOA) and geometric prosthesis internal orifice area (GOA) were evaluated and values were indexed to body surface area (cm(2)m(-2)). PPM was defined as EOAi<0.6 and/or GOAi<1.1. Long-term survival data were obtained from the National Institute of Statistics. RESULTS: One thousand four hundred and eighteen patients were identified. 67/1418 (4.7%) patients had GOAi<1.1; 122/1418 (8.6%) had EOAi<0.6 and 38 (2.6%) patients exhibited both forms of mismatch. One thousand two hundred and sixty-seven patients (89%) demonstrated no mismatch (reference group). There were 75 in-hospital deaths (overall mortality 5.3%) with no significant difference between the mismatch and the reference groups. Survival data were available for up to 8 years (median 36 months, IQR 6-60 months). There were 160 late deaths (13/143 PPM group vs 147/1198 reference group). The 5-year survival estimate was similar for both groups (83% PPM group; 81% reference group; p=0.47). Cox-hazard analysis identified advanced age as the only predictor of reduced survival (age>80, RR 2.13, 95% CI 1.38-4.586, p=0.004). CONCLUSIONS: Severe patient-prosthesis mismatch was predicted in 4-10% of patients undergoing AVR but this did not affect in-hospital mortality or mid-term survival.

National administrative data produces an accurate and stable risk prediction model for short-term and 1-year mortality following cardiac surgery.

OBJECTIVES: Various risk models exist to predict short-term risk-adjusted outcomes after cardiac surgery. Statistical models constructed using clinical registry data usually perform better than those based on administrative datasets. We constructed a procedure-specific risk prediction model based on administrative hospital data for England and we compared its performance with the EuroSCORE (ES) and its variants. METHODS: The Hospital Episode Statistics (HES) risk prediction model was developed using administrative data linked to national mortality statistics register of patients undergoing CABG (35,115), valve surgery (18,353) and combined CABG and valve surgery (8392) from 2008 to 2011 in England and tested using an independent dataset sampled for the financial years 2011-2013. Specific models were constructed to predict mortality within 1-year post discharge. Comparisons with EuroSCORE models were performed on a local cohort of patients (2580) from 2008 to 2013. RESULTS: The discrimination of the HES model demonstrates a good performance for early and up to 1-year following surgery (c-stats: CABG 81.6%, 78.4%; isolated valve 78.6%, 77.8%; CABG & valve 76.4%, 72.0%), respectively. Extended testing in subsequent financial years shows that the models maintained performance outside the development period. Calibration of the HES model demonstrates a small difference (CABG 0.15%; isolated valve 0.39%; CABG & valve 0.63%) between observed and expected mortality rates and delivers a good estimate of risk. Discrimination for the HES model for in-hospital deaths is similar for CABG (logistic ES 79.0%) and combined CABG and valve surgery (logistic ES 71.6%) patients and superior for valve patients (logistic ES 70.9%) compared to the EuroSCORE models. The C-statistics of the EuroSCORE models for longer periods are numerically lower than that of the HES model. CONCLUSION: The national administrative dataset has produced an accurate, stable and clinically useful early and 1-year mortality prediction after cardiac surgery.