Cardiovascular magnetic resonance imaging for sequential assessment of cardiac fibrosis in mice: technical advancements and reverse translation.

Cardiovascular magnetic resonance (CMR) imaging has become an essential technique for the assessment of cardiac function and morphology, and is now routinely used to monitor disease progression and intervention efficacy in the clinic. Cardiac fibrosis is a common characteristic of numerous cardiovascular diseases and often precedes cardiac dysfunction and heart failure. Hence, the detection of cardiac fibrosis is important for both early diagnosis and the provision of guidance for interventions/therapies. Experimental mouse models with genetically and/or surgically induced disease have been widely used to understand mechanisms underlying cardiac fibrosis and to assess new treatment strategies. Improving the appropriate applications of CMR to mouse studies of cardiac fibrosis has the potential to generate new knowledge, and more accurately examine the safety and efficacy of antifibrotic therapies. In this review, we provide 1) a brief overview of different types of cardiac fibrosis, 2) general background on magnetic resonance imaging (MRI), 3) a summary of different CMR techniques used in mice for the assessment of cardiac fibrosis including experimental and technical considerations (contrast agents and pulse sequences), and 4) provide an overview of mouse studies that have serially monitored cardiac fibrosis during disease progression and/or therapeutic interventions. Clinically established CMR protocols have advanced mouse CMR for the detection of cardiac fibrosis, and there is hope that discovery studies in mice will identify new antifibrotic therapies for patients, highlighting the value of both reverse translation and bench-to-bedside research.

Use of artificial intelligence-guided echocardiography to detect cardiac dysfunction and heart valve disease in rural and remote areas: Rationale and design of the AGILE-echo trial.

BACKGROUND: Transthoracic echocardiography (TTE) is essential in the diagnosis of cardiovascular diseases (CVD), including but not limited to heart failure (HF) and heart valve disease (HVD). However, its dependence on expert acquisition means that its accessibility in rural areas may be limited, leading to delayed management decisions and potential missed diagnoses. Artificial intelligence-guided (AI)-TTE offers a solution by permitting non-expert image acquisition. The impact of AI-TTE on the timing of diagnosis and early initiation of cardioprotection is undefined. METHODS: AGILE-Echo (use of Artificial intelligence-Guided echocardiography to assIst cardiovascuLar patient managEment) is a randomized-controlled trial conducted in 5 rural and remote areas around Australia. Adults with CV risk factors and exercise intolerance, or concerns regarding HVD are randomized into AI-TTE or usual care (UC). AI-TTE participants may have a cardiovascular problem excluded, identified (leading to AI-guided interventions) or unresolved (leading to conventional TTE). UC participants undergo usual management, including referral for standard TTE. The primary endpoint is a composite of HVD or HF diagnosis at 12-months. Subgroup analysis, stratified based on age range and sex, will be conducted. All statistical analyses will be conducted using R. RESULTS: Of the first 157 participants, 78 have been randomized into AI-TTE (median age 68 [IQR 17]) and 79 to UC (median age 65 [IQR 17], P = .034). HVD was the primary concern in 37 participants (23.6%) while 84.7% (n = 133) experienced exercise intolerance. The overall 10-year HF incidence risk was 13.4% and 20.0% (P = .089) for UC and AI-TTE arm respectively. Atrial remodeling, left ventricular remodeling and valvular regurgitation were the most common findings. Thirty-three patients (42.3%) showed no abnormalities. CONCLUSIONS: This randomized-controlled trial of AI-TTE will provide proof-of-concept for the role of AI-TTE in identifying pre-symptomatic HF or HVD when access to TTE is limited. Additionally, this could promote the usage of AI-TTE in rural or remote areas, ultimately improving health and quality of life of community dwelling adults with risks, signs or symptoms of cardiac dysfunction.

Use of Imaging-guided Decongestion for Reducing Heart Failure Readmission and Death in High-risk Patients: A Multi-site Randomized Trial of a Nurse-led Strategy at the Point of Care.

