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Background Optimal timing for intervention remains uncertain in asymptomatic patients with primary mitral regurgitation (MR). We aimed to assess the prognostic value of a new cardiac damage staging classification in patients with asymptomatic moderate or severe primary MR. Methods Clinical, Doppler-echocardiographic, and outcome data prospectively collected in 338 asymptomatic patients (64 ± 15 years, 68% men) with at least moderate primary MR were retrospectively analyzed. Patients were hierarchically classified as per the following staging classification: no cardiac damage (stage 0), mild left ventricular or left atrial damage (stage 1), moderate or severe left ventricular or left atrial damage (stage 2), pulmonary vasculature or tricuspid valve damage (stage 3), or right ventricular damage (stage 4). Results There was a stepwise increase in 10-year mortality rates as per cardiac damage stage: 20.0% in stage 0, 25.6% in stage 1, 31.5% in stage 2, and 61.3% in stage 3-4 (p < 0.001). The staging classification was significantly associated with increased risk of mortality (hazard ratio = 1.41 per one-stage increase, 95% confidence interval: 1.07-1.85, p = 0.015) and the composite of cardiovascular mortality or hospitalization (hazard ratio = 1.51 per one-stage increase, 95% confidence interval: 1.07-2.15, p = 0.020) in multivariable analysis adjusted for EuroSCORE II, mitral valve intervention as a time-dependent variable, and other risk factors. The proposed scheme showed incremental value over several clinical variables (net reclassification index = 0.40, p = 0.03). Conclusions The new staging classification provides independent and incremental prognostic value in patients with asymptomatic moderate or severe MR.

The optimal timing for mitral valve (MV) surgery in asymptomatic patients with primary mitral regurgitation (MR) remains controversial. We aimed at evaluating the relation between left ventricular ejection time (LVET) and outcome in patients with moderate or severe chronic primary MR because of prolapse. Clinical, Doppler echocardiographic, and outcome data prospectively collected from 302 patients (median age 61 [54 to 74] years, 34% women) with moderate or severe primary MR were analyzed. Patients were retrospectively stratified by quartiles of LVET. The primary end point of the study was the composite of need for MV surgery or all-cause mortality. During a median follow-up time of 66 (25th to 75th percentile, 33 to 95) months, 178 patients reached the primary end point. Patients in the lowest quartile of LVET (<260 ms) were at high risk for adverse events compared with those in the other quartiles of LVET (global p = 0.005), whereas the rate of events was similar for the other quartiles (p = NS for all). After adjustment for clinical predictors of outcome, including age, gender, history of atrial fibrillation, MR severity, and current recommended triggers for MV surgery in asymptomatic primary MR, LVET <260 ms was associated with an increased risk of events (adjusted hazard ratio 1.49, 95% confidence interval 1.03 to 2.16, p = 0.033). In conclusion, we observed that shorter LVET is associated with increased risk of adverse events in patients with moderate or severe primary MR because of prolapse. Further studies are required to investigate whether shorter LVET has a direct effect on outcomes or is solely a risk marker in primary MR.

Background QT interval has been shown to be associated with cardiovascular events. There is no data regarding the association between QT interval and left ventricular (LV) function and prognosis in patients with low LV ejection fraction (LVEF), low‐flow, low‐gradient aortic stenosis (LF‐LG AS). We aimed to examine the relationship between corrected QT interval (QTc) and LV function and outcome in these patients. Methods and Results Ninety‐three patients (73±10 years; 74% men) with LF‐LG AS (mean gradient <40 mm Hg and indexed aortic valve area ≤0.6 cm2/m2) and reduced LVEF (≤40%) were prospectively included in this analysis and 63 of them underwent aortic valve replacement within 3 months following inclusion. Prolonged QTc was defined as QTc >450 ms in men and >470 ms in women. LV global longitudinal strain was measured by speckle tracking and expressed in absolute value |%|. QTc correlated with the following: global longitudinal strain (r=−0.40, P=0.005), LVEF (r=−0.27, P=0.02), stroke volume (r=−0.35, P=0.007), and B‐type natriuretic peptide (r=0.45, P=0.0006). During a median follow‐up of 2.0 years, 49 patients died. Prolonged QTc was associated with a 2‐fold increase in all‐cause mortality (hazard ratio=2.05; P=0.01) and cardiovascular mortality (hazard ratio=1.89; P=0.04). In multivariable analysis adjusted for EuroSCORE, aortic valve replacement, previous myocardial infarction, LVEF, and ß‐blocker medication, prolonged QTc was independently associated with all‐cause mortality (hazard ratio=2.56; P=0.008) and cardiovascular mortality (hazard ratio=2.50; P=0.02). Conclusions In patients with LF‐LG AS and reduced LVEF, longer QTc interval was associated with worse LV function and increased risk of death. Assessment of QTc may provide a simple and inexpensive tool to enhance risk stratification in LF‐LG AS patients.

