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.

Is "moderate" aortic stenosis still the right name? A review of the literature.

Current guidelines recommend aortic valve replacement for symptomatic or selected asymptomatic high-risk patients with severe aortic stenosis. Conversely, a watchful waiting attitude applies to patients with moderate aortic stenosis, regardless of their risk profile and symptoms, until the echocardiographic thresholds of severe aortic stenosis are reached. This strategy is based on data reporting high mortality in untreated severe symptomatic aortic stenosis, whereas moderate aortic stenosis has always been perceived as a non-threatening condition, with a benefit-risk balance against surgery. Meanwhile, numerous studies have reported a worrying event rate in these patients, surgical techniques and outcomes have improved significantly and the use of transcatheter aortic valve replacement has become more widespread and extended to lower-risk patients, leaving this strategy open to question, especially for patients with moderate aortic stenosis and left ventricular dysfunction. In this review, we summarize the current state of knowledge about moderate aortic stenosis progression and prognosis. We also discuss the particular case of moderate aortic stenosis associated with left ventricular dysfunction, and the ongoing trials that that might change our paradigm for the management of this "moderate" valvular heart disease.

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.

Factors influencing post-surgical survival in degenerative mitral regurgitation.

AIMS: Indications for surgery in patients with degenerative mitral regurgitation (DMR) are increasingly liberal in all clinical guidelines but the role of secondary outcome determinants (left atrial volume index ≥60 mL/m2, atrial fibrillation, pulmonary artery systolic pressure ≥50 mmHg and moderate to severe tricuspid regurgitation) and their impact on post-operative outcome remain disputed. Whether these secondary outcome markers are just reflective of the DMR severity or intrinsically affect survival after DMR surgery is uncertain and may have critical importance in the management of patients with DMR. To address these gaps of knowledge the present study gathered a large cohort of patients with quantified DMR, accounted for the number of secondary outcome markers and examined their independent impact on survival after surgical correction of the DMR. METHODS AND RESULTS: The Mitral Regurgitation International DAtabase-Quantitative registry includes patients with isolated DMR from centres across North America, Europe, and the Middle East. Patient enrolment extended from January 2003 to January 2020. All patients undergoing mitral valve surgery within 1 year of registry enrolment were selected. A total of 2276 patients [65 (55-73) years, 32% male] across five centres met study eligibility criteria. Over a median follow-up of 5.6 (3.6 to 8.7) years, 278 patients (12.2%) died. In a comprehensive multivariable Cox regression model adjusted for age, EuroSCORE II, symptoms, left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LV ESD) and DMR severity, the number of secondary outcome determinants was independently associated with post-operative all-cause mortality, with adjusted hazard ratios of 1.56 [95% confidence interval (CI): 1.11-2.20, P = 0.011], 1.78 (95% CI: 1.23-2.58, P = 0.002) and 2.58 (95% CI: 1.73-3.83, P < 0.0001) for patients with one, two, and three or four secondary outcome determinants, respectively. A model incorporating the number of secondary outcome determinants demonstrated a higher C-index and was significantly more concordant with post-operative mortality than models incorporating traditional Class I indications alone [the presence of symptoms (P = 0.0003), or LVEF ≤60% (P = 0.006), or LV ESD ≥40 mm (P = 0.014)], while there was no significant difference in concordance observed compared with a model that incorporated the number of Class I indications for surgery combined (P = 0.71). CONCLUSION: In this large cohort of patients treated surgically for DMR, the presence and number of secondary outcome determinants was independently associated with post-surgical survival and demonstrated better outcome discrimination than traditional Class I indications for surgery. Randomised controlled trials are needed to determine if patients with severe DMR who demonstrate a cardiac phenotype with an increasing number of secondary outcome determinants would benefit from earlier surgery.

Atrial fibrillation in severe aortic stenosis: Prognostic value and results of aortic valve replacement.