BACKGROUND: Nurse-led disease management programs (DMPs) decrease readmission after acute decompensated heart failure (HF). We sought whether readmissions could be further reduced by lung ultrasound (LUS)-guided decongestion before discharge and during DMP. METHODS AND RESULTS: Of 290 patients hospitalized with acute decompensated HF, 122 at high risk for readmission or mortality were randomized to receive usual care (UC) (n = 64) or UC plus intervention (DMP-Plus) (n = 58), comprising LUS-guided management before discharge and during at-home follow-up. Residual congestion was identified by ≥10 B-lines detected in 8 lung zones. The outcomes included a composite of readmission and/or mortality at 30 and 90 days, and 90-day HF readmission. Residual congestion was detected equally among the patient groups. The 30-day composite outcome occurred in 28% DMP-plus patients and 22% UC patients (odd ratio [OR], 1.36; 95% confidence interval [CI], 0.59-3.1; P = .5) and the 90-day HF readmission outcome occurred in 22% and 31%, respectively (odds ratio, 0.63; 95% CI, 0.28-1.43; P = .3). Residual congestion, identified at predischarge LUS examination in high-risk patients, was associated with early (<14-day) HF readmission (relative risk, 1.19; 95% CI, 1.06-1.32; P = .002) and multiple (≥2) readmissions over 90 days of follow-up (relative risk, 1.09; 95% CI, 1.01-1.16; P = .012), independent of demographics and comorbidities. CONCLUSIONS: Readmission in patients with incomplete decongestion before discharge occurs within the first 2 weeks. However, our DMP-plus strategy did not improve the primary outcome.

Use of the energy waveform electrocardiogram to detect subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Recent guidelines propose N-terminal pro-B-type natriuretic peptide (NT-proBNP) for recognition of asymptomatic left ventricular (LV) dysfunction (Stage B Heart Failure, SBHF) in type 2 diabetes mellitus (T2DM). Wavelet Transform based signal-processing transforms electrocardiogram (ECG) waveforms into an energy distribution waveform (ew)ECG, providing frequency and energy features that machine learning can use as additional inputs to improve the identification of SBHF. Accordingly, we sought whether machine learning model based on ewECG features was superior to NT-proBNP, as well as a conventional screening tool-the Atherosclerosis Risk in Communities (ARIC) HF risk score, in SBHF screening among patients with T2DM. METHODS: Participants in two clinical trials of SBHF (defined as diastolic dysfunction [DD], reduced global longitudinal strain [GLS ≤ 18%] or LV hypertrophy [LVH]) in T2DM underwent 12-lead ECG with additional ewECG feature and echocardiography. Supervised machine learning was adopted to identify the optimal combination of ewECG extracted features for SBHF screening in 178 participants in one trial and tested in 97 participants in the other trial. The accuracy of the ewECG model in SBHF screening was compared with NT-proBNP and ARIC HF. RESULTS: SBHF was identified in 128 (72%) participants in the training dataset (median 72 years, 41% female) and 64 (66%) in the validation dataset (median 70 years, 43% female). Fifteen ewECG features showed an area under the curve (AUC) of 0.81 (95% CI 0.787-0.794) in identifying SBHF, significantly better than both NT-proBNP (AUC 0.56, 95% CI 0.44-0.68, p < 0.001) and ARIC HF (AUC 0.67, 95%CI 0.56-0.79, p = 0.002). ewECG features were also led to robust models screening for DD (AUC 0.74, 95% CI 0.73-0.74), reduced GLS (AUC 0.76, 95% CI 0.73-0.74) and LVH (AUC 0.90, 95% CI 0.88-0.89). CONCLUSIONS: Machine learning based modelling using additional ewECG extracted features are superior to NT-proBNP and ARIC HF in SBHF screening among patients with T2DM, providing an alternative HF screening strategy for asymptomatic patients and potentially act as a guidance tool to determine those who required echocardiogram to confirm diagnosis. Trial registration LEAVE-DM, ACTRN 12619001393145 and Vic-ELF, ACTRN 12617000116325.

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. METHODS: Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. RESULTS: Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. CONCLUSIONS: Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. TRIAL REGISTRATION: ARISE-HF, NCT04083339.

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical siabetic cardiomyopathy.

