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Rapid innovations in cardiovascular magnetic resonance (CMR) now permit the routine acquisition of quantitative measures of myocardial and blood T1 which are key tissue characteristics. These capabilities introduce a new frontier in cardiology, enabling the practitioner/investigator to quantify biologically important myocardial properties that otherwise can be difficult to ascertain clinically. CMR may be able to track biologically important changes in the myocardium by: a) native T1 that reflects myocardial disease involving the myocyte and interstitium without use of gadolinium based contrast agents (GBCA), or b) the extracellular volume fraction (ECV)-a direct GBCA-based measurement of the size of the extracellular space, reflecting interstitial disease. The latter technique attempts to dichotomize the myocardium into its cellular and interstitial components with estimates expressed as volume fractions. This document provides recommendations for clinical and research T1 and ECV measurement, based on published evidence when available and expert consensus when not. We address site preparation, scan type, scan planning and acquisition, quality control, visualisation and analysis, technical development. We also address controversies in the field. While ECV and native T1 mapping appear destined to affect clinical decision making, they lack multi-centre application and face significant challenges, which demand a community-wide approach among stakeholders. At present, ECV and native T1 mapping appear sufficiently robust for many diseases; yet more research is required before a large-scale application for clinical decision-making can be recommended. [ABSTRACT FROM AUTHOR]

Background Analysis of left ventricular (LV) mechanical dyssynchrony may provide incremental prognostic information regarding cardiac resynchronization therapy (CRT) response in addition to QRS width alone. Our objective was to quantify LV dyssynchrony using feature tracking post processing of routine cardiovascular magnetic resonance (CMR) cine acquisitions (FT-CMR) in comparison to speckle tracking echocardiography. Methods We studied 72 consecutive patients who had both steady-state free precession CMR and echocardiography. Mid-LV short axis CMR cines were analyzed using FT-CMR software and compared with echocardiographic speckle tracking radial dyssynchrony (time difference between the anteroseptal and posterior wall peak strain). Results Radial dyssynchrony analysis was possible by FT-CMR in all patients, and in 67 (93%) by echocardiography. Dyssynchrony by FT-CMR and speckle tracking showed limits of agreement of strain delays of ±84 ms. These were large (up to 100% or more) relative to the small mean delays measured in more synchronous patients, but acceptable (mainly <25%) in those with mean delays of >200 ms. Radial dyssynchrony was significantly greater in wide QRS patients than narrow QRS patients by both FT-CMR (radial strain delay 230 ± 94 vs. 77 ± 92* ms) and speckle tracking (radial strain delay 242 ± 101 vs. 75 ± 88* ms, all *p < 0.001). Conclusions FT-CMR delivered measurements of radial dyssynchrony from CMR cine acquisitions which, at least for the patients with more marked dyssynchrony, showed reasonable agreement with those from speckle tracking echocardiography. The clinical usefulness of the method, for example in predicting prognosis in CRT patients, remains to be investigated. [ABSTRACT FROM AUTHOR]

Background: Echocardiography (echo) is a first line test to assess cardiac structure and function. It is not known if cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) ordered during routine clinical practice in selected patients can add additional prognostic information after routine echo. We assessed whether CMR improves outcomes prediction after contemporaneous echo, which may have implications for efforts to optimize processes of care, assess effectiveness, and allocate limited health care resources. Methods and results: We prospectively enrolled 1044 consecutive patients referred for CMR. There were 38 deaths and 3 cardiac transplants over a median follow-up of 1.0 years (IQR 0.4-1.5). We first reproduced previous survival curve strata (presence of LGE and ejection fraction (EF) < 50%) for transplant free survival, to support generalizability of any findings. Then, in a subset (n = 444) with contemporaneous echo (median 3 days apart, IQR 1-9), EF by echo (assessed visually) or CMR were modestly correlated (R2 = 0.66, p < 0.001), and 30 deaths and 3 transplants occurred over a median follow-up of 0.83 years (IQR 0.29-1.40). CMR EF predicted mortality better than echo EF in univariable Cox models (Integrated Discrimination Improvement (IDI) 0.018, 95% CI 0.008-0.034; Net Reclassification Improvement (NRI) 0.51, 95% CI 0.11-0.85). Finally, LGE further improved prediction beyond EF as determined by hazard ratios, NRI, and IDI in all Cox models predicting mortality or transplant free survival, adjusting for age, gender, wall motion, and EF. Conclusions: Among those referred for CMR after echocardiography, CMR with LGE further improves risk stratification of individuals at risk for death or death/cardiac transplant. [ABSTRACT FROM AUTHOR]

Objective--In myocardial infarction (MI), we studied whether documentation of ischemic symptoms is associated with quality of care and outcomes, and compared patient reports of ischaemic symptoms during interviews with chart documentation Design--Observational acute myocardial infarction study from 2003-2004 (Prospective Registry Evaluating Myocardial Infarction: Event and Recovery) Setting--19 diverse US hospitals Patients--2,094 consecutive MI patients (10,911 patients screened; 3,953 patients were eligible and enrolled) with both positive cardiac enzymes and other evidence of infarction (e.g., symptoms, electrocardiographic changes). Transferred patients and those with confounding noncardiac comorbidity were not included (n=1859). Main outcome measures--Quality of care indicators and adjusted in-hospital survival Results--The records of 10% of all MI patients (217/2094) contained no documented ischaemic symptoms at presentation. Patients without documented symptoms were less likely (p<0.05) to: receive aspirin (89% vs. 96%) or beta-blockers (77% vs. 90%) within 24hr, reperfusion therapy for STEMI (7% vs. 58%) or to survive their hospitalization (adjusted OR=3.2, 95% CI 1.8–5.8). Survivors without documented symptoms were also less likely (p<0.05) to be discharged with aspirin (87% vs. 93%), beta-blockers (81% vs. 91%), ACE/ARB (67% vs. 80%), or smoking cessation counseling (46% vs. 66%). In the subset of 1,356 (65%) interviewed patients, most of those without documented ischaemic symptoms (75%) reported presenting symptoms consistent with ischaemia. Conclusions--Failure to document patients’ presenting MI symptoms is associated with poorer quality of care from admission to discharge, and higher in-hospital mortality. Symptom recognition may represent an important opportunity to improve the quality of MI care. [ABSTRACT FROM AUTHOR]

