Quantifying the Survival Loss Linked to Late Therapeutic Indication in High-Gradient Severe Aortic Stenosis.

Background: International guidelines recommend aortic valve replacement (AVR) as Class I triggers in high-gradient severe aortic stenosis (HGSAS) patients with symptoms and/or left ventricular ejection fraction (LVEF) <50%. The association between waiting for these triggers and postoperative survival penalty is poorly studied. Objectives: The purpose of this study was to examine the impact of guideline-based Class I triggers on long-term postoperative survival in HGSAS patients. Methods: 2,030 patients operated for HGSAS were included and classified as follows: no Class I triggers (no symptoms and LVEF >50%, n = 853), symptoms with LVEF >50% (n = 965), or LVEF <50% regardless of symptoms (n = 212). Survival was compared after matching (inverse probability weighting) for clinical differences. Restricted mean survival time was analyzed to quantify lifetime loss. Results: Ten-year survival was better without any Class I trigger than with symptoms or LVEF <50% (67.1% ± 3% vs 56.4% ± 3% vs 53.1% ± 7%, respectively, P < 0.001). Adjusted death risks increased significantly in operated patients with symptoms (HR: 1.45 [95% CI: 1.15-1.82]) or LVEF <50% (HR: 1.47 [95% CI: 1.05-2.06]) than in those without Class I triggers. Performing AVR with LVEF >60% produced similar outcomes to that of the general population, whereas operated patients with LVEF <60% was associated with a 10-year postoperative survival penalty. Furthermore, according to restricted mean survival time analyses, operating on symptomatic patients or with LVEF <60% led to 8.3- and 11.4-month survival losses, respectively, after 10 years, compared with operated asymptomatic patients with a LVEF >60%. Conclusions: Guideline-based Class I triggers for AVR in HGSAS have profound consequences on long-term postoperative survival, suggesting that HGSAS patients should undergo AVR before trigger onset. Operating on patients with LVEF <60% is already associated with a 10-year postoperative survival penalty questioning the need for an EF threshold recommending AVR in HGSAS patients.

Degenerative mitral regurgitation due to flail leaflet: sex-related differences in presentation, management, and outcomes.

BACKGROUND AND AIMS: Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. We analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes. METHODS: In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/heart failure), under medical treatment, post-operatively, and encompassing all follow-up. RESULTS: At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45 (1.27-1.65), P < .001] but was higher in females [SMR 2.00 (1.67-2.38), P < .001]. Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29 (1.04-1.61), P = .02], cardiovascular mortality [adjusted HR 1.58 (1.14-2.18), P = .007], and heart failure [adjusted HR 1.36 (1.02-1.81), P = .04] under medical management. Females vs. males were less offered surgical correction (72% vs. 80%, P < .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females who displayed persistent excess mortality vs. expected [SMR 1.31 (1.16-1.47), P < .001], whereas males enjoyed normal life expectancy restoration [SMR 0.92 (0.85-0.99), P = .036]. CONCLUSIONS: Females with severe DMR were referred to tertiary centers at a more advanced stage, incurred higher mortality and morbidity under conservative management, and were offered surgery less and later after referral. Ultimately, these sex-related differences yielded persistent excess mortality despite surgery in females with DMR, while males enjoyed restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management.

Tricuspid annular dynamics, not diameter, predicts tricuspid regurgitation after mitral valve surgery: Results from a prospective randomized trial.

