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.

Mean platelet volume: a prognostic marker in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with high burden of comorbidities known to increase the mean platelet volume (MPV). This parameter has been associated with morbidity and mortality in HF. However, the role of platelets and the prognostic relevance of MPV in HFpEF remain largely unexplored. We aimed to evaluate the clinical usefulness of MPV as a prognostic marker in HFpEF. We prospectively enrolled 228 patients with HFpEF (79 ± 9 years; 66% females) and 38 controls of similar age and gender (78 ± 5 years; 63% females). All subjects underwent two-dimensional echocardiography and MPV measurements. Patients were followed-up for a primary end point of all-cause mortality or first HF hospitalization. The prognostic impact of MPV was determined using Cox proportional hazard models. Mean MPV was significantly higher in HFpEF patients compared with controls (MPV: 10.7 ± 1.1fL vs. 10.1 ± 1.1fL, p = .005). HFpEF patients (n = 56) with MPV >75th percentile (11.3 fL) displayed more commonly a history of ischemic cardiomyopathy. Over a median follow-up of 26 months, 136 HFpEF patients reached the composite endpoint. MPV >75th percentile was a significant predictor of the primary endpoint (HR: 1.70 [1.08; 2.67], p = .023) adjusted for NYHA class, chronic obstructive pulmonary disease, loop diuretics, renal function, and hemoglobin. We demonstrated that MPV was significantly higher in HFpEF patients compared with controls of similar age and gender. Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients and may be relevant for clinical use.

What is the context? Heart failure with preserved ejection fraction (HFpEF) is associated with several comorbidities known to increase the mean platelet volume (MPV).MPV is a measure of platelet size and a potential marker of platelet reactivity. An increased MPV results from an increased platelet turnover.MPV has been associated with morbidity and mortality from heart failure.No study has previously compared MPV between HFpEF and controls and investigated the prognostic relevance of MPV in HFpEF disease.What is new? In this study, we compared the MPV between HFpEF patients and controls of similar age and gender, prospectively enrolled between 2015 and 2021. We evaluated the prognostic role of elevated MPV in HFpEF patients.Our main results:The MPV was higher in HFpEF patients compared to controls of similar age and gender.HFpEF patients with elevated MPV displayed more commonly a history of ischemic cardiomyopathy.Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients.What is the impact? MPV may be relevant for clinical use to predict clinical outcome in HFpEF patients.Elevated MPV reflecting platelet activity supports the potential role of platelets in HFpEF's pathophysiology.

High-intensity aerobic interval training and resistance training are feasible in rectal cancer patients undergoing chemoradiotherapy: a feasibility randomized controlled study.

Background: There has been growing evidence of the benefits of high-intensity aerobic interval training (HIIT) and resistance training (RES) for populations with cancer. However, these two modalities have not yet been performed alone in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (NACR T). Therefore, this study aimed to determine the feasibility of HIIT and RES in rectal cancer patients undergoing NACR T. Materials and methods: Rectal cancer patients set to undergo NACRT were randomly assigned to HIIT intervention, RES intervention, or the usual care. Feasibility of HIIT and RES was assessed by measuring recruitment rate, adherence (retention rate, attendance rate, and exercise sessions duration and intensity), and adverse events. Endpoints (changes in fatigue, health-related quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity, and executive function) were assessed at baseline and at week 5. Results: Among the 20 eligible patients, 18 subjects were enrolled and completed the study, yielding a 90% recruitment rate and 100% retention rate. Attendance at exercise sessions was excellent, with 92% in HIIT and 88% in RES. No exercise-related adverse events occurred. Conclusion: This study demonstrated that HIIT and RES are feasible in rectal cancer patients undergoing NACR T. Trial registration: www.clinicaltrials.gov, NCT03252821 (date of registration: March 30, 2017).

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.

Pulmonary hypertension due to left heart disease: diagnostic and prognostic value of CT in chronic systolic heart failure.

