Experiences with the implementation of remote monitoring in patients with COVID-19: A qualitative study with patients and healthcare professionals.

INTRODUCTION: This study investigated how patients with COVID-19, telemonitoring (TM) teams, general practitioners (GPs) and primary care nurses in Belgium experienced remote patient monitoring (RPM) in 12 healthcare organizations, in relation to the patients' illness, health, and care needs, perceived quality of care, patient and health system outcomes, and implementation challenges. DESIGN: A qualitative research approach was adopted, including focus group discussions and semi-structured interviews. METHODS: Four different groups of participants were interviewed, that is, patients (n = 17), TM teams (n = 27), GPs (n = 16), and primary care nurses (n = 12). An interview guide was drafted based on a literature review. Interviews were transcribed verbatim, and NVivo was used for managing and analyzing the data. The QUAGOL method was used to guide the data analysis process and was adapted for the purpose of a thematic content analysis. RESULTS: All participants agreed that RPM-reassured patients. The overall perceived value of RPM for individual patients depended on how well the intervention matched with their needs. Patients who did not have the necessary language (Dutch/French speaking) and digital skills, who did not have the right equipment (smartphone or tablet), or who missed the necessary infrastructure (no internet coverage in their region) were often excluded. Remote patient monitoring also reassured healthcare professionals as it gave them information on a disease they had little knowledge about. Professionals involved in RPM experienced a high workload. All TM teams agreed that quality of data was a key factor to ensure an adequate follow-up, but they differed in what they found important. The logistic management of RPM was a challenge because of the contagious character of COVID-19, and the need for an effective information flow between the hospital team and primary care providers. Participants missed clarification about who was accountable for the care for patients in the projects. Primary care nurses and GPs missed access to RPM data. All agreed that the funding they received was not sufficient to cover all the costs associated with RPM. CONCLUSION: Healthcare professionals and patients perceive RPM as valuable and believe that the concept will have its place in the Belgium health system. However, current RPM practice is challenged by many barriers, and the sustainability of RPM implementation is low. CLINICAL RELEVANCE: Remote patient monitoring (RPM) was perceived as a valuable intervention for patients with COVID-19, but there were important concerns about unequal access to care. While the technology for RPM is available, the sustainability of implementation is low because of concerns with data quality, challenging logistics within projects, lack of data integration and communication, and a lack of an overarching guiding framework.

Diagnostic and Prognostic Accuracy of Aortic Valve Calcium Scoring in Patients With Moderate-to-Severe Aortic Stenosis.

Background: Assessing the true severity of aortic stenosis (AS) remains a challenge, particularly when echocardiography yields discordant results. Recent European and American guidelines recommend measuring aortic valve calcium (AVC) by multidetector row computed tomography (MDCT) to improve this assessment. Aim: To define, using a standardized MDCT scanning protocol, the optimal AVC load criteria for truly severe AS in patients with concordant echocardiographic findings, to establish the ability of these criteria to predict clinical outcomes, and to investigate their ability to delineate truly severe AS in patients with discordant echocardiographic AS grading. Methods and Results: Two hundred and sixty-six patients with moderate-to-severe AS and normal LVEF prospectively underwent MDCT and Doppler-echocardiography to assess AS severity. In patients with concordant AS grading, ROC analysis identified optimal cut-off values for diagnosing severe AS using different AVC load criteria. In these patients, 4-year event-free survival was better with low AVC load (60-63%) by these criteria than with high AVC load (23-26%, log rank p < 0.001). Patients with discordant AS grading had higher AVC load than those with moderate AS but lower AVC load than those with severe high-gradient AS. Between 36 and 55% of patients with severe LG-AS met AVC load criteria for severe AS. Although AVC load predicted outcome in these patients as well, its prognostic impact was less than in patients with concordant AS grading. Conclusions: Assessment of AVC load accurately identifies truly severe AS and provides powerful prognostic information. Our data further indicate that patients with discordant AS grading consist in a heterogenous group, as evidenced by their large range of AVC load. MDCT allows to differentiate between truly severe and pseudo-severe AS in this population as well, although the prognostic implications thereof are less pronounced than in patients with concordant AS grading.

Unraveling the Mystery of Polyvalent Immunoglobulins in Belgium: Do We Have an Indication?