Objective: Current guidelines advise using prophylactic tricuspid valve annuloplasty during mitral valve surgery, especially in the presence of annular diameter enlargement. However, several retrospective studies and a prospective randomized study from our department could not confirm that diameter enlargement is predictive of late regurgitation. We examined whether 2- and 3-dimensional echocardiographic and clinical characteristics could identify patients who will develop moderate or severe recurrent tricuspid regurgitation. Methods: Patients with less than severe functional tricuspid regurgitation (FTR) were randomized not to receive tricuspid annuloplasty, and 11 of 53 of them were excluded from the study because 3-dimensional echocardiographic analysis was not possible. Cox regression was used to estimate the model-based probability of moderate or severe FTR (vena contracta ≥3 mm) or progression of TR and FTR regression using valve dimensions (annulus area, diameter perimeter, nonplanar angle, and sphericity index), dynamics (annulus contraction, annulus displacement, and displacement velocity), and clinical parameters as possible predictors. Results: At a median follow-up of 3.8 years (range, 3-5.6 years), 17 patients had moderate or severe FTR or progression, and 13 had FTR regression. Our models identified annular displacement velocity as a significant predictor for FTR recurrence and nonplanar angle as a significant predictor for FTR regression. Conclusions: Annular dynamics, not the dimension, predict recurrence and regression of FTR. Annular contraction should be systematically investigated as a possible surrogate of right ventricle function to prophylactically treat the tricuspid valve.

Impact of early versus class I-triggered surgery on postoperative survival in severe aortic regurgitation: An observational study from the Aortic Valve Insufficiency and Ascending Aorta Aneurysm International Registry.

OBJECTIVES: Class I triggers for severe and chronic aortic regurgitation surgery mainly rely on symptoms or systolic dysfunction, resulting in a negative outcome despite surgical correction. Therefore, US and European guidelines now advocate for earlier surgery. We sought to determine whether earlier surgery leads to improved postoperative survival. METHODS: We evaluated the postoperative survival of patients who underwent surgery for severe aortic regurgitation in the international multicenter registry for aortic valve surgery, Aortic Valve Insufficiency and Ascending Aorta Aneurysm International Registry, over a median follow-up of 37 months. RESULTS: Among 1899 patients (aged 49 ± 15 years, 85% were male), 83% and 84% had class I indication according to the American Heart Association and European Society of Cardiology, respectively, and most were offered repair surgery (92%). Twelve patients (0.6%) died after surgery, and 68 patients died within 10 years after the procedure. Heart failure symptoms (hazard ratio, 2.60 [1.20-5.66], P = .016) and either left ventricular end-systolic diameter greater than 50 mm or left ventricular end-systolic diameter index greater than 25 mm/m2 (hazard ratio, 1.64 [1.05-2.55], P = .030) predicted survival independently over and above age, gender, and bicuspid phenotype. Therefore, patients who underwent surgery based on any class I trigger had worse adjusted survival. However, patients who underwent surgery while meeting early imaging triggers (left ventricular end-systolic diameter index 20-25 mm/m2 or left ventricular ejection fraction 50% to 55%) had no significant outcome penalty. CONCLUSIONS: In this international registry of severe aortic regurgitation, surgery when meeting class I triggers led to postoperative outcome penalty compared with earlier triggers (left ventricular end-systolic diameter index 20-25 mm/m2 or ventricular ejection fraction 50%-55%). This observation, which applies to expert centers where aortic valve repair is feasible, should encourage the global use of repair techniques and the conduction of randomized trials.

3D histopathology of stenotic aortic valve cusps using ex vivo microfocus computed tomography.

Background: Calcific aortic stenosis (AS) is the most prevalent heart valve disease in developed countries. The aortic valve cusps progressively thicken and the valve does not open fully due to the presence of calcifications. In vivo imaging, usually used for diagnosis, does not allow the visualization of the microstructural changes associated with AS. Methods: Ex vivo high-resolution microfocus computed tomography (microCT) was used to quantitatively describe the microstructure of calcified aortic valve cusps in full 3D. As case study in our work, this quantitative analysis was applied to normal-flow low-gradient severe AS (NF-LG-SAS), for which the medical prognostic is still highly debated in the current literature, and high-gradient severe AS (HG-SAS). Results: The volume proportion of calcification, the size and number of calcified particles and their density composition was quantified. A new size-based classification considering small-sized particles that are not detected with in vivo imaging was defined for macro-, meso- and microscale calcifications. Volume and thickness of aortic valve cusps, including the complete thickness distribution, were also determined. Moreover, changes in the cusp soft tissues were also visualized with microCT and confirmed by scanning electron microscopy images of the same sample. NF-LG-SAS cusps contained lower relative amount of calcifications than HG-SAS. Moreover, the number and size of calcified objects and the volume and thickness of the cusps were also lower in NF-LG-SAS cusps than in HG-SAS. Conclusions: The application of high-resolution ex vivo microCT to stenotic aortic valve cusps provided a quantitative description of the general structure of the cusps and of the calcifications present in the cusp soft tissues. This detailed description could help in the future to better understand the mechanisms of AS.

