Tricuspid regurgitation after cardiac resynchronization therapy: evolution and prognostic significance.

AIMS: Tricuspid regurgitation (TR) is common in patients with heart failure (HF) and is associated with worse outcome. This study investigated the effect of cardiac resynchronization therapy (CRT) on TR severity and long-term outcome. METHODS AND RESULTS: Tricuspid regurgitation severity was assessed at baseline and 6 months after CRT implantation, using a multiparametric approach. Patients were divided into four groups: (i) no or mild TR without progression; (ii) no or mild TR with progression to significant (moderate-severe) TR; (iii) significant TR with improvement to no or mild TR; and (iv) significant TR without improvement. The primary endpoint was all-cause mortality. A total of 852 patients (mean age 65 ± 11 years, 77% male) were included. At baseline, 184 (22%) patients had significant TR, with 75 (41%) showing significant improvement at 6-month follow-up. After a median follow-up of 92 (50-137) months, 494 (58%) patients died. Patients with significant TR showing improvement at follow-up had better outcomes than those showing no improvement (P = 0.016). On multivariable analysis, no or mild TR progressing to significant TR [hazard ratio (HR) 1.745; 95% confidence interval (CI): 1.287-2.366; P < 0.001] and significant TR without improvement (HR 1.572; 95% CI: 1.198-2.063; P = 0.001) were independently associated with all-cause mortality, whereas significant TR with improvement at follow-up was not (HR: 1.153; 95% CI: 0.814-1.633; P = 0.424). CONCLUSION: Improvement of significant TR after CRT is observed in a substantial proportion of patients, highlighting the potential benefit of CRT for patients with HF having significant TR. Significant TR at 6 months after CRT is independently associated with increased long-term mortality.

Prognostic significance of right ventricular function during exercise in asymptomatic/minimally symptomatic patients with nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The risk stratification of hypertrophic cardiomyopathy (HCM) without left ventricular outflow tract (LVOT) obstruction and the utility of exercise stress echocardiography (ESE) remains unclear. We investigated the value of right ventricular (RV) function and RV-pulmonary artery (PA) coupling during exercise in asymptomatic/minimally symptomatic patients with nonobstructive HCM (nHCM). METHOD AND RESULTS: This retrospective study evaluated 74 HCM patients (age 63 ± 13 years, 65% men) without LVOT obstruction (≥30 mmHg) who underwent​ ESE. Eight patients (11%) suffered from HCM-related cardiac events during a median 2.5 years follow-up. During exercise, tricuspid annular plane systolic excursion (Ex-TAPSE) and Ex-TAPSE/systolic pulmonary artery pressure [SPAP] ratio were more impaired in patients with than in those without events (22 ± 4 vs 26 ± 4 mm, P = .005; and 0.45 [0.41, 0.47] vs 0.56 [0.47, 0.82] mm/mmHg, P = .002). In Cox regression analysis, Ex-TAPSE (HR: 1.397, P = .002) and the Ex-TAPSE/SPAP ratio (HR: 2.737, P = .006) were associated with cardiac events. In Kaplan-Meier analysis, patients with a low Ex-TAPSE (<24 mm) and Ex-TAPSE/SPAP ratio (<0.50 mm/mmHg) had a higher incidence of adverse outcomes than those with high Ex-TAPSE (Log rank, P < .001 and =.001, respectively). CONCLUSIONS: A low Ex-TAPSE and Ex-TAPSE/SPAP ratio were associated with adverse outcomes in nHCM. Evaluation of RV functional performance during exercise may play a crucial role in the risk stratification of nHCM.

Systemic MEK inhibition enhances the efficacy of 5-aminolevulinic acid-photodynamic therapy.

