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.

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.

Association of ambulatory blood pressure with coronary microvascular and cardiac dysfunction in asymptomatic type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) and hypertension commonly coexist and are associated with subclinical myocardial structural and functional changes. We sought to determine the association between blood pressure (BP) and left ventricular (LV) remodeling, systolic/diastolic function, and coronary microvascular function, among individuals with T2D without prevalent cardiovascular disease. METHODS: Participants with T2D and age-, sex-, and ethnicity-matched controls underwent comprehensive cardiovascular phenotyping including fasting bloods, transthoracic echocardiography, cardiovascular magnetic resonance imaging with quantitative adenosine stress/rest perfusion, and office and 24-h ambulatory BP monitoring. Multivariable linear regression was performed to determine independent associations between BP and imaging markers of remodeling and function in T2D. RESULTS: Individuals with T2D (n = 205, mean age 63 ± 7 years) and controls (n = 40, mean age 61 ± 8 years) were recruited. Mean 24-h systolic BP, but not office BP, was significantly greater among those with T2D compared to controls (128.8 ± 11.7 vs 123.0 ± 13.1 mmHg, p = 0.006). Those with T2D had concentric LV remodeling (mass/volume 0.91 ± 0.15 vs 0.82 ± 0.11 g/mL, p < 0.001), decreased myocardial perfusion reserve (2.82 ± 0.83 vs 3.18 ± 0.82, p = 0.020), systolic dysfunction (global longitudinal strain 16.0 ± 2.3 vs 17.2 ± 2.1%, p = 0.004) and diastolic dysfunction (E/e' 9.30 ± 2.43 vs 8.47 ± 1.53, p = 0.044) compared to controls. In multivariable regression models adjusted for 14 clinical variables, mean 24-h systolic BP was independently associated with concentric LV remodeling (ß = 0.165, p = 0.031), diastolic dysfunction (ß = 0.273, p < 0.001) and myocardial perfusion reserve (ß = - 0.218, p = 0.016). Mean 24-h diastolic BP was associated with LV concentric remodeling (ß = 0.201, p = 0.016). CONCLUSION: 24-h ambulatory systolic BP, but not office BP, is independently associated with cardiac remodeling, coronary microvascular dysfunction, and diastolic dysfunction among asymptomatic individuals with T2D. (Clinical trial registration. URL: https://clinicaltrials.gov/ct2/show/NCT03132129 Unique identifier: NCT03132129).

A systematic review of micro-RNAs in aortic stenosis and cardiac fibrosis.

Aortic stenosis (AS) is the commonest valve lesion requiring surgery in the Western world. The presence of myocardial fibrosis is associated with mortality even after valve replacement. MicroRNAs could serve as biomarkers of fibrosis and risk stratify patients for earlier intervention. This study aimed to systematically review reports of micro-RNA (miR) associated with fibrosis in AS and identify potential biomarkers. We searched EMBASE, Medline, and Web of Science up to May 2020. Studies that reported on the role of miRs in AS and cardiac fibrosis were included. Study quality was assessed using the Newcastle-Ottawa scale. Of 4230 reports screened, 25 were included. All studies were of low to moderate quality. MiRs were analyzed in myocardial tissue (n = 10), aortic valve tissue (n = 5), plasma (n = 5), and serum (n = 5). A total of 365 miRs were reported, of which only a few were reported in more than one paper (3 in the myocardium, 5 in the aortic valve, and 1 in plasma). miR-21 was upregulated in plasma and myocardial tissue. MiR-19b was downregulated in the myocardium. Papers reporting myocardial miR-1 contradicted each other, and miR-133a was associated with increased left ventricular mass regression post-surgery. In the aortic valve, miRs-665, 602 and 939 were downregulated, and miRs-193b and 214 were upregulated. The data on miR in fibrosis in AS is scarce and of low to moderate quality. Further studies are needed to identify novel miRs as biomarkers, especially at an earlier asymptomatic phase of the disease.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Plasma P-selectin is a predictor of mortality in heart failure with preserved ejection fraction.