Chronic kidney disease is a key risk factor for aortic stenosis progression.

BACKGROUND: Rapid progression of aortic stenosis (AS) has been observed in patients undergoing dialysis, but existing cross-sectional evidence is contradictory in non-dialysis-dependent chronic kidney disease (CKD). The present study sought to evaluate whether CKD is associated with the progression of AS over time in a large cohort of patients with AS. METHODS: We retrospectively studied all consecutive patients diagnosed with AS [peak aortic jet velocity (Vmax) ≥2.5 m/s] and left ventricular ejection fraction ≥50% in the echocardiography laboratories of two tertiary centers between 2000 and 2018. The estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) was calculated from serum creatinine values. Patients were divided into five CKD stages according to the baseline eGFR. Annual rates of change in the aortic valve area (AVA) were determined by a linear mixed-effects model. RESULTS: Among the 647 patients included, 261 (40%) had CKD. After a median follow-up of 2.9 (interquartile range 1.8-4.8) years, the mean overall rate of change in AVA was -0.077 (95% confidence interval -0.082; -0.073) cm2/year. There was an inverse relationship between the progression rate and kidney function. The more severe the CKD stage, the greater the AVA narrowing (P < .001). By multivariable linear regression analysis, the eGFR was also negatively associated (P < .001) with AS progression. An eGFR strata below 45 mL/min/1.73 m2 was associated with higher odds of rapid progression of AS than normal kidney function. During the clinical follow-up, event-free survival (patients free of aortic valve replacement or death) decreased as CKD progressed. Rapid progression of AS in patients with kidney dysfunction was associated with worse outcomes. CONCLUSIONS: Patients with CKD exhibit more rapid progression of AS over time and require close monitoring. The link between kidney dysfunction and rapid progression of AS is still unknown and requires further research.

Prognostic Implications of Discordant Low-Gradient Severe Aortic Stenosis: Comprehensive Analysis of a Large Multicenter Registry.

Background: Up to 30% of patients with severe aortic stenosis (SAS) (indexed aortic valve area [AVAi] <0.6 cm2/m2) exhibit low-transvalvular gradient despite normal ejection fraction. There is intense debate regarding the prognostic significance of this entity. Objectives: The purpose of this study was to compare the outcome of patients with discordant low-gradient SAS (DLG-SAS) vs moderate aortic stenosis (MAS) and high-gradient SAS (HG-SAS). Methods: We used the BEL-F-ASt (Belgium-France-Aortic Stenosis) registry including consecutive patients with AS. Survival was compared overall and after matching (inverse probability weighting and propensity-score matching) for clinical and imaging variables. The analysis was first performed in the overall population (n = 2,582) and then in the population of unoperated patients (n = 1,812). Results: After-inverse probability weighting-matching, the 3 groups were balanced. Five-year survival was better in MAS than in DLG-SAS and HG-SAS-patients (58.9% vs 47% vs 41.2%, P < 0.001). Similar results were obtained in unoperated patients (54.1% vs 37.9% vs 28.1%, P < 0.001). To explore the impact of MG (≤40 vs >40 mmHg) and AVAi (<0.6 vs ≥0.6 cm2/m2) on outcomes, survival of propensity score-matched cohorts of HG-vs DLG-SAS and MAS vs DLG-SAS were compared. After matching for MG, survival was better in MAS than in DLG-SAS (52% vs 40%, P < 0.001). After matching for AVAi, survival was better in DLG-SAS than in HG-SAS patients (45% vs 33%, P < 0.001). Conclusions: Survival of DLG-SAS is better than that of HG-SAS and worse than that of MAS patients. At comparable MG, the lower the AVAi, the worse the prognosis, whereas at comparable AVAi, the higher the MG, the worse the prognosis. These data argue that DLG-SAS is an intermediate form in the disease continuum.