BACKGROUND: Protoporphyrin IX (PpIX) gets accumulated preferentially in 5-aminolevulinic acid (5-ALA)-treated cancer cells. Photodynamic therapy (PDT) utilises the accumulated PpIX to trigger cell death by light-induced generation of reactive oxygen species (ROS). We previously demonstrated that oncogenic Ras/MEK decreases PpIX accumulation in cancer cells. Here, we investigated whether combined therapy with a MEK inhibitor would improve 5-ALA-PDT efficacy. METHODS: Cancer cells and mice models of cancer were treated with 5-ALA-PDT, MEK inhibitor or both MEK inhibitor and 5-ALA-PDT, and treatment efficacies were evaluated. RESULTS: Ras/MEK negatively regulates the cellular sensitivity to 5-ALA-PDT as cancer cells pre-treated with a MEK inhibitor were killed more efficiently by 5-ALA-PDT. MEK inhibition promoted 5-ALA-PDT-induced ROS generation and programmed cell death. Furthermore, the combination of 5-ALA-PDT and a systemic MEK inhibitor significantly suppressed tumour growth compared with either monotherapy in mouse models of cancer. Remarkably, 44% of mice bearing human colon tumours showed a complete response with the combined treatment. CONCLUSION: We demonstrate a novel strategy to promote 5-ALA-PDT efficacy by targeting a cell signalling pathway regulating its sensitivity. This preclinical study provides a strong basis for utilising MEK inhibitors, which are approved for treating cancers, to enhance 5-ALA-PDT efficacy in the clinic.

Clinical characteristics of definite or suspected isolated cardiac sarcoidosis: application of cardiac magnetic resonance imaging and 18F-Fluoro-2-deoxyglucose positron-emission tomography/computerized tomography.

BACKGROUND: Isolated cardiac sarcoidosis (iCS) is difficult to diagnose in patients without histologic evidence of sarcoidosis. We aimed to clarify the clinical characteristics of iCS, including imaging features on cardiac magnetic resonance imaging (MRI) and (18)F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography (FDG-PET/CT) scans. We also reviewed the therapeutic effect of corticosteroids and determined the long-term prognosis. METHODS AND RESULTS: We retrospectively reviewed 83 consecutive patients with suspicious CS from 1997 to 2013. Systemic sarcoidosis with CS (sCS, n = 30) and iCS (n = 11) were diagnosed according to clinical criteria. In iCS cases, sarcoidosis was not detected in any other organs. The clinical features did not significantly differ between sCS and iCS cases, except for ejection fraction, which was lower in iCS (P = .025). Nine sCS and 4 iCS cases showed late gadolinium enhancement, and the lesions tended to be on the epicardial side (76.9% P = .011) and septal wall (52.9% P < .001). The coefficient of variance for the myocardial standardized uptake value of FDG-PET/CT was higher in sCS (0.32 ± 0.13; n = 19) and iCS (0.32 ± 0.09; n = 7) than in control cases (n = 31; P < .001). B-Type natriuretic peptide level was improved after prednisolone treatment in both groups. Kaplan-Meier curve indicated that prognosis was not different between sCS and iCS cases. CONCLUSIONS: The clinical cardiac characteristics of iCS cases were similar to those of sCS. Cardiac MRI and FDG-PET, noninvasive imaging modalities, could be useful modalities to detect myocardial involvement in the cases with definite or suspected iCS.

Prognostic Implications and Alterations in Left Atrial Deformation Following Transcatheter Aortic Valve Implantation.

AIMS: To evaluate the prognostic implications of left atrial reservoir strain-defined diastolic dysfunction (LARS-DD) grade in patients undergoing TAVI for severe aortic stenosis (AS) and to determine if post-TAVI LARS was more closely associated with new-onset atrial fibrillation than pre-TAVI LARS. METHODS AND RESULTS: Pre-TAVI LARS-DD was evaluated by speckle-tracking echocardiography and was assigned as grade 0 to 1 (LARS≥24%), grade 2 (LARS≥19 to <24%) and grade 3 (LARS<19%). Patients were followed-up for the primary endpoint of all-cause mortality from the date of TAVI. For the secondary endpoint, patients with pre- and post-TAVI LARS measurements and no history of atrial fibrillation were evaluated for the occurrence of new-onset atrial fibrillation. A total of 601 patients (median age 81 [76-85] years, 53% male) were included. Overall, 169 patients (28%) were LARS-DD grade 0/1, 96 patients (16%) were LARS-DD grade 2 and 336 (56%) were LARS-DD grade 3. Over a median follow-up of 40 (IQR 26-58) months, a total of 258 (43%) patients died. In a comprehensive multivariable Cox regression model, LARS-DD grade was independently associated with all-cause mortality (adjusted HR 1.28 per one-grade increase, 95%CI 1.07-1.53, P=0.007). For the secondary endpoint of new-onset atrial fibrillation, a total of 285 patients were evaluated. Post-TAVI LARS (SDHR 1.14 per 1%<20%, 95%CI 1.05-1.23, P=0.0009), but not pre-TAVI LARS (P=0.93) was independently associated with new-onset atrial fibrillation. CONCLUSIONS: Increasing LARS-DD grade was independently associated with long-term post-TAVI survival in patients with severe AS. Post-TAVI LARS was closely related to the occurrence of new-onset atrial fibrillation.

