A nanobody against the VWF A3 domain detects ADAMTS13-induced proteolysis in congenital and acquired VWD.

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A-group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high-molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.

Subclinical valve leaflet thrombosis following bioprosthetic aortic valve replacement.

PURPOSE OF REVIEW: Subclinical leaflet thrombosis (SLT) is often an incidental finding characterized by a thin layer of thrombus involving one, two or three leaflets, with typical appearance on multi-detector computed tomography (MDCT) of hypo-attenuating defect at the aortic side of the leaflet, also called hypo-attenuating leaflet thickening (HALT). SLT may occur following both transcatheter aortic replacement (TAVR) or biological surgical aortic valve replacement (SAVR). The aim of this review is to present an overview of the current state of knowledge on the incidence, diagnosis, clinical impact, and management of SLT following TAVR or SAVR. RECENT FINDINGS: SLT occurs in 10-20% of patients following TAVR and is somewhat more frequent than following SAVR (5-15%). SLT may regress spontaneously without treatment in about 50% of the cases but may also progress to clinically significant valve thrombosis in some cases. Oral anticoagulation with vitamin K antagonist is reasonable if SLT is detected by echocardiography and/or MDCT during follow-up and is generally efficient to reverse SLT. SLT is associated with mild increase in the risk of stroke but has no impact on survival. SLT has been linked with accelerated structural valve deterioration and may thus impact valve durability and long-term outcomes. SUMMARY: SLT is often an incidental finding on echocardiography or MDCT that occurs in 10-20% of patients following TAVR or 5-15% following biological SAVR and is associated with a mild increase in the risk of thrombo-embolic event with no significant impact on mortality but may be associated with reduced valve durability.

Computed tomography-derived membranous septum length as predictor of conduction abnormalities and permanent pacemaker implantation after TAVI: A meta-analysis of observational studies.

BACKGROUND: Permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) is associated with higher risk of mortality and rehospitalization for heart failure. Efforts to prevent conduction abnormalities (CA) requiring PPI after TAVI should be made. The membranous septum (MS) length and its interaction with implantation depth (ID-ΔMSID) could provide useful information about the risk of CA/PPI following TAVI. OBJECTIVES: To identify MS length and ΔMSID as predictors of CA/PPI following TAVI. METHODS: Study-level meta-analysis of studies published by September 30, 2022. RESULTS: Eighteen studies met our eligibility including 5740 patients. Shorter MS length was associated with a significantly higher risk of CA/PPI (per 1 mm decrease: odds ratio [OR] 1.60, 95% confidence interval [CI] 1.28-1.99, p < 0.001). Similarly, lower ΔMSID was associated with a significantly higher risk of CA/PPI (per 1 mm decrease: OR 1.75, 95% CI 1.32-2.31, p < 0.001). Meta-regression analyses revealed a statistically significant modulation of the effect of shorter MS length and lower ΔMSID on the outcome (CA/PPI) by balloon postdilatation (positive regression coefficients with p < 0.001); with increasing use of balloon postdilatation, the effect of shorter MS length and lower ΔMSID on the outcome increased. MS length and ΔMSID demonstrated excellent discriminative abilities, with diagnostic ORs equaling 9.49 (95% CI 4.73-19.06), and 7.19 (95% CI 3.31-15.60), respectively. CONCLUSION: Considering that short MS length and low ΔMSID are associated with higher risk of CA and PPI, we should include measurement of MS length in the pre-TAVI planning with MDCT and try to establish optimal ID values before the procedure to avoid CA/PPI.

Calcium Scoring to Classify Aortic Valve Stenosis Severity: What Is the Current Data?

PURPOSE OF REVIEW: This review explores current clinical value of aortic valve calcification (AVC) in classifying aortic valve stenosis (AS) severity, refining patient's follow-up, as well as novel and potential applications of this highly accurate marker in improving outcomes for AS patients. AVC limitations and important particularities regarding sex, valve phenotype, and ethnicity will also be addressed. RECENT FINDINGS: Sex-specific AVC cut-offs have been included in current guidelines to identify severe AS when echocardiography is inconclusive. AVC is also associated with AS progression and could help refine the timing for patient's follow-up. In patients with AS, Doppler echocardiography is the gold standard for the assessment of AS severity. However, in more than one-third of patients, echocardiographic parameters are discordant, casting shadow on the true severity of the disease. Considering active leaflet calcification is the driving mechanism of AS, quantification of AVC has been shown to be of great interest for distinguishing true-severe from pseudo-severe AS. Moreover, AVC is closely associated with AS progression and outcomes.