Association of transcatheter edge-to-edge repair with improved survival in older patients with severe, symptomatic degenerative mitral regurgitation.

BACKGROUND: Randomized clinical trials demonstrated transcatheter edge-to-edge repair (TEER) efficacy in improving outcome vs. medical management for functional mitral regurgitation, but limited randomized data are available for the treatment of degenerative mitral regurgitation (DMR). We aimed to compare the outcome of older patients treated with TEER vs. unoperated DMR. METHODS AND RESULTS: Registries including consecutive patients ≥65 years with symptomatic severe DMR treated with TEER (MitraSwiss and Minneapolis Heart Institute registries) or unoperated (MIDA registry) were analysed. Survival was compared overall and after matching for age, sex, EuroSCORE II, and ejection fraction. The study included 1187 patients (872 treated with TEER and 315 unoperated). During 24 ± 17 months of follow-up, 430 patients died, 18 ± 1% at 1 year and 50 ± 2% at 4 years. Patients undergoing TEER had similar age (82 ± 6 vs. 82 ± 7 years) and sex to unoperated patients, but higher surgical risk/comorbidity (EuroSCORE II 3.98 ± 4.28% vs. 2.77 ± 2.46%), more symptoms, and atrial fibrillation (P < 0.0001). Transcatheter edge-to-edge repair was associated with lower mortality accounting for age, sex, EuroSCORE II, New York Heart Association class, atrial fibrillation, and ejection fraction [hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.37-0.58; P < 0.0001]. After propensity matching (247 pairs of patients), TEER consistently showed better survival compared with unoperated patients (49 ± 6% vs. 37 ± 3% at 4 years, P < 0.0001) even in comprehensive multivariable analysis (HR: 0.60, 95% CI: 0.40-0.91; P = 0.03). Procedural failure was infrequent but post-procedural mitral regurgitation, remaining moderate-to-severe in 66 (7.6%) patients, was associated with excess mortality vs. trivial residual regurgitation (30 ± 6% vs. 11 ± 1% at 1 year, P < 0.0001). CONCLUSION: Amongst older patients with severe symptomatic DMR at high surgical risk, mitral TEER was associated with higher survival vs. unoperated patients. Successful control of mitral regurgitation was key to survival improvement with mitral TEER, which should be actively considered in patients deemed inoperable.

Myocardial Contraction Fraction for Risk Stratification in Low-Gradient Aortic Stenosis With Preserved Ejection Fraction.

BACKGROUND: Myocardial contraction fraction (MCF) is a volumetric measure of myocardial shortening independent of left ventricular size and geometry. This multicenter study investigates the usefulness of MCF for risk stratification in low-gradient severe aortic stenosis with preserved ejection fraction. METHODS: We included 643 consecutive patients with low-gradient severe aortic stenosis with preserved ejection fraction in whom MCF was computed at baseline and analyzed mortality during follow-up. RESULTS: Throughout follow-up with medical and surgical management (34.9 [16.1-65.3] months), lower MCF tertiles had higher mortality than the highest tertile. Eighty-month survival was 56±4% for MCF>41%, 41±4% for MCF 30% to 41%, and 40±4% for MCF<30% (P<0.001). After comprehensive adjustment, mortality risk remained high for MCF 30% to 41% (adjusted hazard ratio, 1.53 [1.08-2.18]) and for MCF<30% (adjusted hazard ratio, 1.82 [1.24-2.66]) versus MCF>41%. The optimal MCF cutoff point for mortality prediction was 41%. Age, body mass index, Charlson index, peak aortic velocity, and ejection fraction were independently associated with mortality. MCF (χ2 to improve 10.39; P=0.001), provided greater additional prognostic value over the baseline parameters than stroke volume (SV) index (χ2 to improve 5.41; P=0.042), left ventricular mass index (χ2 to improve 2.15; P=0.137), or global longitudinal strain (χ2 to improve 3.67; P=0.061). MCF outperformed ejection fraction for mortality prediction. When patients were classified by SV index and MCF, mortality risk was low when SV index was ≥30 mL/m2 and MCF>41%, higher for patients with SV index ≥30 mL/m2 and MCF≤41% (adjusted hazard ratio, 1.47 [1.05-2.07]) and extremely high for patients with SV index <30 mL/m2 (adjusted hazard ratio, 2.29 [1.45-3.62]). CONCLUSIONS: MCF is a valuable marker of risk in low-gradient severe aortic stenosis with preserved ejection fraction and could improve decision-making, especially in normal-flow low-gradient severe aortic stenosis with preserved ejection fraction.