INTRODUCTION: Worldwide, polyvalent immunoglobulin (Ig) use is rising. Together with the limited supply, this puts pressure on Ig availability. A clear overview on a country's usage pattern helps in forecasting future needs. This research aims to provide an overview of Ig use in Belgium on the different indications, including an estimation of off-label use. METHODS: Multiple data sources were used. Existing claims data were explored for reimbursed Ig use between 2010 and 2018. General 2018 sales data from the firms were compared to the reimbursed use to serve as a proxy for off-label use. Indication-specific information was retrieved via a proxy: diagnostic codes available during day-care and inpatient hospitalization. RESULTS: In 2018, 7,556 patients had reimbursed Ig. The most prevalent indication, both in terms of patient numbers and volume, was primary immunodeficiency (PID). In Belgian hospitals, the currently reimbursed indications represented 84.4% of patients (PID [≈35%], secondary immunodeficiency [SID] [≈21%], primary immune thrombocytopenia [≈10%], chronic inflammatory demyelinating neuropathy [CIDP] [≈8%], Guillain-Barre syndrome [≈6%], Kawasaki [≈2%], streptococcal toxic shock [≈2%] and multiple motor neuropathy [≈1%]), and 82.4% of Ig use (predominantly PID [≈33%] and CIDP [≈21%]). Although no direct data on off-label use were available, crude estimates derived from indirect sources showed a proportion of around 15.4%. CONCLUSION: Our research offers the first comprehensive overview on Ig use in Belgium, including a detailed description of reimbursed use, as well as approximations to off-label use. In view of increasing pressure on Ig availability, better understanding Ig needs and trends, would benefit from an effective indication-specific national registry system (ideally covering both reimbursed and nonreimbursed use).

Long-term durability of bicuspid aortic valve repair: a comparison of 2 annuloplasty techniques.

OBJECTIVES: To compare long-term outcomes after bicuspid aortic valve (BAV) repair utilizing the Cabrol annuloplasty versus valve sparing Reimplantation technique. METHODS: From 1996 to 2018, 340 consecutive patients underwent BAV repair. Eighty underwent Cabrol annuloplasty and 189 underwent Reimplantation. Exclusion criteria were re-repairs (n = 6), active endocarditis (n = 4), no annuloplasty (n = 41) and ring or suture annuloplasty (n = 20). We compared both groups for survival, reoperations, valve related events and recurrent severe aortic regurgitation (AR > 2+). Inverse probability weighting (IPW) was used to balance the 2 groups. Cox regression analysis was used to identify outcome predictors. RESULTS: After weighting, pre- and intraoperative characteristics were similar between groups, except for aorta replacement techniques and operative time, which was longer in the Reimplantation group (P < 0.001). At 12 years, overall survival was similar between groups (IPW: Cabrol 97 ± 2% vs Reimplantation 94 ± 3%, P = 0.52). Freedom from reoperation and freedom from AR > 2+ were significantly lower in the Cabrol group (reoperation IPW: 69 ± 9% vs 91 ± 4%, P = 0.004 and AR > 2+ IPW: 71 ± 8% vs 97 ± 2%, P < 0.001). The Reimplantation technique was the only independent predictor of reoperation (hazard ratio 0.31; confidence interval 0.19-0.7; P = 0.005). CONCLUSIONS: In this study, comparing 2 annuloplasty strategies for BAV repair, we found statistically significant differences in long-term durability favouring the Reimplantation technique, and no differences in overall survival. The results support our current strategy of Reimplantation technique and repair of AR in patients with BAV. Cabrol annuloplasty is obsolete and should be generally abandoned in patients undergoing BAV repair for AR.

Structural and Functional Correlates of Gradient-Area Patterns in Severe Aortic Stenosis and Normal Ejection Fraction.

OBJECTIVES: The authors sought to characterize the functional and structural myocardial phenotypes of patients with moderate-to-severe aortic stenosis (AS) and to determine whether severe paradoxical low-gradient AS (LG-AS) is specifically associated with left ventricular (LV) remodeling and fibrosis. BACKGROUND: Recently, it was suggested that severe paradoxical LG-AS is a more advanced form of AS, with greater reduction of longitudinal deformation, adverse LV remodeling, and more interstitial fibrosis. METHODS: The study population includes 147 patients with moderate-to-severe AS and a normal LV ejection fraction, and 75 normal control subjects. They prospectively underwent 2-dimensional speckle-tracking echocardiography and cardiac magnetic resonance to evaluate myocardial deformation, LV remodeling, and age- and sex-adjusted extravascular volume fraction (ECV, %). Among AS patients, 18 had moderate AS, 74 had severe high-gradient AS (HG-AS), and 55 had severe paradoxical LG-AS. RESULTS: Reduced longitudinal and circumferential deformation was observed in 21% and 6% of the AS patients, respectively. Multivariate analyses identified increased ECV (ß = 1.99; p = 0.001) and the absence of normal LV geometry (ß = -1.37; p = 0.007) and as independent predictors of reduced longitudinal deformation. Increased ECV was an independent predictor of reduced circumferential deformation (ß = 2.19; p = 0.001). Over a median follow-up of 29 months, reduced longitudinal deformation (hazard ratio: 0.82; p = 0.023) and higher transvalvular gradients (hazard ratio: 1.05; p < 0.001) increased the risk of death or need for aortic valve replacement. LV hypertrophy was more frequently observed among patients with severe HG-AS (65%) than among the other AS patients (14%; p < 0.001). On average, ECV was within normal limits and did not differ among gradient-area subgroups. When present, increased ECV was associated with reduced longitudinal deformation. CONCLUSIONS: This study's data show that patients with severe paradoxical LG-AS less frequently display reduced longitudinal deformation, LV hypertrophy, or myocardial fibrosis than patients with HG-AS. Also, interstitial fibrosis only occurs when reduced longitudinal deformation and severe HG-AS are present together. Finally, this study suggests that reduced longitudinal deformation and higher transvalvular gradients adversely affect patients' outcomes.

Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction.

AIMS: Besides regulating calcium-phosphate metabolism, fibroblast growth factor 23 (FGF-23) has been associated with incident heart failure (HF) and left ventricular hypertrophy. However, data about FGF-23 in HF and preserved ejection fraction (HFpEF) remain limited. The aim of this study was to assess the association between FGF-23 levels, clinical and imaging characteristics, particularly diffuse myocardial fibrosis, and prognosis in HFpEF patients. METHODS AND RESULTS: We prospectively included 143 consecutive HFpEF patients (78 ± 8 years, 61% female patients) and 31 controls of similar age and gender (75 ± 6 years, 61% female patients). All subjects underwent a complete two-dimensional echocardiography and cardiac magnetic resonance with extracellular volume (ECV) assessment by T1 mapping. FGF-23 was measured at baseline. Among the patients, differences in clinical and imaging characteristics across tertiles of FGF-23 levels were analysed with a trend test across the ordered groups. Patients were followed over time for a primary endpoint of all-cause mortality and first HF hospitalization and a secondary endpoint of all-cause mortality. Median FGF-23 was significantly higher in HFpEF patients compared with controls of similar age and gender (247 [115; 548] RU/mL vs. 61 [51; 68] RU/mL, P < 0.001). Among HFpEF patients, higher FGF-23 levels were associated with female sex, higher incidence of atrial fibrillation, lower haemoglobin, worse renal function, and higher N terminal pro brain natriuretic peptide levels (P for trend < 0.05 for all). Regarding imaging characteristics, patients with higher FGF-23 levels had greater left atrial volumes, worse right ventricular systolic function, and more fibrosis estimated by ECV (P for trend < 0.05 for all). FGF-23 was moderately correlated with ECV (r = 0.46, P < 0.001). Over a mean follow-up of 30 ± 8 months, 43 patients (31%) died and 69 patients (49%) were hospitalized for HF. A total of 87 patients (62%) reached the primary composite endpoint of all-cause mortality and/or first HF hospitalization. In multivariate Cox regression analysis for the primary endpoint, FGF-23 (HR: 3.44 [2.01; 5.90], P < 0.001) and E wave velocities (HR: 1.01 [1.00; 1.02], P = 0.034) were independent predictors of the primary composite endpoint. In multivariate Cox regression analysis for the secondary endpoint, ferritin (HR: 1.02 [1.01; 1.03], P < 0.001), FGF-23 (HR: 2.85 [1.26; 6.44], P = 0.012), and ECV (HR: 1.26 [1.03; 1.23], P = 0.008) were independent predictors of all-cause mortality. CONCLUSIONS: Fibroblast growth factor 23 (FGF-23) levels were significantly higher in HFpEF patients compared with controls of similar age and gender. FGF-23 was correlated with fibrosis evaluated by ECV. High levels of FGF-23 were significantly associated with signs of disease severity such as worse renal function, larger left atrial volumes, and right ventricular dysfunction. Moreover, FGF-23 was a strong predictor of poor outcome (mortality and first HF hospitalization).

Right Ventricular Global Longitudinal Strain and Outcomes in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Right ventricular (RV) strain has emerged as an accurate tool for RV function assessment and is a powerful predictor of survival in patients with heart failure with reduced ejection fraction. However, its prognostic impact in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. The aim of this study was to compare the prognostic value of RV global longitudinal strain (RVGLS) by two-dimensional speckle-tracking echocardiographic (STE) imaging in patients with HFpEF against conventional RV function parameters. METHODS: Patients with HFpEF were prospectively recruited, and 149 of 183 (81%) with analyzable STE RVGLS images constituted the final study population (mean age, 78 ± 9 years; 61% women), compared with 28 control subjects of similar age and sex. All control subjects and 120 patients also underwent cardiac magnetic resonance imaging. Patients were followed up for a primary end point of all-cause mortality and first heart failure hospitalization, and Cox regression analysis was performed. RESULTS: Mean STE RVGLS was significantly altered in patients with HFpEF compared with control subjects (-21.7 ± 4.9% vs -25.9 ± 4.2%, P < .001). STE RVGLS correlated well with RV ejection fraction by cardiac magnetic resonance (r = -0.617, P < .001). Twenty-eight patients with HFpEF (19%) had impaired STE RVGLS (>-17.5%). During a mean follow-up period of 30 ± 9 months, 91 patients with HFpEF (62%) reached the primary end point. A baseline model was created using independent predictors of the primary end point: New York Heart Association functional class III or IV, hemoglobin level, estimated glomerular filtration rate, and the presence of moderate or severe tricuspid regurgitation. Impaired STE RVGLS provided significant additional prognostic value over this model (χ2 to enter = 7.85, P = .005). Impaired tricuspid annular plane systolic excursion and fractional area change, however, did not. CONCLUSIONS: In patients with HFpEF, impaired RVGLS has strong prognostic value. STE RVGLS should be considered for systematic evaluation of RV function to identify patients at high risk for adverse events.

