2023 Korean Society of Echocardiography position paper for the diagnosis and management of valvular heart disease, part II: mitral and tricuspid valve disease.

This manuscript represents the official position of the Korean Society of Echocardiography on valvular heart diseases. This position paper focuses on the diagnosis and management of valvular heart diseases with referring to the guidelines recently published by the American College of Cardiology/American Heart Association and the European Society of Cardiology. The committee sought to reflect national data on the topic of valvular heart diseases published to date through a systematic literature search based on validity and relevance. In the part II of this article, we intend to present recommendations for diagnosis and treatment of mitral valve disease and tricuspid valve disease.

Use of Direct-Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Significant Tricuspid Regurgitation.

BACKGROUND: There are limited data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation with significant tricuspid regurgitation (TR), which can lead to hepatic dysfunction and intestinal malabsorption. We aimed to compare the efficacy and safety of DOACs and warfarin for patients with atrial fibrillation with significant (moderate to severe) TR. METHODS AND RESULTS: A total of 1215 patients with significant TR and atrial fibrillation who were treated with warfarin (N=491) or DOACs (N=724) were retrospectively analyzed. The primary outcomes were ischemic stroke, systemic embolic events, and hospitalization for major bleeding. The secondary outcomes were intracranial hemorrhage, hospitalization for gastrointestinal bleeding, all-cause mortality, and a composite outcome. The median follow-up duration was 2.4 years. In the inverse probability treatment weighting-adjusted cohort, DOACs and warfarin had a similar risk for ischemic stroke and systemic embolic events (adjusted hazard ratio [aHR], 0.95 [95% CI, 0.67-1.36]; P=0.79) and major bleeding (aHR, 0.78 [95% CI, 0.57-1.06]; P=0.11). For the secondary outcomes, relative to warfarin, DOACs had a lower risk of intracranial hemorrhage and the composite outcome, and a comparable risk for gastrointestinal bleeding and all-cause mortality. In the subgroup analysis, the effects of DOACs on ischemic stroke and systemic embolic events were comparable to the effects of warfarin, even in patients with inferior vena cava plethora (increased right atrial pressure) or severe TR. CONCLUSIONS: In this study, relative to warfarin, DOACs demonstrated comparable efficacy for ischemic stroke and systemic embolic events and major bleeding, with a lower intracranial hemorrhage risk in patients with significant TR and atrial fibrillation, indicating their effectiveness and safety.

Hydrogen sulfide inhibits gene expression associated with aortic valve degeneration by inducing NRF2-related pro-autophagy effect in human aortic valve interstitial cells.

Aortic valve stenosis (AS) is the most common valvular heart disease but there are currently no effective medical treatments that can delay disease progression due to a lack of knowledge of the precise pathophysiology. The expression of sulfide: quinone oxidoreductase (SQOR) and nuclear factor erythroid 2-related factor 2 (NRF2) was decreased in the aortic valve of AS patients. However, the role of SQOR and NRF2 in the pathophysiology of AS has not been found. We investigated the effects of hydrogen sulfide (H2S)-releasing compounds on diseased aortic valve interstitial cells (AVICs) to explain the cellular mechanism of SQOR and elucidate the medical value of H2S for AS treatment. Sodium hydrosulfide (NaHS) treatment increased the expression of SQOR and NRF2 gene and consequently induced the NRF2 target genes, such as NAD(P)H quinone dehydrogenase 1 and cystathionine γ-lyase. In addition, NaHS dose-dependently decreased the expression level of fibrosis and inflammation-related genes (MMP9, TNF-α, IL6) and calcification-related genes (ALP, osteocalcin, RUNX2, COL1A1) in human AVICs. Furthermore, NaHS activated the AMPK-mTOR pathway and inhibited the PI3K-AKT pathway, resulting in a pro-autophagy effect in human AVICs. An NRF2 inhibitor, brusatol, attenuated NaHS-induced AMPK activation and decreased the autophagy markers Beclin-1 and LC3AB, suggesting that the mechanism of action of H2S is related to NRF2. In conclusion, H2S decreased gene expression levels related to aortic valve degeneration and activated AMPK-mTOR-mediated pro-autophagy function associated with NRF2 in human AVICs. Therefore, H2S could be a potential therapeutic target for the development of AS treatment.