Background: The timing of mitral valve surgery in asymptomatic patients with primary mitral regurgitation (MR) is controversial. We hypothesized that the forward left ventricular (LV) ejection fraction (LVEF; ie, LV outflow tract stroke volume divided by LV end‐diastolic volume) is superior to the total LVEF to predict outcomes in MR. The objective of this study was to examine the association between echocardiographic parameters of MR severity and LV function and outcomes in patients with MR. Methods and Results: The clinical and Doppler‐echocardiographic data of 278 patients with ≥mild MR and no class I indication of mitral valve surgery at baseline were retrospectively analyzed. The primary study end point was the composite of mitral valve surgery or death. During a mean follow‐up of 5.4±3.2 years, there were 147 (53%) events: 96 (35%) MV surgeries and 66 (24%) deaths. Total LVEF and global longitudinal strain were not associated with the occurrence of events, whereas forward LVEF (P<0.0001) and LV end‐systolic diameter (P=0.0003) were. After adjustment for age, sex, MR severity, Charlson probability, coronary artery disease, and atrial fibrillation, forward LVEF remained independently associated with the occurrence of events (adjusted hazard ratio: 1.09, [95% confidence interval]: 1.02–1.17 per 5% decrease; P=0.01), whereas LV end‐systolic diameter was not (P=0.48). Conclusions: The results of this study suggest that the forward LVEF may be superior to the total LVEF and LV end‐systolic diameter to predict outcomes in patients with primary MR. This simple and easily measurable parameter may be useful to improve risk stratification and select the best timing for intervention in patients with primary MR.

Background A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. Methods DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. Results p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. Conclusion This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.

Background : Although aortic valve replacement is associated with a major benefit in high-gradient (HG) severe aortic stenosis (AS), the results in low-gradient (LG, mean gradient <40 mm Hg) AS are conflicting. LG severe AS may be subdivided in classical low-flow (left ventricular ejection fraction <50%) and LG (CLF-LG); paradoxical low-flow (left ventricular ejection fraction ≥50% but stroke volume index <35 mL/m2) and LG; and normal-flow (left ventricular ejection fraction ≥50% and stroke volume index ≥35 mL/m2) and LG. The primary objective is to determine in the PARTNER 2 trial (The Placement of Aortic Transcatheter Valves) and registry the outcomes after aortic valve replacement of the 4 flow-gradient groups. Methods : A total of 3511 patients from the PARTNER 2 Cohort A randomized trial (n=1910) and SAPIEN 3 registry (n=1601) were included. The flow-gradient pattern was determined at baseline transthoracic echocardiography and classified as follows: (1) HG; (2) CLF-LG; (3) paradoxical low-flow-LG; and (4) normal-flow-LG. The primary end point for this analysis was the composite of (1) death; (2) rehospitalization for heart failure symptoms and valve prosthesis complication; or (3) stroke. Results : The distribution was HG, 2229 patients (63.5%); CLF-LG, 689 patients (19.6%); paradoxical low-flow-LG, 247 patients (7.0%); and normal-flow-LG, 346 patients (9.9%). The 2-year rate of primary end point was higher in CLF-LG (38.8%) versus HG: 31.8% (P=0.002) and normal-flow-LG: 32.1% (P=0.05) but was not statistically different from paradoxical low-flow-LG: 33.6% (P=0.18). There was no significant difference in the 2-year rates of clinical events between transcatheter aortic valve replacement versus surgical aortic valve replacement in the whole cohort and within each flow-gradient group. Conclusions : The LG AS pattern was highly prevalent (36.5%) in the PARTNER 2 trial and registry. CLF-LG was the most common pattern of LG AS and was associated with higher rates of