OBJECTIVES: Although atrial fibrillation (AF) is common, its impact on long-term mortality has not been reliably determined in patients with aortic stenosis (AS). We aimed to assess whether AF is associated with survival in patients with severe AS and to determine the impact of AF on the results of aortic valve replacement (AVR). METHODS: The study included 1838 consecutive patients with severe AS (77 ± 11 years, male 47%). Upon AS diagnosis, patients were screened for AF using a 12-lead electrocardiogram. The treatment strategy (conservative management or AVR) was selected by the heart team in accordance with current guidelines. The effect of AVR on survival was analyzed as a time-dependent covariate using the entire follow-up period. RESULTS: AF, diagnosed in 593 (32%) patients was associated with poor survival at 5 years (55 ± 2% vs 74 ± 1% for patients in sinus rhythm, P < .001), even after adjustment for established outcome predictors (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.33-1.84; P < .001). In patients with AF, AVR was associated with lower mortality (HR, 0.16; 95% CI, 0.12-0.22; P < .001) even in those with no or minimal symptoms (HR, 0.12; 95% CI, 0.08-0.20; P < .001). However, among patients who underwent AVR, those in AF had an excess mortality (HR, 1.59; 95% CI, 1.22-2.08; P < .001). CONCLUSIONS: In severe AS, AF is a strong predictor of mortality even in asymptomatic or minimally symptomatic patients. After AVR, AF remains associated with poorer survival than sinus rhythm. In patients in AF, AVR is associated with lower mortality compared with conservative treatment. Further studies are needed to confirm the benefits of AVR in asymptomatic patients in AF with severe AS.

The MIDA-Q Mortality Risk Score: A Quantitative Prognostic Tool for the Mitral Valve Prolapse Spectrum.

BACKGROUND: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. METHODS: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. RESULTS: MVP was associated with DMR absent/mild (ERO <20 mm2) in 50%, moderate (ERO 20-40 mm2) in 25%, and severe or higher (ERO ≥40 mm2) in 25%, with mean ERO 24±24 mm2, regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%-90% range, 0-9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%-90% range, 4-11 versus 0-7) and mediocre correlation (R2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29-1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11-1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02-1.14]) or ≥1% (hazard ratio, 1.11 [1.08-1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10-1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10-1.16], all per 1-point increment with P<0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P<0.0001). CONCLUSIONS: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

Unsupervised clustering of patients with severe aortic stenosis: A myocardial continuum.

BACKGROUND: Traditional statistics, based on prediction models with a limited number of prespecified variables, are probably not adequate to provide an appropriate classification of a condition that is as heterogeneous as aortic stenosis (AS). AIMS: To investigate a new classification system for severe AS using phenomapping. METHODS: Consecutive patients from a referral centre (training cohort) who met the echocardiographic definition of an aortic valve area (AVA) ≤ 1 cm2 were included. Clinical, laboratory and imaging continuous variables were entered into an agglomerative hierarchical clustering model to separate patients into phenogroups. Individuals from an external validation cohort were then assigned to these original clusters using the K nearest neighbour (KNN) function and their 5-year survival was compared after adjustment for aortic valve replacement (AVR) as a time-dependent covariable. RESULTS: In total, 613 patients were initially recruited, with a mean±standard deviation AVA of 0.72±0.17 cm2. Twenty-six variables were entered into the model to generate a specific heatmap. Penalized model-based clustering identified four phenogroups (A, B, C and D), of which phenogroups B and D tended to include smaller, older women and larger, older men, respectively. The application of supervised algorithms to the validation cohort (n=1303) yielded the same clusters, showing incremental cardiac remodelling from phenogroup A to phenogroup D. According to this myocardial continuum, there was a stepwise increase in overall mortality (adjusted hazard ratio for phenogroup D vs A 2.18, 95% confidence interval 1.46-3.26; P<0.001). CONCLUSIONS: Artificial intelligence re-emphasizes the significance of cardiac remodelling in the prognosis of patients with severe AS and highlights AS not only as an isolated valvular condition, but also a global disease.

Implementation of a CT-derived correction factor to refine the measurement of aortic valve area and stroke volume using Doppler echocardiography improves grading of severity and prediction of prognosis in patients with severe aortic stenosis.

