Considerations for drug trials in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition with potentially serious manifestations. Management has traditionally comprised therapies to palliate symptoms and implantable cardioverter-defibrillators to prevent sudden cardiac death. The need for disease-modifying therapies has been recognized for decades. More recently, an increasing number of novel and repurposed therapies hypothesized to target HCM disease pathways have been evaluated, culminating in the recent regulatory approval of mavacamten, a novel oral myosin inhibitor. HCM poses several unique challenges for clinical trials, which are important to recognize when designing trials and interpreting findings. This manuscript discusses the key considerations in the context of recent and ongoing randomized trials, including the roles of genotype, phenotype and symptom status in patient selection, the evidence base for clinical and mechanistic outcome measurements, trial duration and sample size.

Association Between Coronary Microvascular Dysfunction and Exercise Capacity in Dilated Cardiomyopathy.

BACKGROUND: Aerobic exercise capacity is an independent predictor of mortality in dilated cardiomyopathy (DCM), but the central mechanisms contributing to exercise intolerance in DCM are unknown. OBJECTIVES: Characterize coronary microvascular function in DCM and determine if cardiovascular magnetic resonance (CMR) measures are associated with aerobic exercise capacity. METHODS: Prospective case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and automated inline myocardial blood flow quantification, and cardiopulmonary exercise testing (CPET) to determine peak VO2, were performed. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken to identify independent associations with peak VO2. RESULTS: Sixty-six patients with DCM (mean age 61 years, 71% male) were propensity-matched to 66 controls (mean age 59 years, 71% male) based on age, sex, body mass index and diabetes. DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3mL/kg/min; P<0.001). The DCM group had greater left ventricular (LV) volumes, lower systolic function, and had more fibrosis compared to controls. In the DCM group, there was similar rest but lower stress myocardial blood flow (1.53±0.49 versus 2.01±0.60mL/g/min; P<0.001) and lower MPR (2.69±0.84 versus 3.15±0.84; P=0.002). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, were independently associated with percentage predicted peak VO2 in DCM (R2=0.531, P<0.001). CONCLUSIONS: In comparison to controls, DCM patients have lower stress myocardial blood flow and MPR. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Diffuse Interstitial Fibrosis of the Myocardium Predicts Outcome in Moderate and Asymptomatic Severe Aortic Stenosis.

BACKGROUND: Patients with moderate or asymptomatic severe aortic stenosis (AS) are at risk of cardiovascular events. OBJECTIVES: The authors investigated the utility of cardiac magnetic resonance (CMR) to identify drivers of outcome in patients with moderate or asymptomatic severe AS. METHODS: A prospective, international, multicenter cohort (n = 457) of patients with moderate (aortic valve area [AVA]: 1.0-1.5 cm2) or asymptomatic severe AS (AVA ≤1.0 cm2 and NYHA functional class I-II) patients underwent CMR. Diffuse interstitial fibrosis and scar in the myocardium were analyzed with extracellular volume fraction (ECV%) and late gadolinium enhancement (LGE). The outcome was a composite of mortality and heart failure admission. RESULTS: Median ECV% was 26.6% (IQR: 24.4%-29.9%), and LGE was present in 31.5% (median 0.8%; IQR: 0.1%-1.7%). Greater AS severity was associated with greater left ventricular mass and diastolic dysfunction, but not with ECV% or LGE. During a median 5.7 years of follow-up, 83 events occurred. Patients with events had higher ECV% (median ECV% 26.3% vs 28.2%; P = 0.003). Patients in the highest ECV% tertiles (ECV% >28.6%) had worse outcomes both in the entire cohort and in those with NYHA functional class I moderate or severe AS, and ECV% was independently associated with outcome (adjusted HR: 1.05; P = 0.039). The ECV% had significant incremental prognostic value when added to parameters of AS severity and cardiac function, comorbidities, aortic valve replacement, and LGE (P < 0.05). CONCLUSIONS: Increased diffuse interstitial fibrosis of the myocardium is associated with poor outcomes in patients with moderate and asymptomatic severe AS and can help identify those who require closer surveillance for adverse outcomes.

Effect of aortic valve replacement on myocardial perfusion and exercise capacity in patients with severe aortic stenosis.