Impact of chronic obstructive pulmonary disease on right ventricular function and remodeling after aortic valve replacement.

BACKGROUND: Both chronic obstructive pulmonary disease (COPD) and right ventricular (RV) dysfunction are common factors that have been associated with poor prognosis after aortic valve replacement (AVR). Since there is still uncertainty about the impact of COPD on RV function and dilatation in patients undergoing AVR, we sought to explore RV function and remodeling in the presence and absence of COPD as well as their prognostic implications. METHODS: Patients who received surgical or transcatheter AVR due to severe AS were screened for COPD. Demographic and clinical data were collected at baseline while echocardiographic measurements were performed at baseline and 1 year after AVR. The study end-point was all-cause mortality. RESULTS: In total 275 patients were included, with 90 (33%) patients having COPD. At 1-year follow-up, mild worsening of tricuspid annular planar systolic excursion and RV dilatation were observed in patients without COPD, while there were significant improvements in RV longitudinal strain, RV wall thickness but dilatation of RV outflow tract distal dimension in the COPD group compared to the baseline. On multivariable analysis, the presence of COPD provided significant incremental prognostic value over RV dysfunction and remodeling. CONCLUSIONS: At 1-year after AVR, RV function and dimensions mildly deteriorated in non-COPD group whereas COPD group received significant benefit of AVR in terms of RV function and hypertrophy. COPD was independently associated with >2-fold all-cause mortality and had incremental prognostic value over RV dysfunction and remodeling.

Stress echocardiography in valvular heart disease.

Valvular heart disease (VHD) has been a significant health problem, particularly in developed countries, in relation to the aging population. Recent developments in the management of VHD require a more accurate assessment of disease severity to determine the need for transcatheter interventions or open heart surgery. Stress echocardiography is a crucial imaging modality for identifying the underlying pathology of VHD. Optimal administration of exercise or intravenous drugs may reveal hemodynamic abnormalities under stress without posing an invasive risk. Therefore, the implementation of stress echocardiography is recommended for determining interventional indications and risk stratification in mitral regurgitation and aortic stenosis. In addition, recent evidence has accumulated regarding the usefulness of stress echocardiography in various conditions including mitral stenosis, aortic regurgitation, and post-interventional VHD. Here, we summarize the current evidence and future perspectives on stress echocardiography in VHD.

Inflammatory cell death induced by 5-aminolevulinic acid-photodynamic therapy initiates anticancer immunity.

Background: Inflammatory cell death is a form of programmed cell death (PCD) that induces inflammatory mediators during the process. The production of inflammatory mediators during cell death is beneficial in standard cancer therapies as it can break the immune silence in cancers and induce anticancer immunity. Photodynamic therapy (PDT) is a cancer therapy with photosensitizer molecules and light sources to destroy cancer cells, which is currently used for treating different types of cancers in clinical settings. In this study, we investigated if PDT using 5-aminolevulinic (5-ALA-PDT) causes inflammatory cell death and, subsequently, increases the immunogenicity of cancer cells. Methods: Mouse breast cancer (4T1) and human colon cancer (DLD-1) cells were treated with 5-ALA for 4 hours and then irradiated with a light source. PCD induction was measured by western blot analysis and FACS. Morphological changes were determined by transmission electron microscopy (TEM). BALB/c mice were injected with cell-free media, supernatant of freeze/thaw cells or supernatant of PDT cells intramuscular every week for 4 weeks and then challenged with 4T1 cells at the right hind flank of BALB/c. Tumor growth was monitored for 12 days. Results: We found that 5-ALA-PDT induces inflammatory cell death, but not apoptosis, in 4T1 cells and DLD-1 cells in vitro. Moreover, when mice were pretreated with 5-ALA-PDT culture supernatant, the growth of 4T1 tumors was significantly suppressed compared to those pretreated with freeze and thaw (F/T) 4T1 culture supernatant. Conclusion: These results indicate that 5-ALA-PDT induces inflammatory cell death which promotes anticancer immunity in vivo.

Association Between Chronic Obstructive Pulmonary Disease and All-Cause Mortality After Aortic Valve Replacement for Aortic Stenosis.