INTRODUCTION: Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. METHODS: In this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. RESULTS: The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E', or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = - 0.10; p = 0.007), the Physical Activity Scale in the Elderly (rho = - 0.12; p = 0.004), duration of cardiopulmonary exercise testing (rho = - 0.28; p < 0.001), peak VO2 (rho = - 0.26; p < 0.001), and ratio of minute ventilation/carbon dioxide production (rho = 0.12; p = 0.002). After adjustment for known confounders, the correlation with Physical Activity Scale in the Elderly and overall Kansas City Cardiomyopathy Questionnaire score was no longer significant. CONCLUSION: Among patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals. TRIAL REGISTRATION: ARISE-HF, NCT04083339 Date Registered August 23, 2019.

A novel approach to accurately measuring the burden of hospitalisations for cardiovascular disease in people with diabetes: A pilot study.

AIM: To determine the reliability of hospital discharge codes for heart failure (HF), acute myocardial infarction (AMI) and stroke compared with adjudicated diagnosis, and to pilot a scalable approach to adjudicate records on a population-based sample. METHODS: A population-based sample of 685 people with diabetes admitted (1274 admissions) to one of three Australian hospitals during 2018-2020 were randomly selected for this study. All medical records were reviewed and adjudicated. RESULTS: Cardiovascular diseases were the most common primary reason for hospitalisation in people with diabetes, accounting for ~17% (215/1274) of all hospitalisations, with HF as the leading cause. ICD-10 codes substantially underestimated HF prevalence and had the lowest agreement with the adjudicated diagnosis of HF (Kappa = 0.81), compared with AMI and stroke (Kappa ≥ 0.91). While ICD-10 codes provided suboptimal sensitivity (72%) for HF, the performance was better for AMI (sensitivity 84%; specificity 100%) and stroke (sensitivity 85%; specificity 100%). A novel approach to screen possible HF cases only required adjudicating 8% (105/1274) of records, correctly identified 78/81 of HF admissions and yielded 96% sensitivity and 98% specificity. CONCLUSIONS: While ICD-10 codes appear reliable for AMI or stroke, a more complex diagnosis such as HF benefits from a two-stage process to screen for suspected HF cases that need adjudicating. The next step is to validate this novel approach on large multi-centre studies in diabetes.

Evolving Applications of Echocardiography in the Evaluation of Left Atrial and Right Ventricular Strain.

PURPOSE OF REVIEW: Speckle-tracking echocardiography (STE) can assess myocardial motion in non-LV chambers-including assessment of left atrial (LA) and right ventricular (RV) strain. This review seeks to highlight the diagnostic, prognostic, and clinical significance of these parameters in heart failure, atrial fibrillation (AF), diastolic dysfunction, pulmonary hypertension (PH), tricuspid regurgitation, and heart transplant recipients. RECENT FINDINGS: Impaired LA strain reflects worse LV diastolic function in individuals with and without HF, and this is associated with decreased exercise capacity. Initiating treatments targeting these functional aspects may enhance exercise capacity and potentially prevent heart failure (HF). Impaired LA strain also identifies patients with a high risk of AF, and this recognition may lead to preventive strategies. Impaired RV strain has significant clinical and prognostic implications across various clinical scenarios, including HF, PH, tricuspid regurgitation, or in heart transplant recipients. STE should not be limited to the assessment of deformation of the LV myocardium. The use of LA and RV strain is supported by a substantial evidence base, and these parameters should be used more widely.

Comparison of Echocardiography and Multi-Planar Gated Acquisition Scans for Predicting Cancer-Treatment-Related Cardiovascular Dysfunction.