Aortic valve replacement (AVR) leads to reverse cardiac remodeling in patients with aortic stenosis (AS). The aim of this secondary pooled analysis was to assess the degree and determinants of changes in myocardial perfusion post AVR, and its link with exercise capacity, in patients with severe AS. A total of 68 patients underwent same-day echocardiography and cardiac magnetic resonance imaging with adenosine stress pre and 6-12 months post-AVR. Of these, 50 had matched perfusion data available (age 67 ± 8 years, 86% male, aortic valve peak velocity 4.38 ± 0.63 m/s, aortic valve area index 0.45 ± 0.13cm2/m2). A subgroup of 34 patients underwent a symptom-limited cardiopulmonary exercise test (CPET) to assess maximal exercise capacity (peak VO2). Baseline and post-AVR parameters were compared and linear regression was used to determine associations between baseline variables and change in myocardial perfusion and exercise capacity. Following AVR, stress myocardial blood flow (MBF) increased from 1.56 ± 0.52 mL/min/g to 1.80 ± 0.62 mL/min/g (p < 0.001), with a corresponding 15% increase in myocardial perfusion reserve (MPR) (2.04 ± 0.57 to 2.34 ± 0.68; p = 0.004). Increasing severity of AS, presence of late gadolinium enhancement, lower baseline stress MBF and MPR were associated with a greater improvement in MPR post-AVR. On multivariable analysis low baseline MPR was independently associated with increased MPR post-AVR. There was no significant change in peak VO2 post-AVR, but a significant increase in exercise duration. Change in MPR was associated with change in peak VO2 post AVR (r = 0.346, p = 0.045). Those with the most impaired stress MBF and MPR at baseline demonstrate the greatest improvements in these parameters following AVR and the magnitude of change in MPR correlated with improvement in peak VO2, the gold standard measure of aerobic exercise capacity.

In-vivo assessment of myocardial calcium uptake using manganese-enhanced cardiovascular magnetic resonance in aortic stenosis.

BACKGROUND: Dysregulated myocardial calcium handling has been demonstrated in ischemic, non-ischemic and diabetic cardiomyopathy. Manganese-enhanced MRI (MEMRI) provides a unique method to quantify in-vivo myocardial calcium uptake but no studies have so far utilized MEMRI in patients with aortic stenosis (AS). We sought to: 1) determine whether myocardial calcium uptake is perturbed in people with severe AS, and 2) assess change in calcium uptake following aortic valve replacement (AVR). METHODS: In this prospective, pilot, case-control study, adults with severe AS underwent MEMRI before and after AVR. A group of healthy controls were also recruited. The primary outcome was the rate of manganese uptake (Ki) as assessed by Patlak modeling to act as a surrogate of myocardial calcium uptake. Comparison of Ki between groups was adjusted for age, body mass index (BMI) and systolic blood pressure. RESULTS: Twenty-eight controls and ten subjects with severe AS (age 72 [61-75] years, 8 male, 7 symptomatic, valve area 0.81 [0.74-1.0] cm2) were recruited, with seven returning for repeat scans post-AVR. AS patients had higher BMI and blood pressure, and a greater incidence of hyperlipidemia compared to controls. Baseline left ventricular (LV) volumes were similar between the groups, but the AS patients had higher indexed left ventricular mass. Global longitudinal strain and peak early diastolic strain rate were lower in the AS group. There was no significant difference in Ki between patients with severe AS and controls (7.09 [6.33-8.99] vs. 8.15 [7.54-8.78] mL/100g of tissue/min, P=0.815). Following AVR, there was regression in indexed LV mass (68 [51-79] to 49 [47-65] g/m2, P=0.018) and mass-volume ratio (0.94 [0.80-1.13] to 0.74 [0.71-0.82] g/mL, P=0.028) but no change in Ki was seen (7.35 [6.81-8.96] to 7.11 [6.16-8.01] mL/100 g of tissue/min, P=0.499). CONCLUSIONS: Despite clear features of adverse LV remodeling and systolic dysfunction, patients with severe AS demonstrated no alteration in calcium uptake at baseline compared to controls. Moreover, AVR led to reverse LV remodeling but no notable change in calcium uptake was seen. This may suggest that altered myocardial calcium handling does not play a significant pathophysiological role in AS.

Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

Association of epicardial adipose tissue with early structural and functional cardiac changes in Type 2 diabetes.