Cardiovascular magnetic resonance (CMR) is used to investigate suspected acute myocarditis, however most supporting data is retrospective and few studies have included parametric mapping. We aimed to investigate the utility of contemporary multiparametric CMR in a large prospective cohort of patients with suspected acute myocarditis, the impact of real-world variations in practice, the relationship between clinical characteristics and CMR findings and factors predicting outcome. 540 consecutive patients we recruited. The 113 patients diagnosed with myocarditis on CMR performed within 40 days of presentation were followed-up for 674 (504–915) days. 39 patients underwent follow-up CMR at 189 (166–209) days. CMR provided a positive diagnosis in 72% of patients, including myocarditis (40%) and myocardial infarction (11%). In multivariable analysis, male sex and shorter presentation-to-scan interval were associated with a diagnosis of myocarditis. Presentation with heart failure (HF) was associated with lower left ventricular ejection fraction (LVEF), higher LGE burden and higher extracellular volume fraction. Lower baseline LVEF predicted follow-up LV dysfunction. Multiparametric CMR has a high diagnostic yield in suspected acute myocarditis. CMR should be performed early and include parametric mapping. Patients presenting with HF and reduced LVEF require closer follow-up while those with normal CMR may not require it. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Cardiac magnetic resonance techniques permit quantification of the myocardial extracellular volume fraction (ECV), representing a surrogate marker of reactive interstitial fibrosis, and late gadolinium enhancement (LGE), representing replacement fibrosis or scar. ECV and LGE have been independently linked with heart failure (HF) events. In deriving ECV, coronary artery disease type LGE, but not non-coronary artery disease type LGE, has been consistently excluded. We examined the associations between LGE, global ECV derived from myocardial tissue segments free of any detectable scar, and subsequent HF events. Methods: Mid short-axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from only segments without LGE. ECV was considered elevated if >30%, the upper 95% bounds of a reference group without known cardiac disease (n=28). Patients were divided into 4 groups by presence of elevated ECV and of any LGE. Subsequent HF hospitalization and any death were ascertained. Their relationship with ECV was examined separately and as a composite with Cox proportional hazard models. Results: Of 1604 serial patients with T1 maps, 1255 were eligible after exclusions and followed over a median 26.3 (interquartile range, 15.9–37.5) months. Patients with elevated ECV had increased risk for death (hazard ratio [HR] 2.45 [95% CI, 1.76–3.41]), HF hospitalization (HR, 2.45 [95% CI, 1.77–3.40]), and a combined end point of both outcomes (HR, 2.46 [95% CI, 1.94–3.14]). After adjustments for covariates including LGE, the relationship persisted for death (HR, 1.82 [95% CI, 1.28–2.59]), hospitalization (HR, 1.60 [95% CI, 1.12–2.27]), and combined end points (HR, 1.73 [95% CI, 1.34–2.24]). Conclusions: ECV measures of diffuse myocardial fibrosis were associated with HF outcomes, despite exclusion of replacement fibrosis segments from their derivation and even among patients without any scar. ECV may have a synergistic role with LGE in HF risk assessment. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. [ABSTRACT FROM AUTHOR]

The electrocardiogram (ECG) and cardiovascular magnetic resonance imaging (CMR) provide powerful prognostic information. The aim was to determine their relative prognostic value. Patients (n = 783) undergoing CMR and 12-lead ECG with a QRS duration < 120 ms were included. Prognosis scores for one-year event-free survival from hospitalization for heart failure or death were derived using continuous ECG or CMR measures, and multivariable logistic regression, and compared. Patients (median [interquartile range] age 55 [43–64] years, 44% female) had 155 events during 5.7 [4.4–6.6] years. The ECG prognosis score included (1) frontal plane QRS-T angle, and (2) heart rate corrected QT duration (QTc) (log-rank 55). The CMR prognosis score included (1) global longitudinal strain, and (2) extracellular volume fraction (log-rank 85). The combination of positive scores for both ECG and CMR yielded the highest prognostic value (log-rank 105). Multivariable analysis showed an association with outcomes for both the ECG prognosis score (log-rank 8.4, hazard ratio [95% confidence interval] 1.29 [1.09–1.54]) and the CMR prognosis score (log-rank 47, hazard ratio 1.90 [1.58–2.28]). An ECG prognosis score predicted outcomes independently of CMR. Combining the results of ECG and CMR using both prognosis scores improved the overall prognostic performance. [ABSTRACT FROM AUTHOR]

Electrocardiographic (ECG) signs of left ventricular hypertrophy (LVH) lack sensitivity. The aim was to identify LVH based on an abnormal spatial peaks QRS-T angle, evaluate its diagnostic performance compared to conventional ECG criteria for LVH, and its prognostic performance. This was an observational study with four cohorts with a QRS duration < 120 ms. Based on healthy volunteers (n = 921), an abnormal spatial peaks QRS-T angle was defined as ≥ 40° for females and ≥ 55° for males. In other healthy volunteers (n = 461), the specificity of the QRS-T angle to detect LVH was 96% (females) and 98% (males). In patients with at least moderate LVH by cardiac imaging (n = 225), the QRS-T angle had a higher sensitivity than conventional ECG criteria (93–97% vs 13–56%, p < 0.001 for all). In clinical consecutive patients (n = 783), of those who did not have any LVH, 238/556 (43%) had an abnormal QRS-T angle. There was an association with hospitalization for heart failure or all-cause death in univariable and multivariable analysis. An abnormal QRS-T angle rarely occurred in healthy volunteers, was a mainstay of moderate or greater LVH, was common in clinical patients without LVH but with cardiac co-morbidities, and associated with outcomes. [ABSTRACT FROM AUTHOR]

High dose interleukin-2 (IL-2) is known to be associated with cardiopulmonary toxicity. The goal of this study was to evaluate the effects of high dose IL-2 therapy on cardiopulmonary structure and function. Combined cardiopulmonary magnetic resonance imaging (MRI) was performed in 7 patients in the acute period following IL-2 therapy and repeated in 4 patients in the chronic period. Comparison was made to 10 healthy volunteers. IL-2 therapy was associated with myocardial and pulmonary capillary leak, tissue oedema and cardiomyocyte injury, which resulted in acute significant left ventricular (LV) dilatation, a reduction in LV ejection fraction (EF), an increase in LV mass and a prolongation of QT interval. The acute effects occurred irrespective of symptoms. In the chronic period many of the effects resolved, but LV hypertrophy ensued, driven by focal replacement and diffuse interstitial myocardial fibrosis and increased cardiomyocyte mass. In conclusion, IL-2 therapy is ubiquitously associated with acute cardiopulmonary inflammation, irrespective of symptoms, which leads to acute LV dilatation and dysfunction, increased LV mass and QT interval prolongation. Most of these effects are reversible but IL-2 therapy is associated with chronic LV hypertrophy, driven by interstitial myocardial fibrosis and increased cardiomyocyte mass. The findings have important implications for the monitoring and long term impact of newer immunotherapies. Future studies are needed to improve risk stratification and develop cardiopulmonary-protective strategies. [ABSTRACT FROM AUTHOR]

