[Berberine inhibits osteogenic differentiation of aortic valve interstitial cells induced by osteogenic induction medium].

This research focused on the effect and mechanism of berberine on osteogenic differentiation of valve interstitial cells(VICs) induced by osteogenic induction medium, in order to provide new insights into the clinical treatment of calcified aortic valve disease. The expression of osteogenic and fibrotic makers in three cases of calcified valve tissues and one case of normal control was assayed by Western blot. After the porcine aortic VICs were isolated, the effects of different concentrations of berberine on their viability were examined by MTT assay for determining the optimal concentration range. VICs were cultured in osteogenic induction medium and treated with different concentrations of berberine. Western blot and q-PCR were conducted to detect the effects of berberine on the expression of osteogenic and fibrotic makers in VICs. The effects of berberine on osteogenic differentiation of VICs in the early and late stages were separately measured by ALP staining and alizarin red S staining. The effects of berberine on the phosphorylation of ERK1/2 at different time points were assayed by Western blot. And PD98059, an inhibitor of ERK1/2, was added for verification. The results suggested that related osteogenic and fibrotic makers were significantly up-regulated in calcified valve tissues as compared with those in the normal control. The up-regulated fibrosis and osteogenic makers of VICs under osteogenic conditions were reversed by berberine and the ALP activity and calcium deposition in VICs were also reduced obviously. The level of ERK1/2 phosphorylation was decreased. Similarly, the osteogenic and fibrotic makers of VICs induced by osteogenic induction medium were lowered by PD98059. This study has confirmed that berberine is able to inhibit the differentiation of VICs into myofibroblasts or osteoblast-like cells, which may be associated with the inhibition of ERK1/2 signaling pathway.

Trends and Disparities in Valvular Heart Disease Mortality in the United States From 1999 to 2020.

BACKGROUND: Percutaneous heart valve procedures have been increasingly performed over the past decade, yet real-world mortality data on valvular heart disease (VHD) in the United States remain limited. METHODS AND RESULTS: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database among patients ≥15 years old from 1999 to 2020. VHD and its subtypes were listed as the underlying cause of death. We calculated age-adjusted mortality rate (AAMR) per 100 000 individuals and determined overall trends by estimating the average annual percent change using the Joinpoint regression program. Subgroup analyses were performed based on demographic and geographic factors. In the 22-year study, there were 446 096 VHD deaths, accounting for 0.80% of all-cause mortality (56 014 102 people) and 2.38% of the total cardiovascular mortality (18 759 451 people). Aortic stenosis recorded the highest mortality of VHD-related death in both male (109 529, 61.74%) and female (166 930, 62.13%) populations. The AAMR of VHD has declined from 8.4 (95% CI, 8.2-8.5) to 6.6 (95% CI, 6.5-6.7) per 100 000 population. Similar decreasing AAMR trends were also seen for the VHD subtypes. Men recorded higher AAMR for aortic stenosis and aortic regurgitation, whereas women had higher AAMR for mitral stenosis and mitral regurgitation. Mitral regurgitation had the highest change in average annual percent change in AAMR. CONCLUSIONS: The mortality rate of VHD among the US population has declined over the past 2 decades. This highlights the likely efficacy of increasing surveillance and advancement in the management of VHD, resulting in improved outcomes.

Outcomes following TAVR in patients with cardiogenic shock: A systematic review and meta-analysis.