BACKGROUND: Dysregulated epicardial adipose tissue (EAT) may contribute to the development of heart failure in Type 2 diabetes (T2D). This study aimed to evaluate the associations between EAT volume and composition with imaging markers of subclinical cardiac dysfunction in people with T2D and no prevalent cardiovascular disease. METHODS: Prospective case-control study enrolling participants with and without T2D and no known cardiovascular disease. Two hundred and fifteen people with T2D (median age 63 years, 60 % male) and thirty-nine non-diabetics (median age 59 years, 62 % male) were included. Using computed tomography (CT), total EAT volume and mean CT attenuation, as well as, low attenuation (Hounsfield unit range -190 to -90) EAT volume were quantified by a deep learning method and volumes indexed to body surface area. Associations with cardiac magnetic resonance-derived left ventricular (LV) volumes and strain indices were assessed using linear regression. RESULTS: T2D participants had higher LV mass/volume ratio (median 0.89 g/mL [0.82-0.99] vs 0.79 g/mL [0.75-0.89]) and lower global longitudinal strain (GLS; 16.1 ± 2.3 % vs 17.2 ± 2.2 %). Total indexed EAT volume correlated inversely with mean CT attenuation. Low attenuation indexed EAT volume was 2-fold higher (18.8 cm3/m2 vs. 9.4 cm3/m2, p < 0.001) in T2D and independently associated with LV mass/volume ratio (ß = 0.002, p = 0.01) and GLS (ß = -0.03, p = 0.03). CONCLUSIONS: Higher EAT volumes seen in T2D are associated with a lower mean CT attenuation. Low attenuation indexed EAT volume is independently, but only weakly, associated with markers of subclinical cardiac dysfunction in T2D.

Is atrial fibrillation in HFpEF a distinct phenotype? Insights from multiparametric MRI and circulating biomarkers.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently co-exist. There is a limited understanding on whether this coexistence is associated with distinct alterations in myocardial remodelling and mechanics. We aimed to determine if patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) represent a distinct phenotype. METHODS: In this secondary analysis of adults with HFpEF (NCT03050593), participants were comprehensively phenotyped with stress cardiac MRI, echocardiography and plasma fibroinflammatory biomarkers, and were followed for the composite endpoint (HF hospitalisation or death) at a median of 8.5 years. Those with AF were compared to sinus rhythm (SR) and unsupervised cluster analysis was performed to explore possible phenotypes. RESULTS: 136 subjects were included (SR = 75, AF = 61). The AF group was older (76 ± 8 vs. 70 ± 10 years) with less diabetes (36% vs. 61%) compared to the SR group and had higher left atrial (LA) volumes (61 ± 30 vs. 39 ± 15 mL/m2, p < 0.001), lower LA ejection fraction (EF) (31 ± 15 vs. 51 ± 12%, p < 0.001), worse left ventricular (LV) systolic function (LVEF 63 ± 8 vs. 68 ± 8%, p = 0.002; global longitudinal strain 13.6 ± 2.9 vs. 14.7 ± 2.4%, p = 0.003) but higher LV peak early diastolic strain rates (0.73 ± 0.28 vs. 0.53 ± 0.17 1/s, p < 0.001). The AF group had higher levels of syndecan-1, matrix metalloproteinase-2, proBNP, angiopoietin-2 and pentraxin-3, but lower level of interleukin-8. No difference in clinical outcomes was observed between the groups. Three distinct clusters were identified with the poorest outcomes (Log-rank p = 0.029) in cluster 2 (hypertensive and fibroinflammatory) which had equal representation of SR and AF. CONCLUSIONS: Presence of AF in HFpEF is associated with cardiac structural and functional changes together with altered expression of several fibro-inflammatory biomarkers. Distinct phenotypes exist in HFpEF which may have differing clinical outcomes.

Ethnic differences in cardiac structure and function assessed by MRI in healthy South Asian and White European people: A UK Biobank Study.

BACKGROUND: Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI (CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people. METHODS: Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared. RESULTS: 121 matched pairs (77 male/44 female, mean age 58 ± 8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females. CONCLUSIONS: Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.

An attention-based deep learning method for right ventricular quantification using 2D echocardiography: Feasibility and accuracy.