Aortic Valvular Stenosis and Heart Failure: Advances in Diagnostic, Management, and Intervention.

Up to 30% of patients with aortic stenosis (AS) present with heart failure (HF) symptoms with either reduced or preserved left ventricular ejection fraction. Many of these patients present with a low-flow state, reduced aortic-valve-area (≤1.0 cm2) with low aortic-mean-gradient and aortic-peak-velocity (<40 mm Hg and <4.0 m/s). Thus, determination of true severity is essential for correct management, and multi-imaging evaluation must be performed. Medical treatment of HF is imperative and should be optimized concurrently with the determination of AS-severity. Finally, AS should be treated according to guidelines, keeping in mind that HF and low-flow increase interventions risks.

Hemodynamic changes during aortic valve surgery among patients with aortic stenosis.

Introduction. Patients with severe aortic stenosis (AS) undergoing surgery are at increased risk of hypotension and hypoperfusion. Although treatable with inotropic agents or fluid, little is known about how these therapies affect central hemodynamics in AS patients under general anesthesia. We measured changes in central hemodynamics after dobutamine infusion and fluid bolus among patients with severe AS and associated these changes with preoperative echocardiography. Methods. We included 33 patients with severe AS undergoing surgical AVR. After induction of general anesthesia, hemodynamic measurements were obtained with a pulmonary artery catheter, including Cardiac index (CI), stroke volume index (SVi) and pulmonary capillary wedge pressure (PCWP). Measurements were repeated during dobutamine infusion, after fluid bolus and lastly after sternotomy. Results. General anesthesia resulted in a decrease in CI and SVi compared to preoperative values. During dobutamine infusion CI increased but mean SVi did not (38 ± 12 vs 37 ± 13 ml/m2, p = .90). Higher EF and SVi before surgery and a larger decrease in SVi after induction of general anesthesia were associated with an increase in SVi during dobutamine infusion. After fluid bolus both CI, SVi (48 ± 12 vs 37 ± 13 ml/min/m2, p < .0001) and PCWP increased. PCWP increased mostly among patients with a larger LA volume index. Conclusion. In patients with AS, CI can be increased with both dobutamine and fluid during surgery. Dobutamine's effect on SVI was highly variable and associated with baseline LVEF, and an increase in CI was mostly driven by an increase in heart rate. Fluid increased SVi at the cost of an increase in PCWP.

Stress exercise haemodynamic performance and opening reserve of a stented bovine pericardial aortic valve bioprosthesis.

OBJECTIVES: Despite unusual high rates of patient-prosthesis mismatch (PPM), excellent midterm clinical outcomes have been reported after surgical aortic valve replacement (SAVR) with the Avalus™ bioprosthetic valve (Medtronic). To elucidate this "PPM conundrum," the Avalus valve haemodynamics were assessed during exercise testing. METHODS: Of the 148 patients who had undergone SAVR with the Avalus valve at our institution, 30 were randomly selected among those in whom stress test was deemed feasible and underwent a resting transthoracic echocardiography immediately followed by exercise echocardiography. Severe PPM was defined as indexed effective orifice area (iEOA) ≤ 0.65 cm2 /m2 and moderate PPM as iEOA > 0.65 and ≤ 0.85 cm2 /m2 . Measured PPM was determined with the use of the measured iEOA at rest or stress, while the estimated PPM was based on the estimated iEOA, derived from the mean EOA reported for each valve size in the manufacturer chart. RESULTS: Measured EOA significantly increased from rest to peak exercise in all PPM groups (p < .05) and the rates of moderate and severe measured PPM decreased from 40% and 20% to 27% and 0%, respectively. The patients with low-flow state (flow < 250 ml/s) had significantly lower measured rest EOA (p = .03). On the basis of the estimated iEOA, there was no severe PPM and 19 patients had moderate PPM (63.3%), with a significantly lower opening reserve than the patients without estimated PPM (p = .04). The estimated iEOA was more reliably correlated to the measured iEOA at maximal stress than the measured iEOA at rest, especially in patients with a low-flow state. CONCLUSIONS: This study supports the concept of an opening reserve of the Avalus valve to explain the PPM conundrum and promotes the use of exercise Doppler-echocardiography to complete the assessment of mismatch, especially in patients with a low-flow state. Published estimated EOA seems reliable to predict the haemodynamic performance of the Avalus valve, whether the flow conditions at rest.