AIMS: The aim of the study was to assess the association of P-selectin with outcomes in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: This is a prospective, observational study of 130 HFpEF patients who underwent clinical profiling, blood sampling, 6 min walk testing, Minnesota Living with Heart Failure Questionnaire evaluation, echocardiography, cardiovascular magnetic resonance imaging, calculation of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores, and blinded plasma P-selectin measurement. Patients were followed up for the endpoint of all-cause mortality. The HFpEF subgroup with higher P-selectin levels [overall median 26 372, inter-quartile range (19 360-34 889) pg/mL] was associated with lower age, higher heart rate, less prevalent atrial fibrillation, more frequent current smoking status, and lower right ventricular end-diastolic volumes. During follow-up (median 1428 days), there were 38 deaths. Following maximal sensitivity and specificity receiver operating characteristic curve analysis, P-selectin levels above 35 506 pg/mL were associated with greater risk of all-cause mortality [hazard ratio (HR) 2.700; 95% confidence interval (CI) 1.416-5.146; log-rank P = 0.002]. Following multivariable Cox proportional hazards regression analysis and when added to MAGGIC scores, only P-selectin (adjusted HR 1.707; 95% CI 1.099-2.650; P < 0.017) and myocardial infarction detected by cardiovascular magnetic resonance imaging (HR 2.377; 95% CI 1.114-5.075; P < 0.025) remained significant predictors. In a final model comprising all three parameters, only P-selectin (HR 1.447; 95% CI 1.130-1.853; P < 0.003) and MAGGIC scores (HR 1.555; 95% CI 1.136-2.129; P < 0.006) remained independent predictors of death. Adding P-selectin (0.618, P = 0.035) improved the area under the receiver operating characteristic curve for mortality prediction for MAGGIC scores (0.647, P = 0.009) to 0.710, P < 0.0001. CONCLUSIONS: Plasma P-selectin is an independent predictor of mortality and provides incremental prognostic information beyond MAGGIC scores in HFpEF.

Short-term adverse remodeling progression in asymptomatic aortic stenosis.

OBJECTIVES: Aortic stenosis (AS) is characterised by a long and variable asymptomatic course. Our objective was to use cardiovascular magnetic resonance imaging (MRI) to assess progression of adverse remodeling in asymptomatic AS. METHODS: Participants from the PRIMID-AS study, a prospective, multi-centre observational study of asymptomatic patients with moderate to severe AS, who remained asymptomatic at 12 months, were invited to undergo a repeat cardiac MRI. RESULTS: Forty-three participants with moderate-severe AS (mean age 64.4 ± 14.8 years, 83.4% male, aortic valve area index 0.54 ± 0.15 cm2/m2) were included. There was small but significant increase in indexed left ventricular (LV) (90.7 ± 22.0 to 94.5 ± 23.1 ml/m2, p = 0.007) and left atrial volumes (52.9 ± 11.3 to 58.6 ± 13.6 ml/m2, p < 0.001), with a decrease in systolic (LV ejection fraction 57.9 ± 4.6 to 55.6 ± 4.1%, p = 0.001) and diastolic (longitudinal diastolic strain rate 1.06 ± 0.2 to 0.99 ± 0.2 1/s, p = 0.026) function, but no overall change in LV mass or mass/volume. Late gadolinium enhancement increased (2.02 to 4.26 g, p < 0.001) but markers of diffuse interstitial fibrosis did not change significantly (extracellular volume index 12.9 [11.4, 17.0] ml/m2 to 13.3 [11.1, 15.1] ml/m2, p = 0.689). There was also a significant increase in the levels of NT-proBNP (43.6 [13.45, 137.08] pg/ml to 53.4 [19.14, 202.20] pg/ml, p = 0.001). CONCLUSIONS: There is progression in cardiac remodeling with increasing scar burden even in asymptomatic AS. Given the lack of reversibility of LGE post-AVR and its association with long-term mortality post-AVR, this suggests the potential need for earlier intervention, before the accumulation of LGE, to improve the long-term outcomes in AS. KEY POINTS: • Current guidelines recommend waiting until symptom onset before valve replacement in severe AS. • MRI showed clear progression in cardiac remodeling over 12 months in asymptomatic patients with AS, with near doubling in LGE. • This highlights the need for potentially earlier intervention or better risk stratification in AS.

Plasma Tenascin-C: a prognostic biomarker in heart failure with preserved ejection fraction.

INTRODUCTION: Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. MATERIALS AND METHODS: Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. RESULTS: Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8-17.3] vs (11.1 [8.9-12.9] ng/ml, p < 0.0001). Tenascin-C correlated positively with markers of clinical severity (NYHA, E/E', BNP) and plasma biomarkers reflecting interstitial fibrosis (ST-2, Galectin-3, GDF-15, TIMP-1, TIMP-4, MMP-2, MMP-3, MMP-7, MMP-8), cardiomyocyte stress (BNP, NTpro-ANP), inflammation (MPO, hs-CRP, TNFR-1, IL6) and renal dysfunction (urea, cystatin-C, NGAL); p < 0.05 for all. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305-2.360; p < 0.0001) and indexed extracellular volume (HR 1.465, CI 1.019-2.106; p = 0.039) were independently associated with adverse outcomes. CONCLUSIONS: In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593.

Myocardial Scar and Mortality in Severe Aortic Stenosis.