Aims: More than 90% of patients with left bundle branch block (LBBB) and reduced left ventricular (LV) ejection fraction have LV dyssynchrony and a high probability of response to cardiac resynchronization therapy (CRT). A subgroup of patients with non-specific intraventricular conduction delay (IVCD) have a LBBB-like LV activation pattern when studied using invasive mapping and advanced echocardiographic techniques. These patients also frequently benefit from CRT, but these patients have proven difficult to identify using electrocardiogram criteria. Cardiovascular magnetic resonance (CMR) imaging indices of dyssynchrony may identify patients with IVCD who may benefit from CRT, but their relative accuracies for identification of LV dyssynchrony remain unknown. We compared the LV dyssynchrony classification accuracy of two commonly available CMR indices in a study population of patients with severely reduced LV ejection fraction and no scar and either LBBB or QRS duration <120 ms and normal QRS axis (controls)., Methods and Results: In LBBB (n = 44) and controls (n = 36), using CMR feature-tracking circumferential strain, dyssynchrony was quantified as the circumferential uniformity ratio estimate (CURE) and the systolic stretch index (SSI). Deidentified CMR image data were made publicly available. Both CURE and SSI quantified more severe dyssynchrony in LBBB compared with controls (P<0.001 for both). SSI more frequently discriminated LBBB and normal conduction LV activation patterns than CURE [area under the receiver-operating characteristic curve (95% confidence interval) 0.96 (0.92-1.00) for SSI vs. 0.76 (0.65-0.86) for CURE, P < 0.001]., Conclusion: SSI is superior to CURE for discriminating synchronous and dyssynchronous LV activation and should be further studied in the setting of non-LBBB conduction abnormalities., Competing Interests: Conflict of interest: E.H. is the founder of the company Medviso AB, which develops medical image analysis software. R.N. has received research grants from Philips Volcano and Biotronik. R.J.K. is a consultant for Abiomed. B.D.A. has received research grants from Boston Scientific and Abbott and consultation fees from Abbott, Medtronic, Biotronik, and Biosense Webster. M.U. is the principal investigator on a research and development agreement regarding cardiovascular magnetic resonance between Siemens and Karolinska University Hospital. The remaining authors have nothing to disclose that is relevant to the contents of this paper., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Myocardial fibrosis in aortic stenosis (AS) may exhibit sex differences. However, its prognostic significance in women with AS remains unclear., Objective: To investigate sex differences in myocardial fibrosis assessed by cardiovascular magnetic resonance (CMR) and evaluate its prognostic value in women and men with AS., Design, Setting, and Participants: Patients with severe AS who underwent CMR before aortic valve replacement (AVR) were prospectively enrolled from 13 international sites between March 2011 and September 2021. Myocardial fibrosis was evaluated using extracellular volume fraction (ECV%) and late gadolinium enhancement (LGE). The main analysis was conducted on patients without obstructive coronary artery disease (CAD), defined as those with no history of myocardial infarction and no concomitant coronary artery bypass grafting. Data were analyzed from December 2023 to February 2024., Exposures: Surgical or transcatheter AVR., Main Outcomes and Measures: The primary outcome was post-AVR all-cause mortality and the secondary outcome was cardiovascular mortality., Results: Of 822 patients, 670 were without obstructive CAD (368 men [55%] and 302 women [45%]). Among these, women and men had a similar age (median, 72 years vs 71 years, respectively), comorbidities, and AS severity. ECV% was similar between sexes; however, women had less LGE (both infarct and noninfarct LGE). After a median follow-up of 3.7 (IQR, 2.1-4.7) years, there were 76 deaths (11.3%), including 29 adjudicated cardiovascular deaths, in patients without obstructive CAD. Increasing ECV% and LGE were associated with higher all-cause and cardiovascular mortality in both sexes. Cox analyses demonstrated that both ECV% and LGE were associated with higher all-cause mortality without significant interaction by sex (women: adjusted hazard ratio [HR], 1.08 per 1% ECV% increase; 95% CI, 1.04-1.12; P < .001; men: adjusted HR, 1.01; 95% CI, 0.96-1.06; P = .66; P for interaction by sex = .09 and women: adjusted HR, 2.49 for the presence of LGE; 95% CI, 1.07-5.80; P = .03; men: adjusted HR, 1.82; 95% CI, 1.00-3.32; P = .04; P for interaction by sex = .68). In the entire population (n = 822), both noninfarct and infarct-related LGE were associated with increased mortality without significant interaction by sex., Conclusions and Relevance: In this study, patients with severe AS who underwent AVR exhibited similar ECV% between sexes, while women had lower LGE. Increased myocardial fibrosis provided important prognostic value for both sexes.

Background: Peripartum cardiomyopathy (PPCM) is associated with significant morbidity and mortality. Recent studies show recovery of left ventricular ejection fraction (LVEF) can still be associated with longitudinal adverse clinical outcomes. Cardiac MRI (CMR) may yield additional prognostic parameters of serious adverse outcomes (SAE) beyond LVEF., Methods: Individuals with PPCM and CMR within 3 months of diagnosis were analyzed from the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) trial and our institution from 2010-present. Indexed left ventricular (LV) mass, ventricular volumes, cardiac output, global longitudinal strain (GLS), extracellular cellular volume (ECV) as well as epicardial fat volume (EFV) were analyzed. SAEs included left ventricular assist device (LVAD), heart transplant and death. CMR parameters were compared between SAE and no SAEs groups by non-parametric techniques., Results: Among 51 individuals with mean age of 31 years at diagnosis, 6/51 (12 %) experienced 11 adverse outcomes. EF at time of CMR (15.0 vs 37.3 %, p  < 0.001), peak LV GLS (-4.1 % vs -10.0, p  = 0.002) ECV (43.6 vs 28.2, p  = 0.02) and stroke volume differed significantly among groups. In univariate regression analysis, worse LVEF, lower peak GLS and greater LVESVi were predictive of adverse outcomes., Conclusion: Prior studies found baseline LVEF by echo is a predictor of serious adverse outcomes. CMR identified significantly different baseline LVESVi peak LV GLS and ECV among PPCM with SAEs vs no SAEs. If confirmed in larger studies, diffuse myocardial fibrosis may represent a therapeutic target in PPCM., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 The Authors. Published by Elsevier Inc.)