Chronic obstructive pulmonary disease (COPD) and aortic stenosis (AS) are the most common diseases in which age plays a major role in the increase of their prevalence and when they co-exist, the outcomes prognosis worsens significantly. The aim of the present study was to evaluate the association between pulmonary functional parameters and all-cause mortality after aortic valve replacement (transcatheter or surgical). A total of 400 patients with severe AS and preoperative pulmonary functional test were retrospectively analyzed. Echocardiography and pulmonary functional parameters before aortic valve replacement were collected. COPD severity was defined according to criteria from the Society of Thoracic Surgeons. COPD was present in 128 patients (32%) with severe AS. Patients without COPD had smaller left ventricular (LV) mass and LV end-systolic volume and better LV function than the group with COPD. During a median follow-up of 32 months, 92 patients (23%) died. The survival rates were significantly lower in patients with moderate and severe COPD (log-rank p = 0.003). In the multivariable Cox regression analysis, any grade of COPD was associated with an approximately 2-fold increased risk of all-cause mortality (hazard ratio 1.933; 95% confidence interval 1.166 to 3.204; p = 0.011 for mild COPD and hazard ratio 2.028; 95% confidence interval 1.154 to 3.564; p = 0.014 for moderate or severe COPD). In addition to other clinical factors, any grade of COPD was associated with 2-fold increased risk of all-cause mortality.

Incremental value of left ventricular global longitudinal strain in moderate aortic stenosis and reduced left ventricular ejection fraction.

BACKGROUND: Moderate aortic stenosis (AS) often coexists with left ventricular (LV) systolic dysfunction and may affect survival through afterload mismatch. Because outcomes are ultimately driven by the condition of the LV, accurate assessment of LV performance is crucial to improve risk stratification. This study investigated the prognostic value of LV global longitudinal strain (GLS) in patients with moderate AS and reduced LV systolic dysfunction. METHODS: Patients with moderate AS (aortic valve area 1.0-1.5 cm2) and reduced LV ejection fraction (EF) (<50%) were identified. LVGLS was evaluated with speckle-tracking echocardiography. Patients were divided into 2 groups according to an LVGLS value of 11%, based on spline curve analysis. The primary endpoint was all-cause mortality. RESULTS: A total of 166 patients (mean age 73 ± 11 years, 71% male) were included. The cumulative 1- and 5-year mortality rates were higher in patients with LVGLS <11% (25% and 60%) versus LVGLS ≥11% (10% and 27%) (p < 0.001). On multivariable analysis, LVGLS as a continuous variable (HR 0.753; 95% CI 0.673-0.843; p < 0.001) and as a categorical variable (<11%) (HR 3.028; 95% CI 1.623-5.648; p < 0.001) were independently associated with outcomes, whereas LVEF was not. LVGLS provided additional prognostic information in patients with/without coronary artery disease and with mildly versus severely reduced LVEF. In addition, LVGLS had incremental prognostic value over established risk factors, including LVEF. CONCLUSION: The combination of moderate AS and reduced LV systolic dysfunction is associated with a high mortality risk. LVGLS, but not LVEF, is independently associated with mortality and provides incremental prognostic value over established risk factors in patients with moderate AS and reduced LVEF.

Interaction between secondary mitral regurgitation and left atrial function and their prognostic implications after cardiac resynchronization therapy.

AIMS: Left atrial (LA) function is a strong prognostic marker in patients with heart failure and functional mitral regurgitation (MR). Although cardiac resynchronization therapy (CRT) has shown to improve MR severity, the interaction between a reduction in MR severity and an increase in LA function, as well as its association with outcomes, has not been investigated. METHODS AND RESULTS: LA reservoir strain (RS) was evaluated with speckle tracking echocardiography in patients with at least moderate functional MR undergoing CRT implantation. MR improvement was defined as at least 1 grade improvement in MR severity at 6 months after CRT implantation. The primary endpoint was all-cause mortality. A total of 340 patients (mean age 66 ± 10 years, 73% male) were included, of whom 200 (59%) showed MR improvement at 6 months follow-up. On multivariable analysis, an improvement in MR severity was independently associated with an increase in LARS (odds ratio 1.008; 95% confidence interval 1.003-1.013; P = 0.002). After multivariable adjustment, including baseline and follow-up variables, an increase in LARS was significantly associated with lower mortality. MR improvers showing LARS increasement had the lowest mortality rate, whereas outcomes were not significantly different between MR non-improvers and MR improvers showing no LARS increasement (P = 0.236). CONCLUSION: A significant reduction in MR severity at 6 months after CRT implantation is independently associated with an increase in LARS. In addition, an increase in LARS is independently associated with lower all-cause mortality in patients with heart failure and significant functional MR.

