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Abstract Heart rate, a measure of the frequency of the cardiac cycle, reflects the health of the cardiovascular system, metabolic rate, and activity of the autonomic nervous system. Whether changes in resting heart rate are related to lifespan has not yet been explored to our best knowledge. In this study, we examined the association between resting heart rate and lifespan using linear regression in the Paris Prospective Study I, the Whitehall I Study, and the Framingham Heart Study. We used Cox proportional hazards regression to relate changes in heart rate over years to mortality risk. We observed a statistically significant association between increases in resting heart rate over a 5-year period and risk of mortality in the Paris Prospective Study I (HR mortality per 10 bpm increase over time: 1.20; 95% CI: 1.13 to 1.27) and over an 8-year period in the Framingham Heart Study (HR: 1.13; 95% CI: 1.07 to 1.19 for men and HR: 1.09; 95% CI: 1.04 to 1.15 for women), after adjusting for classical risk factors and resting heart rate. Our study shows that men and women who increase their resting heart rate over time increase their risk of mortality.

Background: Although several National Data Registries for Congenital Heart Disease (CHD) exist, few are comprehensive and contemporary. A National Australian CHD Registry has been developed that aims to redress this by creating the first comprehensive data collection for CHD children and adults, initially across Australia. Methods: We defined and collected a minimum dataset of demographics, diagnoses, and procedures from people with CHD presenting at participating quaternary CHD services Australia-wide. Data were collected from a range of clinical data sources. Diagnoses and procedures were standardised to the European Paediatric Congenital Code – Short List. Methodological limitations were carefully documented. Results: From 8 participating institutions, an initial 359,084 patient records were assessed for eligibility and 68,234 unique individuals with structural CHD have been included in the current dataset. There were 20,395 (30 %) people with mild CHD, 25,157 (37 %) with moderate CHD, and 13,530 (20 %) with severe CHD (6 % unknown complexity). The most common diagnoses were Ventricular Septal Defect (16,781, 25 %), Atrial Septal Defect (6,607, 10 %), Aortic Valve Disorders (5516 8 %), Coarctation of the Aorta (5,321, 8 %), Tetralogy of Fallot (4,489, 7 %), Transposition of the Great Arteries (4,009, 6 %). Conclusion: The data presented here represents the most comprehensive cohort collected for the Australian CHD population thus far and is comparable with the largest contemporary CHD registries around the world. This Registry represents a key resource for improved understanding of the CHD population and will drive better care and outcomes for people living with CHD.

Pulmonary hypertension (PH) is a serious potential complication of some congenital heart diseases (CHDs). PH encompasses a range of diseases which may be idiopathic or inherited, or secondary to cardiac, respiratory, systemic or thromboembolic conditions, amongst others. Our increasing understanding of the normal ranges of pulmonary haemodynamics, as well as evidence supporting the benefits of early treatment, has resulted in a number of recent revisions to the haemodynamic definition of PH. In this Review Article, we report on the recent updates to haemodynamic definitions and classification of PH, as reflected in the 2022 Pulmonary Hypertension Guidelines and particularly focus on the CHD related sub-type of PH, where the aetiology is often multi-factorial.

Healthcare is a major generator of greenhouse gases, so consideration of this contribution to climate change needs to be quantified in ways that can inform models of care. Given the availability of activity-based financial data, environmentally-extended input–output (EEIO) analysis can be employed to calculate systemic carbon footprints for healthcare activities, allowing comparison of different patient care pathways. We thus quantified and compared the carbon footprint of two common care pathways for patients with stable coronary artery disease, with similar clinical outcomes: coronary stenting and coronary artery bypass surgery (CABG). Healthcare cost data for these two pathways were disaggregated and the carbon footprint associated with this expenditure was calculated by connecting the flow of money within the economy to the greenhouse gases emitted to support the full range of associated activities. The systemic carbon footprint associated with an average stable patient CABG pathway, at a large tertiary referral hospital in Sydney, Australia in 2021–22, was 11.5 tonnes CO2-e, 4.9 times greater than the 2.4 tonnes CO2-e footprint of an average comparable stenting pathway. These data suggest that a stenting pathway for stable coronary disease should be preferred on environmental grounds and introduces EEIO analysis as a practical tool to assist in health-care related carbon footprinting.

Background To characterize global and health‐related quality of life (QOL) among adults with Fontan physiology enrolled in the Australian and New Zealand Fontan Registry (ANZFR), and identify sociodemographic, clinical, psychological, and relational factors associated with outcomes. Methods and Results Using a cross‐sectional survey design, 66 adults with Fontan physiology (58% women; mean age, 29.6±7.7 years; range, 18–50 years) completed validated self‐report measures. Health‐related QOL was assessed using the Pediatric Quality of Life Inventory, and global QOL was assessed using a visual analog scale (0–10). Participants reported lower total health‐related QOL (P

Summary: Background: Three to 4-weekly intramuscular injections of benzathine penicillin G (BPG) for a prolonged period (e.g., 10 years, until age 40 years, or lifelong) are recommended for preventing group A streptococcal infections that cause recurrent acute rheumatic fever (ARF) and potential progression to rheumatic heart disease (RHD). The duration of treatment, frequency and local pain associated with BPG injections may lead to reduced compliance. Shorter courses of BPG are recommended for the treatment of syphilis and Streptococcal infections. We aimed to assess the effects of local anaesthesia in reducing injection pain in patients who are being treated with BPG. Methods: In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Conference Proceedings Citation Index-Science and LILACS from database inception up to May 4, 2024, and performed additional searches for grey literature. Randomised controlled trials comparing BPG vs. BPG administered alongside local anaesthetics were included. Randomized controlled trials using BPG, irrespectively of indication, and testing any local anaesthetic agent for pain alleviation were considered eligible. We applied GRADE to assess the quality of evidence. Summary data were extracted from included trials. The primary outcome was injection pain, assessed through mean differences. A random-effects model was utilized to account for study heterogeneity. This study is registered with PROSPERO, CRD42022342437. Findings: Database searches identified a total of 3958 records, and 3 additional records were retrieved from grey literature searches. After removal of duplicates, screening of abstracts and full-text review, eight trials were included, combining a total of 489 patients (151 patients with RHD). Immediate pain level, as reported by patients, was of high intensity in most studies. Low intensity pain was still reported at 24 h. Administration of lidocaine mixed with BPG was associated with a significant reduction in immediate post-injection pain (mean difference −3.84, 95% confidence interval −6.19 to −1.48, P = 0.0001; 4 studies; I2 = 98%; GRADE: moderate quality), pain at 5 min (mean difference −2.85, 95% CI confidence interval −3.78 to −1.92, P