Impact of sex on the management and outcome of aortic stenosis patients.

OBJECTIVE: The aim of this study was to assess the impact of sex on the management and outcome of patients according to aortic stenosis (AS) severity. INTRODUCTION: Sex differences in the management and outcome of AS are poorly understood. METHODS: Doppler echocardiography data of patients with at least mild-to-moderate AS [aortic valve area (AVA) ≤1.5 cm2 and peak jet velocity (VPeak) ≥2.5 m/s or mean gradient (MG) ≥25 mmHg] were prospectively collected between 2005 and 2015 and retrospectively analysed. Patients with reduced left ventricular ejection fraction (<50%), or mitral or aortic regurgitation >mild were excluded. RESULTS: Among 3632 patients, 42% were women. The mean indexed AVA (0.48 ± 0.17 cm2/m2), VPeak (3.74 ± 0.88 m/s), and MG (35.1 ± 18.2 mmHg) did not differ between sexes (all P ≥ 0.18). Women were older (72.9 ± 13.0 vs. 70.1 ± 11.8 years) and had more hypertension (75% vs. 70%; P = 0.0005) and less coronary artery disease (38% vs. 55%, P < 0.0001) compared to men. After inverse-propensity weighting (IPW), female sex was associated with higher mortality (IPW-HR: 1.91 [1.14-3.22]; P = 0.01) and less referral to valve intervention (competitive model IPW-HR: 0.88 [0.82-0.96]; P = 0.007) in the whole cohort. This excess mortality in women was blunted in concordant non-severe AS initially treated conservatively (IPW-HR = 1.03 [0.63-1.68]; P = 0.88) or in concordant severe AS initially treated by valve intervention (IPW-HR = 1.25 [0.71-2.21]; P = 0.43). Interestingly, the excess mortality in women was observed in discordant low-gradient AS patients (IPW-HR = 2.17 [1.19-3.95]; P = 0.01) where women were less referred to valve intervention (IPW-Sub-HR: 0.83 [0.73-0.95]; P = 0.009). CONCLUSION: In this large series of patients, despite similar baseline hemodynamic AS severity, women were less referred to AVR and had higher mortality. This seemed mostly to occur in the patient subset with discordant markers of AS severity (i.e. low-gradient AS) where women were less referred to AVR.

Preclinical study of 212Pb alpha-radioimmunotherapy targeting CD20 in non-Hodgkin lymphoma.

BACKGROUND: Despite therapeutic advances, Non-Hodgkin lymphoma (NHL) relapses can occur. The development of radioimmunotherapy (RIT) with α-emitters is an attractive alternative. In this study, we investigated the potential of α-RIT in conjunction with 212Pb-rituximab for the treatment of NHL. METHODS: EL4-hCD20-Luc cells (mouse lymphoma cell line) were used for in vitro and in vivo studies. Biodistribution and efficacy studies were performed on C57BL/6 mice injected intravenously with 25 × 103 cells. RESULTS: 212Pb-rituximab (0.925-7.4 kBq/mL) inhibit proliferation of EL4-hCD20-Luc cells in vitro. Biodistribution of 203/212Pb-rituximab in mice showed a significant tumour uptake and suggested that the liver, spleen, and kidneys were the organs at risk. For efficacy studies, mice were treated at either 11 days (early stage) or 20-30 days after injection of tumour cells (late stage). Treatment with 277.5 kBq 212Pb-rituximab significantly prolonged survival. Even at an advanced tumour stage, significant tumour regression occurred, with an increase in the median survival time to 28 days, compared with 9 days in the controls. CONCLUSIONS: These results show the efficacy of 212Pb-rituximab in a murine syngeneic lymphoma model, in terms of significant tumour regression and increased survival, thereby highlighting the potency of α-RIT for the treatment of NHL.