Impact of routine brain imaging on the prognosis of patients with left-sided valve infective endocarditis without neurological manifestations.

BACKGROUND: There are limited data on the impact of routine use of brain magnetic resonance imaging (MRI) on the prognosis of neurologically asymptomatic patients with left-sided infective endocarditis (IE). METHODS: Among patients diagnosed with possible or definite IE in two tertiary referral centers between January 2005 and March 2019, we identified 527 left-sided IE patients without neurological symptoms or signs at the time of diagnosis. Patients who underwent brain MRI within 1 week after the IE diagnosis were classified as the routine brain imaging group (n = 216), and the rest were categorized as the control group (n = 311). All-cause mortality at 3 months, attributable mortality (defined as death directly related to IE), and fatal neurological events compared after adjustment using inverse probability of treatment weighting (IPTW). RESULTS: During a median follow-up of 57 months, the routine brain imaging group had a similar risk of 3-month all-cause mortality to the control group in the multivariate analysis (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.24-1.14) and IPTW-adjusted cohort (HR, 0.59; 95% CI, 0.25-1.42). The risks of attributable mortality and fatal neurological events were also similar between the two groups in the multivariable analysis and IPTW-adjusted cohort. In the subgroup analysis, the routine brain imaging group showed more favorable outcomes in cases of large vegetation (> 10 mm) or acute-onset microorganisms. CONCLUSIONS: Routine use of brain MRI in left-sided IE patients without neurological manifestations is not associated with improved clinical outcomes. However, routine brain imaging in appropriate clinical settings could improve clinical outcomes.

Association of citrullination with the progression of aortic stenosis.

Despite its clinical importance, biomarkers of disease activity in aortic stenosis (AS) are lacking. We investigated the association between anti-cyclic citrullinated peptide (CCP) antibodies and AS. All 678 patients who underwent echocardiography and anti-CCP antibody testing were analysed. Anti-CCP antibody status was categorized as negative, low-positive, and high-positive. In addition, aortic valve (AV) tissues were obtained from the patients with and without AS to analyze the presence of citrullinated proteins. At baseline, 241 (35.5%) subjects with AV degeneration had a higher rate of anti-CCP antibody positivity (42.7% versus 34.6%, p = 0.035) than those without AV degeneration. Out of the 331 (48.8%) subjects who underwent echocardiographic follow-up, progression of AS was observed in 34 (10.3%) patients, with a higher incidence in the high-positive group compared to the low-positive or negative group (19.0% vs. 11.3% vs. 8.4%, respectively; p = 0.041). On multivariable analysis, high anti-CCP antibody positivity was independently associated with progression to AS (odds ratio: 2.312; 95% confidence interval: 1.006-5.310; p = 0.048). Furthermore, immunohistochemistry and Western blotting revealed increased citrullination in diseased AV compared to normal AV tissue. This study demonstrated that a high positive anti-CCP antibody result is associated with AV degeneration and may be an independent factor for AS progression.

Effect of race on pressure recovery adjustment for prevention of aortic stenosis grading discordance.

OBJECTIVE: We sought to evaluate the potential impact of racial difference (Asians vs Caucasians) on the clinical usefulness of pressure recovery (PR) adjustment for preventing discordant aortic stenosis (AS) grading in patients with severe AS. METHODS: Data from 1450 patients (mean age, 70.2±10.6 years; 290 (20%) Caucasians; aortic valve area (AVA), 0.77±0.26 cm2) were retrospectively analysed. PR-adjusted AVA was calculated using a validated equation. Discordant grading of severe AS was defined as AVA of <1.0 cm2 and mean gradient of <40 mm Hg. The frequency of discordant grading was assessed in the overall cohort and the propensity score-matched cohort. RESULTS: Before PR adjustment, 1186 patients showed AVA values of <1.0 cm2; after PR adjustment, 170 (14.3%) were reclassified as having moderate AS. PR adjustment decreased the frequency of discordant grading from 31.4% to 14.1% in Caucasians and from 13.8% to 7.9% in Asians. Patients with reclassification to moderate AS after PR adjustment had a significantly lower risk of a composite of aortic valve replacement or all-cause death than did those with severe AS after PR adjustment (HR 0.38; 95% CI 0.31-0.46; p<0.001). In propensity score-matched cohorts (173 pairs), the frequency of discordant grading before PR adjustment was 42.2% and 43.9% in the Caucasian and Asian patients, respectively, which decreased to 21.4% and 20.2%, respectively, after PR adjustment. CONCLUSIONS: Clinically relevant PR occurred, regardless of race in patients with moderate to severe AS. Routine PR adjustment may be useful for reconciling discordant AS grading.