AIM: To test the feasibility and accuracy of a new attention-based deep learning (DL) method for right ventricular (RV) quantification using 2D echocardiography (2DE) with cardiac magnetic resonance imaging (CMR) as reference. METHODS AND RESULTS: We retrospectively analyzed images from 50 adult patients (median age 51, interquartile range 32-62 42% women) who had undergone CMR within 1 month of 2DE. RV planimetry of the myocardial border was performed in end-diastole (ED) and end-systole (ES) for eight standardized 2DE RV views with calculation of areas. The DL model comprised a Feature Tokenizer module and a stack of Transformer layers. Age, gender and calculated areas were used as inputs, and the output was RV volume in ED/ES. The dataset was randomly split into training, validation and testing subsets (35, 5 and 10 patients respectively). Mean RVEDV, RVESV and RV ejection fraction (EF) were 163 ± 70 mL, 82 ± 42 mL and 51% ± 8% respectively without differences among the subsets. The proposed method achieved good prediction of RV volumes (R2  = .953, absolute percentage error [APE] = 9.75% ± 6.23%) and RVEF (APE = 7.24% ± 4.55%). Per CMR, there was one patient with RV dilatation and three with RV dysfunction in the testing dataset. The DL model detected RV dilatation in 1/1 case and RV dysfunction in 4/3 cases. CONCLUSIONS: An attention-based DL method for 2DE RV quantification showed feasibility and promising accuracy. The method requires validation in larger cohorts with wider range of RV size and function. Further research will focus on the reduction of the number of required 2DE to make the method clinically applicable.

Resource efficient aortic distensibility calculation by end to end spatiotemporal learning of aortic lumen from multicentre multivendor multidisease CMR images.

Aortic distensibility (AD) is important for the prognosis of multiple cardiovascular diseases. We propose a novel resource-efficient deep learning (DL) model, inspired by the bi-directional ConvLSTM U-Net with densely connected convolutions, to perform end-to-end hierarchical learning of the aorta from cine cardiovascular MRI towards streamlining AD quantification. Unlike current DL aortic segmentation approaches, our pipeline: (i) performs simultaneous spatio-temporal learning of the video input, (ii) combines the feature maps from the encoder and decoder using non-linear functions, and (iii) takes into account the high class imbalance. By using multi-centre multi-vendor data from a highly heterogeneous patient cohort, we demonstrate that the proposed method outperforms the state-of-the-art method in terms of accuracy and at the same time it consumes [Formula: see text] 3.9 times less fuel and generates [Formula: see text] 2.8 less carbon emissions. Our model could provide a valuable tool for exploring genome-wide associations of the AD with the cognitive performance in large-scale biomedical databases. By making energy usage and carbon emissions explicit, the presented work aligns with efforts to keep DL's energy requirements and carbon cost in check. The improved resource efficiency of our pipeline might open up the more systematic DL-powered evaluation of the MRI-derived aortic stiffness.

Impact of diabetes on remodelling, microvascular function and exercise capacity in aortic stenosis.

OBJECTIVE: To characterise cardiac remodelling, exercise capacity and fibroinflammatory biomarkers in patients with aortic stenosis (AS) with and without diabetes, and assess the impact of diabetes on outcomes. METHODS: Patients with moderate or severe AS with and without diabetes underwent echocardiography, stress cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing and plasma biomarker analysis. Primary endpoint for survival analysis was a composite of cardiovascular mortality, myocardial infarction, hospitalisation with heart failure, syncope or arrhythmia. Secondary endpoint was all-cause death. RESULTS: Diabetes (n=56) and non-diabetes groups (n=198) were well matched for age, sex, ethnicity, blood pressure and severity of AS. The diabetes group had higher body mass index, lower estimated glomerular filtration rate and higher rates of hypertension, hyperlipidaemia and symptoms of AS. Biventricular volumes and systolic function were similar, but the diabetes group had higher extracellular volume fraction (25.9%±3.1% vs 24.8%±2.4%, p=0.020), lower myocardial perfusion reserve (2.02±0.75 vs 2.34±0.68, p=0.046) and lower percentage predicted peak oxygen consumption (68%±21% vs 77%±17%, p=0.002) compared with the non-diabetes group. Higher levels of renin (log10renin: 3.27±0.59 vs 2.82±0.69 pg/mL, p<0.001) were found in diabetes. Multivariable Cox regression analysis showed diabetes was not associated with cardiovascular outcomes, but was independently associated with all-cause mortality (HR 2.04, 95% CI 1.05 to 4.00; p=0.037). CONCLUSIONS: In patients with moderate-to-severe AS, diabetes is associated with reduced exercise capacity, increased diffuse myocardial fibrosis and microvascular dysfunction, but not cardiovascular events despite a small increase in mortality.

Aortic valve intervention rates in patients of different ethnicity with severe aortic stenosis in Leicestershire, UK.