Resheathing of self-expanding bioprosthesis: Impact on procedural results, clinical outcome and prosthetic valve durability after transcatheter aortic valve implantation.

BACKGROUND: New transcatheter aortic valves were recently developed, enabling to resheath and reposition the prosthesis. The aim of the present study was to investigate whether the resheath manoeuvre did not impair the outcome of patients and the bioprosthesis durability after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: On the 346 consecutive patients (84 ±â€¯7 yrs-old, mean STS 6.7 ±â€¯5%) undergoing a transfemoral TAVI in our institution since January 2008, 170 patients were implanted using a self-expanding valve (SEV). Among those, 39 (Group 1) required resheathing to achieve a successful implantation, while 131 did not require it (Group 2, N = 131). A balloon-expanding valve (BEV) was used in 176 patients (Group 3). Baseline characteristics were similar between groups. Device success was 98%, the rate of in-hospital death was 2%, and the number of procedural complications was similarly low, with no significant difference between groups. The follow-up was complete in 337 of 338 patients undergoing a successful TAVI (781 patients-year). Kaplan-Meier analysis showed that overall survival was 80 ±â€¯2% and 42 ±â€¯3% at 1 and 5 years respectively, with no difference between groups. On multivariate analysis, acute kidney injury, post-dilatation, pulmonary hypertension, porcelain aorta and STS score, but not resheath, were independant predictors of death after TAVI. The annual event rate of structural valve deterioration was 0.6% patients-year, and similar between groups. CONCLUSIONS: Our study shows that SEV resheath did not impair the procedural results, the outcome of patients nor the valve durability at short term after TAVI.

Relative Contribution of Afterload and Interstitial Fibrosis to Myocardial Function in Severe Aortic Stenosis.

OBJECTIVES: The present study aimed at investigating the respective contribution of afterload and myocardial fibrosis to pre- and post-operative left ventricular (LV) function by using stress-strain relationships. BACKGROUND: Separating the effect of myocardial dysfunction and afterload on pump performance has important implications for the prognosis and management of patients with severe aortic stenosis (AS). METHODS: A total of 101 patients with isolated severe AS (57% men; mean age 71 years) and 75 healthy control subjects underwent resting 2-dimensional and speckle-tracking echocardiography to measure global circumferential strain (GCS) and global longitudinal strain (GLS), as well as end-systolic wall stress (ESWS). Normal stress-strain relationships were constructed using control subjects' data and fitted to linear regression. End-systolic stress-strain indexes (the number of SDs from the mean regression line) were used as an afterload-independent index of myocardial function and compared with myocardial fibrosis, measured on transmural myocardial biopsies harvested at the time of surgery. RESULTS: GCS and GLS were afterload-dependent in both control subjects and patients. The GLS-ESWS relationship of patients was shifted downward compared with control subjects. Patients with reduced pre-operative end-systolic stress-strain indexes exhibited larger degrees of interstitial myocardial fibrosis than patients without (3.8 ± 2.9% vs. 8.3 ± 6.3%, p < 0.001; and 4.9 ± 4.4% vs. 9.5 ± 6.4%; p < 0.001, for GLS and GCS, respectively). By multivariate analysis, pre-operative end-systolic stress-strain indexes were the only predictors of post-operative longitudinal and circumferential end-systolic stress-strain indexes (ß = 0.49 and ß = 0.60, respectively; p < 0.001). CONCLUSIONS: Myocardial strains are afterload-dependent. In patients with severe AS, pre-operative stress-strain indexes allow identification of patients with increased myocardial fibrosis and predict the extent of functional recovery after aortic valve replacement.

Pulmonary hypertension detection by computed tomography pulmonary transit time in heart failure with reduced ejection fraction.

AIMS: To evaluate the relationships between pulmonary transit time (PTT), cardiac function, and pulmonary haemodynamics in patients with heart failure with reduced ejection fraction (HFrEF) and to explore how PTT performs in detecting pulmonary hypertension (PH). METHODS AND RESULTS: In this prospective study, 57 patients with advanced HFrEF [49 men, 51 years ± 8, mean left ventricular (LV) ejection fraction 26% ± 8] underwent echocardiography, right heart catheterization, and cardiac computed tomography (CT). PTT was measured as the time interval between peaks of attenuation in right ventricle (RV) and LV and was compared between patients with or without PH and 15 controls. PTT was significantly longer in HFrEF patients with PH (21 s) than in those without PH (11 s) and controls (8 s) (P < 0.001) but not between patients without PH and controls (P = 0.109). PTT was positively correlated with pulmonary artery wedge pressure (PAWP) (r = 0.74), mean pulmonary artery pressure (r = 0.68), N-terminal pro-B-type natriuretic peptide (r = 0.60), mitral (r = 0.54), and tricuspid (r = 0.37) regurgitation grades, as well as with LV, RV, and left atrial volumes (r from 0.39 to 0.64) (P < 0.01). PTT was negatively correlated with cardiac index (r = -0.63) as well as with LV (r = -0.66) and RV (r = -0.74) ejection fractions. PAWP, cardiac index, mitral regurgitation grade, and RV end-diastolic volume were all independent predictors of PTT. PTT value ≥14 s best-detected PH with 91% sensitivity and 88% specificity (area under the receiver operating characteristic curve: 0.95). CONCLUSION: In patients with HFrEF, PTT correlates with cardiac function and pulmonary haemodynamics, is determined by four independent parameters, and performs well in detecting PH.