BACKGROUND: Current guidelines recommend using sequential cardiac imaging to monitor for cancer treatment-related cardiac dysfunction (CTRCD) in patients undergoing potentially cardiotoxic chemotherapy. Multiple different imaging cardiac modalities are available and there are few prospective head-to-head comparative studies to help guide treatment. OBJECTIVES: To perform an exploratory prospective cohort study of "real-world" CTRCD comparing multigated acquisition nuclear ventriculography (MUGA) at the referring cancer specialist's discretion with a novel echocardiographic strategy at an Australian tertiary hospital. METHOD: Patients were recruited from haematology and oncology outpatient clinics if they were scheduled for treatment with anthracyclines and/or trastuzumab. Patients underwent simultaneous MUGA-based cardiac imaging (conventional strategy) at a frequency according to evidenced-based guidelines in addition to researcher-conducted echocardiographic imaging. The echocardiographic imaging was performed in all patients at time points recommended by international society guidelines. Outcomes included adherence to guideline recommendations, concordance between MUGA and echocardiographic left ventricular ejection fraction (LVEF) measurements, and detection of cardiac dysfunction (defined as >5% LVEF decrement from baseline by three-dimensional [3D]-LVEF). A secondary end point was accuracy of global longitudinal strain in predicting cardiac dysfunction. RESULTS: In total, 35 patients were recruited, including 15 with breast cancer, 19 with haematological malignancy, and one with gastric cancer. MUGA and echocardiographic LVEF measurements correlated poorly with limits of agreement of 30% between 3D-LVEF and MUGA-LVEF and 37% for 3D-LVEF and MUGA-LVEF. Only one case (2.9%) of CTRCD was diagnosed by MUGA, compared with 12 (34.2%) cases by echocardiography. Four (4) patients had >10% decrement in 3D-LVEF that was not detected by MUGA. Global longitudinal strain at 2 months displayed significant ability to predict CTRCD (area under the curve, 0.75, 95% confidence interval, 0.55-0.94). CONCLUSIONS: The MUGA correlates poorly with echocardiographic assessment with substantial discrepancy between MUGA and echocardiography in CTRCD diagnosis. Echocardiographic and MUGA imaging strategies should not be considered equivalent for imaging cancer patients, and a single imaging modality should ideally be used per patient to prevent misdiagnosis by inter-modality variation These findings should be considered hypothesis-generating and require confirmation with larger studies.

Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

BACKGROUND: Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. METHODS: SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. FINDINGS: Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group. INTERPRETATION: In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. FUNDING: Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). METHODS: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. RESULTS: The ARISE-HF Trial is fully enrolled. CONCLUSIONS: This report describes the rationale and study design of ARISE-HF.

The cost-effectiveness of coronary calcium score-guided statin therapy initiation for Australians with family histories of premature coronary artery disease.

OBJECTIVES: To compare the cost-effectiveness of coronary artery calcium (CAC) score-guided statin therapy criteria and American College of Cardiology/American Heart Association (ACC/AHA) guidelines (10-year pooled cohort equation [PCE] risk ≥ 7.5%) with selection according to Australian guidelines (5-year absolute cardiovascular disease risk [ACVDR] ≥ 10%), for people with family histories of premature coronary artery disease. STUDY DESIGN, SETTING: Markov microsimulation state transition model based on data from the Coronary Artery calcium score: Use to Guide management of Hereditary Coronary Artery Disease (CAUGHT-CAD) trial and transition probabilities derived from published statin prescribing and adherence outcomes and clinical data. PARTICIPANTS: 1083 people with family histories of premature coronary artery disease but no symptomatic cardiovascular disease. MAIN OUTCOME MEASURES: Relative cost-effectiveness over fifteen years, from the perspective of the Australian health care system, compared with usual care (Australian guidelines), assessed as incremental cost-effectiveness ratios (ICERs), with a notional willingness-to-pay threshold of $50 000 per quality-adjusted life-year (QALY) gained. RESULTS: Applying the Australian guidelines, 77 people were eligible for statin therapy (7.1%); with ACVDR 5-year risk ≥ 2% and CAC score > 0, 496 people (46%); with ACVDR 5-year risk ≥ 2% and CAC score ≥ 100, 155 people (14%); and with the ACC/AHA guidelines, 256 people (24%). The ICERs for CAC-guided selection were $33 108 (CAC ≥ 100) and $53 028 per QALY gained (CAC > 0); the ACC/AHA guidelines approach (ICER, $909 241 per QALY gained) was not cost-effective. CAC score-guided selection (CAC ≥ 100) was cost-effective for people with 5-year ACVDR of at least 5%. CONCLUSION: Expanding the number of people at low to intermediate CVD risk eligible for statin therapy should selectively target people with subclinical atherosclerosis identified by CAC screening. This approach can be more cost-effective than simply lowering treatment eligibility thresholds.

Use of clinical scores in young Australian adults for prediction of atherosclerosis in middle age.