Background: In order to manage a class of diseases as broad as congenital heart disease (CHD), multiple “manually generated” classification systems defining CHDs as mild, moderate and severe have been developed and used to good effect. As databases have grown, however, such “manual” complexity scoring has become infeasible. Though past attempts have been made to determine CHD complexity algorithmically using a list of diagnoses alone, missing data and lack of procedural information have been significant limitations. Methods: We built an algorithm that can stratify the complexity of patients with CHD by integrating their diagnoses with a list of their previous procedures. Specific procedures which address a missing diagnosis or imply a certain operative status were used to supplement the diagnosis list. To verify this algorithm, CHD specialists manually checked the classification of 100 children and 100 adults across four hospitals in Australia. Results: Our algorithm was 99.5% accurate in the manually checked cohort (100% in children and 99% in adults) and was able to automatically classify more than 90% of a cohort of over 24,000 CHD patients, including 92.5% of children (vs 84.4% without procedures, p

Abstract Background Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. Objectives Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. Methods Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. Results Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. Conclusions Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

Background: Brady- and tachyarrhythmias commonly complicate adult congenital heart disease (ACHD). Permanent pacemakers (PPMs) or implantable cardioverter–defibrillators (ICDs) are often utilised to prevent morbidity or mortality related to arrhythmia, but can also be associated with significant morbidity themselves. Methods: We analysed outcomes from patients in our comprehensive ACHD database who were seen at least twice since 2000 and once since 2018. Of 1953 ACHD patients, 134 had a PPM and 78 had an ICD (47 for primary and 31 for secondary prevention). Results: For PPM patients, 41% had a pacing percentage below 33%, 13% had 33–66%, and 46% had above 66%. One fifth required PPM upgrade, most to cardiac resynchronisation therapy, the rest to ICD. There were 33 appropriate ICD shocks in 15 patients (19%) and 34 inappropriate shocks in 13 patients (17%) over a median follow up of 4.6 years (IQR 0.9–8.3 years). Anti-tachycardia pacing was delivered appropriately for 28% of patients and inappropriately for 9%.Apart from inappropriate therapy, one third of PPM and ICD patients had other device-related complications. Acute PPM complications included lead dysfunction requiring revision (2%), pneumothorax (2%), pleural effusion (2%) and pocket infection (2%). ICDs were also acutely complicated by lead dysfunction (4%) as well as pocket hematoma (3%). The most common long-term complication overall was lead dysfunction, affecting one sixth of both PPM and ICD patients. Finally, the rate of device insertion increased significantly with disease severity. Conclusions: Anti-arrhythmic devices can be lifesaving in ACHD patients, but inappropriate therapy and device-related complications are very common.

Background: Rheumatic Heart Disease (RHD) is the most common cause of valvular heart disease worldwide. Undiagnosed or untreated RHD can complicate pregnancy and lead to poor maternal and fetal outcomes and is a significant factor in non-obstetric morbidity. Echocardiography has an emerging role in screening for RHD. We aimed to critically analyse the evidence on the use of echocardiography for screening pregnant women for RHD in high-prevalence areas. Methods: We searched MEDLINE and Embase to identify the relevant reports. Two independent reviewers assessed the reports against the eligibility criteria in a double-blind process. Results: The searches (date: 4 April 2023) identified 432 records for screening. Ten non-controlled observational studies were identified, five using portable or handheld echocardiography, comprising data from 23,166 women. Prevalence of RHD varied across the studies, ranging from 0.4 to 6.6% (I2, heterogeneity >90%). Other cardiac abnormalities (e.g., congenital heart disease and left ventricular systolic dysfunction) were also detected

Background: Patients with single ventricle (SV) without Fontan palliation are uncommon, and their long-term outcomes remain unclear. Methods: Retrospective study of 35 adult patients with SV without Fontan from two tertiary centers. Primary outcome was mortality. Results: Median age at first follow-up was 31 years (IQR: 20–40). Most common defect was double inlet left ventricle (34%), and 69% had left ventricular morphology. Patients were unoperated (46%), had systemic-to-pulmonary artery shunt (31%) or bidirectional cavopulmonary shunt (23%) as final palliation. Most common reasons for not progressing to Fontan palliation were pulmonary vascular disease (54%), patient refusal (17%), Fontan takedown (14%), and hypoplastic pulmonary arteries (11%). Baseline mean hemoglobin was 195 ± 29 g/L, mean O2 saturation 83 ± 6.9%, and 4 patients in NYHA Class III‒IV. After a mean follow-up of 10 ± 8.3 years, there were 9 deaths with heart failure being the leading cause (n = 6). Age-adjusted survival of these adult SV survivors was 73% and 53% at 40 and 50 years of age, respectively. Deceased patients more frequently had renal impairment (50% vs 0%) and QRS prolongation (75% vs 16%) at baseline (all p

Background: Pulse pressure intensity in middle-aged adults is a risk factor for dementia. The Guardian device (The Brain Protection Company, Sydney, Australia) has been developed to reduce pulse pressure, as a potential therapy. Objectives: The aim of this study was to evaluate the safety of the Guardian, a novel pulse modulation device designed to reduce the intensity of the pulse pressure that penetrates into the cerebral small vessels. The Guardian is a helix that gently wraps around the common carotid artery (CCA) to slightly change its shape, to absorb pulsatility, without lowering flow. Methods: The Guardian was implanted bilaterally on the CCAs of 10 mature sheep for chronic implant periods of 3, 6 or 8 months. The ratio of internal device diameter to outer diameter of the CCA varied from 63% to 92% (n = 20). The implant position on the vessel was marked surgically at implant. Gross pathology and histopathology of the CCA were examined at 3- and 6-months post explant. Most devices were explanted using open surgery, however minimally invasive surgical explant techniques were examined in 2 animals to assess the potential of this approach for explant in humans if required. Results: The Guardian was successfully implanted with no adverse events, and minimally invasive explant appeared to be viable for removal. Following implant, the device was surrounded by a thin fibrous capsule, with similar pathology at 3- and 6-months. Minimal or no movement was observed. CCA sections appeared histologically normal, with no evidence of thrombosis, stenosis, fibrosis, chronic inflammatory response, or vessel degeneration. Conclusions: The feasibility of surgical implantation and biomaterial safety of the Guardian was confirmed over 8 months. Minimally invasive explant of the Guardian has the potential to be viable. Further work is required to demonstrate efficacy in vitro and/or in vivo before evaluation in humans.

