Retrospective analysis of Advanced Heart Failure and/or Cardiogenic Shock in Patients with Aortic Valve Stenosis Treated by Transcatheter Aortic Valve Replacement and a Nomogram Model Construction.

Objective: Currently, there is little information about the risk of sudden cardiac death and its predictors in aortic valve stenosis patients after transcatheter aortic valve replacement (TAVR). Therefore, we conducted a large sample cohort study on TAVR patients to evaluate the predictive factors and incidence of heart failure death caused by advanced heart failure (AHF) and sudden cardiac death. Furthermore, a nomogram model to predict its risk was constructed. Methods: This study retrospectively analyzed the data of 241 consecutive participants who had received TAVR treatment for aortic valve stenosis in our hospital from January 2020 to January 2022. The characteristics of the subjects, including myocardial zymogram, renal function, biochemical parameters, and cardiac ultrasound parameters, were collected. Moreover, a nomogram was constructed to predict the risk of sudden cardiac death and its predictors in patients after transcatheter aortic valve replacement (TAVR). The model was validatedinternally using measures of calibration and decision curve analysis. Results: Six independent risk factors(Age, smoking, diabetes, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and fasting blood glucose) were finally recruited into the nomogram model to predict the risk of advanced heart failure and/or cardiogenic shock in AS patients treated by TAVR. Besides, the decision curve analysis and receiver operating characteristic curve indicated that the nomogram prediction models showed positive clinical benefits. Conclusions: The Age, smoking, diabetes, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and fasting blood glucose are the independent risk factors for advanced heart failure and/or cardiogenic shock in AS patients treated by TAVR. The construction of nomograms is beneficial in predicting the risk of advanced heart failure and/or cardiogenic shock in AS patients treated by TAVR.

Impact of the COVID-19 pandemic on provision of interventional cardiology and cardiac surgery services in Australia: a review of Medicare claims data.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted healthcare service provision worldwide. There is limited information on changes in invasive cardiovascular services during the pandemic, particularly in Australia. AIM: We sought to assess temporal trends on the use of interventional cardiology and cardiac surgery services before and following the COVID-19 pandemic in Australia. METHODS: Medicare Benefits Schedule items data from the Australian Government Services Australia on outpatient and private hospital interventional cardiology procedures (coronary angiogram, percutaneous coronary intervention and transcatheter aortic valve implantation) and cardiac surgery procedures (coronary artery bypass grafting [CABG] and surgical valve replacement, repair and annuloplasty) were analysed from March 2019 to 2021. This was superimposed on monthly COVID-19 case data obtained from the Australian Department of Health and Aged Care epidemiology reports. RESULTS: A sustained reduction in CABG (-10.1%) and surgical valve intervention (-11.1%) was appreciated from March 2019-2020 to March 2020-2021, in the first year of the COVID-19 pandemic. During this period, an overall increase (+25.9%) in the use of transcatheter aortic valve implantation was observed. Following the initial period of mandated isolation in March-April 2020, a reduction in coronary angiography (-29.1%) and percutaneous coronary intervention (-19.5%) was observed in comparison to March-April 2019; however, this was largely attenuated over time. CONCLUSIONS: The COVID-19 pandemic has resulted in reductions in the use of interventional cardiology and cardiac surgery services, with cardiac surgery most affected. However, an increase in uptake of transcatheter aortic valve implantation has been observed during the pandemic. This may have implications for future planning and resource allocation in the aftermath of the pandemic.