Paravalvular regurgitation is a frequent complication after transcatheter aortic valve replacement and its association with worse outcomes depends on the degree of its severity. Despite substantial improvement in transcatheter heart valve design, sizing and implantation technique, moderate or severe paravalvular regurgitation still occurs in 2% to 7% of patients and is associated with a more than 2-fold increase in mortality. This review provides a state-of-the-art approach to (i) paravalvular regurgitation prevention by optimizing patient selection, valve sizing, and positioning and (ii) the detection, quantitation and management of paravalvular regurgitation during and after valve implantation.

Background: The timing of mitral valve surgery in asymptomatic patients with primary mitral regurgitation (MR) is controversial. We hypothesized that the forward left ventricular (LV) ejection fraction (LVEF; ie, LV outflow tract stroke volume divided by LV end‐diastolic volume) is superior to the total LVEF to predict outcomes in MR. The objective of this study was to examine the association between echocardiographic parameters of MR severity and LV function and outcomes in patients with MR. Methods and Results: The clinical and Doppler‐echocardiographic data of 278 patients with ≥mild MR and no class I indication of mitral valve surgery at baseline were retrospectively analyzed. The primary study end point was the composite of mitral valve surgery or death. During a mean follow‐up of 5.4±3.2 years, there were 147 (53%) events: 96 (35%) MV surgeries and 66 (24%) deaths. Total LVEF and global longitudinal strain were not associated with the occurrence of events, whereas forward LVEF (P<0.0001) and LV end‐systolic diameter (P=0.0003) were. After adjustment for age, sex, MR severity, Charlson probability, coronary artery disease, and atrial fibrillation, forward LVEF remained independently associated with the occurrence of events (adjusted hazard ratio: 1.09, [95% confidence interval]: 1.02–1.17 per 5% decrease; P=0.01), whereas LV end‐systolic diameter was not (P=0.48). Conclusions: The results of this study suggest that the forward LVEF may be superior to the total LVEF and LV end‐systolic diameter to predict outcomes in patients with primary MR. This simple and easily measurable parameter may be useful to improve risk stratification and select the best timing for intervention in patients with primary MR.

Background: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. Methods: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. Results: p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. Conclusion: This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.

Background QT interval has been shown to be associated with cardiovascular events. There is no data regarding the association between QT interval and left ventricular (LV) function and prognosis in patients with low LV ejection fraction (LVEF), low‐flow, low‐gradient aortic stenosis (LF‐LG AS). We aimed to examine the relationship between corrected QT interval (QT c) and LV function and outcome in these patients. Methods and Results Ninety‐three patients (73±10 years; 74% men) with LF‐LG AS (mean gradient <40 mm Hg and indexed aortic valve area ≤0.6 cm2/m2) and reduced LVEF (≤40%) were prospectively included in this analysis and 63 of them underwent aortic valve replacement within 3 months following inclusion. Prolonged QT c was defined as QT c >450 ms in men and >470 ms in women. LV global longitudinal strain was measured by speckle tracking and expressed in absolute value |%|. QT c correlated with the following: global longitudinal strain (r=−0.40, P=0.005), LVEF (r=−0.27, P=0.02), stroke volume (r=−0.35, P=0.007), and B‐type natriuretic peptide (r=0.45, P=0.0006). During a median follow‐up of 2.0 years, 49 patients died. Prolonged QT c was associated with a 2‐fold increase in all‐cause mortality (hazard ratio=2.05; P=0.01) and cardiovascular mortality (hazard ratio=1.89; P=0.04). In multivariable analysis adjusted for EuroSCORE, aortic valve replacement, previous myocardial infarction, LVEF, and ß‐blocker medication, prolonged QT c was independently associated with all‐cause mortality (hazard ratio=2.56; P=0.008) and cardiovascular mortality (hazard ratio=2.50; P=0.02). Conclusions In patients with LF‐LG AS and reduced LVEF, longer QT c interval was associated with worse LV function and increased risk of death. Assessment of QT c may provide a simple and inexpensive tool to enhance risk stratification in LF‐LG AS patients.