Hemodynamic implications of mitral annular calcification in patients undergoing transcatheter aortic valve implantation for severe aortic stenosis.

PURPOSES: Predicting hemodynamic changes of stenotic mitral valve (MV) lesions with mitral annular calcification (MAC) following transcatheter aortic valve implantation (TAVI) may inform clinical decision-making. This study aimed to investigate the association between the MAC severity quantified by computed tomography (CT) and changes in mean transmitral gradient (mTMG), mitral valve area (MVA) and stroke volume index (SVi) following TAVI. METHODS AND RESULTS: A total of 708 patients (median age 81, 52% male) with severe aortic stenosis (AS) underwent pre-procedural CT and pre- and post-TAVI transthoracic echocardiography. According to the classification of MAC severity determined by CT, 299 (42.2%) patients had no MAC, 229 (32.3%) mild MAC, 102 (14.4%) moderate MAC, and 78 (11.0%) severe MAC. After adjusting for age and sex, there was no significant change in mTMG following TAVI (Δ mTMG = 0.07 mmHg, 95% CI -0.10 to 0.23, P = 0.92) for patients with no MAC. In contrast, patients with mild MAC (Δ mTMG = 0.21 mmHg, 95% CI 0.01 to 0.40, P = 0.018), moderate MAC (Δ mTMG = 0.31 mmHg, 95% CI 0.02 to 0.60, P = 0.019) and severe MAC (Δ mTMG = 0.43 mmHg, 95% CI 0.10 to 0.76, P = 0.0012) had significant increases in mTMG following TAVI, with greater changes associated with increasing MAC severity. In contrast, there was no significant change in MVA or SVi following TAVI. CONCLUSION: In patients with severe AS undergoing TAVI, MAC severity was associated with greater increases in post-procedural mTMG whereas MVA or SVi remained unchanged. MAC severity should be considered for potential subsequent MV interventions if TAVI does not improve symptoms.

Risk Factors for Short-Term Versus Long-Term Mortality in Patients Who Underwent Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) is an effective therapy in selected patients with advanced heart failure that reduces all-cause mortality at short-term follow-up. However, data regarding long-term mortality after CRT implantation are scarce, with no separate analysis available of the covariates associated with respectively short-term and long-term outcomes. Accordingly, the present study evaluated the risk factors associated with short-term (2-year follow-up) versus long-term (10-year follow-up) mortality after CRT implantation. Patients who underwent CRT implantation and had echocardiographic evaluation before implantation were included in the present study. The primary end point was all-cause mortality, and independent associates of short-term (2-year follow-up) and long-term (10-year follow-up) mortality were compared. In total, 894 patients (mean age 66 ± 10 years, 76% males) who underwent CRT implantation were included in the present study. The cumulative overall survival rates for the total population were 91%, 71%, and 45% at 2-, 5- and 10-year follow-up, respectively. Multivariable Cox regression analysis showed that short-term mortality was associated with both clinical and echocardiographic variables at the moment of CRT implantation; whereas long-term mortality was predominantly associated with baseline clinical parameters and was less strongly associated with baseline echocardiographic parameters. In conclusion, at long-term (10-year) follow-up, a significant proportion (45%) of patients with advanced heart failure who underwent CRT implantation were still alive. Importantly, the risk assessment for short-term (2-year follow-up) and long-term (10-year follow-up) mortality differ considerably, which may influence clinical decision making.

Evolution and Prognostic Impact of Right Ventricular-Pulmonary Artery Coupling After Transcatheter Aortic Valve Replacement.