We sought to apply a simple cardiovascular health tool not requiring laboratory tests (the Fuster-BEWAT score, FBS) to predict subclinical atherosclerosis. This study included 2657 young adults (< 40 years of age). In the prognostic group (n = 894, followed for 13 years until aged 40-50 years at follow-up), the primary outcome was presence of carotid plaque measured by carotid ultrasound at follow-up. Of these 894 participants, 86 (9.6%) had unilateral, and 23 participants (2.6%) had bilateral, carotid plaques at follow-up. The baseline FBS was predictive of carotid plaque at follow-up [odds ratio OR = 0.86 (95% CI 0.77-0.96) per 1-SD increase in FBS], similar to prediction from Pooled Cohort Equation [PCE, OR = 0.72 (0.61-0.85) per 1-SD decrease in PCE]. Risk scores at baseline predicted outcomes more strongly than those at follow-up, and did so independently of any changes over 13 years of follow-up. Similar discrimination for predicting carotid plaque after 13 years was found for both baseline FBS [C-statistic = 0.68 (95% CI 0.62-0.74)] and PCE [C-statistic = 0.69 (95% CI 0.63-0.75)]. Application of this FBS prognostic information to a contemporary cohort of 1763 young adults anticipates the future development of plaque in 305 (17.3%), especially in the 1494 participants (85%) with ≤ 2 metrics of ideal health. In conclusions, FBS measured in young adulthood predicted atherosclerosis 13 years later in middle age, independent of score changes over the follow-up period, emphasizing the importance of early damage to vascular health. FBS may be a simple and feasible risk score for engaging low-risk young people with reduction of future cardiovascular risk.

Cost-effectiveness of screening for paroxysmal atrial fibrillation in patients undergoing echocardiography.

BACKGROUND: Screening for atrial fibrillation is recommended for patients > 65 years on current guidelines. Targeted screening may be more efficient, however the appropriate location for screening programs has not been well defined. Our aim was to compare the cost-effectiveness of unselected electrocardiographic (ECG) screening for atrial fibrillation (AF), and selective screening based on an abnormal echocardiogram. METHODS: Two strategies of portable ECG screening for AF were compared in the base case of a hypothetical asymptomatic 65-year-old man (CHA2 DS2 -VASC = 3 based on hypertension and diabetes mellitus) with previous echocardiography but without a cause for AF (e.g. mitral valve disease, left ventricular (LV) dysfunction). With age-based screening (AgeScreen; 3% AF detection rate) all patients underwent ECG. With imaging-guided screening (ImagingScreen; 5% detection rate), only patients with left atrial (LA) volume ≥34 mL/m2 and LA reservoir strain <34% or LV global longitudinal strain > -18% underwent ECG screening. A Markov model was informed by published transition probabilities, costs and quality-adjusted life years (QALY). Costs, effects and incremental cost-effectiveness ratio were assessed for each screening strategy over a 20-year period. The willingness-to-pay threshold was $53 000/QALY. RESULTS: ImagingScreen dominated AgeScreen, with a lower cost ($54 823 vs $57842) and better outcome (11.56 vs 11.52 QALY over 20 years). Monte Carlo simulation demonstrated that 61% of observations were more efficacious with ImagingScreen, with cost below willingness to pay. The main cost determinants were annual costs of stroke or heart failure and AF detection rates. ImagingScreen was more cost-effective for AF detection rates up to 14%, and more cost-effective across a range of annual stroke ($24 000-$102 000) and heart failure ($4000-$12 000) costs. CONCLUSION: In patients with a previous echocardiogram, AF screening of those with baseline clinical and imaging risk parameters is more cost-effective than age-based screening.

Associations between symptoms and functional capacity in patients after COVID-19 infection and community controls.

