1-year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study.

Background: In patients with coronavirus disease 2019 (COVID-19) requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) 1 year after discharge. Methods: Adults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies (Post-hospitalisation COVID-19 and the International Severe Acute Respiratory and emerging Infection Consortium). HRQoL, assessed by the EuroQol-Five Dimensions-Five Levels utility index (EQ-5D-5L UI), pre-hospital and 1 year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient-reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. Findings: Of the 1888 participants included in the primary analysis, 1149 received corticosteroids. There was no between-group difference in EQ-5D-5L UI at 1 year (mean difference 0.004, 95% CI -0.026-0.034). A similar reduction in EQ-5D-5L UI was seen at 1 year between corticosteroid exposed and nonexposed groups (mean±sd change -0.12±0.22 versus -0.11±0.22). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a cohort of 109 318 patients admitted to hospital with COVID-19, EQ-5D-5L UI at 1 year remained similar between the two groups. Interpretation: Systemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL 1 year after hospital discharge. Treatments to address the persistent reduction in HRQoL are urgently needed.

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

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

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

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

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

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

Clinical Significance of Myocardial Injury in Patients Hospitalized for COVID-19: A Prospective, Multicenter, Cohort Study.

BACKGROUND: Hospitalized COVID-19 patients with troponin elevation have a higher prevalence of cardiac abnormalities than control individuals. However, the progression and impact of myocardial injury on COVID-19 survivors remain unclear. OBJECTIVES: This study sought to evaluate myocardial injury in COVID-19 survivors with troponin elevation with baseline and follow-up imaging and to assess medium-term outcomes. METHODS: This was a prospective, longitudinal cohort study in 25 United Kingdom centers (June 2020 to March 2021). Hospitalized COVID-19 patients with myocardial injury underwent cardiac magnetic resonance (CMR) scans within 28 days and 6 months postdischarge. Outcomes were tracked for 12 months, with quality of life surveys (EuroQol-5 Dimension and 36-Item Short Form surveys) taken at discharge and 6 months. RESULTS: Of 342 participants (median age: 61.3 years; 71.1% male) with baseline CMR, 338 had a 12-month follow-up, 235 had a 6-month CMR, and 215 has baseline and follow-up quality of life surveys. Of 338 participants, within 12 months, 1.2% died; 1.8% had new myocardial infarction, acute coronary syndrome, or coronary revascularization; 0.8% had new myopericarditis; and 3.3% had other cardiovascular events requiring hospitalization. At 6 months, there was a minor improvement in left ventricular ejection fraction (1.8% ± 1.0%; P < 0.001), stable right ventricular ejection fraction (0.4% ± 0.8%; P = 0.50), no change in myocardial scar pattern or volume (P = 0.26), and no imaging evidence of continued myocardial inflammation. All pericardial effusions (26 of 26) resolved, and most pneumonitis resolved (95 of 101). EuroQol-5 Dimension scores indicated an overall improvement in quality of life (P < 0.001). CONCLUSIONS: Myocardial injury in severe hospitalized COVID-19 survivors is nonprogressive. Medium-term outcomes show a low incidence of major adverse cardiovascular events and improved quality of life. (COVID-19 Effects on the Heart; ISRCTN58667920).

Device-measured physical activity and cardiac structure by magnetic resonance.

BACKGROUND AND AIMS: Although extreme cardiac adaptions mirroring phenotypes of cardiomyopathy have been observed in endurance athletes, adaptions to high levels of physical activity within the wider population are under-explored. Therefore, in this study, associations between device-measured physical activity and clinically relevant cardiac magnetic resonance volumetric indices were investigated. METHODS: Individuals without known cardiovascular disease or hypertension were included from the UK Biobank. Cardiac magnetic resonance data were collected between 2015 and 2019, and measures of end-diastolic chamber volume, left ventricular (LV) wall thickness, and LV ejection fraction were extracted. Moderate-to-vigorous-intensity physical activity (MVPA), vigorous-intensity physical activity (VPA), and total physical activity were assessed via wrist-worn accelerometers. RESULTS: A total of 5977 women (median age and MVPA: 62 years and 46.8 min/day, respectively) and 4134 men (64 years and 49.8 min/day, respectively) were included. Each additional 10 min/day of MVPA was associated with a 0.70 [95% confidence interval (CI): 0.62, 0.79] mL/m2 higher indexed LV end-diastolic volume (LVEDVi) in women and a 1.08 (95% CI: 0.95, 1.20) mL/m2 higher LVEDVi in men. However, even within the top decile of MVPA, LVEDVi values remained within the normal ranges [79.1 (95% CI: 78.3, 80.0) mL/m2 in women and 91.4 (95% CI: 90.1, 92.7) mL/m2 in men]. Associations with MVPA were also observed for the right ventricle and the left/right atria, with an inverse association observed for LV ejection fraction. Associations of MVPA with maximum or average LV wall thickness were not clinically meaningful. Results for total physical activity and VPA mirrored those for MVPA. CONCLUSIONS: High levels of device-measured physical activity were associated with cardiac remodelling within normal ranges.