Data-driven mortality risk prediction of severe degenerative mitral regurgitation patients undergoing mitral valve surgery.

AIMS: The outcomes of mitral valve replacement/repair (MVR) in severe degenerative mitral regurgitation (MR) patients depend on various risk factors. We aimed to develop a risk prediction model for post-MVR mortality in severe degenerative MR patients using machine learning. METHODS AND RESULTS: Consecutive severe degenerative MR patients undergoing MVR were analysed (n = 1521; 70% training/30% test sets). A random survival forest (RSF) model was constructed, with 3-year post-MVR all-cause mortality as the outcome. Partial dependency plots were used to define the thresholds of each risk factor. A simple scoring system (MVR-score) was developed to stratify post-MVR mortality risk. At 3 years following MVR, 90 patients (5.9%) died in the entire cohort (59 and 31 deaths in the training and test sets). The most important predictors of mortality in order of importance were age, haemoglobin, valve replacement, glomerular filtration rate, left atrial dimension, and left ventricular (LV) end-systolic diameter. The final RSF model with these six variables demonstrated high predictive performance in the test set (3-year C-index 0.880, 95% confidence interval 0.834-0.925), with mortality risk increased strongly with left atrial dimension >55 mm, and LV end-systolic diameter >45 mm. MVR-score demonstrated effective risk stratification and had significantly higher predictability compared to the modified Mitral Regurgitation International Database score (3-year C-index 0.803 vs. 0.750, P = 0.034). CONCLUSION: A data-driven machine learning model provided accurate post-MVR mortality prediction in severe degenerative MR patients. The outcome following MVR in severe degenerative MR patients is governed by both clinical and echocardiographic factors.

Systemic proinflammatory-profibrotic response in aortic stenosis patients with diabetes and its relationship with myocardial remodeling and clinical outcome.

BACKGROUND: Previous studies have mainly focused more on how diabetes affects the valve than the myocardium in aortic stenosis (AS). In the pressure-overloaded heart, myocardial fibrosis is an important driver of the progression from compensated hypertrophy to heart failure. Using comprehensive noninvasive imaging and plasma proteomics, we investigated whether and how diabetes aggravates the remodeling of the myocardium and its relation with prognosis in AS patients. METHODS: Severe AS patients were enrolled in two prospective cohorts for imaging and biomarker analysis. The imaging cohort (n = 253) underwent echocardiography and cardiac magnetic resonance, and the biomarker cohort (n = 100) blood sampling with multiplex proximity extension assay for 92 proteomic biomarkers. The composite outcome of hospitalization for heart failure admissions and death was assessed in the imaging cohort. RESULTS: Diabetic patients were older (70.4 ± 6.8 versus 66.7 ± 10.1 years) with more advanced ventricular diastolic dysfunction and increased replacement and diffuse interstitial fibrosis (late gadolinium enhancement % 0.3 [0.0-1.6] versus 0.0 [0.0-0.5], p = 0.009; extracellular volume fraction % 27.9 [25.7-30.1] versus 26.7 [24.9-28.5], p = 0.025) in the imaging cohort. Plasma proteomics analysis of the biomarker cohort revealed that 9 proteins (E-selectin, interleukin-1 receptor type 1, interleukin-1 receptor type 2, galectin-4, intercellular adhesion molecule 2, integrin beta-2, galectin-3, growth differentiation factor 15, and cathepsin D) were significantly elevated and that pathways related to inflammatory response and extracellular matrix components were enriched in diabetic AS patients. During follow-up (median 6.3 years), there were 53 unexpected heart failure admissions or death in the imaging cohort. Diabetes was a significant predictor of heart failure and death, independent of clinical covariates and aortic valve replacement (HR 1.88, 95% CI 1.06-3.31, p = 0.030). CONCLUSIONS: Plasma proteomic analyses indicate that diabetes potentiates the systemic proinflammatory-profibrotic milieu in AS patients. These systemic biological changes underlie the increase of myocardial fibrosis, diastolic dysfunction, and worse clinical outcomes in severe AS patients with concomitant diabetes.