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.

Multivendor comparison of global and regional 2D cardiovascular magnetic resonance feature tracking strains vs tissue tagging at 3T.

BACKGROUND: Cardiovascular magnetic resonance (CMR) 2D feature tracking (FT) left ventricular (LV) myocardial strain has seen widespread use to characterize myocardial deformation. Yet, validation of CMR FT measurements remains scarce, particularly for regional strain. Therefore, we aimed to perform intervendor comparison of 3 different FT software against tagging. METHODS: In 61 subjects (18 healthy subjects, 18 patients with chronic myocardial infarction, 15 with dilated cardiomyopathy, and 10 with LV hypertrophy due to hypertrophic cardiomyopathy or aortic stenosis) were prospectively compared global (G) and regional transmural peak-systolic Lagrangian longitudinal (LS), circumferential (CS) and radial strains (RS) by 3 FT software (cvi42, Segment, and Tomtec) among each other and with tagging at 3T. We also evaluated the ability of regional LS, CS, and RS by different FT software vs tagging to identify late gadolinium enhancement (LGE) in the 18 infarct patients. RESULTS: GLS and GCS by all 3 software had an excellent agreement among each other (ICC = 0.94-0.98 for GLS and ICC = 0.96-0.98 for GCS respectively) and against tagging (ICC = 0.92-0.94 for GLS and ICC = 0.88-0.91 for GCS respectively), while GRS showed inconsistent agreement between vendors (ICC 0.10-0.81). For regional LS, the agreement was good (ICC = 0.68) between 2 vendors but less vs the 3rd (ICC 0.50-0.59) and moderate to poor (ICC 0.44-0.47) between all three FT software and tagging. Also, for regional CS agreement between 2 software was higher (ICC = 0.80) than against the 3rd (ICC = 0.58-0.60), and both better agreed with tagging (ICC = 0.70-0.72) than the 3rd (ICC = 0.57). Regional RS had more variation in the agreement between methods ranging from good (ICC = 0.75) to poor (ICC = 0.05). Finally, the accuracy of scar detection by regional strains differed among the 3 FT software. While the accuracy of regional LS was similar, CS by one software was less accurate (AUC 0.68) than tagging (AUC 0.80, p < 0.006) and RS less accurate (AUC 0.578) than the other two (AUC 0.76 and 0.73, p < 0.02) to discriminate segments with LGE. CONCLUSIONS: We confirm good agreement of CMR FT and little intervendor difference for GLS and GCS evaluation, with variable agreement for GRS. For regional strain evaluation, intervendor difference was larger, especially for RS, and the diagnostic performance varied more substantially among different vendors for regional strain analysis.

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C). METHODS: We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves. RESULTS: Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m2, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m2, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels). CONCLUSION: Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.