Accuracy of stroke volume measurement with phase-contrast cardiovascular magnetic resonance in patients with aortic stenosis.

BACKGROUND: Phase contrast (PC) cardiovascular magnetic resonance (CMR) in the ascending aorta (AAo) is widely used to calculate left ventricular (LV) stroke volume (SV). The accuracy of PC CMR may be altered by turbulent flow. Measurement of SV at another site is suggested in the presence of aortic stenosis, but very few data validates the accuracy or inaccuracy of PC in that setting. Our objective is to compare flow measurements obtained in the AAo and LV outflow tract (LVOT) in patients with aortic stenosis. METHODS: Retrospective analysis of patients with aortic stenosis who had CMR and echocardiography. Patients with mitral regurgitation were excluded. PC in the AAo and LVOT were acquired to derive SV. LV SV from end-systolic and end-diastolic tracings was used as the reference measure. A difference ≥ 10% between the volumetric method and PC derived SVs was considered discordant. Metrics of turbulence and jet eccentricity were assessed to explore the predictors of discordant measurements. RESULTS: We included 88 patients, 41% with bicuspid aortic valve. LVOT SV was concordant with the volumetric method in 79 (90%) patients vs 52 (59%) patients for AAo SV (p = 0.015). In multivariate analysis, aortic stenosis flow jet angle was a strong predictor of discordant measurement in the AAo (p = 0.003). Mathematical correction for the jet angle improved the concordance from 59 to 91%. Concordance was comparable in patients with bicuspid and trileaflet valves (57% and 62% concordance respectively; p = 0.11). Accuracy of SV measured in the LVOT was not influenced by jet eccentricity. For aortic regurgitation quantification, PC in the AAo had better correlation to volumetric assessments than LVOT PC. CONCLUSION: LVOT PC SV in patients with aortic stenosis and eccentric jet might be more accurate compared to the AAo SV. Mathematical correction for the jet angle in the AAo might be another alternative to improve accuracy.

Low and elevated B-type natriuretic peptide levels are associated with increased mortality in patients with preserved ejection fraction undergoing transcatheter aortic valve replacement: an analysis of the PARTNER II trial and registry.

AIMS: B-type natriuretic peptide (BNP) is a cardiac neurohormone that is secreted in response to ventricular volume expansion and pressure overload. There are conflicting data regarding the association between BNP levels and outcomes after transcatheter aortic valve replacement (TAVR). We therefore sought to assess the association between baseline BNP and adverse outcomes in patients with symptomatic, severe aortic stenosis (AS), and left ventricular ejection fraction (LVEF) ≥50%, undergoing TAVR in the PARTNER 2 Trial and Registry. METHODS AND RESULTS: A total of 1782 patients were included in the analysis, and BNP was evaluated both as a continuous log-transformed value and by a priori categories: low (<50 pg/mL), normal (≥50 and <100 pg/mL), moderately elevated (≥100 and <400 pg/mL), or markedly elevated (≥400 pg/mL). Clinical outcomes from discharge to 2 years were compared between patients according to their baseline BNP level, using Kaplan-Meier event rates and multivariable Cox proportional hazards regression models. After adjustment, spline curves revealed a non-linear association between log-transformed BNP and all-cause and cardiovascular mortality in which both the lowest and highest values were associated with increased mortality. Two-year all-cause mortality rates for those with low (n = 86), normal (n = 202), moderately elevated (n = 885), and markedly elevated (n = 609) baseline BNP were 20.0%, 9.8%, 17.7%, and 26.1%, respectively. In adjusted models, compared to a normal baseline BNP, low [adjusted hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.3-5.0, P-value 0.005], moderately elevated (adjusted HR 1.6, 95% CI 1.0-2.6, P-value 0.06), and markedly elevated (adjusted HR 2.1, 95% CI 1.3-3.5, P-value 0.003) BNP were associated with increased all-cause mortality, driven by cardiovascular mortality. CONCLUSIONS: In a large cohort of patients with severe symptomatic AS and preserved LVEF undergoing TAVR, all-cause and cardiovascular mortality rates at 2 years were higher in patients with low and markedly elevated BNP levels. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ unique identifier #NCT01314313, #NCT02184442, #NCT03222128, and #NCT03222141.