Considering alternatives to transcatheter heart valves for managing patients with severe aortic valve stenosis.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is becoming the standard of care for severe symptomatic aortic stenosis (AS). Yet, some patients with AS are not indicated/eligible for TAVI. Several noninvasive, catheter-based or surgical alternatives exist, and other therapeutic options are emerging. AREAS COVERED: This review provides an overview of non-TAVI options for severe AS. Non-invasive, transcatheter, and alternative surgical strategies are discussed, emphasizing their backgrounds, techniques, and outcomes. EXPERT OPINION: Alternative therapies to TAVI, whether device-based or non-device-based, continue to evolve or emerge and provide either alternative treatments or a bridge to TAVI, for patients not meeting indications for, or having contraindications to TAVI.Although TAVI and SAVR are the current dominant therapies, there are still some patients that could benefit in the future from other alternatives.Data on alternative options for such patients are scarce. Many advantages and disadvantages arise when selecting a specific treatment strategy for individual patients.Head-to-head comparison studies could guide physicians toward better patient selection and procedural planning. Awareness of therapeutic options, indications, techniques, and outcomes should enable heart teams to achieve optimized patient selection. Furthermore, it can increase the use of these alternatives to optimize the management of AS among different patient populations.

α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice.

BACKGROUND: In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD+ levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes. METHODS: In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD+ levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis. RESULTS: AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD+ levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed. CONCLUSION: Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD+, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.

Prevalence of Aortic Valve Calcium and the Long-Term Risk of Incident Severe Aortic Stenosis.

BACKGROUND: Aortic valve calcification (AVC) is a principal mechanism underlying aortic stenosis (AS). OBJECTIVES: This study sought to determine the prevalence of AVC and its association with the long-term risk for severe AS. METHODS: Noncontrast cardiac computed tomography was performed among 6,814 participants free of known cardiovascular disease at MESA (Multi-Ethnic Study of Atherosclerosis) visit 1. AVC was quantified using the Agatston method, and normative age-, sex-, and race/ethnicity-specific AVC percentiles were derived. The adjudication of severe AS was performed via chart review of all hospital visits and supplemented with visit 6 echocardiographic data. The association between AVC and long-term incident severe AS was evaluated using multivariable Cox HRs. RESULTS: AVC was present in 913 participants (13.4%). The probability of AVC >0 and AVC scores increased with age and were generally highest among men and White participants. In general, the probability of AVC >0 among women was equivalent to men of the same race/ethnicity who were approximately 10 years younger. Incident adjudicated severe AS occurred in 84 participants over a median follow-up of 16.7 years. Higher AVC scores were exponentially associated with the absolute risk and relative risk of severe AS with adjusted HRs of 12.9 (95% CI: 5.6-29.7), 76.4 (95% CI: 34.3-170.2), and 380.9 (95% CI: 169.7-855.0) for AVC groups 1 to 99, 100 to 299, and ≥300 compared with AVC = 0. CONCLUSIONS: The probability of AVC >0 varied significantly by age, sex, and race/ethnicity. The risk of severe AS was exponentially higher with higher AVC scores, whereas AVC = 0 was associated with an extremely low long-term risk of severe AS. The measurement of AVC provides clinically relevant information to assess an individual's long-term risk for severe AS.

Local versus General Anaesthesia for Transcatheter Aortic Valve Implantation (TAVI): A Systematic Review, Meta-Analysis, and Trial Sequential Analysis of Randomised and Propensity-Score Matched Studies.

Transcatheter aortic valve implantation (TAVI) is a common practice for severe aortic stenosis, but the choice between general (GA) and local anesthesia (LA) remains uncertain. We conducted a comprehensive literature review until April 2023, comparing the safety and efficacy of LA versus GA in TAVI procedures. Our findings indicate significant advantages of LA, including lower 30-day mortality rates (RR: 0.69; 95% CI [0.58, 0.82]; p < 0.001), shorter in-hospital stays (mean difference: -0.91 days; 95% CI [-1.63, -0.20]; p = 0.01), reduced bleeding/transfusion incidents (RR: 0.64; 95% CI [0.48, 0.85]; p < 0.01), and fewer respiratory complications (RR: 0.56; 95% CI [0.42, 0.76], p<0.01). Other operative outcomes were comparable. Our findings reinforce prior evidence, presenting a compelling case for LA's safety and efficacy. While patient preferences and clinical nuances must be considered, our study propels the discourse towards a more informed anaesthesia approach for TAVI procedures.

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.

Improved Reversion of Calcifications in Porcine Aortic Heart Valves Using Elastin-Targeted Nanoparticles.