Background: Congenital Heart Disease (CHD) encompasses a huge variety of rare diagnoses that range in complexity and comorbidity. To help build clinical guidelines, plan health services and conduct statistically powerful research on such a disparate set of diseases there have been various attempts to group pathologies into mild, moderate, or severe disease. So far, however, these complexity scores have required manual specialist input for every case, and are therefore missing in large databases where this is impractical, or quickly outdated when guidelines are revised. Methods: We used the up-to-date European Society of Cardiology guidelines to create an algorithm to assign complexity scores to CHD patients using only their diagnosis list. Two CHD specialists then independently assigned complexity scores to a random sample of patients. Results: Our algorithm was 96% accurate where both specialists agreed on a complexity score; this occurred 68% of the time overall, and 79% of the time in moderate or complex CHD. The algorithm “failed” mainly when diagnoses were insufficiently specific, usually for septal defects (where size was unspecified), or where complexity depends on the procedure performed (e.g. atrial/arterial switch for transposition of the great arteries). Conclusions: We were able to algorithmically determine the complexity scores of a majority of patients with CHD based on their diagnosis list alone. This could allow for automatic complexity scoring of most patients in large CHD databases, for example our own Registry of the Congenital Heart Alliance of Australia and New Zealand. This will facilitate targeted research into the management, outcomes and burden of CHD.

Abstract Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to “uncoupling” of endothelial nitric oxide synthase (eNOS). Stimulation of β3 adrenergic receptors (β3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of β3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective β3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)–pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RV–PA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p

Background Exercise is associated with a reduced risk of cardiovascular disease. Increased high‐density lipoprotein cholesterol (HDL‐C) levels are thought to contribute to these benefits, but much of the research in this area has been limited by lack of well‐controlled subject selection and exercise interventions. We sought to study the effect of moderate and high‐intensity exercise on HDL function, lipid/lipoprotein profile, and other cardiometabolic parameters in a homogeneous population where exercise, daily routine, sleep patterns, and living conditions were carefully controlled. Methods and Results Male Army recruits (n=115, age 22±0.3 years) completed a 12‐week moderate‐intensity exercise program. A subset of 51 subsequently completed a 15‐week high‐intensity exercise program. Fitness increased and body fat decreased after moderate‐ and high‐intensity exercise (P

Background The long‐term impact of fenestration at the time of Fontan operation remains unclear. We aimed to review the early and long‐term impact of Fontan fenestration in the Australia and New Zealand cohort. Methods and Results We reviewed 1443 patients (621 fenestrated, 822 nonfenestrated) from the Australia and New Zealand Fontan registry. Data were collected on preoperative demographics, operative details, and follow‐up. Propensity‐score matching was performed to account for the various preoperative and operative differences and risk factors. Primary outcomes were survival and freedom from failure. Median follow‐up was 10.6 years. After propensity‐score matching (407 matched pairs), there was no difference in survival (87% versus 90% at 20 years; P=0.16) or freedom from failure (73% versus 80% at 20 years; P=0.10) between patients with and without fenestration, respectively. Although patients with fenestration had longer bypass and cross‐clamp times (P

Background: Exercise training is important for people with congenital heart disease (CHD). However, accurate exercise intensity prescription remains challenging. We sought to evaluate the validity of using the percentage of peak HR (%HRpeak) and HR reserve (%HRR) methods to estimate exercise intensity in people with CHD. Methods: Cardiopulmonary exercise tests from 2009 to 2017 were reviewed. Light, moderate, and vigorous exercise intensity were characterized using guideline-based percentage of peak oxygen uptake (VO2) ranges, and corresponding HRs were averaged at each intensity. The estimated average HR for each exercise intensity category was calculated using the %HRR and %HRpeak methods. Differences between the average HR at each intensity (reference HR) and the estimated HRs were determined. Results: 265 subjects were included (mean age, 29 ± 10 years, 48% females). The %HRR and age-predicted maximal HR (%HRmax) methods were the most accurate, but were still only within the guideline-defined HR ranges less than 65% of the time. Age-predicted %HRmax was the most accurate in the light and moderate-intensity categories, within the defined intensity range 59% and 63% of the time respectively. For vigorous-intensity exercise, %HRpeak was the most accurate, with the average HR within the defined intensity range 84% of the time. %HRpeak tended to underestimate exercise intensity, while %HRR overestimated it. Conclusions: Using common HR methods for estimating exercise intensity may not be valid in many people with CHD. The %HRR and age-predicted %HRmax methods were the most accurate but were out of range for around one-third of the cohort.