BACKGROUND: There is limited evidence regarding the association between right ventricular-to-pulmonary artery (RV-PA) coupling and outcomes after transcatheter aortic valve replacement (TAVR). OBJECTIVES: This study aimed to explore the evolution of RV-PA coupling in patients with severe aortic stenosis undergoing TAVR and its prognostic impact. METHODS: A total of 900 patients who underwent TAVR in 2 tertiary centers and with echocardiographic analysis performed within 3 months before and after the procedure were included. RV-PA coupling was measured as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP). RV-PA uncoupling was defined by TAPSE/PASP <0.55, whereas a TAPSE/PASP <0.32 identified a severe uncoupling. The primary endpoint was all-cause mortality. RESULTS: A total of 520 patients (58%) showed RV-PA uncoupling before TAVR, whereas post-TAVR RV-PA uncoupling was observed in 407 patients (45%). During a median follow-up of 40 months, 250 deaths (28%) occurred. Post-TAVR RV-PA uncoupling was independently associated with an increased risk of mortality (adjusted HR: 1.474; 95% CI: 1.115-1.948; P = 0.006), whereas pre-TAVR uncoupling did not. Among patients with post-TAVR RV-PA uncoupling, the presence of severe uncoupling identified a subgroup with the worst survival (P = 0.008). Patients with RV-PA coupling recovery after TAVR showed similar outcomes as compared with patients with normal coupling. Conversely, the presence of either persistent or new-onset RV-PA uncoupling following TAVR was associated with an increased mortality risk. CONCLUSIONS: Post-TAVR RV-PA uncoupling is an independent predictor of long-term mortality, irrespective of coupling before intervention. Assessment of TAPSE/PASP response after TAVR may be helpful to improve risk stratification.

Prognostic Value of Nonalcoholic Fatty Liver Disease in Patients With Severe Aortic Stenosis Who Underwent Transcatheter Aortic Valve Implantation.

Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular events. Although the association between NAFLD and aortic valve sclerosis has been described, the prevalence and prognostic implications of NAFLD among patients with severe aortic stenosis (AS) have not been described. In addition, the effect of the presence of severe tricuspid regurgitation (TR) on the prevalence of NAFLD remains unexplored. Accordingly, we investigated the prognostic implications of NAFLD among patients with severe AS with and without concomitant significant TR. A total of 538 patients (aged 80 ± 7 y, 49.6% men) who underwent noncontrast computed tomography before transcatheter aortic valve implantation (TAVI) between 2007 and 2019 were included. NAFLD was defined as a liver-to-spleen attenuation ratio <1.0 on noncontrast computed tomography. NAFLD was present in 118 patients (21.9%). There were no significant differences in pulmonary arterial pressure, right atrial pressure, or the prevalence of significant TR between patients with and without NAFLD. During a median follow-up of 47 months (interquartile range 20 to 70 months), 224 patients (41.6%) died. Univariate Cox regression analysis demonstrated that NAFLD was not significantly associated with all-cause death among patients treated with TAVI (hazard ratio 1.32, 95% confidential interval 0.97 to 1.79, p = 0.07). In conclusion, among patients with severe AS who underwent TAVI, the prevalence of significant TR and the clinical outcomes were similar in patients with and without NAFLD.

Feature-tracking computed tomography left atrial strain and long-term survival after transcatheter aortic valve implantation.

AIMS: Aortic stenosis (AS) induces left atrial (LA) remodelling through the increase of left ventricular (LV) filling pressures. Peak LA longitudinal strain (PALS), reflecting LA reservoir function, has been proposed as a prognostic marker in patients with AS. Feature-tracking (FT) multi-detector computed tomography (MDCT) allows assessment of LA strain from MDCT data. The aim of this study is to investigate the association between PALS using FT MDCT and survival in patients with severe AS who underwent transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: A total of 376 patients (mean age 80 ± 7 years, 53% male) who underwent MDCT before TAVI and had suitable data for assessment of PALS using dedicated FT software, were included. The patients were classified into four groups according to PALS quartiles; PALS > 19.3% (Q1, highest reservoir function), 15.0-19.3% (Q2), 9.1-14.9% (Q3), and ≤9.0% (Q4, lowest reservoir function). The primary outcome was all-cause mortality. During a median of 45 (22-68) months follow-up, 148 patients (39%) died. On multivariable Cox regression analysis, PALS was independently associated with all-cause mortality [hazard ratio (HR): 1.044, 95% confidence interval (CI): 1.012-1.076, P = 0.006]. Compared with patients in Q1, patients in Q3 and Q4 were associated with higher risk of mortality after TAVI [HR: 2.262 (95% CI: 1.335-3.832), P = 0.002 for Q3, HR: 3.116 (95% CI: 1.864-5.210), P < 0.001 for Q4]. CONCLUSION: PALS assessed with FT MDCT is independently associated with all-cause mortality after TAVI.

