Identification of heart failure hospitalization from NHS Digital data: comparison with expert adjudication.

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.

Growth differentiation factor-15 in patients with or at risk of heart failure but before first hospitalisation.

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 (R2 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.

Accumulated physical activity and the association with obesity, fitness, and cardiometabolic risk factors in healthy adults.

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/m2 ) 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.

Comprehensive Myocardial Assessment by Computed Tomography: Impact on Short-Term Outcomes After Transcatheter Aortic Valve Replacement.

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.

Prognostic utility and characterization of left ventricular hypertrophy using global thickness.

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).

Heart age gap estimated by explainable advanced electrocardiography is associated with cardiovascular risk factors and survival.

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.

Evaluating semi-supervision methods for medical image segmentation: applications in cardiac magnetic resonance imaging.

Purpose: Neural networks have potential to automate medical image segmentation but require expensive labeling efforts. While methods have been proposed to reduce the labeling burden, most have not been thoroughly evaluated on large, clinical datasets or clinical tasks. We propose a method to train segmentation networks with limited labeled data and focus on thorough network evaluation. Approach: We propose a semi-supervised method that leverages data augmentation, consistency regularization, and pseudolabeling and train four cardiac magnetic resonance (MR) segmentation networks. We evaluate the models on multiinstitutional, multiscanner, multidisease cardiac MR datasets using five cardiac functional biomarkers, which are compared to an expert's measurements using Lin's concordance correlation coefficient (CCC), the within-subject coefficient of variation (CV), and the Dice coefficient. Results: The semi-supervised networks achieve strong agreement using Lin's CCC ( > 0.8 ), CV similar to an expert, and strong generalization performance. We compare the error modes of the semi-supervised networks against fully supervised networks. We evaluate semi-supervised model performance as a function of labeled training data and with different types of model supervision, showing that a model trained with 100 labeled image slices can achieve a Dice coefficient within 1.10% of a network trained with 16,000+ labeled image slices. Conclusion: We evaluate semi-supervision for medical image segmentation using heterogeneous datasets and clinical metrics. As methods for training models with little labeled data become more common, knowledge about how they perform on clinical tasks, how they fail, and how they perform with different amounts of labeled data is useful to model developers and users.

Treatment Adherence in a Randomized Controlled Trial of Pirfenidone in HFpEF: Determinants and Impact on Efficacy.

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.

Importance of imaging-acquisition protocol and post-processing analysis for extracellular volume fraction assessment by computed tomography.

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 â€‹= â€‹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 â€‹= â€‹2.26, p â€‹= â€‹0.036), along with the presence of intracardiac leads (OR â€‹= â€‹4.91, p â€‹= â€‹0.002), and BMI≥35 â€‹kg/m2 (OR â€‹= â€‹2.80, p â€‹= â€‹0.026). Septal ECV [median â€‹= â€‹29.4%] and Averaged ECVsep [29.0%] were similar (p â€‹= â€‹0.108), while Averaged ECVlat [27.5%] was lower than Averaged ECVsep (p â€‹< â€‹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.

Diffuse myocardial fibrosis associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients.

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.

Effect of behavioral weight-loss program on biomarkers of cardiometabolic disease risk: Heart Health Study randomized trial.

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.

An electrocardiography score predicts heart failure hospitalization or death beyond that of cardiovascular magnetic resonance imaging.

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.

Improved evaluation of left ventricular hypertrophy using the spatial QRS-T angle by electrocardiography.

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.

Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure with Preserved Ejection Fraction.

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).

Characteristics Associated With Growth Differentiation Factor 15 in Heart Failure With Preserved Ejection Fraction and the Impact of Pirfenidone.

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.

Acute and Chronic Cardiopulmonary Effects of High Dose Interleukin-2 Therapy: An Observational Magnetic Resonance Imaging Study.

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.

Predicting hospitalisation for heart failure and death in patients with, or at risk of, heart failure before first hospitalisation: a retrospective model development and external validation study.

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.

Comprehensive myocardial characterization using cardiac magnetic resonance associates with outcomes in low gradient severe aortic stenosis.

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.

Impact of weight loss with diet or diet plus physical activity on cardiac magnetic resonance imaging and cardiovascular disease risk factors: Heart Health Study randomized trial.

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.