BACKGROUND: Post-acute sequelae of COVID-19 (PASC or 'long COVID') reflect ongoing symptoms, but these are non-specific and common in the wider community. Few reports of PASC have been compared with a control group. AIMS: To compare symptoms and objective impairment of functional capacity in patients with previous COVID-19 infection with uninfected community controls. METHODS: In this community-based, cross-sectional study of functional capacity, 562 patients from Western Melbourne who had recovered from COVID-19 infections in 2021 and 2022 were compared with controls from the same community and tested for functional capacity pre-COVID-19. Functional impairment (<85% of the predicted response) was assessed using the Duke Activity Status Index (DASI) and 6-min walk distance (6MWD) test. A subgroup underwent cardiopulmonary exercise testing before and after exercise training. RESULTS: Of 562 respondents (age 54 ± 12 years, 69% women), 389 were symptomatic. Functional impairment (<85% predicted metabolic equivalent of tasks) was documented by DASI in 149 participants (27%), and abnormal 6MWD (<85% predicted) was observed in 14% of the symptomatic participants. Despite fewer risk factors and younger age, patients with COVID-19 had lower functional capacity by 6MWD (P < 0.001) and more depression (P < 0.001) than controls. In a pilot group of seven participants (age 58 ± 12 years, two women, VO2 18.9 ± 5.7 mL/kg/min), repeat testing after exercise training showed a 20% increase in peak workload. CONCLUSIONS: Although most participants (69%) had symptoms consistent with long COVID, significant subjective functional impairment was documented in 27% and objective functional impairment in 14%. An exercise training programme might be beneficial for appropriately selected patients.

Phenotyping the hypertensive heart.

Arterial hypertension remains the most frequent cardiovascular (CV) risk factor, and is responsible for a huge global burden of disease. Echocardiography is the first-line imaging method for the evaluation of cardiac damage in hypertensive patients and novel techniques, such as 2D and D speckle tracking and myocardial work, provide insight in subclinical left ventricular (LV) impairment that would not be possible to detect with conventional echocardiography. The structural, functional, and mechanical cardiac remodelling that are detected with imaging are intermediate stages in the genesis of CV events, and initiation or intensification of antihypertensive therapy in response to these findings may prevent or delay progressive remodelling and CV events. However, LV remodelling-especially LV hypertrophy-is not specific to hypertensive heart disease (HHD) and there are circumstances when other causes of hypertrophy such as athlete heart, aortic stenosis, or different cardiomyopathies need exclusion. Tissue characterization obtained by LV strain, cardiac magnetic resonance, or computed tomography might significantly help in the distinction of different LV phenotypes, as well as being sensitive to subclinical disease. Selective use of multimodality imaging may therefore improve the detection of HHD and guide treatment to avoid disease progression. The current review summarizes the advanced imaging tests that provide morphological and functional data about the hypertensive cardiac injury.

Telehealth Rapid Access Chest Pain Clinic: Initial Experience During COVID-19 Pandemic.

Objectives: Rapid Access Chest Pain Clinics (RACPCs) provide safe and efficient follow-up for outpatients presenting with new-onset chest pain. RACPC delivery by telehealth has not been reported. We sought to evaluate a telehealth RACPC established during the coronavirus disease 2019 (COVID-19) pandemic. There was a need to reduce the frequency of additional testing arranged by the RACPC during this time, and the safety of this approach was also explored. Methods: This was a prospective evaluation of a cohort of RACPC patients reviewed by telehealth during the COVID-19 pandemic compared with a historical control group of face-to-face consultations. The main outcomes included emergency department re-presentation at 30 days and 12 months, major adverse cardiovascular events at 12 months, and patient satisfaction scores. Results: One hundred forty patients seen in the telehealth clinic were compared with 1,479 in-person RACPC controls. Baseline demographics were similar; however, telehealth patients were less likely to have a normal prereferral electrocardiogram than RACPC controls (81.4% vs. 88.1%, p = 0.03). Additional testing was ordered less often for telehealth patients (35.0% vs. 80.7%, p < 0.001). Rates of adverse cardiovascular events were low in both groups. One hundred twenty (85.7%) patients reported being satisfied or highly satisfied with the telehealth clinic service. Conclusions: In the setting of COVID-19, a telehealth RACPC model with reduced use of additional testing facilitated social distancing and achieved clinical outcomes equivalent to a face-to-face RACPC control. Telehealth may have an ongoing role beyond the pandemic, supporting specialist chest pain assessment for rural and remote communities. Pending further study, it may be safe to reduce the frequency of additional testing following RACPC review.

Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins.

Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut-derived hormones that may explain these divergent responses. Ten healthy individuals underwent a 120 min oral glucose tolerance test (OGTT; 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast-enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C-peptide, glucagon, non-esterified fatty acids and a range of gut-derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(GLP-1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3-fold versus 0.5-fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8-fold higher plasma insulin concentrations (P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations (r = -0.665, P < 0.0001). The natural log ratio of incretins GLP-1:GIP was positively associated with ΔMBF (r = 0.658, P < 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. KEY POINTS: Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients; however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people; however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose-mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin-mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.