OBJECTIVES: To evaluate the ability of chest computed tomography (CT) to predict pulmonary hypertension (PH) and outcome in chronic heart failure with reduced ejection fraction (HFrEF). METHODS: We reviewed 119 consecutive patients with HFrEF by CT, transthoracic echocardiography (TTE) and right heart catheterization (RHC). CT-derived pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio), left atrial, right atrial, right ventricular (RV) and left ventricular volumes were correlated with RHC mean pulmonary arterial pressure (mPAP) . Diagnostic accuracy to predict PH and ability to predict primary composite endpoint of all-cause mortality and HF events were evaluated. RESULTS: RV volume was significantly higher in 81 patients with PH compared to 38 patients without PH (133 ml/m2 vs. 79 ml/m2, p < 0.001) and was moderately correlated with mPAP (r=0.55, p < 0.001). Also, RV volume had higher ability to predict PH (area under the curve: 0.88) than PA diameter (0.79), PA:A ratio (0.76) by CT and tricuspid regurgitation gradient (0.83) and RV basal diameter by TTE (0.84, all p < 0.001). During the follow-up period (median: 3.4 years), 51 patients (43%) had HF events or died. After correction for important clinical, TTE and RHC parameters, RV volume (adjusted hazard ratio [HR]: 1.71, 95% CI 1.31-2.23, p < 0.001) and PA diameter (HR: 1.61, 95% CI 1.18-2.22, p = 0.003) were independent predictors of the primary endpoint. CONCLUSION: In patients with HFrEF, measurement of RV volume and PA diameter on ungated CT are non-invasive markers of PH and may help to predict the patient outcome. KEY POINTS: • Right ventricular (RV) volume measured by chest CT has good ability to identify pulmonary hypertension (PH) in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). • The accuracy of pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio) to predict PH was similar to previous studies, however, with lower cut-offs (28.1 mm and 0.92, respectively). • Chest CT-derived PA diameter and RV volume independently predict all-cause mortality and HF events and improve outcome prediction in patients with advanced HFrEF.

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.

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.

Impact of left ventricular outflow tract ellipticity on the grading of aortic stenosis in patients with normal ejection fraction.

BACKGROUND: The pathophysiology of paradoxical low-gradient (LG) severe aortic stenosis (SAS) remains controversial. As low transvalvular flow has been implicated, we sought to investigate the impact of left ventricular outflow tract (LVOT) ellipticity on the estimation of the LV stroke volume, the calculation of the aortic valve area (AVA) by use of the continuity equation and on AS severity grading. METHODS: We studied 190 consecutive patients (mean age: 72 ± 13 years; male: 57%) with SAS (indexed AVA < 0.6 cm2/m2) and preserved LV ejection fraction, including 120 patients with severe high gradient (HG) AS and 70 with severe paradoxical LG-AS. AS severity, LV volumes and LVOT ellipticity were assessed by 2D-Doppler echocardiography and cardiac magnetic resonance (CMR). RESULTS: The LVOT exhibited an elliptical shape on CMR images, with a shorter anterior-posterior than median-lateral diameter (2.2 ± 0.2 vs 2.8 ± 0.3 cm, p < 0.01). Accordingly, the LVOT area measured by planimetry was larger than by 2D-echocardiography, assuming a circular orifice (4.9 ± 0.9 cm2 vs 3.7 ± 0.8 cm2, p < 0.01). Inputting the elliptical LVOT area into the continuity equation resulted in a 29% increase in the indexed AVA (from 0.41 ± 0.09 cm2 to 0.54 ± 0.10 cm2). Accordingly, 30 (43%) patients with severe paradoxical LG-SAS were reclassified as having moderate AS. Similar results were obtained when considering 3D-echo for direct planimetry of the LVOT in a subset of 75 patients. CONCLUSIONS: Our results confirm that the LVOT is elliptical in shape and that taking this parameter into account in the calculation of the AVA results in reclassification of 43% of patients with severe paradoxical LG-AS into moderate AS.

Histological Validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T.