Epidemiologic Profile of Patients With Valvular Heart Disease in Korea: A Nationwide Hospital-Based Registry Study.

BACKGROUND: Valvular heart disease (VHD) is a common cause of cardiovascular morbidity and mortality worldwide; however, its epidemiological profile in Korea requires elucidation. METHODS: In this nationwide retrospective cohort study from the Korean valve survey, which collected clinical and echocardiographic data on VHD from 45 medical centers, we identified 4,089 patients with VHD between September and October 2019. RESULTS: The aortic valve was the most commonly affected valve (n = 1,956 [47.8%]), followed by the mitral valve (n = 1,598 [39.1%]) and tricuspid valve (n = 1,172 [28.6%]). There were 1,188 cases of aortic stenosis (AS) and 926 cases of aortic regurgitation. The most common etiology of AS was degenerative disease (78.9%). The proportion of AS increased with age and accounted for the largest proportion of VHD in patients aged 80-89 years. There were 1,384 cases of mitral regurgitation (MR) and 244 cases of mitral stenosis (MS). The most common etiologies for primary and secondary MR were degenerative disease (44.3%) and non-ischemic heart disease (63.0%), respectively, whereas rheumatic disease (74.6%) was the predominant cause of MS. There were 1,172 tricuspid regurgitation (TR) cases, of which 46.9% were isolated and 53.1% were associated with other valvular diseases, most commonly with MR. The most common type of TR was secondary (90.2%), while primary accounted for 6.1%. CONCLUSIONS: This report demonstrates the current epidemiological status of VHD in Korea. The results of this study can be used as fundamental data for developing Korean guidelines for VHD.

Long-term outcomes in distinct phenogroups of patients with primary mitral regurgitation undergoing valve surgery.

OBJECTIVES: Patients with mitral regurgitation (MR) may be heterogeneous with different risk profiles. We aimed to identify distinct phenogroups of patients with severe primary MR and investigate their long-term prognosis after mitral valve (MV) surgery. METHODS: The retrospective cohort of patients with severe primary MR undergoing MV surgery (derivation, n=1629; validation, n=692) was analysed. Latent class analysis was used to classify patients into subgroups using 15 variables. The primary outcome was all-cause mortality after MV surgery. RESULTS: During follow-up (median 6.0 years), 149 patients (9.1%) died in the derivation cohort. In the univariable Cox analysis, age, female, atrial fibrillation, left ventricular (LV) end-systolic dimension/volumes, LV ejection fraction, left atrial dimension and tricuspid regurgitation peak velocity were significant predictors of mortality following MV surgery. Five distinct phenogroups were identified, three younger groups (group 1-3) and two older groups (group 4-5): group 1, least comorbidities; group 2, men with LV enlargement; group 3, predominantly women with rheumatic MR; group 4, low-risk older patients; and group 5, high-risk older patients. Cumulative survival was the lowest in group 5, followed by groups 3 and 4 (5-year survival for groups 1-5: 98.5%, 96.0%, 91.7%, 95.6% and 83.4%; p<0.001). Phenogroups had similar predictive performance compared with the Mitral Regurgitation International Database score in patients with degenerative MR (3-year C-index, 0.763 vs 0.750, p=0.602). These findings were reproduced in the validation cohort. CONCLUSION: Five phenogroups of patients with severe primary MR with different risk profiles and outcomes were identified. This phenogrouping strategy may improve risk stratification when optimising the timing and type of interventions for severe MR.

Transcatheter versus surgical closure of atrial septal defect in adult patients with tricuspid regurgitation.