Do Guideline-Based Indications Result in an Outcome Penalty for Patients With Severe Aortic Regurgitation?

OBJECTIVES: The present study examines whether improvements have reduced the negative impact of guideline triggers on postoperative outcomes. BACKGROUND: European and American guidelines for the management of severe aortic regurgitation (AR) define the triggers for AR surgery. These triggers are based on the results of studies performed in the 1990s analyzing outcomes of patients who underwent AR surgery in the 1980s. Although these triggers are used to indicate surgery, they have all been associated with poorer postoperative outcomes. In the meantime, innovations in operative techniques, including aortic valve repair, have allowed reducing the risk of surgery. METHODS: A total of 356 consecutive patients undergoing surgical correction of severe AR were included in this study. Among them, 204 were operated on for a Class I, 17 for a Class IIa, 49 for a Class IIb, and 86 without any guideline triggers. Cox proportional hazards regression models and Kaplan-Meier survival curves were used to compare postoperative outcomes in the different groups. Inverse probability weighing was used to adjust for mismatched baseline characteristics. RESULTS: Adjusted 10-year survival was better among patients without operative triggers (89 ± 4%) or with Class II triggers (85 ± 6%) than in patients with Class I triggers (71 ± 4%, p = 0.010). Similar results were obtained for cardiovascular survival and hospitalizations for heart failure. Spline function analyses indicated that mortality started to increase for left ventricular (LV) ejection fraction <55% and LV end-systolic dimensions >20 to 22 mm/m2. LV end-diastolic dimensions did not influence outcomes. CONCLUSIONS: Guideline-based Class I triggers for AR surgery carry major risks for long-term outcomes. This suggests that patients with severe AR should be operated on before the onset of these triggers; that is, at an asymptomatic stage, before LV ejection fraction falls below 55% or LV end-systolic dimensions exceeds 20 to 22 mm/m2.

Assessment of Left Ventricular Reverse Remodeling by Cardiac MRI in Patients Undergoing Repair Surgery for Severe Aortic or Mitral Regurgitation.

OBJECTIVE: To evaluate left ventricular (LV) reverse remodeling after repair surgery for mitral regurgitation (MR) or aortic regurgitation (AR), aiming at determining optimal preoperative thresholds for normalization of LV volumes and function after surgery. DESIGN: Observational prospective cohort study. SETTING: Single-center, academic, tertiary care cardiovascular center. PARTICIPANTS: Patients and volunteers. INTERVENTIONS: Cardiac magnetic resonance with measurement of indexed LV end-diastolic volume (LVEDVi) and end-systolic volume (LVESVi), mass (LVmassi), and ejection fraction (LVEF) was performed preoperatively and postoperatively. MEASUREMENTS AND MAIN RESULTS: The authors included 29 patients with AR and 59 patients with MR (46 ± 12 and 56 ± 12 years, follow-up 222 ± 57 days). Both AR and MR repair resulted in a significant reduction of LV volumes and mass (respectively, delta change in LVEDVi -55 mL/m² and -43 mL/m²; in LVESVi -26 mL/m² and -10 mL/m²; and in LVmassi -24 g/m² and -12 g/m²; p < 0.001 for all). Yet despite the absence of perioperative necrosis, 7 (24%) patients with AR had persistent LV dilatation (LVEDVi >106 mL/m²) relative to controls and 16 (27%) patients with MR developed systolic LV dysfunction (LVEF <50%) postoperatively. Binary logistic regression analysis indicated preoperative LV volumes as the most accurate parameter for predicting both incomplete LV reverse remodeling in AR and LV dysfunction in MR. Receiver operating characteristic-determined thresholds were LVEDVi >155 mL/m² for AR and >129 mL/m² for MR. CONCLUSION: Although both AR and MR repair allow significant reverse postoperative LV remodeling, persistent LV dilatation after AR correction and systolic LV dysfunction after MR repair are common and best predicted by increased preoperative LV volumes. This highlights the importance of considering LV volumes in the decision-making process.

Associations and prognostic significance of diffuse myocardial fibrosis by cardiovascular magnetic resonance in heart failure with preserved ejection fraction.