BACKGROUND: While transcatheter aortic valve replacement (TAVR) has broadened treatment options for critically ill patients, outcomes among those with concomitant cardiogenic shock (CS) are not well-explored. METHODS: We conducted a comprehensive search of major databases for studies comparing outcomes following TAVR in patients with and without CS since inception up to October 31, 2023. Our meta-analysis included five non-randomized observational. Dichotomous outcomes were assessed using the Mantel-Haenszel method (risk ratio, 95 % CI), and continuous outcomes were evaluated using mean difference and 95 % CI with the inverse variance method. Statistical heterogeneity was determined using the inconsistency test (I2). RESULTS: Among 26,283 patients across five studies, 30-day mortality was higher in the CS group (7267 patients; 27.6 %) compared to those without CS (OR 3.41, 95 % CI [2.01, 5.76], p < 0.01), as well as 30-day major vascular complications (OR 1.72, 95 % CI [1.54, 1.92], p < 0.01). At 1-year follow-up, there was no statistically significant difference in mortality rates between the compared groups (OR 2.68, 95 % CI [0.53, 13.46], p = 0.12). No significant between-group differences were observed in the likelihood of 30-day aortic valve reintervention (OR 3.20, 95 % CI [0.63, 16.22], p = 0.09) or post-TAVR aortic insufficiency (OR 0.91, 95 % CI [0.33, 2.51], p = 0.73). Furthermore, 30-day stroke, pacemaker implantation, and in-hospital major bleeding were comparable between both cohorts. CONCLUSION: Among patients undergoing TAVR, short-term mortality is higher but one-year outcomes are similar when comparing those with, to those without, CS. Future studies should examine whether TAVR outcomes are improved when the procedure is delayed to optimize CS and when delay is not possible, whether particular management strategies lead to more favorable periprocedural outcomes.

Micromechanical force promotes aortic valvular calcification.

OBJECTIVE: Calcified aortic valvular disease is known as an inflammation-related process related to force. The purpose of this study was to determine whether micromechanical force could induce valve calcification of porcine valvular interstitial cells and to examine the role of integrin αvß3 in valvular calcification by using a novel method: magnetic twisting cytometry. METHODS: Porcine valvular interstitial cells were cultured in vitro, and micromechanical force was applied to porcine valvular interstitial cells using magnetic twisting cytometry. Changes in calcification-related factors osteopontin and RUNX2 were detected. By using the calcification medium, the optimal magnetic twisting cytometry parameters for inducing valvular interstitial cell calcification were determined, and a magnetic twisting cytometry calcification promotion model was established. The role of αvß3 in calcification was studied by using αvß3 antagonists to block the function of αvß3. RESULTS: Reverse transcription polymerase chain reaction assays showed that the expression of osteopontin was enhanced 30 minutes after 25G-1Hz 5 minutes of stimulation. Western blotting assays showed that the expression of osteopontin and RUNX2 was upregulated 24 hours after 25G-1Hz 5 minutes of stimulation. The optimal magnetic twisting cytometry parameter for inducing porcine valvular interstitial cell calcification was 25G-2Hz for 10 minutes. The expression of osteopontin and RUNX2 decreased significantly after the addition of αvß3 antagonist. Clinically, patients with bicuspid aortic valves had high expression of RUNX2 and ß3 in the aortic valve, and ß3 significantly correlated with RUNX2. CONCLUSIONS: By using magnetic twisting cytometry, we established a porcine valvular interstitial cell calcification model by micromechanical force stimulation and obtained the optimal parameters. Integrin αvß3 plays a key role in the aortic valve calcification process.

Clinical Applications of 4D Flow MR Imaging in Aortic Valvular and Congenital Heart Disease.

4D flow MRI allows time-resolved 3D velocity-encoded phase-contrast imaging for 3D visualization and quantification of aortic and intracardiac flow. Radiologists should be familiar with the principles of 4D flow MRI and methods for evaluating blood flow qualitatively and quantitatively. The most substantial benefits of 4D flow MRI are that it enables the simultaneous comprehensive assessment of different vessels, and that retrospective analysis can be achieved in all vessels in any direction in the field of view, which is especially beneficial for patients with complicated congenital heart disease (CHD). For aortic valvular diseases, new parameters such as wall shear stress and energy loss may provide new prognostic values for 4D flow MRI. In this review, we introduce the clinical applications of 4D flow MRI for the visualization of blood flow and quantification of hemodynamic metrics in the setting of aortic valvular disease and CHD, including intracardiac shunt and coronary artery anomaly.

Short and long-term clinical impact of transcatheter aortic valve implantation in Portugal according to different access routes: Data from the Portuguese National Registry of TAVI.