OBJECTIVES: Transcatheter closure using a device has been established as an effective atrial septal defect (ASD) treatment, but its value in treating patients with concomitant functional tricuspid regurgitation (TR) is relatively unknown. We sought to evaluate outcomes of patients with ASD and significant TR after transcatheter ASD closure or surgical treatment. METHODS: A total of 252 consecutive adult patients (53.8±13.8 years, 180 females) who had a significant functional TR before ASD closure were retrospectively analysed. The primary end point was a composite of all-cause death, stroke and heart failure. The secondary end point was significant residual TR early and at 1 year after ASD closure. RESULTS: Transcatheter ASD closure alone and surgical ASD closure along with tricuspid annuloplasty (TAP) were performed in 68 and 184 patients, respectively. Significant TR remained in 32% (81/252) early after ASD closure and in 29% (52/182) after 1 year. The severity of TR was significantly decreased after transcatheter ASD closure (p<0.001). In multivariable analysis, TAP (OR 0.07; p<0.001) and ASD diameter (OR 0.90; p=0.040) were independent predictors of the significant residual TR early after treatment, while only TAP (OR 0.08; p<0.001) was a significant predictor at 1 year after treatment. After propensity score matching in patients with moderate or severe TR, there were no significant differences between the transcatheter ASD closure group and surgical ASD closure plus TAP group in terms of the event rates at 5 years (10.3% vs 5.5%, p=0.963). CONCLUSIONS: While TAP was effective for the treatment of significant TR, transcatheter ASD closure also significantly reduced TR as well. Transcatheter ASD closure may be considered an alternative treatment option in patients with moderate or severe TR.

Comparison of Dabigatran Versus Warfarin Treatment for Prevention of New Cerebral Lesions in Valvular Atrial Fibrillation.

Warfarin is the standard anticoagulation therapy for valvular atrial fibrillation (AF); however, new oral anticoagulants have emerged as an alternative. We compared the efficacy and safety of dabigatran with conventional treatment in AF associated with left-sided valvular heart disease (VHD), including mitral stenosis (MS). Patients with AF and left-sided VHD were randomly assigned to receive dabigatran or conventional treatment. The primary end point was the occurrence of clinical stroke or a new brain lesion (silent brain infarct and microbleed) on 1-year follow-up brain magnetic resonance imaging. Patients in the dabigatran group were switched from warfarin (n = 52), antiplatelets alone (n = 5), or no therapy (n = 2) to dabigatran. In the conventional group, 53 used warfarin (including 42 MS patients), and 7 used antiplatelets. No death or clinical stroke event occurred in either group during follow-up. Silent brain infarct and microbleed occurred in 20 and 2 patients in the dabigatran group and 20 and 4 patients in the conventional treatment group. The incidence rate of the primary end point did not significantly differ between groups (34% vs 40%, relative risk 0.87, 95% confidence interval 0.59 to 1.29, p = 0.491). The primary end point rate was similar between groups in 82 patients (40 in the dabigatran group and 42 in the conventional group) with MS (32% vs 34%, relative risk 0.93, 95% confidence interval: 0.57 to 1.50, p = 0.759). In conclusion, primary end point rates after treatment with dabigatran were similar to conventional treatment in patients with significant VHD and AF. New oral anticoagulants could be a reasonable alternative to warfarin in patients with AF and VHD, which should be confirmed in future large-scale studies.