Interferon regulatory factor 3 mediates effective antiviral responses to human coronavirus 229E and OC43 infection.

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of human coronaviruses to IFNs has been characterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3 activation effectively promotes transcription of antiviral genes during OC43 or 229E infection. Our study suggests that IRFs may be effective antiviral regulators against human coronavirus infection.

The impact of atrial fibrillation on prognosis in aortic stenosis.

BACKGROUND: Atrial fibrillation (AF) and aortic stenosis (AS) are both highly prevalent and often coexist. Various studies have focused on the prognostic value of AF in patients with AS, but rarely considered left ventricular (LV) diastolic function as a prognostic factor. OBJECTIVE: To evaluate the prognostic impact of AF in patients with AS while correcting for LV diastolic function. METHODS: Patients with first diagnosis of significant AS were selected and stratified according to history of AF. The endpoint was all-cause mortality. RESULTS: In total, 2849 patients with significant AS (mean age 72 ± 12 years, 54.8% men) were evaluated, and 686 (24.1%) had a history of AF. During a median follow-up of 60 (30-97) months, 1182 (41.5%) patients died. Ten-year mortality rate in patients with AF was 46.8% compared to 36.8% in patients with sinus rhythm (SR) (log-rank P < 0.001). On univariable (HR: 1.42; 95% CI: 1.25-1.62; P < 0.001) and multivariable Cox regression analysis (HR: 1.19; 95% CI: 1.02-1.38; P = 0.026), AF was independently associated with mortality. However, when correcting for indexed left atrial volume, E/e' or both, AF was no longer independently associated with all-cause mortality. CONCLUSION: Patients with significant AS and AF have a reduced survival as compared to patients with SR. Nonetheless, when correcting for markers of LV diastolic function, AF was not independently associated with outcomes in patients with significant AS.

Promotion of viral internal ribosomal entry site-mediated translation under amino acid starvation.

Cap-dependent and internal ribosomal entry site (IRES)-mediated translation are regulated differently within cells. Viral IRES-mediated translation often remains active when cellular cap-dependent translation is severely impaired under cellular stresses induced by virus infection. To investigate how cellular stresses influence the efficiency of viral IRES-mediated translation, we used a bicistronic luciferase reporter construct harbouring IRES elements from the following viruses: encephalomyocarditis virus (EMCV), foot-and-mouth disease virus (FMDV), hepatitis C virus (HCV) or human rhinovirus (HRV). NIH3T3 cells transfected with these bicistronic reporter constructs were subjected to different cellular stresses. Increased translation initiation was only observed under amino acid starvation when EMCV or FMDV IRES elements were present. To identify cellular mechanisms that promoted viral IRES-mediated translation, we tested the involvement of eukaryotic initiation factor 4E-binding protein (4E-BP), general control non-depressed 2 (GCN2) and eukaryotic initiation factor 2B (eIF2B), as these are known to be modulated under amino acid starvation. Knockdown of 4E-BP1 impaired the promotion of EMCV and FMDV IRES-mediated translation under amino acid starvation, whereas GCN2 and eIF2B were not involved. To further investigate how 4E-BP1 regulates translation initiated by EMCV and FMDV IRES elements, we used a phosphoinositide kinase-3 inhibitor (LY294002), an mTOR inhibitor (Torin1) or leucine starvation to mimic 4E-BP1 dephosphorylation induced by amino acid starvation. 4E-BP1 dephosphorylation induced by the treatments was not sufficient to promote viral IRES-mediated translation. These results suggest that 4E-BP1 regulates EMCV and FMDV IRES-mediated translation under amino acid starvation, but not via its dephosphorylation.

Role of 3D Transesophageal Echocardiography for Transcatheter Mitral Valve Repair-A Mini Review.

Edge-to-edge transcatheter mitral valve repair (TMVr) using MitraClip has been evolving rapidly in patients with severe mitral regurgitation (MR) at high surgical risk or having contraindications for surgery. Three-dimensional (3D) echocardiography plays an important role in the management of severe MR. In particular, 3D transesophageal echocardiography (TEE) imaging allows the evaluation of MV geometry and quantification of MR severity with dedicated software. Real-time 3D TEE is also commonly used to guide TMVr and facilitate the procedure. Further development of 3D echocardiography may help achieve safer and more beneficial results. The following article summarizes the current knowledge and the future perspectives of 3D TEE in TMVr.