OBJECTIVES: To explore the ethnic differences in patients undergoing aortic valve (AV) intervention for severe aortic stenosis (AS) in Leicestershire, UK. METHODS: Retrospective cohort study of all surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) at a single tertiary centre between April 2017 and March 2022, using local registry data. RESULTS: Of the 1231 SAVR and 815 TAVI performed, 6.5% and 3.7% were in ethnic minority patients, respectively. Based on the 2011 Census data for those with a Leicestershire postcode, crude cumulative rate of SAVR (n=489) was 0.64 per 1000 population overall and 0.69, 0.46 and 0.36 in White, Asian and Black populations, respectively; and 0.50 per 1000 population overall for TAVI (n=383), with 0.59, 0.16 and 0.06 for White, Asian and Black populations, respectively. Asians undergoing SAVR and TAVI were 5 and 3 years younger, respectively, than white patients with more comorbidities and a worse functional status.The age-adjusted cumulative rates for SAVR were 0.62 vs 0.72 per 1000 population for White and Asian patients and 0.51 vs 0.39 for TAVI. Asians were less likely to undergo SAVR and TAVI than White patients, with a risk ratio (RR) of 0.66 (0.50-0.87) and 0.27 (0.18-0.43), respectively, but the age-adjusted RR was not statistically significant. CONCLUSION: The crude rates of AV interventions are lower in Asian patients compared with the White population in Leicestershire, although age-adjusted rates were not statistically different. Further research to determine the sociodemographic differences in prevalence, incidence, mechanisms and treatment of AS across the UK is required.

Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy (LVH), myocardial fibrosis, enhanced oxidative stress and energy depletion. Unbound/loosely bound tissue copper II ions are powerful catalysts of oxidative stress and inhibitors of antioxidants. Trientine is a highly selective copper II chelator. In preclinical and clinical studies in diabetes, trientine is associated with reduced LVH and fibrosis, and improved mitochondrial function and energy metabolism. Trientine was associated with improvements in cardiac structure and function in an open-label study in patients with HCM. METHODS: The Efficacy and Mechanism of Trientine in Patients with Hypertrophic Cardiomyopathy (TEMPEST) trial is a multicentre, double-blind, parallel group, 1:1 randomised, placebo-controlled phase II trial designed to evaluate the efficacy and mechanism of action of trientine in patients with HCM. Patients with a diagnosis of HCM according to the European Society of Cardiology Guidelines and in New York Heart Association classes I-III are randomised to trientine or matching placebo for 52 weeks. Primary outcome is change in left ventricular (LV) mass indexed to body surface area, measured using cardiovascular magnetic resonance. Secondary efficacy objectives will determine whether trientine improves exercise capacity, reduces arrhythmia burden, reduces cardiomyocyte injury, improves LV and atrial function, and reduces LV outflow tract gradient. Mechanistic objectives will determine whether the effects are mediated by cellular or extracellular mass regression and improved myocardial energetics. CONCLUSION: TEMPEST will determine the efficacy and mechanism of action of trientine in patients with HCM. TRIAL REGISTRATION NUMBERS: NCT04706429 and ISRCTN57145331.

The AFLETES Study: Atrial Fibrillation in Veteran Athletes and the Risk of Stroke.

OBJECTIVES: Endurance athletes are at an increased risk of atrial fibrillation (AF) when compared with the general population. However, the risk of stroke in athletes with AF is unknown. DESIGN AND SETTING: We aimed to assess this risk using an international online survey. PATIENTS: Individuals that had competed in ≥1 competitive events and were ≥40 years old were included. INTERVENTIONS: Self-reported demographic, medical history, and training history data were collected, and a CHA 2 DS 2 -VASc was calculated. MAIN OUTCOME MEASURES: Binary logistic regression was used to assess variables associated with AF and stroke. RESULTS: There were 1002 responses from participants in 41 countries across Africa, Asia, Australasia, Europe, and North and South America, and 942 were included in the final analysis. The average age was 52.4 ± 8.5 years, and 84% were male. The most common sports were cycling (n = 677, 72%), running (n = 558, 59%), and triathlon (n = 245, 26%). There were 190 (20%) individuals who reported AF and 26 individuals (3%) who reported stroke; of which, 14 (54%) had AF. Lifetime exercise dose [odds ratio (OR), 1.02, 95% confidence interval (95% CI),1.00-1.03, P = 0.02] and swimming (OR, 1.56, 95% CI, 1.02-2.39, P = 0.04) were associated with AF in multivariable analysis, independent of other risk factors. Atrial fibrillation was associated with stroke (OR, 4.18, 95% CI, 1.80-9.72, P < 0.01), even in individuals with a low (0/1) CHA 2 DS 2 -VASc score (OR, 4.20, 95% CI, 1.83-9.66, P < 0.01). CONCLUSIONS: This survey provides early evidence that veteran endurance athletes who develop AF may be at an increased risk of developing stroke, even in those deemed to be at low risk by CHA 2 DS 2 -VASc score.