Airway smooth muscle adapting in dynamic conditions is refractory to the bronchodilator effect of a deep inspiration.

Airway smooth muscle (ASM) is continuously strained during breathing at tidal volume. Whether this tidal strain influences the magnitude of the bronchodilator response to a deep inspiration (DI) is not clearly defined. The present in vitro study examines the effect of tidal strain on the bronchodilator effect of DIs. ASM strips from sheep tracheas were mounted in organ baths and then subjected to stretches (30% strain), simulating DIs at varying time intervals. In between simulated DIs, the strips were either held at a fixed length (isometric) or oscillated continuously by 6% (length oscillations) to simulate tidal strain. The contractile state of the strips was also controlled by adding either methacholine or isoproterenol to activate or relax ASM, respectively. Although the time-dependent gain in force caused by methacholine was attenuated by length oscillations, part of the acquired force in the oscillating condition was preserved postsimulated DIs, which was not the case in the isometric condition. Consequently, the bronchodilator effect of simulated DIs (i.e., the decline in force postsimulated versus presimulated DIs) was attenuated in oscillating versus isometric conditions. These findings suggest that an ASM operating in a dynamic environment acquired adaptations that make it refractory to the decline in contractility inflicted by a larger strain simulating a DI.

Calcific Aortic Valve Stenosis and Atherosclerotic Calcification.

PURPOSE OF REVIEW: This review summarizes the pathophysiology of calcific aortic valve stenosis (CAVS) and surveys relevant clinical data and basic research that explain how CAVS arises. RECENT FINDINGS: Lipoprotein(a) [Lp(a)], lipoprotein-associated phospholipase A2 (Lp-PLA2), oxidized phospholipids (OxPL), autotaxin, and genetic driving forces such as mutations in LPA gene and NOTCH gene seem to play a major role in the development of CAVS. These factors might well become targets of medical therapy in the coming years. CVAS seems to be a multifactorial disease that has much in common with coronary artery disease, mainly regarding lipidic accumulation and calcium deposition. No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering and anti-calcific therapies confer a benefit in terms of reducing incidence or progression of CAVS, although additional outcome trials are ongoing.

Rate, Timing, Correlates, and Outcomes of Hemodynamic Valve Deterioration After Bioprosthetic Surgical Aortic Valve Replacement.

BACKGROUND: The incidence of structural valve deterioration after bioprosthesis (BP) aortic valve replacement (AVR) established on the basis of reoperation may substantially underestimate the true incidence. The objective is to determine the rate, timing, correlates, and association between hemodynamic valve deterioration (HVD) and outcomes assessed by Doppler echocardiography after surgical BP AVR. METHODS: A total of 1387 patients (62.2% male, 70.5±7.8 years of age) who underwent BP AVR were included in this retrospective study. Baseline echocardiography was performed at a median time of 4.1 (1.3-6.5) months after AVR. All patients had an echocardiographic follow-up ≥2 years after AVR (926 at least 5 years and 385 at least 10 years). HVD was defined by Doppler assessment as a ≥10 mm Hg increase in mean gradient or worsening of transprosthetic regurgitation ≥1/3 class. HVD was classified according to the timing after AVR: "very early," during the first 2-years; "early," between 2 and 5 years; "midterm," between 5 and 10 years; and "long-term," >10 years. RESULTS: A total of 428 patients (30.9%) developed HVD. Among these patients, 52 (12.0%) were classified as "very early," 129 (30.1%) as "early," 158 (36.9%) as "midterm," and 89 (20.8%) as "long-term" HVD. Factors independently associated with HVD occurring within the first 5 years after AVR were diabetes mellitus ( P=0.01), active smoking ( P=0.01), renal insufficiency ( P=0.01), baseline postoperative mean gradient ≥15 mm Hg ( P=0.04) or transprosthetic regurgitation ≥mild ( P=0.04), and type of BP (stented versus stentless, P=0.003). Factors associated with HVD occurring after the fifth year after AVR were female sex ( P=0.03), warfarin use ( P=0.007), and BP type ( P<0.001). HVD was independently associated with mortality (hazard ratio, 2.18; 95% CI, 1.86-2.57; P<0.001). CONCLUSIONS: HVD as identified by Doppler echocardiography occurred in one third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes mellitus and renal insufficiency were associated with early HVD, whereas female sex, warfarin use, and stented BPs (versus stentless) were associated with late HVD.