Aims: An explainable advanced electrocardiography (A-ECG) Heart Age gap is the difference between A-ECG Heart Age and chronological age. This gap is an estimate of accelerated cardiovascular aging expressed in years of healthy human aging, and can intuitively communicate cardiovascular risk to the general population. However, existing A-ECG Heart Age requires sinus rhythm. We aim to develop and prognostically validate a revised, explainable A-ECG Heart Age applicable to both sinus and non-sinus rhythms., Methods and Results: An A-ECG Heart Age excluding P-wave measures was derived from the 10-s 12-lead ECG in a derivation cohort using multivariable regression machine learning with Bayesian 5-min 12-lead A-ECG Heart Age as reference. The Heart Age was externally validated in a separate cohort of patients referred for cardiovascular magnetic resonance imaging by describing its association with heart failure hospitalization or death using Cox regression, and its association with comorbidities. In the derivation cohort ( n = 2771), A-ECG Heart Age agreed with the 5-min Heart Age ( R 2 = 0.91, bias 0.0 ± 6.7 years), and increased with increasing comorbidity. In the validation cohort [ n = 731, mean age 54 ± 15 years, 43% female, n = 139 events over 5.7 (4.8-6.7) years follow-up], increased A-ECG Heart Age gap (≥10 years) associated with events [hazard ratio, HR (95% confidence interval, CI) 2.04 (1.38-3.00), C-statistic 0.58 (0.54-0.62)], and the presence of hypertension, diabetes mellitus, hypercholesterolaemia, and heart failure ( P ≤ 0.009 for all)., Conclusion: An explainable A-ECG Heart Age gap applicable to both sinus and non-sinus rhythm associates with cardiovascular risk, cardiovascular morbidity, and survival., Competing Interests: Conflict of interest: Z.S.A., T.L., I.L.-P., A.L., E.B.S., L.N., and M.M.: none; T.T.S. is owner and founder of Nicollier-Schlegel SARL, which performs ECG interpretation consultancy using software that can quantify the advanced ECG measures used in the current study. T.T.S. and M.U. are the owners and founders of Advanced ECG Systems, a company that is developing commercial applications of advanced ECG technology used in the current study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Quantification of myocardial changes in severe aortic stenosis (AS) is prognostically important. The potential for comprehensive myocardial assessment pre-transcatheter aortic valve replacement (TAVR) by computed tomography angiography (CTA) is unknown., Objectives: This study sought to evaluate whether quantification of left ventricular (LV) extracellular volume-a marker of myocardial fibrosis-and global longitudinal strain-a marker of myocardial deformation-at baseline CTA associate with post-TAVR outcomes., Methods: Consecutive patients with symptomatic severe AS between January 2021 and June 2022 who underwent pre-TAVR CTA were included. Computed tomography extracellular volume (CT-ECV) was derived from septum tracing after generating the 3-dimensional CT-ECV map. Computed tomography global longitudinal strain (CT-GLS) used semi-automated feature tracking analysis. The clinical endpoint was the composite outcome of all-cause mortality and heart failure hospitalization., Results: Among the 300 patients (80.0 ± 9.4 years of age, 45% female, median Society of Thoracic Surgeons Predicted Risk of Mortality score 2.80%), the left ventricular ejection fraction (LVEF) was 58% ± 12%, the median CT-ECV was 28.5% (IQR: 26.2%-32.1%), and the median CT-GLS was -20.1% (IQR: -23.8% to -16.3%). Over a median follow-up of 16 months (IQR: 12-22 months), 38 deaths and 70 composite outcomes occurred. Multivariable Cox proportional hazards model, accounting for clinical and echocardiographic variables, demonstrated that CT-ECV (HR: 1.09 [95% CI: 1.02-1.16]; P = 0.008) and CT-GLS (HR: 1.07 [95% CI: 1.01-1.13]; P = 0.017) associated with the composite outcome. In combination, elevated CT-ECV and CT-GLS (above median for each) showed a stronger association with the outcome (HR: 7.14 [95% CI: 2.63-19.36]; P < 0.001)., Conclusions: Comprehensive myocardial quantification of CT-ECV and CT-GLS associated with post-TAVR outcomes in a contemporary low-risk cohort with mostly preserved LVEF. Whether these imaging biomarkers can be potentially used for the decision making including timing of AS intervention and post-TAVR follow-up will require integration into future clinical trials., Competing Interests: Funding Support and Author Disclosures This research was supported unrestricted research grant by Ziosoft. Dr Treibel is a shareholder of Mycardium AI Ltd. Dr Enriquez-Sarano has received consulting fees from CryoLife, Edwards Lifesciences, Highlife, and ChemImage. Dr Sorajja has received consulting fees from 4C Medical, Anteris, Abbott Structural, Boston Scientific, Edwards Lifesciences, Evolution Medical, Foldax, GLG, Medtronic, Phillips, Siemens, Shifamed, W.L. Gore, vDyne, and xDot; has served on the REPAIR MR Steering Committee, EXPAND Steering Committee, W.L. Gore Pipeline Executive Committee, SUMMIT Steering Committee, TRILUMINATE Steering Committee, TRILUMINATE Eligibility Committee for Anatomy, G4 Adverse Leaflet Events Committee, and Neovasc Executive Steering Committee; and has served as a national or global principal investigator for the TRILUMINATE Pivotal US Trial, SUMMIT MAC Pivotal Trial, EXPAND EFS and Pivotal US Trial, HighLife (USA) EFS, VDyne EFS, SOAR EFS, and AMEND EFS. Dr Bapat has received consulting fees from Abbott Structural, Boston Scientific, Edwards Lifesciences, and Medtronic. Dr Leipsic has received consulting fees from Circle CVI; personal CT core lab fees from MVRX; and institutional core lab fees from Boston Scientific, Abbott, Medtronic, Edwards Lifesciences, and Pi-Cardia. Dr Cavalcante has received consulting fees from 4C Medical, Abbott Structural, Anteris, AriaCV, Boston Scientific, Edwards Lifesciences, Medtronic, VDyne, W.L. Gore, and Xylocor; and research grant support from the Abbott Northwestern Hospital Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Population-wide, person-level, linked electronic health record data are increasingly used to estimate epidemiology, guide resource allocation, and identify events in clinical trials. The accuracy of data from NHS Digital (now part of NHS England) for identifying hospitalization for heart failure (HHF), a key HF standard, is not clear. This study aimed to evaluate the accuracy of NHS Digital data for identifying HHF., Methods and Results: Patients experiencing at least one HHF, as determined by NHS Digital data, and age- and sex-matched patients not experiencing HHF, were identified from a prospective cohort study and underwent expert adjudication. Three code sets commonly used to identify HHF were applied to the data and compared with expert adjudication (I50: International Classification of Diseases-10 codes beginning I50; OIS: Clinical Commissioning Groups Outcomes Indicator Set; and NICOR: National Institute for Cardiovascular Outcomes Research, used as the basis for the National Heart Failure Audit in England and Wales). Five hundred four patients underwent expert adjudication, of which 10 (2%) were adjudicated to have experienced HHF. Specificity was high across all three code sets in the first diagnosis position {I50: 96.2% [95% confidence interval (CI) 94.1-97.7%]; NICOR: 93.3% [CI 90.8-95.4%]; OIS: 95.6% [CI 93.3-97.2%]} but decreased substantially as the number of diagnosis positions expanded. Sensitivity [40.0% (CI 12.2-73.8%)] and positive predictive value (PPV) [highest with I50: 17.4% (CI 8.1-33.6%)] were low in the first diagnosis position for all coding sets. PPV was higher for the National Heart Failure Audit criteria, albeit modestly [36.4% (CI 16.6-62.2%)]., Conclusions: NHS Digital data were not able to accurately identify HHF and should not be used in isolation for this purpose., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: Identification of patients at risk of adverse outcome from heart failure (HF) at an early stage is a priority. Growth differentiation factor (GDF)-15 has emerged as a potentially useful biomarker. This study sought to identify determinants of circulating GDF-15 and evaluate its prognostic value, in patients at risk of HF or with HF but before first hospitalisation., Methods: Prospective, longitudinal cohort study of 2166 consecutive patients in stage A-C HF undergoing cardiovascular magnetic resonance and measurement of GDF-15. Multivariable linear regression investigated determinants of GDF-15. Cox proportional hazards modelling, Net Reclassification Improvement and decision curve analysis examined its incremental prognostic value. Primary outcome was a composite of first hospitalisation for HF or all-cause mortality. Median follow-up was 1093 (939-1231) days., Results: Major determinants of GDF-15 were age, diabetes and N-terminal pro-B-type natriuretic peptide, although despite extensive phenotyping, only around half of the variability of GDF-15 could be explained (R 2 0.51). Log-transformed GDF-15 was the strongest predictor of outcome (HR 2.12, 95% CI 1.71 to 2.63) and resulted in a risk prediction model with higher predictive accuracy (continuous Net Reclassification Improvement 0.26; 95% CI 0.13 to 0.39) and with greater clinical net benefit across the entire range of threshold probabilities., Conclusion: In patients at risk of HF, or with HF but before first hospitalisation, GDF-15 provides unique information and is highly predictive of hospitalisation for HF or all-cause mortality, leading to more accurate risk stratification that can improve clinical decision making., Trial Registration Number: NCT02326324., Competing Interests: Competing interests: EBS serves as an advisor for HAYA Therapeutics and consults for PureTech Health. PFB was in receipt of a joint Alliance Medical and University Hospital of South Manchester Fellowship Salary support grant. JHN has a part-time appointment at Bioxydyn Ltd. TM serves as the clinical lead for the National Heart Failure Audit and has received speaker fees from Novartis, AstraZeneca and Vifor. CAM, Advanced Fellowship (NIHR301338), is funded by the National Institute for Health Research (NIHR), UK. CAM has participated on advisory boards/consulted for AstraZeneca, Boehringer Ingelheim and Lilly Alliance, Novartis and PureTech Health, serves as an advisor for HAYA Therapeutics, has received speaker fees from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, conference attendance support from AstraZeneca, and research support from Amicus Therapeutics, AstraZeneca, Guerbet Laboratories Limited, Roche and Univar Solutions BV. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: This study examined the prevalence of ≥150 min/wk of moderate-to-vigorous physical activity (MVPA) using different criteria for bout length and to examine associations with measures of obesity, cardiorespiratory fitness, and cardiometabolic risk factors in healthy adults with overweight or obesity., Methods: Baseline data from healthy adults (N = 375; age [mean ± SD] = 45.2 ± 7.7 years; BMI = 32.3 ± 3.8 kg/m 2 ) enrolled in a behavioral weight-loss intervention were examined cross-sectionally. Categorization was by objectively measured MVPA as follows: 1) LOW-MVPA: <150 min/wk (n = 122, 32.5%); 2) MVPA-NON-BOUTED: ≥150 min/wk in bouts < 10 min (n = 72, 19.2%); 3) MVPA-COMBINED: ≥150 min/wk with a combination of bouts < 10 and ≥10 min (n = 50, 13.3%); and 4) MVPA-BOUTED: ≥150 min/wk with bouts ≥ 10 min (n = 131, 34.9%)., Results: Weight, BMI, and waist circumference were higher in the LOW-MVPA category versus the other categories. Body fatness was significantly lower in the MVPA-BOUTED category compared with the LOW-MVPA category (p < 0.05). Differences by category for cardiorespiratory fitness and cardiometabolic risk factors were limited., Conclusions: Some adults with overweight or obesity may be more active than they perceived themselves to be, and accumulation of ≥150 min/wk of MVPA may have favorable effects on weight and adiposity status. Findings may influence physical activity recommendations, and confirmation with prospective and randomized studies is needed., (© 2023 The Obesity Society.)