Abstract Background In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters. Methods We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index (stress/rest signal intensity) was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment. Results The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (– 7.4–42.8) vs 12.5 (9–24.6)%, p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness (r = – 0.7, p

Macronutrients are a major component of the human diet. However, few studies have assessed their collective association with mortality. We sought to evaluate the associations of macronutrient intake with all-cause, cardiovascular, and cancer mortality in US adults using a multi-nutrient approach. This prospective cohort analysis used data from the National Health and Nutrition Examination Survey from the years 1999 to 2014. The participants included 33,681 US adults aged 20–85 years (52.5% female). The maximum follow-up time was 16.8 years, with a total of 4398 total deaths, including 772 cardiovascular deaths and 952 cancer deaths. The associations between mortality and dietary macronutrients were explored using three-dimensional generalized additive models, allowing for visual and statistical inference of complex nonlinear associations. Absolute macronutrient intake demonstrated a three-way interactive association with all-cause mortality (p < 0.001), cardiovascular mortality (p = 0.02), and cancer mortality (p = 0.05), adjusted for age, sex, ethnicity, socioeconomic status, dietary quality, and lifestyle. Compositionally, a high caloric diet composed of moderately high protein (20%), moderate fat (30%), and moderate carbohydrate (50%) levels was associated with the highest mortality risk. Across the total energy intake levels, lower mortality risk was observed in two separate regions consisting of higher protein (30%), higher carbohydrate (60%), and lower fat levels (10%) or lower protein (10%), moderate carbohydrate (45%), and higher fat levels (45%). These findings highlight a complex nonlinear and interactive association between macronutrients and all-cause mortality such that several distinct dietary compositions are associated with similarly high or low risk. Future research is needed to explore the drivers of these associations and whether they differ across varying dietary patterns and populations.

Background: Hospital discharge codes are relied upon for research, accounting/invoicing and health systems planning. Congenital heart disease (CHD), however, is uniquely difficult for non-cardiologists to code due to the rarity, variety and complexity of lesions. It is therefore important that the accuracy of hospital discharge codes is regularly checked to ensure that the prevalence and burden of CHD is being correctly estimated and recorded. Methods and results: We identified all inpatient admissions of adults with CHD to Royal Prince Alfred Hospital in Sydney, Australia from January 2018 to March 2021 (257 admissions, 106 unique patients). The associated discharge coding summaries were extracted and compared to the codes in the separately collected and audited Adult CHD database. Only a quarter of discharge coding summaries contained any diagnosis of CHD, and just one-tenth accurately recorded all appropriate CHD diagnoses. Patients with simple lesions were most likely to have a coded diagnosis of CHD, while those with moderate and complex lesions were much less likely. Moreover, patients admitted under a cardiovascular specialty were twice as likely to have a coded diagnosis of CHD, compared with those admitted under non-cardiovascular specialties (p ​= ​0.006). Overall, less than half of patients had any hospital-coded diagnosis of CHD in any admission over the three-year study period. Conclusions: Hospital discharge coding dramatically underreports CHD, especially for patients with moderate and severe CHD lesions and for admissions under non-cardiovascular specialties. This suggests that discharge coding-based estimates of the burden of CHD on hospitals and health systems may be substantially underestimated.

BackgroundExercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability.MethodsA total of 110 apolipoprotein (apo)E−/− mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2).ResultsA total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (−16%), free cholesterol (−13%), triglyceride (TG) (−35%), and phospholipid (−27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (−25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (−18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (−59%, p < 0.01 and −51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels.ConclusionA 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage.

Background: Significant right ventricular (RV) dilatation has long been considered integral to the pathogenesis of functional tricuspid regurgitation (FTR). Objectives: To explore the relationship of RV dilatation and FTR in patients with ‘pure’ RV volume overload. Methods: Patients (>17yrs) with RV dilatation due to pre-tricuspid shunts (atrial septal defect; ASD and/or partial anomalous pulmonary venous drainage; PAPVD) referred to our service (2000–2019) were retrospectively identified. Those with pulmonary hypertension, primum ASD or left-heart disease were excluded. Using standard cardiac MRI protocols, RV, right atrial and TV parameters were measured and compared. Results: Of 52 consecutively eligible patients (42 ± 15yrs, 25 males), 25 had ASDs, 13 had PAPVD and 14 had both conditions. All were in sinus rhythm and none had pulmonary regurgitation. Left and right ventricular ejection fractions were normal (LVEF 63 ± 8%, RVEF 56 ± 8%). Indexed RV end-diastolic volumes (RVEDVi) were moderately increased (males 148 ± 33 mL/m2 and females 141 ± 42 mL/m2, range 95–267 mL/m2). Despite substantial RV volume overload, no patients had severe tricuspid regurgitation (TR). Only two had > mild TR. There was a weak correlation between tricuspid annular diameter and both degree of RV dilatation (r = 0.37; p = 0.01) and degree of TR (r = 0.38; p = 0.006). There was a similarly poor correlation between right atrial dimensions and the degree of TR (r = 0.34; p = 0.02). Conclusion: When RV dilatation is simply due to volume overload, we find that significant TR is extremely rare. This gives an important and novel insight; that RV dilatation per se does not result in FTR.

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe—and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials.Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)—a phase III clinical trial—aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (

Background: People with a Fontan circulation usually have moderately impaired exercise performance, although a subset have high physical performance (“Super-Fontan”), which may represent a low-risk phenotype.Methods: People with a “Super-Fontan” phenotype were defined as achieving normal exercise performance [≥80% predicted peak oxygen uptake (VO2) and work rate] during cardiopulmonary exercise testing (CPET) and were identified from the Australian and New Zealand Fontan Registry. A Fontan control group that included people with impaired exercise performance (

Background The prevalence and outcomes of the different subtypes of severe low‐gradient aortic stenosis (AS) in routine clinical cardiology practice have not been well characterized. Methods and Results Data were derived from the National Echocardiography Database of Australia. Of 192 060 adults (aged 62.8±17.8 [mean±SD] years) with native aortic valve profiling between 2000 and 2019, 12 013 (6.3%) had severe AS. Of these, 5601 patients (47%) had high‐gradient and 6412 patients (53%) had low‐gradient severe AS. The stroke volume index was documented in 2741 (42.7%) patients with low gradient; 1750 patients (64%) with low flow, low gradient (LFLG); and 991 patients with normal flow, low gradient. Of the patients with LFLG, 1570 (89.7%) had left ventricular ejection fraction recorded; 959 (61%) had paradoxical LFLG (preserved left ventricular ejection fraction), and 611 (39%) had classical LFLG (reduced left ventricular ejection fraction). All‐cause and cardiovascular‐related mortality were assessed in the 8162 patients with classifiable severe AS subtype during a mean±SD follow‐up of 88±45 months. Actual 1‐year and 5‐year all‐cause mortality rates varied across these groups and were 15.8% and 49.2% among patients with high‐gradient severe AS, 11.6% and 53.6% in patients with normal‐flow, low‐gradient severe AS, 16.9% and 58.8% in patients with paradoxical LFLG severe AS, and 30.5% and 72.9% in patients with classical LFLG severe AS. Compared with patients with high‐gradient severe AS, the 5‐year age‐adjusted and sex‐adjusted mortality risk hazard ratios were 0.94 (95% CI, 0.85–1.03) in patients with normal‐flow, low‐gradient severe AS; 1.01 (95% CI, 0.92–1.12) in patients with paradoxical LFLG severe AS; and 1.65 (95% CI, 1.48–1.84) in patients with classical LFLG severe AS. Conclusions Approximately half of those patients with echocardiographic features of severe AS in routine clinical practice have low‐gradient hemodynamics, which is associated with long‐term mortality comparable with or worse than high‐gradient severe AS. The poorest survival was associated with classical LFLG severe AS.

