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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Surgical management of left ventricular outflow obstruction in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is the single most common form of inherited heart disease. Left ventricular outflow tract obstruction (LVOTO) is a recognised feature of this condition which arises when blood leaving the outflow tract is impeded by systolic anterior motion of the mitral valve. In an important minority of patients, breathlessness, chest pain and syncope may result and persist despite the use of medications. In suitable candidates, surgery may relieve obstruction and its associated symptoms, and normalise life expectancy. Refinements in surgical techniques have marked improvements in the understanding of mechanisms underlying LVOTO. In this review, we hope to provide the reader with an understanding of how contemporary surgical practice has developed, which patients should be considered for surgery, and what results are anticipated. The role echocardiography plays in this area is highlighted throughout.

Methodology manual for European Association for Cardio-Thoracic Surgery (EACTS) clinical guidelines.

The goal of all clinical guidelines is to assist patients and practitioners in making healthcare decisions. However, clinical guidelines have been questioned about their quality, transparency and independence. Based on the revision of manuals by other scientific cardiothoracic organizations, this document provides instructions for the development of European Association for Cardio-Thoracic Surgery (EACTS) clinical guidelines and other types of evidence-based documents. Four key areas have been addressed: (i) selection of taskforce members and transparency of relations with the industry, (ii) methods for critical appraisal of medical evidence, (iii) rules for writing recommendations and (iv) review process. It is hoped that, by adopting this methodology, clinical guidelines produced by the EACTS will be well balanced, objective and, importantly, trusted by physicians and patients who benefit from their implementation.

Coronary ostial compromise in aortic valve replacement: an avoidable complication.

BACKGROUND: We sought to determine the incidence of hospital death due to surgical compromise of the coronary ostia in aortic valve replacement. The mechanism of coronary ostium blockage was also investigated. METHODS: A retrospective review was conducted of prospectively collected clinical data and autopsy findings in 322 patients who died in hospital after aortic valve replacement with or without concomitant procedures in a single institution from January 1998 to March 2013. RESULTS: Over the 15-year period, more than 17 surgeons performed 7507 aortic valve replacements with or without other procedures. The mean age of the patients was 70.8 ± 11.78 years and 63% were male. Bioprosthetic valves were used in 75%, mechanical valves in 24.7%, and homografts in only 0.3%. Early mortality for all patients (combined, emergency, and redo procedures) was 4.29% (mean logistic EuroSCORE 10.7). There were 322 deaths after procedures involving the aortic valve. Autopsy examinations were carried out in all patients and showed that 3.4% (n = 11) of deaths were at least partly attributed to encroachment on one or both coronary ostia. Causes of ostial compromise included the valve sutures, the valve sewing ring, and the aortotomy suture line. CONCLUSIONS: Coronary ostial compromise in aortic valve replacement is a very rare but real problem occurring in at least 0.15% of aortic valve replacements and contributing to or directly causing one in every 29 aortic valve replacement deaths. Surgeons should have a high level of awareness of the risk of this rare but fatal and avoidable complication.

Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery.

OBJECTIVES: Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR). METHODS: In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR ± coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures. RESULTS: The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups. CONCLUSIONS: Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited.

The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics. RESULTS: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis. CONCLUSIONS: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery. CLINICALTRIALSGOV ID: NCT00845364.

Clinical outcomes of Carbomedics Top Hat valve with a robust follow-up system.

AIM: Late failure of bioprosthetic valves may limit their use in patients < 60 years. The superior hemodynamic performance offered by the Carbomedics Top Hat supraannular valve enables greater effective orifice areas to be achieved. The aim of this study was to assess the clinical outcomes of this valve, using a robust follow-up system. METHODS: Patients who underwent aortic valve replacement with or without coronary artery bypass grafting between July 1997 and January 2010 with Carbomedics supraannular Top Hat valves were identified. Details of readmissions and late deaths were obtained from the National Hospital Episodes Statistics data and the Office of National Statistics, tracked by the Quality and Outcomes Research Unit. Late complications associated with this prosthesis were evaluated. RESULTS: Of 253 patients identified, 181 underwent isolated aortic valve replacement and 72 had aortic valve replacement with coronary artery bypass grafting. The 30-day mortality was 1.6%, and 5- and 10-year survival rates were 91.4% and 80.5%, respectively. Detailed readmission data were available after 2001 (n = 170). Two (1.2%) patients required reoperation for endocarditis and pannus formation. Of the 17 late deaths in this subset, 4 were attributable to cardiac causes. One patient was treated for heart failure, and 2 developed bleeding complications. CONCLUSIONS: Implantation of the Carbomedics Top Hat supraannular valve in our unit resulted in satisfactory in-hospital and midterm survival with low incidences of endocarditis and late heart failure.