BACKGROUND: Aortic valve replacement (AVR) for aortic stenosis is timed primarily on the development of symptoms, but late surgery can result in irreversible myocardial dysfunction and additional risk. The aim of this study was to determine whether the presence of focal myocardial scar preoperatively was associated with long-term mortality. METHODS: In a longitudinal observational outcome study, survival analysis was performed in patients with severe aortic stenosis listed for valve intervention at 6 UK cardiothoracic centers. Patients underwent preprocedural echocardiography (for valve severity assessment) and cardiovascular magnetic resonance for ventricular volumes, function and scar quantification between January 2003 and May 2015. Myocardial scar was categorized into 3 patterns (none, infarct, or noninfarct patterns) and quantified with the full width at half-maximum method as percentage of the left ventricle. All-cause mortality and cardiovascular mortality were tracked for a minimum of 2 years. RESULTS: Six hundred seventy-four patients with severe aortic stenosis (age, 75±14 years; 63% male; aortic valve area, 0.38±0.14 cm2/m2; mean gradient, 46±18 mm Hg; left ventricular ejection fraction, 61.0±16.7%) were included. Scar was present in 51% (18% infarct pattern, 33% noninfarct). Management was surgical AVR (n=399) or transcatheter AVR (n=275). During follow-up (median, 3.6 years), 145 patients (21.5%) died (52 after surgical AVR, 93 after transcatheter AVR). In multivariable analysis, the factors independently associated with all-cause mortality were age (hazard ratio [HR], 1.50; 95% CI, 1.11-2.04; P=0.009, scaled by epochs of 10 years), Society of Thoracic Surgeons score (HR, 1.12; 95% CI, 1.03-1.22; P=0.007), and scar presence (HR, 2.39; 95% CI, 1.40-4.05; P=0.001). Scar independently predicted all-cause (26.4% versus 12.9%; P<0.001) and cardiovascular (15.0% versus 4.8%; P<0.001) mortality, regardless of intervention (transcatheter AVR, P=0.002; surgical AVR, P=0.026 [all-cause mortality]). Every 1% increase in left ventricular myocardial scar burden was associated with 11% higher all-cause mortality hazard (HR, 1.11; 95% CI, 1.05-1.17; P<0.001) and 8% higher cardiovascular mortality hazard (HR, 1.08; 95% CI, 1.01-1.17; P<0.001). CONCLUSIONS: In patients with severe aortic stenosis, late gadolinium enhancement on cardiovascular magnetic resonance was independently associated with mortality; its presence was associated with a 2-fold higher late mortality.

Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in heart failure with preserved ejection fraction - implications for clinical trials.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a poorly characterized condition. We aimed to phenotype patients with HFpEF using multiparametric stress cardiovascular magnetic resonance imaging (CMR) and to assess the relationship to clinical outcomes. METHODS: One hundred and fifty four patients (51% male, mean age 72 ± 10 years) with a diagnosis of HFpEF underwent transthoracic echocardiography and CMR during a single study visit. The CMR protocol comprised cine, stress/rest perfusion and late gadolinium enhancement imaging on a 3T scanner. Follow-up outcome data (death and heart failure hospitalization) were captured after a minimum of 6 months. RESULTS: CMR detected previously undiagnosed pathology in 42 patients (27%), who had similar baseline characteristics to those without a new diagnosis. These diagnoses consisted of: coronary artery disease (n = 20, including 14 with 'silent' infarction), microvascular dysfunction (n = 11), probable or definite hypertrophic cardiomyopathy (n = 10) and constrictive pericarditis (n = 5). Four patients had dual pathology. During follow-up (median 623 days), patients with a new CMR diagnosis were at higher risk of adverse outcome for the composite endpoint (log rank test: p = 0.047). In multivariate Cox proportional hazards analysis, a new CMR diagnosis was the strongest independent predictor of adverse outcome (hazard ratio: 1.92; 95% CI: 1.07 to 3.45; p = 0.03). CONCLUSIONS: CMR diagnosed new significant pathology in 27% of patients with HFpEF. These patients were at increased risk of death and heart failure hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03050593 . Retrospectively registered; Date of registration: February 06, 2017.

Unusual Case of Three Total Occlusions.

This case highlights the value of extensive coronary collaterals in maintaining myocardial viability in severe coronary artery disease, and the role of cardiac MRI in guiding revascularization decisions.

Myocardial strain and symptom severity in severe aortic stenosis: insights from cardiovascular magnetic resonance.