Diagnostic utility of electrocardiogram for screening of cardiac injury on cardiac magnetic resonance in post-hospitalised COVID-19 patients: a prospective multicenter study.

BACKGROUND: The role of ECG in ruling out myocardial complications on cardiac magnetic resonance (CMR) is unclear. We examined the clinical utility of ECG in screening for cardiac abnormalities on CMR among post-hospitalised COVID-19 patients. METHODS: Post-hospitalised patients (n = 212) and age, sex and comorbidity-matched controls (n = 38) underwent CMR and 12­lead ECG in a prospective multicenter follow-up study. Participants were screened for routinely reported ECG abnormalities, including arrhythmia, conduction and R wave abnormalities and ST-T changes (excluding repolarisation intervals). Quantitative repolarisation analyses included corrected QT (QTc), corrected QT dispersion (QTc disp), corrected JT (JTc) and corrected T peak-end (cTPe) intervals. RESULTS: At a median of 5.6 months, patients had a higher burden of ECG abnormalities (72.2% vs controls 42.1%, p = 0.001) and lower LVEF but a comparable cumulative burden of CMR abnormalities than controls. Patients with CMR abnormalities had more ECG abnormalities and longer repolarisation intervals than those with normal CMR and controls (82% vs 69% vs 42%, p < 0.001). Routinely reported ECG abnormalities had poor discriminative ability (area-under-the-receiver-operating curve: AUROC) for abnormal CMR, AUROC 0.56 (95% CI 0.47-0.65), p = 0.185; worse among female than male patients. Adding JTc and QTc disp improved the AUROC to 0.64 (95% CI 0.55-0.74), p = 0.002, the sensitivity of the ECG increased from 81.6% to 98.0%, negative predictive value from 84.7% to 96.3%, negative likelihood ratio from 0.60 to 0.13, and reduced sex-dependence variabilities of ECG diagnostic parameters. CONCLUSION: Post-hospitalised COVID-19 patients have more ECG abnormalities than controls. Normal ECGs, including normal repolarisation intervals, reliably exclude CMR abnormalities in male and female patients.

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

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

Long COVID and cardiovascular disease: a prospective cohort study.

BACKGROUND: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. OBJECTIVES: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. METHODS: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. RESULTS: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). CONCLUSION: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need. TRAIL REGISTRATION NUMBER: ISRCTN10980107.

The Effectiveness of Lifestyle Interventions in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: To perform a network meta-analysis to determine the effectiveness of lifestyle interventions in exercise tolerance and quality of life (QoL) in people with HFpEF. METHODS: Ten databases were searched for randomized controlled trials that evaluated a diet and/or exercise intervention in people with heart failure with preserved ejection fraction until May 2022. The co-primary outcomes were peak oxygen uptake (V̇O2peak) and Quality of Life as assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). We synthesized data using network meta-analysis. RESULTS: We identified 13 trials, including a total of 869 participants, and we incorporated 6 different interventions. Improvements in V̇O2peak compared to controls were seen for all exercise interventions (2.88 [95% CI: 1.36; 4.39] mL/kg/min) for high-intensity interval training (HIIT); 2.37 [95% CI: 1.02; 3.71] mL/kg/min for low-intensity exercise (LIT) combined with a hypocaloric diet; 2.05 [95% CI: 0.81; 3.29] mL/kg/min for moderate-intensity continuous training (MICT); 1.94 [95% CI: 0.59; 3.29] mL/kg/min for LIT; 1.85 [95% CI: 0.27; 3.44] mL/kg/min for MICT combined with resistance training) but not a hypocaloric diet alone (1.26 [95%CI: -0.08; 2.61] mL/kg/min). Only HIIT (-14.45 [95%CI: -24.81; -4.10] points) and LIT (95% CI: -11.05 [-20.55; -1.54] mL/kg/min) significantly improved MLHFQ scores. Network meta-analysis indicated that HIIT was the most effective intervention for improving both V̇O2peak (mean improvement 2.88 [95% CI: 1.36; 4.39] mL/kg/min, follow-up range, 4 weeks-3 years) and QoL (-14.45 [95% CI: -24.81; -4.10] points, follow-up range, 12-26 weeks) compared to usual care. CONCLUSIONS: This network meta-analysis indicates that HIIT is the most effective lifestyle intervention studied to improve exercise capacity and QoL, with mean improvements exceeding the minimum clinically meaningful thresholds. HIIT is likely to be an underused management strategy in HFpEF, but further studies are needed to confirm long-term improvements in symptoms and clinical outcomes.