BACKGROUND: Increased myocardial fibrosis may play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology. The study aim was to evaluate the presence, associations, and prognostic significance of diffuse fibrosis in HFpEF patients compared to age- and sex-matched controls. METHODS: We prospectively included 118 consecutive HFpEF patients. Diffuse myocardial fibrosis was estimated by extracellular volume (ECV) quantified by cardiovascular magnetic resonance with the modified Look-Locker inversion recovery sequence. We determined an ECV age- and sex-adjusted cutoff value (33%) in 26 controls. RESULTS: Mean ECV was significantly higher in HFpEF patients versus healthy controls (32.9 ± 4.8% vs 28.2 ± 2.4%, P <  0.001). Multivariate logistic regression showed that body mass index (BMI) (odds ratio (OR) =0.92 [0.86-0.98], P = 0.011), diabetes (OR = 2.62 [1.11-6.18], P = 0.028), and transmitral peak E wave velocity (OR = 1.02 [1.00-1.03], P = 0.022) were significantly associated with abnormal ECV value. During a median follow-up of 11 ± 6 months, the primary outcome (all-cause mortality or first heart failure hospitalization) occurred in 38 patients. In multivariate Cox regression analysis, diabetes (hazard ratio (HR) =1.98 [1.04; 3.76], P = 0.038) and hemoglobin level (HR = 0.81 [0.67; 0.98], P = 0.028) were significant predictors of composite outcome. The ECV ability to improve this model added significant prognostic information. We then developed a risk score including diabetes, hemoglobin and ECV > 33% demonstrating significant prediction of risk and validated this score in a validation cohort of 53 patients. Kaplan-Meier curves showed a significant difference according to tertiles of the probability score (P <  0.001). CONCLUSION: Among HFpEF patients, high ECV, likely reflecting abnormal diffuse myocardial fibrosis, was associated with a higher rate of all-cause death and first HF hospitalization in short term follow up. TRIAL REGISTRATION: Characterization of Heart Failure With Preserved Ejection Fraction. TRIAL REGISTRATION NUMBER: NCT03197350 . Date of registration: 20/06/2017. This trial was retrospectively registered.

Improvements of Myocardial Deformation Assessment by Three-Dimensional Speckle-Tracking versus Two-Dimensional Speckle-Tracking Revealed by Cardiac Magnetic Resonance Tagging.

BACKGROUND: In prior work, the authors demonstrated that two-dimensional speckle-tracking (2DST) correlated well but systematically overestimated global longitudinal strain (LS) and circumferential strain (CS) compared with two-dimensional cardiac magnetic resonance tagging (2DTagg) and had poor agreement on a segmental basis. Because three-dimensional speckle-tracking (3DST) has recently emerged as a new, more comprehensive evaluation of myocardial deformation, this study was undertaken to evaluate whether it would compare more favorably with 2DTagg than 2DST. METHODS: In a prospective two-center trial, 119 subjects (29 healthy volunteers, 63 patients with left ventricular dysfunction, and 27 patients with left ventricular hypertrophy) underwent 2DST, 3DST, and 2DTagg. Global, regional (basal, mid, and apical), and segmental (18 and 16 segments per patient) LS and CS by 2DST and 3DST were compared with 2DTagg using intraclass correlation coefficients (ICCs) and Bland-Altman analysis. Test-retest reproducibility of 3DST and 2DST was compared in 48 other patients. RESULTS: Both global LS and CS by 3DST agreed better with 2DTagg (ICC = 0.89 and ICC = 0.83, P < .001 for both; bias = 0.5 ± 2.3% and 0.2 ± 3%) than 2DST (ICC = 0.65 and ICC = 0.55, P < .001 for both; bias = -5.5 ± 2.5% and -7 ± 5.3%). Unlike 2DST, 3DST did not overestimate deformation at the regional and particularly the apical levels and at the segmental level had lower bias (LS, 0.8 ± 2.8% vs -5.3 ± 2.4%; CS, -0.01 ± 2.8% vs -7 ± 2.8%, respectively) but similar agreement with 2DST (LS: ICC = 0.58 ± 0.16 vs 0.56 ± 0.12; CS: ICC = 0.58 ± 0.12 vs 0.51 ± 0.1) with 2DTagg. Finally, 3DST had similar global LS, but better global CS test-retest variability than 2DST. CONCLUSIONS: Using 2DTagg as reference, 3DST had better agreement and less bias for global and regional LS and CS. At the segmental level, 3DST demonstrated comparable agreement but lower bias versus 2DTagg compared with 2DST. Also, test-retest variability for global CS by 3DST was better than by 2DST. This suggests that 3DST is superior to 2DST for analysis of global and regional myocardial deformation, but further refinement is needed for both 3DST and 2DST at the segmental level.

Cardiac myocyte ß3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling.