Outcome and undertreatment of mitral regurgitation: a community cohort study.

BACKGROUND: Mitral regurgitation is the most common valve disease worldwide but whether the community-wide prevalence, poor patient outcomes, and low rates of surgical treatment justify costly development of new therapeutic interventions remains uncertain. Therefore, we did an observational cohort study to assess the clinical characteristics, outcomes, and degree of undertreatment of mitral regurgitation in a community setting. METHODS: We used data from Mayo Clinic electronic health records and the Rochester Epidemiology Project to identify all cases of moderate or severe isolated single-valvular mitral regurgitation (with no other severe left-sided valvular disease or previous mitral surgery) diagnosed during a 10-year period in the community setting in Olmsted County (MN, USA). We assessed clinical characteristics, mortality, heart failure incidence, and results of cardiac surgery post-diagnosis. FINDINGS: Between Jan 1, 2000, and Dec 31, 2010, 1294 community residents (median age at diagnosis 77 years [IQR 66-84]) were diagnosed with moderate or severe mitral regurgitation by Doppler echocardiography (prevalence 0·46% [95% CI 0·42-0·49] overall; 0·59% [0·54-0·64] in adults). Left-ventricular ejection fraction below 50% was frequent (recorded in 538 [42%] patients), and these patients had a slightly lower regurgitant volume than those with an ejection fraction of 50% or higher (mean 39 mL [SD 16] vs 45 mL [21], p<0·0001). Post-diagnosis mortality was mainly cardiovascular in nature (in 420 [51%] of 824 patients for whom the cause of death was available) and higher than expected for residents of the county for age or sex (risk ratio [RR] 2·23 [95% CI 2·06-2·41], p<0·0001). This excess mortality affected all subsets of patients, whether they had a left-ventricular ejection fraction lower than 50% (RR 3·17 [95% CI 2·84-3·53], p<0·0001) or of 50% or higher (1·71 [1·53 -1·91], p<0·0001) and with primary mitral regurgitation (RR 1·73 [95% CI 1·53-1·96], p<0·0001) or secondary mitral regurgitation (2·72 [2·48-3·01], p<0·0001). Even patients with a low comorbidity burden combined with favourable characteristics such as left-ventricular ejection fraction of 50% or higher (RR 1·28 [95% CI 1·10-1·50], p<0·0017) or primary mitral regurgitation (1·29 [1·09-1·52], p=0·0030) incurred excess mortality. Heart failure was frequent (mean 64% [SE 1] at 5 years postdiagnosis), even in patients with left-ventricular ejection fraction of 50% or higher (49% [2] at 5 years postdiagnosis) or in those with primary mitral regurgitation (48% [2]). Mitral surgery was ultimately done in only 198 (15%) of 1294 patients, of which the predominant type of surgery was valve repair (in 149 [75%] patients). Mitral surgery was done in 28 (5%) of 538 patients with left-ventricular ejection fraction below 50% and in 170 (22%) of 756 patients with ejection fraction of 50% or higher, and in 34 (5%) of 723 with secondary mitral regurgitation versus 164 (29%) of 571 with primary regurgitation. All other types of cardiac surgery combined were performed in only 3% more patients (237 [18%] patients) than the number who underwent mitral surgery. INTERPRETATION: In the community, isolated mitral regurgitation is common and is associated with excess mortality and frequent heart failure postdiagnosis in all patient subsets, even in those with normal left-ventricular ejection fraction and low comorbidity. Despite these poor outcomes, only a minority of affected patients undergo mitral (or any type of cardiac) surgery even in a community with all means of diagnosis and treatment readily available and accessible. This suggests that in a wider population there might be a substantial unmet need for treatment for this disorder. FUNDING: Mayo Clinic Foundation.