BACKGROUND: Gadolinium (Gd) Extracellular volume fraction (ECV) by Cardiovascular Magnetic Resonance (CMR) has been proposed as a non-invasive method for assessment of diffuse myocardial fibrosis. Yet only few studies used 3 T CMR to measure ECV, and the accuracy of ECV measurements at 3 T has not been established. Therefore the aims of the present study were to validate measurement of ECV by MOLLI T1 mapping by 3 T CMR against fibrosis measured by histopathology. We also evaluated the recently proposed hypothesis that native-T1 mapping without contrast injection would be sufficient to detect fibrosis. METHODS: 31 patients (age = 58 ± 17 years, 77% men) with either severe aortic stenosis (n = 12) severe aortic regurgitation (n = 9) or severe mitral regurgitation (n = 10), all free of coronary artery disease, underwent 3 T-CMR with late gadolinium enhancement (LGE) and pre- and post-contrast MOLLI T1 mapping and ECV computation, prior to valve surgery. LV biopsies were performed at the time of surgery, a median 13 [1-30] days later, and stained with picrosirius red. Pre-, and post-contrast T1 values, ECV, and amount of LGE were compared against magnitude of fibrosis by histopathology by Pearson correlation coefficients. RESULTS: The average amount of interstitial fibrosis by picrosirius red staining in biopsy samples was 6.1 ± 4.3%. ECV computed from pre-post contrast MOLLI T1 time changes was 28.9 ± 5.5%, and correlated (r = 0.78, p < 0.001) strongly with the magnitude of histological fibrosis. By opposition, neither amount of LGE (r = 0.17, p = 0.36) nor native pre-contrast myocardial T1 time (r = -0.18, p = 0.32) correlated with fibrosis by histopathology. CONCLUSIONS: ECV determined by 3 T CMR T1 MOLLI images closely correlates with histologically determined diffuse interstitial fibrosis, providing a non-invasive estimation for quantification of interstitial fibrosis in patients with valve diseases. By opposition, neither non-contrast T1 times nor the amount of LGE were indicative of the magnitude of diffuse interstitial fibrosis measured by histopathology.

Continuous or interrupted pledgeted suture technique in stented bioprosthetic aortic valve replacement: a comparison of in-hospital outcomes.

BACKGROUND: There is ambiguity in the literature regarding the continuous suture technique (CST) for aortic valve replacement (AVR). At our center, there has been a gradual shift towards CST over the interrupted pledgeted technique (IPT). This study aims at comparing outcomes for both techniques. METHODS: We performed a retrospective analysis of a single-center study of patients undergoing AVR between January 2011 and July 2020. Patients were divided into two groups: Continuous suture technique and interrupted pledget-reinforced sutures. The pre-operative and In-hospital clinical characteristics and echocardiographic hemodynamics (i.e. transvalvular gradients and paravalvular leakage) were compared between CST and IPT. RESULTS: We compared 791 patients with CST to 568 patients with IPT (median age: 73 and 74 years, respectively, p = 0.02). In CST there were 35% concomitant procedure vs. 31% in IPT (p = 0.16). Early mortality was 3.2% in CST versus 4.8% in IPT (p = 0.15), and a second cross-clamp due to a paravalvular-leak in 0.5% vs. 1.2%, respectively (p = 0.22). The CST was not associated with new-onset conduction-blocks mandating pacemaker implants(OR 1.07, 95% CI 0.54-2.14; P = 0.85). The postoperative gradients on echocardiography were lower in CST compared to IPT, especially in smaller annuli (peak gradients: 15.7mmHg vs. 20.5mmHg, in valve size < 23 mm, p < 0.001). CONCLUSIONS: The continuous suture technique was associated with lower postoperative gradients and shorter cross-clamp time compared to interrupted pledgeted technique. Differences in paravalvular leaks were non-significant, although slightly less in the continuous suture technique. There were no further differences in valve-related complications. Hence, continues suture technique is safe, with better hemodynamics compared to the interrupted pledgeted technique. This may be of clinical importance, especially in smaller size annular size.

Cardiac structure, function, and coronary anatomy 10 years after isolated contemporary adjuvant radiotherapy in breast cancer patients with low cardiovascular baseline risk.

AIMS: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function. METHODS AND RESULTS: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT. CONCLUSION: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients.

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.