Aims: Human and mouse cardiac beta3-adrenergic receptors (beta3AR) exert antipathetic effects to those of beta1-2AR stimulation. We examined their role in modulating myocardial remodelling, particularly fibrosis in response to haemodynamic stress. Methods and results: Mice with cardiac myocyte-specific expression of beta3AR (ADRB3-tg) or tamoxifen-inducible homozygous deletion (c-Adrb3-ko, with loxP-targeted Adrb3) were submitted to transaortic constriction. A superfusion assay was used for proteomic analysis of paracrine mediators between beta3AR-expressing cardiac myocytes and cardiac fibroblasts cultured separately. We show that cardiac beta3AR attenuate myocardial fibrosis in response to haemodynamic stress. Interstitial fibrosis and collagen content were reduced in ADRB3-tg, but augmented in c-Adrb3-ko. ADRB3 and collagen (COL1A1) expression were also inversely related in ventricular biopsies of patients with valve disease. Incubation of cardiac fibroblasts with media conditioned by hypertrophic myocytes induced fibroblast proliferation, myo-differentiation, and collagen production. These effects were abrogated upon ADRB3 expression in myocytes. Comparative shotgun proteomic analysis of the myocyte secretomes revealed a number of factors differentially regulated by beta3AR, among which connective tissue growth factor [CTGF (CCN2)] was prominently reduced. CTGF was similarly reduced in stressed hearts from ADRB3-tg, but increased in hearts from c-Adrb3-ko mice. CTGF expression was mediated by reactive oxygen species production which was reduced by ADRB3 expression in vitro and in vivo. This antioxidant and anti-fibrotic effect involved beta3AR coupling to the neuronal isoform of nitric oxide synthase (nNOS) in cardiac myocytes, as both were abrogated upon nNOS inhibition or Nos1 homozygous deletion. Conclusion: Cardiac beta3AR protect from fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress-dependent paracrine signaling to fibroblasts. Specific agonism at beta3AR may offer a new therapeutic modality to prevent cardiac fibrosis.

Inference in a survival cure model with mismeasured covariates using a simulation-extrapolation approach.

In many situations in survival analysis, it may happen that a fraction of individuals will never experience the event of interest: they are considered to be cured. The promotion time cure model takes this into account. We consider the case where one or more explanatory variables in the model are subject to measurement error, which should be taken into account to avoid biased estimators. A general approach is the simulation-extrapolation algorithm, a method based on simulations which allows one to estimate the effect of measurement error on the bias of the estimators and to reduce this bias. We extend this approach to the promotion time cure model. We explain how the algorithm works, and we show that the proposed estimator is approximately consistent and asymptotically normally distributed, and that it performs well in finite samples. Finally, we analyse a database in cardiology: among the explanatory variables of interest is the ejection fraction, which is known to be measured with error.

Head-to-Head Comparison of Global and Regional Two-Dimensional Speckle Tracking Strain Versus Cardiac Magnetic Resonance Tagging in a Multicenter Validation Study.

BACKGROUND: Despite widespread use to characterize and refine prognosis, validation data of two-dimensional (2D) speckle tracking (2DST) echocardiography myocardial strain measurement remain scarce. METHODS AND RESULTS: Global and regional subendocardial peak-systolic Lagrangian longitudinal (LS) and circumferential strain (CS) by 2DST and 2D-tagged (2DTagg) cardiac magnetic resonance imaging were compared against sonomicrometry in a dynamic heart phantom and among each other in 136 patients included prospectively at 2 centers. The ability of regional LS and CS 2DST and 2DTagg to identify late gadolinium enhancement was compared using receiver operating characteristics curves. In vitro, both LS-2DST and 2DTagg highly agreed with sonomicrometry (intraclass correlation coefficient [ICC], 0.89 and ICC, 0.90, both P<0.001 with -3±2.8% and 0.34±4.35% bias, respectively). In patients, both global LS and global CS 2DST agreed well with 2DTagg (ICC, 0.89 and ICC, 0.80; P<0.001); however, they provided systematically greater values (relative bias of -37±27% and -25±37% for global LS and global CS, respectively). On regional basis, however, ICC (from 0.17 to 0.81) and relative bias (from -9 to -98%) between 2DST and 2DTagg varied strongly among segments. Ability to discriminate infarcted versus noninfarcted segments by late gadolinium enhancement was similarly good for regional LS 2DTagg and 2DST (area under the curve, 0.66 versus 0.59; P=0.08), while it was lower for CS 2DST than 2DTagg (area under the curve, 0.61 versus 0.75; P<0.001). CONCLUSIONS: The high accuracy against sonomicrometry and good agreement of global LS and global CS by 2DST and 2DTagg confirm the overall validity of 2DST strain measurement. Yet, higher intertechnique segmental variability and lower ability for detecting infarct suggest that 2DST strain estimates may be less performant on regional than on global basis.

Age and sex corrected normal reference values of T1, T2 T2* and ECV in healthy subjects at 3T CMR.