Biomarkers of aortic bioprosthetic valve structural degeneration.

PURPOSE OF REVIEW: Bioprosthetic valves are now used for the majority of surgical aortic valve replacements and for all transcatheter aortic valve replacements. However, bioprostheses are subject to structural valve deterioration (SVD) and have, therefore limited durability. RECENT FINDINGS: Clinical, imaging, and circulating biomarkers may help to predict or indicate the presence of bioprosthetic valve SVD. The most important biomarkers of SVD includes: patient-related clinical biomarkers, such as diabetes and renal failure; valve-related biomarkers, such as absence of antimineralization process and severe prosthesis-patient mismatch; imaging biomarkers: the presence of valve leaflet mineralization on multidetector computed tomography or sodium fluoride uptake on positron emission tomography; and circulating biomarkers including: increased levels of HOMA index, ApoB/ApoA-I ratio, PCSK9, Lp-PLA2, phosphocalcic product. The assessment of these biomarkers may help to enhance risk stratification for SVD following AVR and may contribute to open novel pharmacotherapeutic avenues for the prevention of SVD. SUMMARY: SVD may affect all bioprostheses after aortic valve replacement, and is the main cause of bioprosthetic valve failure and reintervention during the follow-up. Comprehensive assessment of clinical, imaging, and circulating biomarkers associated with earlier SVD could help strengthen the follow-up in high-risk patients and provide novel pharmacologic therapeutic strategies.

Sex-Related Discordance Between Aortic Valve Calcification and Hemodynamic Severity of Aortic Stenosis: Is Valvular Fibrosis the Explanation?

RATIONALE: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification loads than men for the same AS hemodynamic severity. OBJECTIVE: We, thus, aimed to assess sex differences in aortic valve fibrocalcific remodeling. METHODS AND RESULTS: One hundred and twenty-five patients underwent Doppler echocardiography and multidetector computed tomography within 3 months before aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed, and fibrosis degree was determined. Sixty-four men and 39 women were frequency matched for age, body mass index, hypertension, renal disease, diabetes mellitus, and AS severity. Mean age (75±9 years), mean gradient (41±18 mm Hg), and indexed aortic valve area (0.41±0.12 cm2/m2) were similar between men and women (all P≥0.18). Median aortic valve calcification (1973 [1124-3490] Agatston units) and mean valve weight (2.36±0.99 g) were lower in women compared with men (both P<0.0001). Aortic valve calcification density correlated better with valve weight in men (r2=0.57; P<0.0001) than in women (r2=0.26; P=0.0008). After adjustment for age, body mass index, aortic valve calcification density, and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (P=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (P=0.01), and Masson trichrome staining revealed a greater proportion of dense connective tissue (P=0.02) in women compared with men. CONCLUSIONS: In this series of patients with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared with men. These findings suggest that the pathophysiology of AS and thus potential targets for drug development may be different according to sex.

The MIDA Mortality Risk Score: development and external validation of a prognostic model for early and late death in degenerative mitral regurgitation.

Aims: In degenerative mitral regurgitation (DMR), lack of mortality scores predicting death favours misperception of individual patients' risk and inappropriate decision-making. Methods and results: The Mitral Regurgitation International Database (MIDA) registries include 3666 patients (age 66 ± 14 years; 70% males; follow-up 7.8 ± 5.0 years) with pure, isolated, DMR consecutively diagnosed by echocardiography at tertiary (European/North/South-American) centres. The MIDA Score was derived from the MIDA-Flail-Registry (2472 patients with DMR and flail leaflet-Derivation Cohort) by weighting all guideline-provided prognostic markers, and externally validated in the MIDA-BNP-Registry (1194 patients with DMR and flail leaflet/prolapse-Validation Cohort). The MIDA Score ranged from 0 to 12 depending on accumulating risk factors. In predicting total mortality post-diagnosis, the MIDA Score showed excellent concordance both in Derivation Cohort (c = 0.78) and Validation Cohort (c = 0.81). In the whole MIDA population (n = 3666 patients), 1-year mortality with Scores 0, 7-8, and 11-12 was 0.4, 17, and 48% under medical management and 1, 7, and 14% after surgery, respectively (P < 0.001). Five-year survival with Scores 0, 7-8, and 11-12 was 98 ± 1, 57 ± 4, and 21 ± 10% under medical management and 99 ± 1, 82 ± 2, and 57 ± 9% after surgery (P < 0.001). In models including all guideline-provided prognostic markers and the EuroScoreII, the MIDA Score provided incremental prognostic information (P ≤ 0.002). Conclusion: The MIDA Score may represent an innovative tool for DMR management, being able to position a given patient within a continuous spectrum of short- and long-term mortality risk, either under medical or surgical management. This innovative prognostic indicator may provide a specific framework for future clinical trials aiming to compare new technologies for DMR treatment in homogeneous risk categories of patients.