Calcified aortic valve disease in its final stage leads to aortic valve stenosis, limiting cardiac function. To date, surgical intervention is the only option for treating calcific aortic valve stenosis. This study combined controlled drug delivery by nanoparticles (NPs) and active targeting by antibody conjugation. The chelating agent diethylenetriaminepentaacetic acid (DTPA) was covalently bound to human serum albumin (HSA)-based NP, and the NP surface was modified using conjugating antibodies (anti-elastin or isotype IgG control). Calcification was induced ex vivo in porcine aortic valves by preincubation in an osteogenic medium containing 2.5 mM sodium phosphate for five days. Valve calcifications mainly consisted of basic calcium phosphate crystals. Calcifications were effectively resolved by adding 1-5 mg DTPA/mL medium. Incubation with pure DTPA, however, was associated with a loss of cellular viability. Reversal of calcifications was also achieved with DTPA-coupled anti-elastin-targeted NPs containing 1 mg DTPA equivalent. The addition of these NPs to the conditioned media resulted in significant regression of the valve calcifications compared to that in the IgG-NP control without affecting cellular viability. These results represent a step further toward the development of targeted nanoparticular formulations to dissolve aortic valve calcifications.

[Emergent Transcatheter Aortic Valve Implantation for Degenerated Surgical Aortic Valve Under Local Anesthesia:Report of a Case].

An 89-year-old man who had undergone aortic valve replacement with a 21 mm Mosaic bioprosthetic valve at another hospital 14 years ago was admitted to the emergency room for a sudden respiratory distress two days prior and was diagnosed with severe aortic regurgitation( AR) caused by valve insufficiency and acute heart failure secondary to low cardiac function. Upon admission, he was found to have severe hypoxia with PaO2 of 40 mmHg range, and transcatheter aortic valve replacement (TAVI, TAV in SAV) with a 20 mm SAPIEN3 was performed under local anesthesia for fear of hypotension while under general anesthesia. After confirming that AR had completely disappeared, the patient was intubated and discharged from the operating room on a mechanical ventilator. The patient was weaned from the ventilator on the second postoperative day and was transferred to the other hospital for rehabilitation, 48 days postoperatively. Although there is no report on the comparative study of anesthesia methods for emergency transcatheter aortic valve implantation( TAVI), TAVI under regional anesthesia is minimally invasive with a lower risk for hypotension than general anesthesia. Therefore, we believe it is useful for patients with acute heart failure and hypotension. In addition, it is important to use a balloon expandable valve with excellent implantability to complete the procedure in a short time.

Virtual reality-assisted distraction during transcatheter aortic valve implantation under local anaesthesia: A randomised study.

BACKGROUND: A minimal approach, using local anaesthesia alone, has been advocated to promote faster transcatheter aortic valve replacement (TAVR) procedures in intermediate-risk patients. Pre- and periprocedural anxiety and pain remain a concern. Virtual reality (VR) is a form of non-pharmacological distraction that can potentially modulate pain and anxiety. This randomised study explored whether VR reduces pain and anxiety during TAVR without sedation and compared the effects of VR with those of standard care. METHODS AND RESULTS: Between June 2022 and March 2023, 207 patients underwent transfemoral TAVR (TF-TAVR). Of these, 117 (56.5%) patients were willing to participate in the study and met the educational background and mental status criteria for assessment. Fifty-nine patients underwent TF-TAVR with VR glasses (VR group). Fifty-eight patients underwent standard TF-TAVR without VR (control group; CG). Post-interventional anxiety scores (STAI-S) (31.5 ± 13.4 vs. 38.5 ± 19.2, p = 0.02) and the perceived duration of the procedure (60.1 ± 32.3 vs. 73.0 ± 32.4, p = 0.04) were lower in the VR than in the CG. Procedure time, pain, and anxiety scores (visual analogue scale) were similar between the groups. The complication rate was low and not associated with VR. Post-interventional delirium occurred in nine patients, and was similar between the groups (VR: 4 [6.8%] vs. CG: 5 [8.6%], p = 0.71). No periprocedural strokes were observed. CONCLUSION: VR for TAVR is feasible and safe and expands the non-drug spectrum of therapy for anxiety and pain in patients undergoing TAVR with a minimalistic approach.