INTRODUCTION: The Portuguese National Registry of Transcatheter Aortic Valve Implantation records prospectively the characteristics and outcomes of transcatheter aortic valve implantation (TAVI) procedures in Portugal. OBJECTIVES: To assess the 30-day and one-year outcomes of TAVI procedures in Portugal. METHODS: We compared TAVI results according to the principal access used (transfemoral (TF) vs. non-transfemoral (non-TF)). Cumulative survival curves according to access route, other procedural and clinical variables were obtained. The Valve Academic Research Consortium-2 (VARC-2) composite endpoint of early (30-days) safety was assessed. VARC-2 predictors of 30-days and 1-year all-cause mortality were identified. RESULTS: Between January 2007 and December 2018, 2346 consecutive patients underwent TAVI (2242 native, 104 valve-in-valve; mean age 81±7 years, 53.2% female, EuroSCORE-II - EuroS-II, 4.3%). Device success was 90.1% and numerically lower for non-TF (87.0%). Thirty-day all-cause mortality was 4.8%, with the TF route rendering a lower mortality rate (4.3% vs. 10.1%, p=0.001) and higher safety endpoint (86.4% vs. 72.6%, p<0.001). The one-year all-cause mortality rate was 11.4%, and was significantly lower for TF patients (10.5% vs. 19.4%, p<0.002). After multivariate analysis, peripheral artery disease, previous percutaneous coronary intervention, left ventricular dysfunction and NYHA class III-IV were independent predictors of 30-day all-cause mortality. At one-year follow-up, NYHA class III-IV, non-TF route and occurrence of life-threatening bleeding predicted mortality. Kaplan-Meier survival analysis of the first year of follow-up shows decreased survival for patients with an EuroS-II>5% (p<0.001) and who underwent non-TF TAVI (p<0.001). CONCLUSION: Data from our national real-world registry showed that TAVI was safe and effective. The use of a non-transfemoral approach demonstrated safety in the short term. Long-term prognosis was, however, adversely associated with this route, with comorbidities and the baseline clinical status.

Living Donor Liver Transplantation Following Transcatheter Aortic Valve Implantation for Aortic Valvular Disease.

Over the last few decades, outcomes with living donor liver transplantation (LDLT) have improved significantly. This has resulted in patients who were denied liver transplantation previously, due to various comorbidities and high risk, now being considered for LDLT. This includes patients with severe valvular heart disease such as aortic stenosis. These patients require aortic valve replacement to help cope with significant perioperative hemodynamic changes. High-risk cardiac procedures like aortic valve replacement are associated with serious perioperative morbidity and mortality in patients with end-stage liver disease. Since the advent of transcatheter aortic valve implantation (TAVI) in 2002, there have been a few case reports of its successful use prior to deceased donor liver transplantation, but there is no literature on this procedure before LDLT. In this article, we report our experience with 2 patients, the first patient with infective endocarditis-induced acute aortic regurgitation and the second patient with bicuspid aortic stenosis who underwent uneventful TAVI followed by successful LDLT. In conclusion, with the increasing expertise and experience in this procedure, an increasing number of potential recipients, previously considered as high-risk transplant candidates, can now be offered liver transplantation by performing pretransplant TAVI.

HDAC I inhibitor regulates RUNX2 transactivation through canonical and non-canonical Wnt signaling in aortic valvular interstitial cells.