Prognostic Value of Pulmonary Transit Time by Cardiac Magnetic Resonance on Mortality and Heart Failure Hospitalization in Patients With Advanced Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Pulmonary transit time (PTT) from first-pass perfusion imaging is a novel parameter to evaluate hemodynamic congestion by cardiac magnetic resonance (cMR). We sought to evaluate the additional prognostic value of PTT in heart failure with reduced ejection fraction over other well-validated predictors of risk including the Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. METHODS: We prospectively followed 410 patients with chronic heart failure with reduced ejection fraction (61±13 years, left ventricular (LV) ejection fraction 24±7%) who underwent a clinical cMR to assess the prognostic value of PTT for a primary endpoint of overall mortality and secondary composite endpoint of cardiovascular death and heart failure hospitalization. Normal reference values of PTT were evaluated in a population of 40 asymptomatic volunteers free of cardiovascular disease. Results PTT was significantly increased in patients with heart failure with reduced ejection fraction as compared to controls (9±6 beats and 7±2 beats, respectively, P<0.001), and correlated not only with New York Heart Association class, cMR-LV and cMR-right ventricular (RV) volumes, cMR-RV and cMR-LV ejection fraction, and feature tracking global longitudinal strain, but also with cardiac output. Over 6-year median follow-up, 182 patients died and 200 reached the secondary endpoint. By multivariate Cox analysis, PTT was an independent and significant predictor of both endpoints after adjustment for Meta-Analysis Global Group in Chronic Heart Failure risk score and ischemic cause. Importantly in multivariable analysis, PTT in beats had significantly higher additional prognostic value to predict not only overall mortality (χ2 to improve, 12.3; hazard ratio, 1.35 [95% CI, 1.16-1.58]; P<0.001) but also the secondary composite endpoints (χ2 to improve=20.1; hazard ratio, 1.23 [95% CI, 1.21-1.60]; P<0.001) than cMR-LV ejection fraction, cMR-RV ejection fraction, LV-feature tracking global longitudinal strain, or RV-feature tracking global longitudinal strain. Importantly, PTT was independent and complementary to both pulmonary artery pressure and reduced RV ejection fraction<42% to predict overall mortality and secondary combined endpoints. CONCLUSIONS: Despite limitations in temporal resolution, PTT derived from first-pass perfusion imaging provides higher and independent prognostic information in heart failure with reduced ejection fraction than clinical and other cMR parameters, including LV and RV ejection fraction or feature tracking global longitudinal strain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03969394.

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.

Heart failure with preserved ejection fraction in Belgium: characteristics and outcome of a real-life cohort.

BACKGROUND: Due to aging of the population and the increase of cardiovascular risk factors, heart failure and preserved ejection fraction (HFpEF) is a rising health issue. Few data exist on the phenotype of HFpEF patients in Belgium and on their prognosis. OBJECTIVES: We describe clinical characteristics and outcomes of Belgian HFpEF patients. METHODS: We prospectively enrolled 183 HFpEF patients. They underwent clinical examination, comprehensive biological analysis and echocardiography, and were followed for a combined outcome of all-cause mortality and first HF hospitalisation. RESULTS: Belgian patients with HFpEF were old (78 ± 8 years), predominantly females (62%) with multiple comorbidities. Ninety-five per cent were hypertensive, 38% diabetic and 69% overweight. History of atrial fibrillation was present in 63% of population, chronic kidney disease in 60% and anaemia in 58%. Over 30 ± 9 months, 55 (31%) patients died, 87 (49%) were hospitalised and 111 (63%) reached the combined outcome. In multivariate Cox analysis, low body mass index (BMI), NYHA class III and IV, diabetes, poor renal function and loop diuretic intake were independent predictors of the combined outcome (p < .05). BMI and renal function were also independent predictors of mortality, as were low haemoglobin, high E/e' and poor right ventricular function. CONCLUSION: Belgian patients with HFpEF are elderly patients with a high burden of comorbidities. Their prognosis is poor with high rates of hospitalisation and mortality. Although obesity is a risk factor for developing HFpEF, low BMI is the strongest independent predictor of mortality in those patients.

Test-retest reliability of left and right ventricular systolic function by new and conventional echocardiographic and cardiac magnetic resonance parameters.