Background Bicuspid aortic valve (BAV) is the most common congenital heart disease in adults but is clinically heterogeneous. We aimed to describe the echocardiographic characteristics of BAV and compare patients with BAV with moderate‐to‐severe aortic stenosis (AS) with those with tricuspid aortic valve (TAV) stenosis. Methods and Results Using the National Echo Database of Australia, patients in whom BAV was identified were studied. Those with moderate‐to‐severe AS (mean gradient >20 mm Hg [BAV‐AS]) were compared with those with TAV and moderate‐to‐severe AS (TAV‐AS). Of 264 159 adults whose aortic valve morphology was specified, 4783 (1.8%) had confirmed BAV (aged 49.6±17.4 years, 69% men). Of these, 42% had no AS, and 46% had no aortic regurgitation. Moderate‐to‐severe AS was detected in a greater proportion of patients with BAV with a recorded mean gradient (n=1112, 34%) compared with those with TAV (n=4377, 4%; P

Background: This review identifies the predictors of late mortality and heart transplantation that remain relevant in the contemporary population of patients with a Fontan circulation, focusing on the potential impact of post-Fontan morbidities on the late outlook of these patients. Methods and Results: A total of 1561 patients who had survived the Fontan operation in Australia or New Zealand from 1975 to 2018 were included in this review. Over a median duration of 11.4 years, there was a total of 117 deaths (7%) and 32 heart transplantations (2%). Freedom from death and heart transplantation at 10, 20 and 35 years post Fontan surgery were 94% (95% CI 93–95%), 87% (95 %CI 85–90%) and 66% (95 %CI 57–78%) respectively. Being male, having an atriopulmonary Fontan, pre-Fontan atrioventricular valve intervention, or prolonged pleural effusions post Fontan were predictive of late death or heart transplantation. However, time-dependent variables such as the development of atrial arrhythmia, protein/losing enteropathy or late ventricular dysfunction were stronger predictors of the same outcome. Patients who developed a time-dependent risk factor had a freedom from death and heart transplantation rate of 54% (95 %CI 43–66) at 15 years and 44% (95 %CI 33–57) at 25 years post Fontan. However, 95% (95 %CI 91–99) of patients without any of the identified risk factors were free from death or heart transplantation rate at 25 years post Fontan. Conclusion: In conclusion, the occurrence of post-operative complications such as PLE, arrhythmia and ventricular dysfunction will likely precede the late demise of these patients.

Background: Tricuspid valve (TV) pathology can occur in a diverse range of patients with adult congenital heart disease (ACHD). Data is lacking to guide indications and timing for surgical TV intervention and few series have documented the outcomes of TV surgery in this heterogenous cohort. Methods: We reviewed the records of 36 patients with congenital heart disease and biventricular circulations who had undergone TV surgery. Fourteen were men (38%) and mean age at the time of TV surgery was 36 ± 13years. 19 had Ebstein's anomaly (53%) and 17 had alternative diagnoses (47%), including TV disease associated with pulmonary stenosis (20%), Tetralogy of Fallot (11%), atrioventricular septal defects (11%) or TV dysplasia (5%). Results: The most common indication for surgery was severe tricuspid regurgitation (TR) and right-sided heart failure. The TV was repaired in 22 (61%) and replaced in 14 (39%). There was no peri-operative or 30-day mortality, and only one patient died during medium-term follow-up. At last follow up (9.8±8years from operation), 25 (71%) patients were functional New York Heart Association (NYHA) Class I. Four patients required re-operation at a mean age of 48 ± 11years and 9.2±7years after their initial TV surgery. In patients who underwent a single TV surgery, 83% had trivial or mild TR at 8.1 ± 7.5years from date of surgery, and no patients had more than mild obstruction to TV inflow. Conclusion: Irrespective of the underlying pathology for TV disease in patients with ACHD, surgical TV intervention is associated with very low early mortality and good medium to long-term outcomes, when patients are cared for at a specialised ACHD centre.

Background: The atrioventricular (AV) delay may be altered in ventricularly paced patients with either dual-chamber pacemakers or cardiac resynchronization therapy (CRT), to optimize diastolic filling and cardiac output, but such modifications are virtually unstudied in the setting of complex congenital heart disease (CHD). We sought to assess the optimal AV delay in a pilot study of ventricularly paced adults with CHD. Methods: AV delay optimization was performed by the iterative method utilising pulsed wave Doppler of systemic AV valve inflow, in the patient's presenting rhythm (atrial-sensed or paced). Diastolic filling time (DFT), inflow and outflow velocity time integrals (VTI) were compared at optimal and nominal AV delay settings. Results: Nine patients were studied with the following CHD diagnoses: congenitally corrected transposition of the great arteries (TGA) in 4, D-TGA post Senning in 2, tetralogy of Fallot in 2 and Fontan circulation in 1. The median optimal AV delay was 100 ± 20 ms, shorter than the median nominal AV delay of 150 ± 20 ms. The median difference between optimal and nominal AV delay setting was 50 ± 40 ms, with the optimal AV delay shorter than the nominal in all but one patient. At optimal AV delay, the DFT was longer, and inflow and outflow VTIs were larger, compared to nominal. Conclusions: AV delay optimization in ventricularly paced adult CHD patients resulted in an optimal AV delay that differed to the nominal setting in all patients, and typically was shorter.