BACKGROUND: Myocardial T1, T2 and T2* imaging techniques become increasingly used in clinical practice. While normal values for T1, T2 and T2* times are well established for 1.5 Tesla (T) cardiovascular magnetic resonance (CMR), data for 3T remain scarce. Therefore we sought to determine normal reference values relative to gender and age and day to day reproducibility for native T1, T2, T2* mapping and extracellular volume (ECV) at 3T in healthy subjects. METHODS: After careful exclusion of cardiovascular abnormality, 75 healthy subjects aged 20 to 90 years old (mean 56 ± 19 years, 47% women) underwent left-ventricular T1 (3-(3)-3-(3)-5 MOLLI)), T2 (8 echo- spin echo-imaging) and T2 * (8 echo gradient echo imaging) mapping at 3T CMR (Philips Ingenia 3T and computation of extracellular volume after administration of 0.2 mmol/kg Gadovist). Inter- and intra-observer reproducibility was estimated by intraclass correlation coefficient (ICC). Day to day reproducibility was assessed in 10 other volunteers. RESULTS: Mean myocardial T1 at 3T was 1122 ± 57 ms, T2 52 ± 6 ms, T2* 24 ± 5 ms and ECV 26.6 ± 3.2%. T1 (1139 ± 37 vs 1109 ± 73 ms, p < 0.05) and ECV (28 ± 3 vs 25 ± 2%, p < 0.001), but not T2 (53 ± 8 vs 51 ± 4, p = NS) were significantly greater in age matched women than in men. T1 (r = 0.40, p < 0.001) and ECV (r = 0.37, p = 0.001) increased, while T2 decreased significantly (r = -0.25, p < 0.05) with increasing age. T2* was not influenced by either gender or age. Intra and inter-observer reproducibility was high (ICC ranging between 0.81-0.99), and day to day coefficient of variation was low (6.2% for T1, 7% for T2, 11% for T2* and 11.5% for ECV). CONCLUSIONS: We provide normal myocardial T2, T2*,T1 and ECV reference values for 3T CMR which are significantly different from those reported at 1.5 Tesla CMR. Myocardial T1 and ECV values are gender and age dependent. Measurement had high inter and intra-observer reproducibility and good day-to-day reproducibility.

Assessment of aortic valve calcium load by multidetector computed tomography. Anatomical validation, impact of scanner settings and incremental diagnostic value.

OBJECTIVES: To validate aortic valve calcium (AVC) load measurements by multidetector row computed tomography (MDCT), to evaluate the impact of tube potential and slice thickness on AVC scores, to examine the accuracy of AVC load in distinguishing severe from nonsevere aortic stenosis (AS) and to investigate its effectiveness as an alternative diagnosis method when echocardiography remains inconclusive. METHODS: We prospectively studied 266 consecutive patients with moderate to severe AS who underwent MDCT to measure AVC load and a comprehensive echocardiographic examination to assess AS severity. AVC load was validated against valve weight in 57 patients undergoing aortic valve replacement. The dependence of AVC scores on tube potential and slice thickness was also tested, as well as the relationship between AVC load and echocardiographic criteria of AS severity. RESULTS: MDCT Agatston score correlated well with valve weight (r = 0.82, p < 0.001) and hemodynamic indices of AS severity (all p < 0.001). Ex-vivo Agatston scores decreased significantly with increasing tube potential and slice thickness (repeated measures ANOVA p < 0.001). Multivariate analysis identified mean gradient, the indexed effective orifice area, male gender and left ventricular outflow tract cross-sectional area as independent correlates of the in-vivo AVC load. CONCLUSIONS: MDCT-derived AVC load correlated well with valve weight and hemodynamic indices of AS severity. It also depends on tube potential and slice thickness, thus suggesting that these parameters should be standardized to optimize reproducibility and accuracy.

Head-to-Head Comparison of Inflammation and Neovascularization in Human Carotid Plaques: Implications for the Imaging of Vulnerable Plaques.

BACKGROUND: Inflammation and intraplaque neovascularization are acknowledged to be 2 features of plaque vulnerability, although their temporal expression and their respective value in predicting clinical events are poorly understood. To determine their respective temporal associations, we conducted a comprehensive assessment of inflammation and intraplaque neovascularization in the carotid plaque of symptomatic and asymptomatic patients. METHODS AND RESULTS: Thirty patients with severe carotid stenosis underwent 18F-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging. Plaque 18F-fluorodeoxyglucose-uptake, indicative of inflammation, was measured by calculating the target:background ratio. The presence of intraplaque neovascularization during contrast-enhanced ultrasound was judged semiquantitatively; low-grade contrast enhancement (CE) suggested its absence, and high-grade CE, the presence of neovascularization. Carotid surgery was performed 1.6±1.8 days after completing both imaging modalities in all patients, and the presence of macrophages and neovessels was quantified by immunohistochemistry. We identified a significant correlation between the target:background ratio and macrophage quantification (R=0.78; P<0.001). The number of vessels was also significantly higher in carotid plaque with high-CE (P<0.001). Surprisingly, immunohistochemistry showed that high-CE and vessel number were neither associated with an elevated target:background ratio (P=0.28 and P=0.60, respectively) nor macrophage infiltration (P=0.59 and P=0.40, respectively). Finally, macrophage infiltration and target:background ratio were higher in the carotid plaque of symptomatic patients (P=0.021 and P=0.05, respectively), whereas CE grade and the presence of neovessels were not. CONCLUSIONS: Inflammation and intraplaque neovascularization are not systematically associated in carotid plaques, suggesting a temporal separation between the 2 processes. Inflammation seems more pronounced when symptoms are present. These data highlight the challenges that face any imaging strategy designed to assess plaque vulnerability.