Background: Heart failure (HF) most commonly occurs in patients who have had a myocardial infarction (MI), but factors other than MI size may be deterministic. Fibrosis of myocardium remote from the MI is associated with adverse remodeling. We aimed to 1) investigate the association between remote myocardial fibrosis, measured using cardiovascular magnetic resonance (CMR) extracellular volume fraction (ECV), and HF and death following MI, 2) identify predictors of remote myocardial fibrosis in patients with evidence of MI and determine the relationship with infarct size., Methods: Multicenter prospective cohort study of 1199 consecutive patients undergoing CMR with evidence of MI on late gadolinium enhancement. Median follow-up was 1133 (895-1442) days. Cox proportional hazards modeling was used to identify factors predictive of the primary outcome, a composite of first hospitalization for HF (HHF) or all-cause mortality, post-CMR. Linear regression modeling was used to identify determinants of remote ECV., Results: Remote myocardial fibrosis was a strong predictor of primary outcome (χ 2 : 15.6, hazard ratio [HR]: 1.07 per 1% increase in ECV, 95% confidence interval [CI]: 1.04-1.11, p < 0.001) and was separately predictive of both HHF and death. The strongest predictors of remote ECV were diabetes, sex, natriuretic peptides, and body mass index, but, despite extensive phenotyping, the adjusted model R 2 was only 0.283. The relationship between infarct size and remote fibrosis was very weak., Conclusion: Myocardial fibrosis, measured using CMR ECV, is a strong predictor of HHF and death in patients with evidence of MI. The mechanisms underlying remote myocardial fibrosis formation post-MI remain poorly understood, but factors other than infarct size appear to be important., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christopher Miller reports financial support was provided by National Institute for Health and Care Research. Christopher Miller reports financial support was provided by Guerbet. Christopher Miller reports equipment, drugs, or supplies were provided by Roche. Christopher Miller reports financial support was provided by British Heart Foundation. Christopher Miller reports a relationship with HAYA therapeutics that includes consulting or advisory, PureTech Health that includes consulting or advisory, Amicus Therapeutics Inc that includes funding grants, Roche that includes funding grants, Univar Solutions that includes funding grants, Novartis that includes consulting or advisory, Boehringer Ingelheim Ltd that includes consulting or advisory, Lilly Alliance that includes consulting or advisory, and AstraZeneca PLC that includes consulting or advisory. Erik Schelbert reports a relationship with HAYA therapeutics that includes consulting or advisory, PureTech Health that includes consulting or advisory, and Amicus Therapeutics Inc that includes funding grants and travel reimbursement. Joao L. Cavalcante reports a relationship with Abbott Vascular Inc that includes consulting or advisory and funding grants, Boston Scientific Corp that includes consulting or advisory and funding grants, Edwards Lifesciences Corporation that includes consulting or advisory and funding grants, Medtronic that includes consulting or advisory and funding grants, WL Gore and Associates that includes consulting or advisory and funding grants, Circle Cardiovascular Imaging Inc that includes funding grants, Siemens Healthineers that includes funding grants, 3Mension that includes funding grants, Medis that includes funding grants, and Ziosoft that includes funding grants. Theresa McDonagh reports a relationship with Novartis that includes speaking and lecture fees, AstraZeneca Pharmaceuticals LP that includes speaking and lecture fees, and Vifor Pharma Ltd that includes speaking and lecture fees. Fredrika Fröjdh and Martin Ugander were supported in part by grants from the Swedish Research Council, Swedish Heart and Lung Foundation, Stockholm County Council, and Karolinska Institutet. Martin Ugander is the principal investigator on a research and development agreement regarding cardiovascular magnetic resonance between Siemens and Karolinska University Hospital. Timothy C. Wong was supported by an American Heart Association Scientist Development grant and a Children’s Cardiomyopathy Foundation grant. Josephine Naish has a part-time appointment at Bioxydyn Ltd. The remaining authors have nothing to disclose. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects having undergone CMR were studied (cardiac patients, n = 2543; healthy volunteers, n = 100). A new measure, global wall thickness (GT, GTI if indexed to body surface area) was accurately calculated from LV mass and end-diastolic volume. Among patients with follow-up (n = 1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12-1.20], p < 0.001), followed by GTI (HR 1.14[1.09-1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35-1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease)., (© 2023. The Author(s).)