AIMS: Reproducible evaluation of left (LV) and right ventricular (RV) function is crucial for clinical decision-making and risk stratification. We evaluated whether speckle-tracking echocardiography (STE) and cardiac magnetic resonance feature-tracking (cMR-FT) global longitudinal (GLS) and circumferential strains allow better test-retest reproducibility of LV and RV systolic function than conventional cMR and echocardiographic parameters. METHODS AND RESULTS: Thirty healthy volunteers and 20 chronic heart failure patients underwent cMR and STE twice on separate days to evaluate test-retest coefficient of variation (CV), intraclass correlation coefficient (ICC) and estimated sample sizes for significant changes in LV and RV function. Among LV parameters, cMR-left ventricular ejection fraction (LVEF) had the highest reproducibility (CV = 6.7%, ICC = 0.98), significantly better than cMR-FT-GLS (CV = 15.1%, ICC = 0.84), global circumferential strains (CV = 11.5%, ICC = 0.94) and echocardiographic LVEF (CV = 11.3%, ICC = 0.93). STE-LV-GLS (CV = 8.9%, ICC = 0.94) had significantly better reproducibility than cMR-FT-LV-GLS. Among RV parameters, STE-RV-GLS (CV = 7.3%, ICC = 0.93) had significantly better CV than cMR-right ventricular ejection fraction (RVEF) (CV = 13%, ICC = 0.82). cMR-FT-RV-GLS (CV = 43%, ICC = 0.39) performed poorly with significantly lower reproducibility than all other RV parameters. Owing to their superior interstudy reproducibility, cMR-LVEF (n = 12), cMR-RVEF (n = 41), STE-LV-GLS and STE-RV-GLS (both n = 14) were the parameters allowing the lowest calculated sample sizes to detect 10% change in LV or RV systolic function. CONCLUSION: STE-LV-GLS and STE-RV-GLS showed higher test-retest reliability than other echocardiographic measurements of LV and RV function. They also allowed smaller calculated sample sizes, supporting the use of STE-LV and RV-GLS for longitudinal follow-up of LV and RV function.

Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide.

Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but strategies using systemic antioxidants have generally failed to prevent it. We sought to identify key regulators of oxidant-mediated cardiac hypertrophy amenable to targeted pharmacological therapy. Specific isoforms of the aquaporin water channels have been implicated in oxidant sensing, but their role in heart muscle is unknown. RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalized with NADPH oxidase-2 and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2 Deletion of Aqp1 or selective blockade of the AQP1 intrasubunit pore inhibited H2O2 transport in mouse and human cells and rescued the myocyte hypertrophy in human induced pluripotent stem cell-derived engineered heart muscle. Treatment of mice with a clinically approved AQP1 inhibitor, Bacopaside, attenuated cardiac hypertrophy. We conclude that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 by the water channel AQP1 and that inhibitors of AQP1 represent new possibilities for treating hypertrophic cardiomyopathies.

Severe Aortic Stenosis and Chronic Kidney Disease: Outcomes and Impact of Aortic Valve Replacement.

Background The prognostic significance of chronic kidney disease (CKD) in severe aortic stenosis is poorly understood and no studies have yet evaluated the effect of aortic-valve replacement (AVR) versus conservative management on long-term mortality by stage of CKD. Methods and Results We included 4119 patients with severe aortic stenosis. The population was divided into 4 groups according to the baseline estimated glomerular filtration rate: no CKD, mild CKD, moderate CKD, and severe CKD. The 5-year survival rate was 71±1% for patients without CKD, 62±2% for those with mild CKD, 54±3% for those with moderate CKD, and 34±4% for those with severe CKD (P<0.001). By multivariable analysis, patients with moderate or severe CKD had a significantly higher risk of all-cause (hazard ratio [HR] [95% CI]=1.36 [1.08-1.71]; P=0.009 and HR [95% CI]=2.16 [1.67-2.79]; P<0.001, respectively) and cardiovascular mortality (HR [95% CI]=1.39 [1.03-1.88]; P=0.031 and HR [95% CI]=1.69 [1.18-2.41]; P=0.004, respectively) than patients without CKD. Despite more symptoms, AVR was less frequent in moderate (P=0.002) and severe CKD (P<0.001). AVR was associated with a marked reduction in all-cause and cardiovascular mortality versus conservative management for each CKD group (all P<0.001). The joint-test showed no interaction between AVR and CKD stages (P=0.676) indicating a nondifferentialeffect of AVR across stages of CKD. After propensity matching, AVR was still associated with substantially better survival for each CKD stage relative to conservative management (all P<0.0017). Conclusions In severe aortic stenosis, moderate and severe CKD are associated with increased mortality and decreased referral to AVR. AVR markedly reduces all-cause and cardiovascular mortality, regardless of the CKD stage. Therefore, CKD should not discourage physicians from considering AVR.