Air pollution (PM2.5) has been associated with cardiovascular disease (CVD) globally and with early atherosclerosis surrogate markers in modernized China. A sizeable number of Chinese have migrated overseas, with an increase in their vulnerability to CVD. To evaluate the impact of PM2.5 air pollution on atherogenesis in native vs. overseas Chinese, we recruited 756 asymptomatic native Chinese and 507 age- and gender-matched overseas Chinese from Sydney and San Francisco. Their cardiovascular profiles were evaluated. PM2.5 was derived from remote sensing technology; atherosclerosis surrogate markers, flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) were measured by ultrasound. The native Chinese had a higher proportion of smokers as well as higher blood pressure, glucose, metabolic syndrome and PM2.5 exposure (p < 0.001), but lower lipids and folate than the overseas Chinese (p < 0.0001). Carotid IMT was lower in the native Chinese (p < 0.0001), but the other vascular parameters were similar. A multivariate regression revealed that FMD in the native Chinese was related to the male gender, age and location; in the overseas Chinese, it was related to age, but not to PM2.5. Carotid IMT in the native Chinese was related to PM2.5, independent of atherosclerotic risk factors and location (R2 = 0.384, F = 34.5, p < 0.0001) whereas in the overseas Chinese, IMT was related to the male gender and age, but not to PM2.5 or overseas location (R2 = 0.282, F = 19.7, p < 0.0001). PM2.5 had a greater impact on atherogenesis in the native Chinese, independent of traditional risk factors, with implications for preventive strategies.

Background: Patients with bicuspid aortic valve (BAV) with zero or two raphes have been under-represented in previous studies. Whether these patients have unique clinical courses remains unclear. We describe the indications for and types of surgery in patients with BAV, and describe differences between valve morphotypes. Methods: Adults who had undergone aortic and/or aortic valve surgery for BAV disease at our centres were identified and classified according to the Sievers definitions. Results: 317 patients were included (74.4% male, median age at surgery 62 years). Of these, 187 (59.0%) had aortic valve surgery, 7 (2.2%) aortic surgery, 120 (37.9%) combined valve and aortic surgery and 3 had a Ross procedure. Most patients had aortic stenosis (71.9%), followed by aortic regurgitation (16.7%). 30-day mortality was low (1.6%).The commonest valve morphology was type-1 (one raphe) in 89.6%; type-0 (no raphes) occurred in 7.9% and type-2 (two raphes) in 2.5%. Patients with type-2 valves were substantially younger at time of surgery than type-1 patients (median 36 vs 63 years, p = 0.008). A higher proportion of patients with type-0 valves required aortic surgery than those with type-1 (68.0% vs 37.3%, p = 0.007). There were no differences between groups for the indication for surgery, valvular abnormality or 30-day mortality. Conclusions: The number of BAV raphes was independently and significantly associated with age at surgery and the need for aortic intervention. Patients with type 0 and type 2 valves are a small but important proportion of the BAV population, potentially requiring different clinical surveillance and management.

Central Systolic Blood Pressure (cSBP) and Central Augmentation Index (cAIx) have been independently associated with cardiovascular risk in adults, and can be estimated using a generalized peripheral-to-central transfer function. We hypothesize that transfer function accuracy and precision will be influenced by degree of growth and change in body habitus during periods of growth, such as in childhood. We studied the pulse pressure waveforms of 91 healthy children at 8-years of age, and subsequently at 14-years of age. Waveforms were obtained by high-fidelity applanation tonometry of the radial and carotid arteries. Individualized radial-to-carotid transfer functions were formulated at 8-years of age and applied at 14-years of age to estimate cSBP and cAIx. Accuracy was defined as the difference between directly measured and predicted values, and precision as the residuals. Changes in weight (vs. error: β = −0.22, p = 0.04; vs. residuals: β = 0.30; p < 0.01) and body mass index (vs. residuals: β = 0.28, p < 0.01), between 8 and 14 years of age were associated with accuracy and precision of individualized transfer functions in predicting cSBP at 14 years of age. Change in weight (vs. residuals: β = 0.30; p < 0.01) and heart rate (vs. residuals β = 0.32, p < 0.01) were associated with the precision in predicting cAIx. Changes in body habitus and heart rate over a 6-year period of growth are associated with the predictive accuracy and precision of individualized transfer functions in children suggestive of changes in the frequency response characteristics of an individual’s vascular system during growth periods.

Cardiac biomarkers have become pivotal to the clinical practice of cardiology, but there remains much to discover that could benefit cardiology patients. We review the discovery of key protein biomarkers in the fields of acute coronary syndrome, heart failure, and atherosclerosis, giving an overview of the populations they were studied in and the statistics that were used to validate them. We review statistical approaches that are currently in use to assess new biomarkers and overview a framework for biomarker discovery and evaluation that could be incorporated into clinical trials to evaluate cardiovascular outcomes in the future.

Elevated pulse pressure can cause blood-brain barrier dysfunction and subsequent adverse neurological changes that may drive or contribute to the development of dementia with age. In short, elevated pulse pressure dysregulates cerebral endothelial cells and increases cellular production of oxidative and inflammatory molecules. The resulting cerebral microvascular damage, along with excessive pulsatile mechanical force, can induce breakdown of the blood-brain barrier, which in turn triggers brain cell impairment and death. We speculate that elevated pulse pressure may also reduce the efficacy of other therapeutic strategies for dementia. For instance, BACE1 inhibitors and anti-amyloid-β biologics reduce amyloid-β deposits in the brain that are thought to be a cause of Alzheimer’s disease, the most prevalent form of dementia. However, upregulation of oxidative and inflammatory molecules and increased amyloid-β secretion by cerebral endothelial cells exposed to elevated pulse pressure may hinder cognitive improvements with these drugs. Additionally, stem or progenitor cell therapy has the potential to repair blood-brain barrier damage, but chronic oxidative and inflammatory stress due to elevated pulse pressure can inhibit stem and progenitor cell regeneration. Finally, we discuss current efforts to repurpose blood pressure medications to prevent or treat dementia. We propose that new drugs or devices should be developed to safely reduce elevated pulse pressure specifically to the brain. Such novel technologies may alleviate an entire downstream pathway of cellular dysfunction, oxidation, inflammation, and amyloidogenesis, thereby preventing pulse-pressure-induced cognitive decline. Furthermore, these technologies may also enhance efficacy of other dementia therapeutics when used in combination.