BACKGROUND: Symptomatic severe aortic stenosis (AS) is a class I indication for replacement in patients when left ventricular ejection fraction (LVEF) is preserved. However, symptom reporting is often equivocal and decision making can be challenging. We aimed to quantify myocardial deformation using cardiovascular magnetic resonance (CMR) in patients classified by symptom severity. METHODS: Forty-two patients with severe AS referred to heart valve clinic were studied using tagged CMR imaging. All had preserved LVEF. Patients were grouped by symptoms as either "none/mild" (n=21, NYHA class I, II) or "significant" (n=21, NYHA class III, IV, angina, syncope) but were comparable for age (72.8±5.4 vs. 71.0±6.8 years old, P=0.345), surgical risk (EuroSCORE II: 1.90±1.7 vs. 1.31±0.4, P=0.302) and haemodynamics (peak aortic gradient: 55.1±20.8 vs. 50.4±15.6, P=0.450). Thirteen controls matched in age and LVEF were also studied. LV circumferential strain was calculated using inTag© software and longitudinal strain using feature tracking analysis. RESULTS: Compared to healthy controls, patients with severe AS had significantly worse longitudinal and circumferential strain, regardless of symptom status. Patients with "significant" symptoms had significantly worse peak longitudinal systolic strain rates (-83.352±24.802%/s vs. -106.301±43.276%/s, P=0.048) than those with "no/mild" symptoms, with comparable peak longitudinal strain (PLS), peak circumferential strain and systolic and diastolic strain rates. CONCLUSIONS: Patients with severe AS who have no or only mild symptoms exhibit comparable reduction in circumferential and longitudinal fibre function to those with significant symptoms, in whom AVR is clearly indicated. Given these findings of equivalent subclinical dysfunction, reportedly borderline symptoms should be handled cautiously to avoid potentially adverse delays in intervention.

Comparison of exercise testing and CMR measured myocardial perfusion reserve for predicting outcome in asymptomatic aortic stenosis: the PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis (PRIMID AS) Study.

AIMS: To assess cardiovascular magnetic resonance (CMR) measured myocardial perfusion reserve (MPR) and exercise testing in asymptomatic patients with moderate-severe AS. METHODS AND RESULTS: Multi-centre, prospective, observational study, with blinded analysis of CMR data. Patients underwent adenosine stress CMR, symptom-limited exercise testing (ETT) and echocardiography and were followed up for 12-30 months. The primary outcome was a composite of: typical AS symptoms necessitating referral for AVR, cardiovascular death and major adverse cardiovascular events. 174 patients were recruited: mean age 66.2 ± 13.34 years, 76% male, peak velocity 3.86 ± 0.56 m/s and aortic valve area index 0.57 ± 0.14 cm2/m2. A primary outcome occurred in 47 (27%) patients over a median follow-up of 374 (IQR 351-498) days. The mean MPR in those with and without a primary outcome was 2.06 ± 0.65 and 2.34 ± 0.70 (P = 0.022), while the incidence of a symptom-limited ETT was 45.7% and 27.0% (P = 0.020), respectively. MPR showed moderate association with outcome area under curve (AUC) = 0.61 (0.52-0.71, P = 0.020), as did exercise testing (AUC = 0.59 (0.51-0.68, P = 0.027), with no significant difference between the two. CONCLUSIONS: MPR was associated with symptom-onset in initially asymptomatic patients with AS, but with moderate accuracy and was not superior to symptom-limited exercise testing. ClinicalTrials.gov (NCT01658345).

Rationale and design of the PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with Aortic Stenosis (PRIMID-AS): a multicentre observational study with blinded investigations.

INTRODUCTION: Aortic stenosis (AS) is the commonest valve disorder in the developed world requiring surgery. Surgery in patients with severe asymptomatic AS remains controversial. Exercise testing can identify asymptomatic patients at increased risk of death and symptom development, but with limited specificity, especially in older adults. Cardiac MRI (CMR), including myocardial perfusion reserve (MPR) may be a novel imaging biomarker in AS. AIMS: (1) To improve risk stratification in asymptomatic patients with AS and (2) to determine whether MPR is a better predictor of outcome than exercise testing and brain natriuretic peptide (BNP). METHOD/DESIGN: Multicentre, prospective observational study in the UK, comparing MPR with exercise testing and BNP (with blinded CMR analysis) for predicting outcome. POPULATION: 170 asymptomatic patients with moderate-to-severe AS, who would be considered for aortic valve replacement (AVR). PRIMARY OUTCOME: Composite of: typical symptoms necessitating referral for AVR and major adverse cardiovascular events. FOLLOW-UP: 12-30 months (minimum 12 months). PRIMARY HYPOTHESIS: MPR will be a better predictor of outcome than exercise testing and BNP. ETHICS/DISSEMINATION: The study has full ethical approval and is actively recruiting patients. Data collection will be completed in November 2014 and the study results will be submitted for publication within 6 months of completion. CLINICALTRIALSGOV IDENTIFIER: NCT01658345.