Incremental Prognostic Value of Left Ventricular Global Longitudinal Strain in Patients with Preserved Ejection Fraction Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: Evaluation of left ventricular global longitudinal strain (LVGLS) has allowed better characterization than left ventricular ejection fraction (LVEF) of subtle differences in left ventricular performance. The aim of this study was to determine whether LVGLS has prognostic value in patients with severe aortic stenosis and preserved LVEF undergoing transcatheter aortic valve implantation (TAVI). METHODS: Among 412 consecutive patients who underwent TAVI, 344 patients (mean age, 78.9 ± 5.0 years; 161 men) with preserved LVEF (≥50%) at baseline were analyzed. Patients with low LVEF (<50%) were used as a comparison group in the survival analysis. The primary and secondary end points were all-cause death and a composite of cardiovascular death and heart failure hospitalization, respectively. RESULTS: The mean LVGLS and LVEF were -17.1 ± 2.7% and 63 ± 5%, respectively. Impaired LVGLS was defined as >-16%, which was the first LVGLS quartile (cutoff value, -16%). The estimated actuarial 5-year survival rate was 81.7 ± 4.2% in the normal LVGLS group and 66.8 ± 7.5% in the impaired LVGLS group (P = .005). In the multivariable analysis, impaired LVGLS was an independent predictor of all-cause death (adjusted hazard ratio, 2.26; 95% CI, 1.11-4.60) and the composite outcome (adjusted hazard ratio, 3.03; 95% CI, 1.45-6.33). Moreover, the impaired LVGLS group had a poor prognosis, similar to the impaired LVEF group (<50%). The addition of the absolute value of LVGLS to the clinical parameters and LVEF led to significant improvement in the prediction of all-cause mortality. CONCLUSIONS: In patients with severe aortic stenosis and preserved LVEF undergoing TAVI, subclinical LV dysfunction defined by impaired LVGLS is independently associated with poor clinical outcomes. LVGLS measurement provides incremental prognostic value above the established clinical and echocardiographic parameters.

Percutaneous coronary intervention in patients with documented coronary vasospasm during long-term follow-up.

OBJECTIVE: Although recurring coronary artery spasm (CAS) may lead to the development of fixed atherosclerotic coronary stenosis (FS), the relationship between coronary atherosclerosis and CAS is still speculative. We evaluated the incidence of FS requiring percutaneous coronary intervention (PCI) in patients with documented CAS during long-term follow-up and analysed their clinical features. METHODS: Clinical data of 3556 patients during a median follow-up of 9.4 years after non-invasive ergonovine spasm provocation testing with echocardiographic monitoring of left ventricular wall motion (erg echo) were analysed. RESULTS: Erg echo documented CAS in 830 (23.3%) patients, who had higher frequencies of coronary risk factors than those without CAS. Patients with documented CAS on erg echo showed significantly lower 10-year overall (90.5% vs 94.2%, p<0.001) and PCI-free (97.4% vs 98.4%, p=0.002) survival rates than those without CAS. Documented CAS was an independent factor associated with later PCI after adjustment by either Cox regression model or Fine-Gray competing risk model. There was no significant difference in baseline clinical characteristics between patients who needed later PCI and those who did not. Among 28 patients who needed later PCI after documentation of CAS, the original CAS and later PCI territory were concordant in 25 (89.3%), while 3 (10.7%) showed discordance. CONCLUSIONS: CAS is a risk factor for the development of FS requiring PCI during long-term follow-up, and warrants physicians' vigilance and careful follow-up of patients with documented CAS and insignificant stenosis of major epicardial coronary arteries at the time of initial diagnosis.

Different Clinical Features between Definite and Possible Takotsubo Syndrome in a Tertiary Referral Hospital.

BACKGROUND: Although imaging examination to exclude coronary artery disease (CAD) is an indispensable step for a definite diagnosis of takotsubo syndrome (TTS), this step may be overlooked in a substantial proportion of patients with secondary TTS admitted to a tertiary hospital. However, the clinical profiles and outcomes of these patients with "possible TTS" have rarely been investigated. METHODS: Among 420 consecutive TTS patients with characteristic transient ventricular ballooning on repeated echocardiography, 244 patients (58.1%) who underwent an imaging study for CAD were diagnosed with "definite TTS," whereas the remaining 176 were designated with "possible TTS." RESULTS: Overall, hypoxia (67.6%) and dyspnea (55.5%) were predominant presentations. The possible group was characterized by higher prevalence of male gender (46.6% vs. 35.2%, p = 0.019), secondary TTS (97.2% vs. 86.5%, p < 0.001), cancer (43.2% vs. 29.1%, p = 0.003), sepsis (46.0% vs. 32.0%, p = 0.003), and nonapical ballooning pattern (30.7% vs. 21.3%, p = 0.001) with less common ST-segment elevation on electrocardiogram (18.8% vs. 34.0%, p = 0.001). The possible group showed higher frequency of mechanical ventilation (56.2% vs. 40.2%, p = 0.001), pulmonary edema (72.2% vs. 61.5%, p = 0.023), and shock management (70.5% vs. 54.1%, p = 0.001) with similar in-hospital mortality (17.2% vs. 17.0%, p = 0.964). CONCLUSIONS: In real-world clinical practice, coronary evaluation for strict diagnosis of TTS is not frequently feasible. Addition of the possible group without coronary evaluation to the clinical spectrum of TTS would be helpful for fair estimation of clinical implication of TTS.