Background We sought to characterize body composition abnormalities in young patients living with a Fontan circulation and explore potential pathophysiologic associations. Methods and Results Twenty‐eight patients with a Fontan circulation were prospectively recruited in this cross‐sectional study. Participants underwent cardiopulmonary exercise testing, dual‐energy X‐ray absorptiometry, echocardiography, and biochemical assessment. Mean age was 26±7 years. Skeletal muscle mass, estimated by appendicular lean mass index Z score, was reduced compared with reference data (−1.49±1.10, P

Background People with a Fontan circulation experience a range of physical, psychosocial and neurodevelopmental challenges alongside, or caused by, their cardiac condition, with significant consequences for health‐related quality of life (HRQOL). We meta‐analyzed HRQOL outcomes reported by people with a Fontan circulation or their proxies and evaluated predictors of poorer HRQOL. Methods and Results Six electronic databases were searched for peer‐reviewed, English‐language articles published before March 2019. Standardized mean differences (SMD) were calculated using fixed and random‐effects models. Fifty articles reporting on 29 unique studies capturing HRQOL outcomes for 2793 people with a Fontan circulation and 1437 parent‐proxies were analyzed. HRQOL was lower in individuals with a Fontan circulation compared with healthy referents or normative samples (SMD, −0.92; 95% CI, −1.36 to −0.48; P

Summary: Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral. Key Words: atherosclerosis, cholesterol, high-density lipoproteins

To evaluate the impact of PM2.5 air pollution on atherogenic processes in modernizing Southern versus Northern China, we studied 1323 asymptomatic Chinese in Southern and Northern China in 1996–2007. PM2.5 exposure and metabolic syndrome (MS) were noted. Brachial flow-mediated dilation (endothelial function FMD) and carotid intima-media thickness (IMT) were measured by ultrasound. Although age and gender were similar, PM2.5 was higher in Northern China than in Southern China. The Northern Chinese were characterized by lower lipids, folate and vitamin B12, but higher age, blood pressures, MS and homocysteine (HC) (p = 0.0015). Brachial FMD was significantly lower and carotid IMT was significantly greater (0.68 ± 0.13) in Northern Chinese, compared with FMD and IMT (0.57 ± 0.13, p < 0.0001) in Southern Chinese. On multivariate regression, for the overall cohort, carotid IMT was significantly related to PM2.5, independent of location and traditional risk factors (Model R2 = 0.352, F = 27.1, p < 0.0001), while FMD was inversely related to gender, age, and northern location, but not to PM2.5. In Southern Chinese, brachial FMD was inversely correlated to PM2.5, independent of age, whereas carotid IMT was significantly related to PM2.5, independent of age and gender. In Northern Chinese, brachial FMD was inversely related to gender only, but not to PM2.5, while carotid IMT was related to traditional risk factors. Despite a higher PM2.5 pollution in Northern China, PM2.5 pollution was more significantly associated with atherogenic surrogates in Southern compared to Northern Chinese. This has potential implications for atherosclerosis prevention.

The atherothrombotic substrates for acute coronary syndromes (ACS) consist of plaque ruptures, erosions and calcified nodules, while the non-atherothrombotic etiologies, such as spontaneous coronary artery dissection, coronary artery spasm and coronary embolism are the rarer causes of ACS. The purpose of this comprehensive review is to (1) summarize the histopathologic insights into the atherothrombotic plaque subtypes in acute ACS from postmortem studies; (2) provide a brief overview of atherogenesis, while mainly focusing on the events that lead to plaque destabilization and disruption; (3) summarize mechanistic data from clinical studies that have used intravascular imaging, including high-resolution optical coherence tomography, to assess culprit plaque morphology and its underlying pathobiology, especially the newly described role of innate and adaptive immunity in ACS secondary to plaque erosion; (4) discuss the utility of intravascular imaging for effective treatment of patients presenting with ACS by percutaneous coronary intervention; and (5) discuss the opportunities that these mechanistic and imaging insights may provide for more individualized treatment of patients with ACS.

Background: It has been established that the central elastic arteries of the mammalian circulation dampen the high pulse pressure emanating from the left ventricle, so that the pulsations in distal arterioles, such as in the cerebral circulation, are of lower amplitude than more centrally. However, the contribution of the common carotid artery (CCA) to protection of the cerebral microvasculature from high pulse pressure is not known, specifically to what extent viscoelastic energy dissipation in the arterial wall might contribute to the shock absorbing function of the large conduit arteries. Methods: Young adult sheep (n = 6) were anaesthetised and their CCAs (n = 7) exposed. Pressure catheters were inserted 10–15 cm apart, proximally and distally in the CCA; a flow probe was placed proximally on the vessel. Results: The median dp/dtmax on the pressure rise of the arterial wave upstroke for the proximal CCA was 619 mm Hg/s and for the distal CCA it was significantly lower, at 197 mm Hg/s (p = 0.0156; n = 7). The median pulse pressure of the proximal CCA was 24 mm Hg/s; distal pulse pressure was significantly lower, at 18 mm Hg/s (p = 0.0156; n = 7). The median flow rate was 0.97 L/min with an interquartile range from 0.51 to 1.15 L/min. Conclusions: The native CCA in the young adult sheep is an effective “pressure dampener” in the arterial circulation, reducing both pressure slope and pulse pressure, most likely via viscous dampening in the arterial wall. Keywords: Common carotid artery, Pulse pressure wave, Dampening

Vegetarian diets have been associated with atherosclerosis protection, with healthier atherosclerosis risk profiles, as well as lower prevalence of, and mortality from, ischemic heart disease and stroke. However, there are few data concerning the possible cardiovascular effects of a vegan diet (with no meat, dairy or egg products). Vitamin B-12 deficiency is highly prevalent in vegetarians; this can be partially alleviated by taking dairy/egg products in lact-ovo-vegetarians. However, metabolic vitamin B-12 deficiency is highly prevalent in vegetarians in Australia, Germany, Italy and Austria, and in vegans (80%) in Hong Kong and India, where vegans rarely take vitamin B-12 fortified food or vitamin B-12 supplements. Similar deficiencies exist in northern Chinese rural communities consuming inadequate meat, egg or dairy products due to poverty or dietary habits. Vascular studies have demonstrated impaired arterial endothelial function and increased carotid intima-media thickness as atherosclerosis surrogates in such metabolic vitamin B-12 deficient populations, but not in lactovegetarians in China. Vitamin B-12 supplementation has a favourable impact on these vascular surrogates in Hong Kong vegans and in underprivileged communities in northern rural China. Regular monitoring of vitamin B-12 status is thus potentially beneficial for early detection and treatment of metabolic vitamin B-12 deficiency in vegans, and possibly for prevention of atherosclerosis-related diseases.

Obesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor κB (NF-κB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFα-induced NF-κB activation, correlating with decreased NF-κB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-κB activation.

Background: Chronic cyanosis in adults with congenital heart disease (CHD) may cause structural brain changes that could contribute to impaired neurological functioning. The extent of these changes has not been adequately characterized. Hypothesis: We hypothesized that adults with cyanotic CHD would have widespread changes including abnormal brain volumetric measures, decreased cortical thickness and an increased burden of small and large vessel ischemic changes. Methods: Ten adults with chronic cyanosis from CHD (40 ± 4 years) and mean oxygen saturations of 82 ± 2% were investigated using quantitative MRI. Hematological and biochemical parameters were also assessed. All subjects were free from major physical or intellectual impairment. Brain volumetric results were compared with randomly selected age- and sex-matched controls from our database of normal subjects. Results: Five of 10 cyanotic subjects had cortical lacunar infarcts. The white matter (WM) hyperintensity burden was also abnormally high (Scheltens Scale was 8 ± 2). Quantitative MRI revealed evidence of extensive generalized WM and gray matter (GM) volumetric loss; global GM volume was reduced in cyanosed subjects (630 ± 16 vs. 696 ± 14 mL in controls, p = 0.01) as was global WM volume (471 ± 10 vs. 564 ± 18 mL, p = 0.003). Ventricular cerebrospinal fluid volume was increased (35 ± 10 vs. 26 ± 5 mL, p = 0.002). There were widespread regions of local cortical thickness reduction observed across the brain. These changes included bilateral thickness reductions in the frontal lobe including the dorsolateral prefrontal cortex and precentral gyrus, the posterior parietal lobe and the middle temporal gyrus. Sub-cortical volume changes were observed in the caudate, putamen and in the thalamus (p ≤ 0.005 for all regions). Cortical GM volume negatively correlated with brain natriuretic peptide (R = −0.89, p = 0.009), high sensitivity C-reactive protein (R = −0.964, p

Atherosclerosis underlies most myocardial infarctions and ischemic strokes. The timing of onset and the rate of progression of atherosclerosis differ between individuals and among arterial sites. Physical manifestations of atherosclerosis may begin in early life, particularly in the abdominal aorta. Measurement of the abdominal aortic intima-media thickness by external ultrasound is a non-invasive methodology for quantifying the extent and severity of early atherosclerosis in children, adolescents, and young adults. This review provides an evidence-based rationale for the assessment of abdominal aortic intima-media thickness—particularly as an age-appropriate methodology for studying the natural history of atherosclerosis in the young in comparison to other methodologies—establishes best practice methods for assessing abdominal aortic intima-media thickness, and identifies key gaps in the literature, including those that will identify the clinical relevance of this measure.

Birth weight is associated with cardiovascular disease, with those at both ends of the spectrum at increased risk. However, birth weight is a crude surrogate of fetal growth. Measures of body composition may more accurately identify high risk infants. We aimed to determine whether aortic wall thickening, cardiac autonomic control, and cardiac structure/function differ in newborns with high or low body fatness compared to those with average body fatness. 189 healthy singleton term born neonates were recruited and stratified by body fat percentiles (sex and gestation-specific). Infants with low body fat had higher aortic intima-media thickness (43 µm (95% confidence interval (CI) 7, 78), p = 0.02), lower heart rate variability (log total power, −0.5 (95% CI −0.8, −0.1), p = 0.008), and thicker ventricular walls (posterior wall thickness, 3.1 mm (95% CI 1.6, 4.6), p < 0.001) compared to infants with average body fatness. Infants with high body fat showed no differences in aortic intima-media thickness (−2 µm (95% CI −37, 33), p = 0.91) or cardiac structure compared to average body fatness, although stroke volume (−0.3 mL/kg (95% CI −0.6, −0.0), p = 0.003) and heart rate variability were lower (log total power, −0.8 (95% CI −1.1, −0.5), p < 0.001). The non-linear association of body fatness with heart rate variability was independent of birth weight. Infants born with low or high body fat have altered markers of cardiovascular health. Assessment of body fatness alongside birth weight may assist in identifying high risk individuals.

The fetal environment has an important influence on health and disease over the life course. Maternal nutritional status during pregnancy is potentially a powerful contributor to the intrauterine environment, and may alter offspring physiology and later life cardio-metabolic risk. Putative early life markers of cardio-metabolic risk include newborn body fatness and cardiac autonomic control. We sought to determine whether maternal dietary carbohydrate quantity and/or quality during pregnancy are associated with newborn body composition and cardiac autonomic function. Maternal diet during pregnancy was assessed in 142 mother-infant pairs using a validated food frequency questionnaire. Infant adiposity and body composition were assessed at birth using air-displacement plethysmography. Cardiac autonomic function was assessed as heart rate variability. The quantity of carbohydrates consumed during pregnancy, as a percentage of total energy intake, was not associated with meaningful differences in offspring birth weight, adiposity or heart rate variability (p > 0.05). There was some evidence that maternal carbohydrate quality, specifically higher fibre and lower glycemic index, is associated with higher heart rate variability in the newborn offspring (p = 0.06). This suggests that poor maternal carbohydrate quality may be an important population-level inter-generational risk factor for later cardiac and hemodynamic risk of their offspring.