The Interfield Strength Agreement of Left Ventricular Strain Measurements at 1.5 T and 3 T Using Cardiac MRI Feature Tracking.

BACKGROUND: Left ventricular (LV) strain measurements can be derived using cardiac MRI from routinely acquired balanced steady-state free precession (bSSFP) cine images. PURPOSE: To compare the interfield strength agreement of global systolic strain, peak strain rates and artificial intelligence (AI) landmark-based global longitudinal shortening at 1.5 T and 3 T. STUDY TYPE: Prospective. SUBJECTS: A total of 22 healthy individuals (mean age 36 ± 12 years; 45% male) completed two cardiac MRI scans at 1.5 T and 3 T in a randomized order within 30 minutes. FIELD STRENGTH/SEQUENCE: bSSFP cine images at 1.5 T and 3 T. ASSESSMENT: Two software packages, Tissue Tracking (cvi42, Circle Cardiovascular Imaging) and QStrain (Medis Suite, Medis Medical Imaging Systems), were used to derive LV global systolic strain in the longitudinal, circumferential and radial directions and peak (systolic, early diastolic, and late diastolic) strain rates. Global longitudinal shortening and mitral annular plane systolic excursion (MAPSE) were measured using an AI deep neural network model. STATISTICAL TESTS: Comparisons between field strengths were performed using Wilcoxon signed-rank test (P value < 0.05 considered statistically significant). Agreement was determined using intraclass correlation coefficients (ICCs) and Bland-Altman plots. RESULTS: Minimal bias was seen in all strain and strain rate measurements between field strengths. Using Tissue Tracking, strain and strain rate values derived from long-axis images showed poor to fair agreement (ICC range 0.39-0.71), whereas global longitudinal shortening and MAPSE showed good agreement (ICC = 0.81 and 0.80, respectively). Measures derived from short-axis images showed good to excellent agreement (ICC range 0.78-0.91). Similar results for the agreement of strain and strain rate measurements were observed with QStrain. CONCLUSION: The interfield strength agreement of short-axis derived LV strain and strain rate measurements at 1.5 T and 3 T was better than those derived from long-axis images; however, the agreement of global longitudinal shortening and MAPSE was good. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Myocardial Calcium Handling in Type 2 Diabetes: A Novel Therapeutic Target.

Type 2 diabetes (T2D) is a multisystem disease with rapidly increasing global prevalence. Heart failure has emerged as a major complication of T2D. Dysregulated myocardial calcium handling is evident in the failing heart and this may be a key driver of cardiomyopathy in T2D, but until recently this has only been demonstrated in animal models. In this review, we describe the physiological concepts behind calcium handling within the cardiomyocyte and the application of novel imaging techniques for the quantification of myocardial calcium uptake. We take an in-depth look at the evidence for the impairment of calcium handling in T2D using pre-clinical models as well as in vivo studies, following which we discuss potential novel therapeutic approaches targeting dysregulated myocardial calcium handling in T2D.

The role of 4-dimensional flow in the assessment of bicuspid aortic valve and its valvulo-aortopathies.

Bicuspid aortic valve is the most common congenital cardiac malformation and the leading cause of aortopathy and aortic stenosis in younger patients. Aortic wall remodelling secondary to altered haemodynamic flow patterns, changes in peak velocity, and wall shear stress may be implicated in the development of aortopathy in the presence of bicuspid aortic valve and dysfunction. Assessment of these parameters as potential predictors of disease severity and progression is thus desirable. The anatomic and functional information acquired from 4D flow MRI can allow simultaneous visualisation and quantification of the pathological geometric and haemodynamic changes of the aorta. We review the current clinical utility of haemodynamic quantities including velocity, wall sheer stress and energy losses, as well as visual descriptors such as vorticity and helicity, and flow direction in assessing the aortic valve and associated aortopathies.