Twenty-Year Outcome After Mitral Repair Versus Replacement for Severe Degenerative Mitral Regurgitation: Analysis of a Large, Prospective, Multicenter, International Registry.

BACKGROUND: Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation. However, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative mitral regurgitation with a flail leaflet. METHODS: MIDA (Mitral Regurgitation International Database) is a multicenter registry enrolling patients with degenerative mitral regurgitation with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1709) and replacement (n=213) overall, by propensity score matching, and by inverse probability-of-treatment weighting. RESULTS: At baseline, patients undergoing MV repair were younger, had more comorbidities, and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching and inverse probability-of-treatment weighting, the 2 treatments groups were balanced, and absolute standardized differences were usually <10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement in both the entire population (1.3% versus 4.7%; P<0.001) and the propensity-matched population (0.2% versus 4.4%; P<0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement in both the entire population (46% versus 23%; P<0.001) and the matched population (41% versus 24%; P<0.001). Similar superiority of MV repair was obtained in patient subsets on the basis of age, sex, or any stratification criteria (all P<0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications. CONCLUSIONS: Among patients with degenerative mitral regurgitation with a flail leaflet referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival, and fewer valve-related complications compared with MV replacement.

Blood, tissue and imaging biomarkers in calcific aortic valve stenosis: past, present and future.

PURPOSE OF REVIEW: Calcific aortic valve stenosis is the most prevalent valvular heart disease in the high-income countries. To this date, no medical therapy has been proven to prevent or to stop the progression of aortic valve stenosis. The physiopathology of aortic valve stenosis is highly complex and involves several signalling pathways, as well as genetic related factors, which delay the elaboration of effective pharmacotherapies. Moreover, it is difficult to predict accurately the progression of the valve stenosis and finding the optimal timing for aortic valve replacement remains challenging. Therefore, the present review makes an inventory of the most recent and promising circulating and imaging biomarkers related to the underlying mechanisms involved in the physiopathology of aortic valve stenosis, as well as the biomarkers associated with the left ventricular (LV) remodelling and subsequent dysfunction in patients with aortic valve stenosis. RECENT FINDINGS: Over the last decade, several blood, tissue and imaging biomarkers have been investigated in aortic valve stenosis patients. At the aortic valve level, these biomarkers are mostly associated and/or involved with processes such as lipid infiltration and oxidation, chronic inflammation and fibrocalcific remodelling of the valve. Moreover, recent findings suggest that aging and sex hormones might interact with these multiple processes. Several studies demonstrated the usefulness of circulating biomarkers such as lipoprotein(a), brain natriuretic peptides and high-sensitivity cardiac troponin, which are very close to clinical routine. Furthermore, noninvasive imaging biomarkers including positron emission tomography and cardiac magnetic resonance, which provide a detailed view of the disease activity within the aortic valve and its repercussion on the left ventricle, may help to improve the understanding of aortic valve stenosis physiopathology and enhance the risk stratification. Other biomarkers such as von Willebrand factor and microRNAs are promising but further studies are needed to prove their additive value in aortic valve stenosis. SUMMARY: Most of the biomarkers are used in research and thus, are still being investigated. However, some biomarkers including plasma level of lipoprotein(a), F-sodium fluoride, brain natriuretic peptides and high-sensitivity cardiac troponin can be or are very close to be used for the clinical management of patients with aortic valve stenosis. Moreover, a multibiomarker approach might provide a more global view of the disease activity and improve the management strategies of these patients.