Early percutaneous mitral commissurotomy or conventional management for asymptomatic mitral stenosis: a randomised clinical trial.

OBJECTIVE: The decision to perform percutaneous mitral commissurotomy (PMC) on asymptomatic patients requires careful weighing of the potential benefits against the risks of PMC, and we conducted a multicentre, randomised trial to compare long-term outcomes of early PMC and conventional treatment in asymptomatic, severe mitral stenosis (MS). METHODS: We randomly assigned asymptomatic patients with severe MS (defined as mitral valve area between 1.0 and 1.5 cm2) to early PMC (84 patients) or to conventional treatment (83 patients). The primary endpoint was a composite of major cardiovascular events, including PMC-related complications, cardiovascular mortality, cerebral infarction and systemic thromboembolic events. The secondary endpoints were death from any cause and mitral valve (MV) replacement during follow-up. RESULTS: In the early PMC group, there were no PMC-related complications. During the median follow-up of 6.4 years, the composite primary endpoint occurred in seven patients in the early PMC group (8.3%) and in nine patients in the conventional treatment group (10.8%) (HR 0.77; 95% CI 0.29 to 2.07; p=0.61). Death from any cause occurred in four patients in the early PMC group (4.8%) and three patients in the conventional treatment group (3.6%) (HR 1.30; 95% CI 0.29 to 5.77). Ten patients (11.9%) in the early PMC group and 17 patients (20.5%) in the conventional treatment group underwent MV replacement (HR 0.59; 95% CI 0.27 to 1.29). CONCLUSIONS: Compared with conventional treatment, early PMC did not significantly reduce the incidence of cardiovascular events among asymptomatic patients with severe MS during the median follow-up of 6 years. TRIAL REGISTRATION NUMBER: NCT01406353.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury.

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.

Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases.

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.

Effect of Rosuvastatin on Coronary Flow Reserve in Hypertensive Patients at Cardiovascular Risk.

BACKGROUND: It has been unclear whether statin therapy directly improves coronary flow reserve (CFR) in hypertensive patients at cardiovascular risk, independent of lifestyle modification and antihypertensive medications. METHODS: In this double-blind, randomized controlled trial, we randomly assigned 95 hypertensive patients at cardiovascular risk to receive either rosuvastatin 10 mg or placebo for 12 months, in addition to antihypertensive therapy and lifestyle modification for hypercholesterolemia. Using Doppler echocardiography, coronary flow velocity in the distal left anterior descending artery was measured and CFR was calculated as the ratio of hyperemic to basal averaged peak diastolic flow velocity. The primary end point was change in CFR from baseline to 12 months follow-up. RESULTS: Low-density lipoprotein-cholesterol was changed from 157 ± 23 to 84 ± 16 mg/dL in the rosuvastatin group (p < 0.001) and from 152 ± 19 to 144 ± 22 mg/dL in the control group (p = 0.041, but there were no significant differences between the treatment groups in the changes in C-reactive protein, high-density lipoprotein cholesterol, and blood pressures. CFR was changed from 3.03 ± 0.44 to 3.25 ± 0.49 in the rosuvastatin group (p < 0.001) and from 3.15 ± 0.54 to 3.17 ± 0.56 in the control group (p = 0.65). The primary end point of change in CFR was significantly different between the rosuvastatin group and the control group (0.216 ± 0.279 vs. 0.015 ± 0.217; p < 0.001). CONCLUSIONS: Compared with lifestyle modification alone, addition of rosuvastatin significantly improved CFR in hypertensive patients at cardiovascular risk.