Use of coronary computed tomography or polygenic risk scores to prompt action to reduce coronary artery disease risk: the CAPAR-CAD trial.

BACKGROUND: The traditional primary prevention paradigm for coronary artery disease (CAD) centers on population-based algorithms to classify individual risk. However, this approach often misclassifies individuals and leaves many in the 'intermediate' category, for whom there is no clear preferred prevention strategy. Coronary artery calcium (CAC) and polygenic risk scoring (PRS) are 2 contemporary tools for risk prediction to enhance the impact of effective management. AIMS: To determine how these CAC and PRS impact adherence to pharmacotherapy and lifestyle measures in asymptomatic individuals with subclinical atherosclerosis. METHODS: The CAPAR-CAD study is a multicenter, open, randomized controlled trial in Victoria, Australia. Participants are self-selected individuals aged 40 to 70 years with no prior history of cardiovascular disease (CVD), intermediate 10-year risk for CAD as determined by the pooled cohort equation (PCE), and CAC scores >0. All participants will have a health assessment, a full CT coronary angiogram (CTCA), and PRS calculation. They will then be randomized to receive their risk presented either as PCE and CAC, or PCE and PRS. The intervention includes e-Health coaching focused on risk factor management, health education and pharmacotherapy, and follow-up to augment adherence to a statin medication. The primary endpoint is a change in low-density lipoprotein cholesterol (LDL-C) from baseline to 12 months. The secondary endpoint is between-group differences in behavior modification and adherence to statin pharmacotherapy. RESULTS: As of July 31, 2021, we have screened 1,903 individuals. We present the results of the 574 participants deemed eligible after baseline assessment.

Association of biomarkers and risk scores with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Subclinical LV dysfunction (LVD) identifies heart failure (HF) risk in type 2 diabetes mellitus (T2DM). We sought the extent to which clinical scores (ARIC-HF, WATCH-DM), natriuretic peptides (NTpBNP) and troponin (hs-TnT) were associated with subclinical LV dysfunction (LVD). These associations could inform the ability of these tests to identify which patients should undergo echocardiography. METHODS: Participants with T2DM were prospectively recruited from three community-based populations. ARIC-HF risk at 4 years and WATCH-DM scores were calculated from clinical data. NTpBNP and hs-TnT were measured using an electro-chemiluminescence assay. All underwent a comprehensive echocardiogram. We calculated the sensitivity and specificity of clinical scores and biomarkers to identify abnormal global longitudinal strain (GLS ≥ -16%)), diastolic function (E/e' ≥ 14 or e' < 8 cm/s), left atrial volume index (LAV > 34 ml/m2) and LV hypertrophy (LV mass index > 88 g/m2 (F) > 102 g/m2(M)). RESULTS: Of 804 participants (median age 69 years [inter-quartile range (IQR) 65-73], 36% female), clinical scores suggested significant HF risk (median ARIC-HF 8% [IQR 4-12]; WATCH-DM 10 points [IQR 8-12]), and the median NTpBNP was 50 pg/mL [IQR 25-101] and hs-TnT 9.6 pg/mL [IQR 6.8-13.6]. Abnormal GLS was present in 126 (17%), elevated E/e' in 114 (15%), impaired e' in 629 (78%), increased LAV in 351 (44%) and LV hypertrophy in 113 (14%). After adjustments for age, body-mass index, and renal function, each standard deviation increase in NTpBNP was associated with a GLS increase of 0.32 (p < 0.001) and hs-TnT increase by 0.26 (p < 0.001). Similar trends were observed with ARIC-HF (standardised ß = 0.22, p < 0.001) and WATCH-DM (standardised ß = 0.22, p < 0.001) in univariable analyses. However, none of the risk assessment tools provided satisfactory discrimination for abnormal GLS (AUC 63%), diastolic indices (e' AUC 54-61%) or LV mass (AUC 59-67%). At a sensitivity of 90%, there was an unacceptably low (< 50%) specificity. CONCLUSION: Although risk assessment based on clinical scores or biomarkers would be desirable to stratify HF risk in people with T2DM, they show a weak relationship with subclinical LVD.