AIMS: To assess rates of reclassification of severity and associated 5-year survival in patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) after application of a CT-derived correction factor (CF) to refine the measurement of aortic valve area (AVA) and stroke volume index (SVi) using Doppler echocardiography. METHODS AND RESULTS: We enrolled 1450 patients with severe AS and preserved LVEF from a French registry. Multiplication of echocardiographic LV outflow tract diameter by a CT-derived CF of 1.13 to calculate the AVA and SVi using the continuity equation resulted in reclassification of 39% of patients from severe to moderate AS (AVA > 1 cm2) and 77% from low flow (LF, SVi < 35 ml/m2) to normal flow (NF, SVi ≥ 35 ml/m2). After application of the CF, 5-year survival with conservative management was 50 ± 4% for severe AS compared to 62 ± 4% for moderate AS (p < 0.001). A strategy of medical management followed by intervention for severe AS was associated with higher risk of mortality over 5-year follow-up after adjustment for covariates and application of the CF (HR 1.35 [1.10-1.55], p = 0.015). Five-year survival was also poorer in patients remaining in the LF group after application of the CF, even after valve intervention (72%, 66% and 47% for NF to NF, LF to NF and LF to LF, respectively). After adjustment for covariates (including intervention), risk of mortality was higher in LF to LF patients compared to NF to NF (HR 1.78 [1.25-2.56]), but similar for NF to NF and LF to NF (HR 1.20 [0.90-1.60]). CONCLUSION: Refined accuracy of echocardiographic LV outflow tract diameter measurement using a CF of 1.13 before derivation of AVA and SVi in patients with severe AS and preserved LVEF allows improved grading of severity, and prediction of prognosis. We recommend implementation of the CF during routine echocardiography when using the continuity equation for Doppler haemodynamic measurements.

Resting Left Ventricular Global Longitudinal Strain to Identify Silent Myocardial Ischemia in Asymptomatic Patients with Diabetes Mellitus.

BACKGROUND: Screening for silent coronary artery disease in asymptomatic patients with diabetes mellitus (DM) is challenging and controversial. In this context, it seems crucial to identify early markers of coronary artery disease. METHODS: The aim of this study was to investigate the incremental value of resting left ventricular (LV) global longitudinal strain (GLS) for the prediction of positive results on stress (exercise or dobutamine) transthoracic echocardiography in 273 consecutive asymptomatic high-risk patients with DM. Positive results on stress transthoracic echocardiography were defined as stress-induced LV wall motion abnormalities (new or worsening preexisting abnormalities). RESULTS: Compared with patients with negative stress results, those with positive stress results (n = 28 [10%]) more frequently had cardiovascular risk factors, complications of DM, vascular disease, moderate and severe calcification of the aortic valve and mitral annulus, and worse resting LV GLS (-16.7 ± 2.9% vs -19.0 ± 1.9%, P < .001). On multivariable logistic regression analysis, DM duration > 10 years, diabetic retinopathy, LV hypertrophy, and impaired LV GLS (odds ratio, 1.39 [95% CI, 1.14-1.70] per percentage increase; odds ratio, 5.16 [95% CI, 1.96-13.59] for LV GLS worse than -18%) were independently associated with positive results on stress transthoracic echocardiography. The area under the curve to predict positive results was 0.74 for LV GLS with a cutoff of -18.0% (sensitivity 68%, specificity 78%). The area under the curve of the multivariable model to predict test results was improved by the addition of LV GLS (P < .001), with a bias-corrected area under the curve after bootstrapping of 0.842 [95% CI, 0.753-0.893]. CONCLUSIONS: The present findings show that resting LV GLS is associated with the presence of silent ischemia and could be useful to better identify asymptomatic patients with DM who might benefit from coronary artery disease screening.

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.

Clinical Outcomes of Adults With Bicuspid Aortic Valve: A European Perspective.