Carbohydrate antigen 125: a useful marker of congestion, fibrosis, and prognosis in heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality, for which it is difficult to identify patients with the poorest prognosis in routine clinical practice. Carbohydrate antigen 125 (CA 125) has been shown to be a potential marker of congestion and prognosis in HF. We sought to better characterize HFpEF patients with high CA 125 levels by using a multimodal approach. METHODS AND RESULTS: We prospectively enrolled 139 HFpEF patients (78 ± 8 years; 60% females) and 25 controls matched for age and sex (77 ± 5 years; 60% females). They underwent two-dimensional echocardiography, cardiac magnetic resonance with late gadolinium enhancement [including extracellular volume (ECV) measurement], and serum measurements of CA 125 level. The primary endpoint of the study was a composite of all-cause mortality or first HF hospitalization. The prognostic impact of CA 125 was determined using Cox proportional hazard models. Median CA 125 levels were significantly higher in HFpEF patients compared with controls [CA 125: 23.5 (14.5-44.7) vs. 14.6 (10.3-21.0) U/mL, P = 0.004]. CA 125 levels were positively correlated with a congestion marker [N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, Pearson's r = 0.37, P < 0.001] and markers of cardiac fibrosis estimated by both ECV (Pearson's r = 0.26, P = 0.003) and fibroblast growth factor 23 levels (Pearson's r = 0.50, P < 0.001). Over a median follow-up of 49 (22-64) months, 97 HFpEF patients reached the composite endpoint. Even after adjustment for the Meta-Analysis Global Group in Chronic risk score, a CA 125 level ≥35 U/mL was still a significant predictor of the composite endpoint [hazard ratio (HR): 1.58 (1.04-2.41), P = 0.032] and more particularly of HF hospitalization [HR: 1.81 (1.13-2.92), P = 0.014]. In contrast, NT-proBNP levels were not an independent predictor. CONCLUSIONS: CA 125 levels were significantly higher in HFpEF patients compared with controls matched for age and sex and were associated with markers of congestion and cardiac fibrosis. CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients. These data suggest a potential value of CA 125 as a biomarker for staging and risk prediction in HFpEF.

Echocardiography of the aortic root: a practical approach for aortic valve-sparing surgery.

Owing to its excellent long-term results, aortic valve-sparing surgery is increasingly used in patients with aortic regurgitation and/or ascending aortic aneurysm. Moreover, in patients with a bicuspid valve who meet the criteria for replacement of the aortic sinuses or aortic regurgitation surgery, valve-sparing surgery may be considered if performed at a comprehensive valve center (Class 2b indication in both the American and European guidelines). Reconstructive valve surgery aims at restoring a normal aortic valve function and a normal aortic root shape as well. Echocardiography plays a central role in defining abnormal valve morphologies, in quantifying aortic regurgitation and mechanisms, and in appreciating tissue valve quality and surgical results. Therefore, despite the emergence of other tomographic techniques, 2D and 3D echocardiography represents the cornerstone for patient selection and prediction of the probability of a reliable repair. The present review focuses on echocardiographic evaluation to detect aortic valve and aortic root abnormalities, to quantify aortic valve regurgitation, to predict aortic valve reparability, and to assess immediate postoperative results in the operating room. Echocardiographic predictors of successful valve and root repair are presented in a practical way.

18F-Sodium Fluoride PET/CT in Assessing Valvular Heart and Atherosclerotic Diseases.

Aortic valve stenosis is the most common valvular disease in Western countries, while atherosclerotic cardiovascular disease is the foremost cause of death and disability worldwide. Valve degeneration and atherosclerosis are mediated by inflammation and calcification and inevitably progress over time. Computed tomography can visualise the later stages of macroscopic calcification but fails to assess the early stages of microcalcification and cannot differentiate active from burnt out disease states. Molecular imaging has the ability to provide complementary information related to disease activity, which may allow us to detect disease early, to predict disease progression and to monitor preventive or therapeutic strategies for in both aortic stenosis and atherosclerosis. PET/CT is a non-invasive imaging technique that enables visualization of ongoing molecular processes within small structures, such as the coronary arteries or heart valves. 18F-sodium fluoride (18F-NaF) binds hydroxyapatite deposits in the extracellular matrix, with preferential binding to newly developing deposits of microcalcification, which provides an assessment of calcification activity. In recent years, 18F-NaF has attracted the attention of many research groups and has been evaluated in several pathological cardiovascular processes. Histologic validation of the 18F-NaF PET signal in valvular disease and atherosclerosis has been reported in multiple independent studies. The selective high-affinity binding of 18F-NaF to microscopic calcified deposits (beyond the resolution of µCT) has been demonstrated ex vivo, as well as its ability to distinguish between areas of macro- and active microcalcification. In addition, prospective clinical studies have shown that baseline 18F-NaF uptake in patients with aortic stenosis and mitral annular calcification is correlated with subsequent calcium deposition and valvular dysfunction after a follow-up period of 2 years. In patients with surgical bioprosthetic aortic valves but without morphological criteria for prosthetic degeneration, increased 18F-NaF uptake at baseline was associated with subsequent bioprosthetic degeneration over time. Similar data were obtained in a cohort of patients with transcatheter aortic valve implantation. Furthermore, several studies have confirmed the association of coronary 18F-NaF uptake with adverse atherosclerotic plaque features, active disease and future disease progression. 18F-NaF uptake is also associated with future fatal or nonfatal myocardial infarction in patients with established coronary artery disease. The link between 18F-NaF uptake and active atherosclerotic disease has not only been demonstrated in the coronary arteries, but also in peripheral arterial disease, abdominal aortic aneurysms and carotid atherosclerosis. It can be assumed that 18F-NaF PET/CT will strengthen the diagnostic toolbox of practitioners in the coming years. Indeed, there is a strong medical need to diagnose degenerative valvular disease and to detect active atherosclerotic disease states. Finally, the use of 18F-NaF as a biomarker to monitor the efficacy of drug therapies in preventing these pathological processes is attractive. In this review, we consider the role of 18F-NaF PET/CT imaging in cardiac valvular diseases and atherosclerosis.