OBJECTIVES: The cellular mechanisms of calcific aortic valve (AV) disease and optimal medications for its treatment are poorly elucidated. Glycogen synthase kinase (GSK)-3ß and non-canonical wingless-related integration site (Wnt) signaling play crucial roles in regulating the pathogenesis of valvular interstitial cell (VIC) calcification. Histone acetylation was found to regulate VIC calcification. However, whether histone deacetylases (HDACs) modulate the pathophysiology of AV calcification is unclear. Different HDAC isoforms have dissimilar cardiovascular effects. We hypothesized that distinctive HDAC inhibitors modulate runt-related transcription factor 2 (RUNX2) in aortic VICs through the regulation of Wnt signaling. METHODS: Western blotting, real-time polymerase chain reaction, and proliferation assay were used to analyze osteogenesis marker expression, Wnt signaling, bone morphogenetic protein (BMP) signaling, and proliferation in porcine VICs treated with osteogenic (OST) medium alone or in combination with HDAC inhibitors. RESULTS: VICs treated with OST medium for 5 days exhibited higher RUNX2 and GSK-3ß expression levels than did control cells. A class I HDAC inhibitor (MS-275 at 1 µM) reduced the RUNX2 mRNA and protein expression levels and alkaline phosphatase activity and downregulated non-canonical Wnt/GSK-3ß signaling, canonical Wnt/ß-catenin signaling, and BMP signaling. By contrast, a combined class IIa (MC1568) and IIb HDAC (tubacin) inhibitor (0.1 µM) increased RUNX2 expression. MS-275, MC1568, and tubacin reduced VIC proliferation; however, the extent of reduction differed. MS-275 reduced RUNX2 and osteocalcin expression in VICs treated with OST medium for an extended period (14 days). CONCLUSIONS: MS-275 critically regulates RUNX2 transactivation in VICs through both canonical and non-canonical Wnt signaling pathways.

Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: Seven case series and discussion.

BACKGROUND AND AIMS: For patients with homozygous familial hypercholesterolemia (HoFH), atherogenic lipoprotein changes and increased stress on cardiovascular system during pregnancy may pose substantial risk for both the mother and her fetus. Although lipoprotein apheresis (LA) is reported as the most effective therapy to control LDL-C levels during pregnancy in HoFH patients, only case reports have been published, and there is no guidance for management. METHODS: We report twelve pregnancies and ten deliveries in seven patients with HoFH, and compare the clinical outcomes between patients who received LA during pregnancy and those who did not. RESULTS: One patient who refused LA during pregnancy died from acute myocardial infarction after delivery. Another patient whose adherence to LA was poor also died of myocardial infarction during pregnancy. One patient who initiated LA at the age of 18 had to discontinue LA due to severe symptoms of angina pectoris during pregnancy. Another had symptoms of nausea, hypotension, and bradycardia with increased levels of serum bradykinin during a dextran sulfate cellulose absorption-based LA procedure. Although two of the other three patients had already had coronary artery disease by the time of pregnancy, early initiation of LA from childhood and good adherence to it during pregnancy resulted in the delivery of healthy infants without adverse effects. CONCLUSIONS: LA is essential for managing pregnancy safely in patients with HoFH. Increasing numbers of documented cases, including ours, will be helpful to guide future therapeutic decisions.

Value of three-dimensional speckle-tracking in detecting left ventricular dysfunction in patients with aortic valvular diseases.

BACKGROUND: The aim of this study was to investigate the value of three-dimensional speckle-tracking echocardiography for the detection of subclinical left ventricular dysfunction in patients with aortic valvular disease (AVD). METHODS: Fifty-nine patients with AVD in New York Heart Association functional class I or II as well as 48 controls were recruited. Patients with AVD were divided further into those with aortic stenosis (AS; n = 34) and those with aortic regurgitation (AR; n = 25). All patients underwent conventional echocardiography and three-dimensional speckle-tracking echocardiography. RESULTS: Analysis of variance showed global longitudinal strain to be compromised in the AR group (-16.9% vs -19.3%, P = .015) and more dramatically decreased in the AS group (-14.3% vs -19.3%, P < .001) compared with healthy controls. Impairment of global circumferential strain was observed in patients with AR (-15.9% vs -18.5%, P = .009) but not in those with AS (-18.2% vs -18.5%, P = .768). Global area strain and global radial strain were decreased in patients with AS and those with AR compared with controls, but the difference between the two subgroups was not significant. CONCLUSIONS: Strains measured by three-dimensional speckle-tracking echocardiography are useful indices of early-stage heart dysfunction caused by AVD. Longitudinal strain is more vulnerable to pressure overload caused by AS, whereas circumferential strain is more sensitive to volume overload due to AR.