OBJECTIVE: To describe the clinical history of patients with a wide age range diagnosed with bicuspid aortic valve (BAV) and no surgical indication and to evaluate the long-term outcome of patients with BAV referred for elective surgery. PATIENTS AND METHODS: Between 2005 and 2017, 350 consecutive patients with no surgical indication (surveillance group, mean age 53±16, 71% men) and 191 with a surgical indication (surgical group, mean age 59±13, 71% men) were prospectively included. Median follow-up was 80 (32 to 115) months. RESULTS: In the surveillance group, the 5-year and 10-year survival rates were 93±1% and 89±2%, respectively, with a relative survival of patients with BAV compared with an age- and sex-matched control population of 98.7%. During follow-up, the cumulative 10-year incidence of aortic valve and aorta surgery was high; of 35±4%, the incidence of native valve infective endocarditis (IE) of 0.2% per patient-year, and no cases of aortic dissection were observed. In the surgical group, the 5-year and 10-year survival rates were 97±1% and 89±3%, respectively, with a relative survival of 99.4% compared with the general population. The incidence of IE was 0.4% per patient-year, and no cases of aortic dissection were observed. CONCLUSION: This regional cohort shows that the 10-year survival rates of patients with BAV and a wide age range, but mostly middle-aged adults, were similar to those of the general population with a very low rate of complications. Adherence to prophylactic surgical indications and younger age might have contributed to this lack of difference.

Excess Mortality and Undertreatment of Women With Severe Aortic Stenosis.

Background Although women represent half of the population burden of aortic stenosis (AS), little is known whether sex affects the presentation, management, and outcome of patients with AS. Methods and Results In a cohort of 2429 patients with severe AS (49.5% women) we aimed to evaluate 5-year excess mortality and performance of aortic valve replacement (AVR) stratified by sex. At presentation, women were older (P<0.001), with less comorbidities (P=0.030) and more often symptomatic (P=0.007) than men. Women had smaller aortic valve area (P<0.001) than men but similar mean transaortic pressure gradient (P=0.18). The 5-year survival was lower compared with expected survival, especially for women (62±2% versus 71% for women and 69±1% versus 71% for men). Despite longer life expectancy in women than men, women had lower 5-year survival than men (66±2% [expected-75%] versus 68±2% [expected-70%], P<0.001) after matching for age. Overall, 5-year AVR incidence was 79±2% for men versus 70±2% for women (P<0.001) with male sex being independently associated with more frequent early AVR performance (odds ratio, 1.49; 1.18-1.97). After age matching, women remained more often symptomatic (P=0.004) but also displayed lower AVR use (64.4% versus 69.1%; P=0.018). Conclusions Women with severe AS are diagnosed at later ages and have more symptoms than men. Despite prevalent symptoms, AVR is less often performed in women and 5-year excess mortality is noted in women versus men, even after age matching. These imbalances should be addressed to ensure that both sexes receive equivalent care for severe AS.

Characteristics and Prognosis of Patients With Left-Sided Native Bivalvular Infective Endocarditis.

BACKGROUND: Most cases of left-sided native valve infective endocarditis (IE) involve a single valve and little is known concerning IE that simultaneously affects the aortic and mitral valves. METHODS: We aimed to determine the characteristics, identify the prognostic factors, and define the effect of early surgery for patients with left-sided native bivalvular IE. This analysis included 1340 consecutive patients who presented with definite acute left-sided native valve IE in a 2-centre cohort study. RESULTS: A bivalvular involvement was present in 257 patients (19%). Patients with bivalvular IE had more embolic events (P = 0.044), congestive heart failure (P = 0.016), vegetations, and perivalvular complications (both P < 0.001) than those with monovalvular IE. Early surgery was more frequent for patients with bivalvular IE (P < 0.001). Thirty-day mortality was higher for patients with bivalvular IE than for those with monovalvular IE (24.5% vs 17.6%; P = 0.008), even after adjustment (odds ratio, 1.86 [95% confidence interval, 1.26-2.73]; P < 0.001). Estimated 10-year survival was 70% ± 1% for monovalvular IE and 59% ± 3% for bivalvular IE (P = 0.002). Bivalvular IE was still associated with mortality in multivariable Cox analysis, after adjustment for covariates including age, neurological events, congestive heart failure, Staphylococcus spp infection, perivalvular complications, and early surgery (hazard ratio, 1.70 [95% confidence interval, 1.31-2.11]; P < 0.001). Early surgery was associated with increased survival for patients with bivalvular IE (79% ± 4% vs 35% ± 6%; P < 0.001). CONCLUSIONS: Bivalvular involvement is frequent in left-sided native valve IE, is associated with more embolic events and congestive heart failure than monovalvular IE, and patients are at a high risk of death. Early surgery is associated with improved survival and should be systematically discussed in the absence of contraindication.