Late results of aortic valve repair for isolated severe aortic regurgitation.

OBJECTIVES: The objectives were to analyze the long-term outcomes of tricuspid aortic valve repair for isolated severe aortic regurgitation and the impact of different annuloplasty techniques. METHODS: The study cohort consists of 127 consecutive patients who received aortic valve repair for isolated severe aortic regurgitation in the tricuspid aortic valve between 1996 and 2019 in our institution. Exclusion criteria were aorta dilatation (≥45 mm), connective tissue disease, active endocarditis, type A dissection, and rheumatic disease. Mean age of patients was 55.6 ± 16 years, and 80% were male. Median follow-up was 6.4 years. Time-to-event analysis was performed, as well as risk of death, reoperation, and aortic regurgitation recurrence. RESULTS: Cusp repair was performed in 117 patients (92%), and annuloplasty was performed in 126 patients (99%) with Cabrol stitch (73%), reimplantation technique (19.7%), or ring annuloplasty (6.3%). There was no hospital mortality. At 10 and 14 years, overall survival was 81% ± 5% and 71% ± 6%, respectively, and freedom from reoperation was 80% ± 5% and 73% ± 6%, respectively. Age and left coronary cusp repair were independent predictors of reoperation. Freedom from recurrent severe aortic regurgitation (>2+) was 73% ± 5% and 66% ± 7% at 10 and 12 years, respectively. Age, left ventricular end-diastolic diameter, and patch repair were independent predictors of recurrent aortic regurgitation. Type of annuloplasty had no impact on survival or reoperation. CONCLUSIONS: Aortic valve repair for isolated severe aortic regurgitation in the tricuspid aortic valve is a safe procedure, and durability at 14 years is acceptable. In this study, the annuloplasty technique did not influence repair durability as was found in bicuspid aortic valve repair or aortic valve-sparing surgery. Severity of cusp pathology seems to be the main determinant of repair durability.

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.

Quantification of primary mitral regurgitation by echocardiography: A practical appraisal.

The accurate quantification of primary mitral regurgitation (MR) and its consequences on cardiac remodeling is of paramount importance to determine the best timing for surgery in these patients. The recommended echocardiographic grading of primary MR severity relies on an integrated multiparametric approach. It is expected that the large number of echocardiographic parameters collected would offer the possibility to check the measured values regarding their congruence in order to conclude reliably on MR severity. However, the use of multiple parameters to grade MR can result in potential discrepancies between one or more of them. Importantly, many factors beyond MR severity impact the values obtained for these parameters including technical settings, anatomic and hemodynamic considerations, patient's characteristics and echocardiographer' skills. Hence, clinicians involved in valvular diseases should be well aware of the respective strengths and pitfalls of each of MR grading methods by echocardiography. Recent literature highlighted the need for a reappraisal of the severity of primary MR from a hemodynamic perspective. The estimation of MR regurgitation fraction by indirect quantitative methods, whenever possible, should be central when grading the severity of these patients. The assessment of the MR effective regurgitant orifice area by the proximal flow convergence method should be used in a semi-quantitative manner. Furthermore, it is crucial to acknowledge specific clinical situations in MR at risk of misevaluation when grading severity such as late-systolic MR, bi-leaflet prolapse with multiple jets or extensive leak, wall-constrained eccentric jet or in older patients with complex MR mechanism. Finally, it is debatable whether the 4-grades classification of MR severity would be still relevant nowadays, since the indication for mitral valve (MV) surgery is discussed in clinical practice for patients with 3+ and 4+ primary MR based on symptoms, specific markers of adverse outcome and MV repair probability. Primary MR grading should be seen as a continuum integrating both quantification of MR and its consequences, even for patients with presumed "moderate" MR.

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.

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.