Mortalidad a 30 días y factores de riesgo preoperatorios en la cirugía de reemplazo valvular aórtico en Uruguay / Mortality to 30 days and risk factors in preoperative replacement surgery valvular aortic in Uruguay

El Fondo Nacional de Recursos (FNR) es un sistema nacional de financiación de medicina altamente especializada; financia 380 reemplazos valvulares aórticos (RVA) anualmente. Objetivo: evaluar la mortalidad a los 30 días de la cirugía y los factores de riesgo preoperatorios en los RVA realizados en Uruguay entre el 1 de enero de 2003 y el 31 de diciembre de 2007. Métodos: se incluyeron todos los pacientes operados de RVA aislado y combinado (RVAC) con by pass coronario. La base de datos del FNR registra todas las cirugías cardíacas realizadas en Uruguay. Realizamos un análisis de regresión logística binaria para desarrollar un modelo de riesgo.Resultados: incluimos 1.930 pacientes (edad promedio 68,4 años, masculino 60,2%); mortalidad a 30 días 6,6% (127), RVA aislado 5,6% (59/1061) y RVAC 7,8% (68/869). Las variables retenidas en el modelo fueron género femenino y edad entre 60-69 años (OR 4,96; IC95% 1,33-18,55), femenino entre 70-79 años (OR 3.6; IC95% 0,99-13,13) femenino y ³ 80 años (OR 4,86; IC95% 1,09-21,72), masculino y ³ 80 años (OR 6,97; IC95% 1,60-30,37), endocarditis infecciosa activa (OR 4,1; IC95% 1,28-13,11), fracción de eyección del ventrículo izquierdo (FEVI) disminuida: fracci{on de eyección (FE) 30%-50% (OR 1,84; IC95% 1,20-2,81) y FEVI < 30%, (OR 2,23; IC95% 1,32-3,78), cirugía cardíaca previa (OR 3,79; IC95% 2,25-6,36), situación crítica pre-operatoria (OR 6,18; IC95% 2,34-16,32) e insuficiencia cardíaca clase IV (OR 2,13; IC95% 0,97-4,66). La discriminación y la calibración interna del modelo fueron buenas (índice-C= 0,72 y p=0,928 en la prueba de Hosmer-Lemeshow, respectivamente). Conclusiones: la mortalidad a 30 días en el RVA fue 6,6% y estuvo asociada a factores propios del paciente ...

FNR is a national system to grant financing for highly specialized medical services; finances 380 aortic valve replacements (AVR) annually. Objective: to evaluate 30-day mortality and preoperative risk factors in AVR made in Uruguay between 1st January 2003 and 31st December 2007. Methods: all consecutive isolated AVR and combined with coronary bypass (AVRC) were included. Register of FNR database included data about all cardiac surgeries in the country. Multivariable logistic regression analysis was used for develop a risk model. Results: 1.930 patients (age 68,4 years, male 60,2%) were included. 30-day mortality was 6,6% (127), isolate AVR 5,6% (59/1.061) and AVRC 7,8% (68/869). Variables in the model were female and age between 60-69 years (OR 4,96; IC95% 1,33-18,55), female and age between 70-79 years (OR 3,6; IC95% 0,99-13,13), female and age 80 years (OR 4,86; IC95% 1,09-21,72), male and age 80 years (OR 6,97; IC95% 1,60-30,37), active endocarditis (OR 4,1; IC95% 1,28-13,11), diminished ejection fraction (EF): EF 30 to 50% (OR 1,84; IC95% 1,20-2,81) and EF <30% (OR 2,23; IC95% 1,32-3,78), previous cardiac surgery (OR 3,79; IC95% 2,25-6,36), preoperative critical state (OR 6.18; IC95% 2.34-16.32) and class IV cardiac failure of NYHA (OR 2.13; IC95% 0,97-4,66). The discrimination of logistic risk model was good (c-index: 0,72) and the internal calibration also (Hosmer-Lemeshow test, p=0,928).Conclusions: 30-day mortality in AVR was 6,6% and was associated to patient factors (age, sex), cardiovascular disease factors (active endocarditis, previous cardíac surgery, class IV of cardíac failure, EF) and to preoperative clinical state. The risk model could be useful for clinical decisions and patient information.