Aims: Deep neural network artificial intelligence (DNN-AI)-based Heart Age estimations have been presented and used to show that the difference between an electrocardiogram (ECG)-estimated Heart Age and chronological age is associated with prognosis. An accurate ECG Heart Age, without DNNs, has been developed using explainable advanced ECG (A-ECG) methods. We aimed to evaluate the prognostic value of the explainable A-ECG Heart Age and compare its performance to a DNN-AI Heart Age., Methods and Results: Both A-ECG and DNN-AI Heart Age were applied to patients who had undergone clinical cardiovascular magnetic resonance imaging. The association between A-ECG or DNN-AI Heart Age Gap and cardiovascular risk factors was evaluated using logistic regression. The association between Heart Age Gaps and death or heart failure (HF) hospitalization was evaluated using Cox regression adjusted for clinical covariates/comorbidities. Among patients [ n = 731, 103 (14.1%) deaths, 52 (7.1%) HF hospitalizations, median (interquartile range) follow-up 5.7 (4.7-6.7) years], A-ECG Heart Age Gap was associated with risk factors and outcomes [unadjusted hazard ratio (HR) (95% confidence interval) (5 year increments): 1.23 (1.13-1.34) and adjusted HR 1.11 (1.01-1.22)]. DNN-AI Heart Age Gap was associated with risk factors and outcomes after adjustments [HR (5 year increments): 1.11 (1.01-1.21)], but not in unadjusted analyses [HR 1.00 (0.93-1.08)], making it less easily applicable in clinical practice., Conclusion: A-ECG Heart Age Gap is associated with cardiovascular risk factors and HF hospitalization or death. Explainable A-ECG Heart Age Gap has the potential for improving clinical adoption and prognostic performance compared with existing DNN-AI-type methods., Competing Interests: Conflict of interest: T.T.S. is owner and founder of Nicollier-Schlegel SARL, which performs ECG interpretation consultancy using software that can quantify the advanced ECG measures used in the current study. T.T.S. and M.U. are owners and founders of Advanced ECG Systems, a company that is developing commercial applications of advanced ECG technology used in the current study., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Medication adherence in patients with heart failure with preserved ejection fraction is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial., Methods and Results: Adherence was evaluated through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis. Complete adherence data were available in 54 of 80 participants completing the trial. Mean adherence to study medication was 94.7% and 96.9% in the pirfenidone and placebo groups, respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (-0.004%; 95% confidence interval: -0.007% to -0.001%; P = 0.007). Associations with adherence included older age, higher symptom burden, lower body weight, and smaller right ventricular size., Conclusion: Adherence to study medication in the PIROUETTE trial was very high among patients for whom complete adherence data were available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required., Competing Interests: Disclosures CAM has served on advisory boards for Novartis, Boehringer Ingelheim, Lilly Alliance, and AstraZeneca, serves as an advisor for HAYA Therapeutics and PureTech Health and has received research support from Amicus Therapeutics, Guerbet Laboratories, Roche, and Univar Solutions., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Computed tomography angiography (CTA) assessment of myocardial extracellular volume fraction (CT-ECV) is feasible, although the protocols for imaging acquisition and post-processing methodology have varied. We aimed to identify a pragmatic protocol for CT-ECV assessment encompassing both imaging acquisition and post-processing methodologies to facilitate its clinical implementation., Methods: We evaluated consecutive patients with severe aortic stenosis undergoing evaluation for transcatheter aortic valve replacement (TAVR). Pre-contrast and 3-min-delayed CTA were obtained in systole using either helical prospective-ECG-triggered (high-pitch) or axial sequential-ECG-gated acquisition, adding to standard TAVR CTA protocol. Using a dedicated software for co-registration of CTA datasets, three methodologies for ECV measurement were evaluated: (1) mid-septum region of interest (Septal ECV), (2) averaged-global ECV (Global ECV) encompassing 16-AHA segments, and (3) average of septal and lateral segments (Averaged ECVsep and Averaged ECVlat)., Results: Among the 142 patients enrolled (median ​= ​81 years, 44% females), 8 were excluded due to significant imaging artifacts precluding Global ECV assessment. High-pitch scan mode was performed in 68 patients (48%). Suboptimal image quality for Global ECV assessment was associated with high-pitch scan mode (odds ratio: OR ​= ​2.26, p ​= ​0.036), along with the presence of intracardiac leads (OR ​= ​4.91, p ​= ​0.002), and BMI≥35 ​kg/m 2 (OR ​= ​2.80, p ​= ​0.026). Septal ECV [median ​= ​29.4%] and Averaged ECVsep [29.0%] were similar (p ​= ​0.108), while Averaged ECVlat [27.5%] was lower than Averaged ECVsep (p ​< ​0.001), resulting in lower Global ECV [28.6%]., Conclusions: Myocardial CT-ECV assessment is feasible using a systolic sequential acquisition pre-contrast, and similar additional 3-min delayed scan. Septal ECV measurement provides similar values to Global ECV and is equally reproducible., Competing Interests: Declaration of competing interest Dr. Cavalcante has received consulting fees from 4C, Abbott Structural, Anteris, AriaCV, Boston Scientific, Edwards Lifesciences, Medtronic, VDyne, WL Gore, Xylocor; has received research grant support from Abbott Northwestern Hospital Foundation. Dr. Enriquez-Sarano has received consulting fees from Cryolife, Edwards Lifescience, Highlife, and ChemImage. Dr. Sorajja has received consulting fees from Abbott Structural, Anteris, Boston Scientific, EvolutionMed, Medtronic, Shifamed, vDyne, and WL Gore; has received research grant support from Abbott Structural, Medtronic and Boston Scientific, and has been a speaker for Abbott Structural. The remaining authors have nothing to disclosure., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate)., Objectives: To evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing., Methods: Among patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy., Results: After a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not., Conclusions: DMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation., Competing Interests: Conflict of Interest Disclosures: Dr. Miller received research support from Roche and Guerbet and serves as Scientific Advisor to Haya Therapeutics. Dr. Schelbert has accepted contrast material from Bracco Diagnostics for research purposes and serves as Scientific Advisor to Haya Therapeutics. Dr. Ugander is principal investigator on a research and development agreement regarding CMR between Siemens and Karolinska University Hospital. Dr. Saba has received research support from Boston Scientific. Dr. Cavalcante has received consulting fees from Boston Scientific, Medtronic and Abbott Vascular; and research grant support from Abbott Vascular, Edwards Lifesciences, Medtronic, Boston Scientific, Circle Cardiovascular Imaging and Medis. The remaining authors have nothing to disclose.

Objective: This study aimed to determine whether novel biomarkers of cardiometabolic health improve in response to a 12-month behavioral weight-loss intervention and to compare benefits of diet alone with diet plus physical activity for these biomarkers., Methods: Participants (N = 374) were randomized to either diet alone (DIET), diet plus 150 min/wk of prescribed moderate-intensity physical activity (DIET + PA150), or diet plus 250 min/wk of prescribed moderate-intensity physical activity (DIET + PA250). Biomarker concentrations were determined using nuclear magnetic resonance spectroscopy. Mixed models assessed for a time effect, group effect, or group by time interaction., Results: All groups significantly improved body weight (time: p < 0.0001), Lipoprotein Insulin Resistance Index score (time: p < 0.0001), Diabetes Risk Index score (time: p < 0.0001), branched-chain amino acid concentration (time: p < 0.0001), and GlycA concentration (time: p < 0.0001), with no group effect or group by time interactions., Conclusions: All intervention groups prompted a notable beneficial change among biomarkers of insulin resistance and cardiometabolic health. However, the addition of at least moderate-intensity physical activity to a diet-only intervention did not provide any additional benefit. These findings highlight that an average weight loss of approximately 10% profoundly impacts biomarkers of insulin resistance and cardiometabolic disease in adults with overweight or obesity., (© 2023 The Obesity Society.)

Aims: This study sought to compare cardiac magnetic resonance (CMR) characteristics according to different flow/gradient patterns of aortic stenosis (AS) and to evaluate their prognostic value in patients with low-gradient AS., Methods and Results: This international prospective multicentric study included 147 patients with low-gradient moderate to severe AS who underwent comprehensive CMR evaluation of left ventricular global longitudinal strain (LVGLS), extracellular volume fraction (ECV), and late gadolinium enhancement (LGE). All patients were classified as followings: classical low-flow low-gradient (LFLG) [mean gradient (MG) < 40 mmHg and left ventricular ejection fraction (LVEF) < 50%]; paradoxical LFLG [MG < 40 mmHg, LVEF ≥ 50%, and stroke volume index (SVi) < 35 ml/m2]; and normal-flow low-gradient (MG < 40 mmHg, LVEF ≥ 50%, and SVi ≥ 35 ml/m2). Patients with classical LFLG (n = 90) had more LV adverse remodelling including higher ECV, and higher LGE and volume, and worst LVGLS. Over a median follow-up of 2 years, 43 deaths and 48 composite outcomes of death or heart failure hospitalizations occurred. Risks of adverse events increased per tertile of LVGLS: hazard ratio (HR) = 1.50 [95% CI, 1.02-2.20]; P = 0.04 for mortality; HR = 1.45 [1.01-2.09]; P < 0.05 for composite outcome; per tertile of ECV, HR = 1.63 [1.07-2.49]; P = 0.02 for mortality; HR = 1.54 [1.02-2.33]; P = 0.04 for composite outcome. LGE presence also associated with higher mortality, HR = 2.27 [1.01-5.11]; P < 0.05 and composite outcome, HR = 3.00 [1.16-7.73]; P = 0.02. The risk of mortality and the composite outcome increased in proportion to the number of impaired components (i.e. LVGLS, ECV, and LGE) with multivariate adjustment., Conclusions: In this international prospective multicentric study of low-gradient AS, comprehensive CMR assessment provides independent prognostic value that is cumulative and incremental to clinical and echocardiographic characteristics., Competing Interests: Conflict of interest: P.P. received funding from Edwards Lifesciences, Medtronic, Pi-Cardia for echocardiography core laboratory analyses or for research studies in the field of transcatheter therapy of AS, for which he received no personal compensation. M.-A.C. received funding from Edwards Lifesciences for computed tomography core laboratory analyses and research grant from Medtronic. J.L.C. has received consulting fees from Boston Scientific and Abbott Vascular; has received research grant support from Circle Cardiovascular Imaging, Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott Vascular and has been a speaker for Medtronic, Circle Cardiovascular Imaging, and Siemens Healthineers. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume (ECV), is associated with adverse outcome in heart failure with preserved ejection fraction, but the mechanisms by which myocardial fibrosis exerts this deleterious effect are unclear. We performed mediation analyses of data from the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial to determine whether myocardial fibrotic regression causes changes in cardiovascular function and functional status following antifibrotic therapy. Regression of myocardial fibrosis correlated with improvements in 6-min walk test and KCCQ clinical summary score. The only outcome variable that demonstrated a treatment effect was an increase in left ventricular ejection fraction (LVEF). The estimated average causal mediation effects of myocardial ECV, absolute myocardial extracellular matrix volume and absolute myocardial cellular volume on LVEF were 6.1%, 21.5% and 13.7%, respectively, none of which was significant and therefore not mediated by myocardial fibrosis. (PIROUETTE; NCT02932566)., (© 2022. The Author(s).)

Background Growth differentiation factor 15 (GDF-15) is elevated in heart failure with preserved ejection fraction and is associated with adverse outcome, but its relationship with myocardial fibrosis and other characteristics remains unclear. We sought to evaluate the effect of pirfenidone, a novel antifibrotic agent, on GDF-15 in heart failure with preserved ejection fraction and identify characteristics that associate with GDF-15 and with change in GDF-15 over 1 year. Methods and Results Among patients enrolled (n=107) in the PIROUETTE (Pirfenidone in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, GDF-15 was measured at baseline and at prespecified time points in patients randomized (n=94) to pirfenidone or placebo. The response of GDF-15 to pirfenidone and the association with baseline patient characteristics were evaluated. Pirfenidone had no impact on circulating GDF-15 at any time point during the 52-week trial period. In multivariable analysis, male sex, diabetes, higher circulating levels of N-terminal pro-B-type natriuretic peptide, lower renal function, and shorter 6-minute walk test distance at baseline were associated with baseline log-GDF-15. Impaired global longitudinal strain at baseline was the strongest predictor of increased GDF-15 over 52 weeks. Conclusions In patients with heart failure with preserved ejection fraction, circulating levels of GDF-15 were unaffected by treatment with pirfenidone and do not appear to be determined by myocardial fibrosis. Circulating GDF-15 was associated with a spectrum of important heart failure characteristics and it may represent a marker of overall physiological disruption. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02932566; Unique identifier: NCT02932566.

Myocardial fibrosis, measured using magnetic resonance extracellular volume (ECV), associates with adverse outcome in heart failure with preserved ejection fraction (HFpEF). In the PIROUETTE (The Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, the novel anti-fibrotic agent pirfenidone reduced myocardial fibrosis. We sought to identify baseline characteristics that associate with myocardial fibrotic burden, the change in myocardial fibrosis over a year, and predict response to pirfenidone in patients with HFpEF. Amongst patients enrolled in the PIROUETTE trial (n = 107), linear regression models were used to assess the relationship between baseline variables and baseline myocardial ECV, with change in myocardial ECV adjusting for treatment allocation, and to identify variables that modified the pirfenidone treatment effect. Body mass index, left atrial reservoir strain, haemoglobin and aortic distensibility were associated with baseline ECV in stepwise modelling, and systolic blood pressure, and log N-terminal pro B-type natriuretic peptide were associated with baseline ECV in clinically-guided modelling. QRS duration, left ventricular mass and presence of an infarct at baseline were associated with an increase in ECV from baseline to week 52. Whilst QRS duration, presence of an infarct, global longitudinal strain and left atrial strain modified the treatment effect of pirfenidone when considered individually, no variable modified treatment effect on multivariable modelling. Baseline characteristics were identified that associate with myocardial fibrosis and predict change in myocardial fibrosis. No variables that independently modify the treatment effect of pirfenidone were identified (PIROUETTE, NCT02932566)., (© 2022. The Author(s).)

Background: Identifying people who are at risk of being admitted to hospital (hospitalised) for heart failure and death, and particularly those who have not previously been hospitalised for heart failure, is a priority. We aimed to develop and externally validate a prognostic model involving contemporary deep phenotyping that can be used to generate individual risk estimates of hospitalisation for heart failure or all-cause mortality in patients with, or at risk of, heart failure, but who have not previously been hospitalised for heart failure., Methods: Between June 1, 2016, and May 31, 2018, 3019 consecutive adult patients (aged ≥16 years) undergoing cardiac magnetic resonance (CMR) at Manchester University National Health Service Foundation Trust, Manchester, UK, were prospectively recruited into a model development cohort. Candidate predictor variables were selected according to clinical practice and literature review. Cox proportional hazards modelling was used to develop a prognostic model. The final model was validated in an external cohort of 1242 consecutive adult patients undergoing CMR at the University of Pittsburgh Medical Center Cardiovascular Magnetic Resonance Center, Pittsburgh, PA, USA, between June 1, 2010, and March 25, 2016. Exclusion criteria for both cohorts included previous hospitalisation for heart failure. Our study outcome was a composite of first hospitalisation for heart failure or all-cause mortality after CMR. Model performance was evaluated in both cohorts by discrimination (Harrell's C-index) and calibration (assessed graphically)., Findings: Median follow-up durations were 1118 days (IQR 950-1324) for the development cohort and 2117 days (1685-2446) for the validation cohort. The composite outcome occurred in 225 (7·5%) of 3019 patients in the development cohort and in 219 (17·6%) of 1242 patients in the validation cohort. The final, externally validated, parsimonious, multivariable model comprised the predictors: age, diabetes, chronic obstructive pulmonary disease, N-terminal pro-B-type natriuretic peptide, and the CMR variables, global longitudinal strain, myocardial infarction, and myocardial extracellular volume. The median optimism-adjusted C-index for the externally validated model across 20 imputed model development datasets was 0·805 (95% CI 0·793-0·829) in the development cohort and 0·793 (0·766-0·820) in the external validation cohort. Model calibration was excellent across the full risk profile. A risk calculator that provides an estimated risk of hospitalisation for heart failure or all-cause mortality at 3 years after CMR for individual patients was generated., Interpretation: We developed and externally validated a risk prediction model that provides accurate, individualised estimates of the risk of hospitalisation for heart failure and all-cause mortality in patients with, or at risk of, heart failure, before first hospitalisation. It could be used to direct intensified therapy and closer follow-up to those at increased risk., Funding: The UK National Institute for Health Research, Guerbet Laboratories, and Roche Diagnostics International., Competing Interests: Declaration of interests EBS serves as an adviser for HAYA Therapeutics and consults for PureTech Health. PFB was in receipt of a Joint Alliance Medical and University Hospital of South Manchester Fellowship Salary Support Grant. JHN has a part-time appointment at Bioxydyn. TM serves as the clinical lead for the National Heart Failure Audit and has received speaker fees from Novartis, AstraZeneca, and Vifor. CAM has served on advisory boards for Novartis, Boehringer Ingelheim and Lilly Alliance, and AstraZeneca; serves as an adviser for HAYA Therapeutics and PureTech Health; and has received research support from Amicus Therapeutics, Guerbet Laboratories, Roche, and Univar Solutions (none are relevant to the contents of this Article, except where described in the Role of the funding source). All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m 2 vs. control 50 ± 8 g/m 2 ; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7-29.8]% vs. control 24.8 [22.9-26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = - 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity., (© 2022. The Author(s).)

Objective: The primary aim of this study was to examine the change in left ventricular mass (LVM) in adults with overweight or obesity in response to a behavioral weight-loss intervention, with variable physical activity (PA) prescriptions., Methods: A total of 383 adults were randomized to a 12-month intervention of diet modification (DIET), DIET plus 150 min/wk of PA (DIET+MODPA), or DIET plus prescription of 250 min/wk of PA (DIET+HIGHPA). LVM was measured with cardiac magnetic resonance imaging., Results: Twelve-month weight loss was -10.2% (95% CI: -11.7% to -8.8%) in the DIET group, -11.0% (95% CI: -12.4% to -9.5%) in the DIET+MODPA group, and -10.3% (95% CI: -11.8% to -8.9%) in the DIET+HIGHPA group. LVM decreased at 12 months in the DIET group (-2.9 g [95% CI: -5.2 to -0.7]; p = 0.0114), with no change observed in the DIET+MODPA group (-0.8 g [95% CI: -3.0 to 1.5]; p = 0.4979) or the DIET+HIGHPA group (-1.1 g [95% CI: -3.3 to 1.1]; p = 0.3299)., Conclusions: Weight loss through dietary modification resulted in reduced LVM, whereas, when combined with at least 150 min/wk of prescribed moderate-to-vigorous PA, LVM was preserved. These may both be favorable adaptations to weight loss and PA in adults with overweight or obesity that warrant further investigation to understand the clinical implications of these changes on cardiovascular disease risk., (© 2022 The Obesity Society.)