Application and Evaluation of Real-time Three-dimensional Echocardiography in Transcatheter Aortic Valve Implantation.

Objective: This assessed the value of real-time three-dimensional echocardiography in patients with aortic valve lesions before and after transcatheter aortic valve implantation. Methods: A total of 61 patients were admitted for transcatheter aortic valve implantation due to aortic valve lesions between October 2021 and August 2022 (research group), and 55 patients who underwent a healthy physical examination during the same period (control group) were included. All participants underwent real-time three-dimensional echocardiography. Changes in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left ventricular ejection fraction, maximum velocity, and left ventricular mass index were observed at 1 week and 1 month after the surgery. Additionally, the research group was further divided based on the type of lesion to investigate the differences in real-time three-dimensional echocardiography findings between patients with moderate to severe aortic stenosis and moderate to severe aortic insufficiency. The occurrence of postoperative complications in the research group was also recorded to assess the role of real-time three-dimensional echocardiography in postoperative complication assessment after transcatheter aortic valve implantation. Results: Preoperative left ventricular ejection fraction did not differ significantly between the two groups (P > .05). However, the research group exhibited higher preoperative left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left ventricular mass index, and maximum velocity compared to the control group (P < .05). At 1 week postoperatively, the research group showed significant reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left ventricular mass index, and maximum velocity compared to preoperative values (P < .05). Furthermore, at 1 month postoperatively, the left ventricular mass index was further reduced (P < .05). Among the research group, patients with aortic stenosis had lower preoperative left ventricular end-diastolic volume index and left ventricular end-systolic volume index compared to patients with aortic insufficiency, while maximum velocity was higher (P < .05). Patients who experienced postoperative complications after transcatheter aortic valve implantation had lower left ventricular end-diastolic volume index, left ventricular end-systolic volume index and left ventricular mass index, and higher maximum velocity before and at 1 week after surgery (P < .05). Conclusions: Real-time three-dimensional echocardiography demonstrated excellent assessment capabilities for aortic valve lesions and accurately guided the determination of left ventricular mass index, showcasing its significant clinical applications.

Single-Stage Procedure of Transcatheter Aortic Valve Replacement and Endovascular Aneurysm Repair Under Local Anaesthesia and Percutaneous Access.

PURPOSE: Abdominal aortic aneurysms (AAA) are observed in 6% of patients with concomitant aortic valve stenosis (AS) requiring aortic valve replacement. Optimal management of these concomitant pathologies is still debated. CASE REPORT: An 80-year-old man presented with acute heart failure due to a severe AS. Past medical history included AAA under regular surveillance. A thoracic and abdominal computed tomography angiography (CTA) confirmed a 6 mm increase of AAA over an 8-month period (max 55 mm). A multidisciplinary team prescribed a simultaneous endovascular approach of transcatheter aortic valve implantation (TAVI) followed by endovascular aneurysm repair (EVAR) under local anaesthesia with bilateral femoral percutaneous access. No intra or post-procedural complications were registered; technical success was confirmed by completion angiography and post-operative ultrasound. The patient was discharged on postoperative day 5. A 2-month post-operative CTA confirmed ongoing technical success. CONCLUSION: Combined TAVI and EVAR under local anaesthesia for AS and AAA was associated with reduced hospital stay and technical success at 2 months from intervention in this case report.

Structural Heart Interventions in the Elderly Population.

Aortic stenosis is the most common valvular heart disease in the elderly population. Since the advent of transcatheter aortic valve implantation (TAVI) in 2002, the clinical indications for this alternative to a surgical replacement have continually expanded. While the treatment of octo- and nonagenarians can present significant challenges, here we present a case of TAVI in an elderly patient. Given her suitable anatomy and active lifestyle that had been limited by her disease state, the patient successfully underwent TAVI 3 weeks later and was discharged post-operative day 1. This case is the basis for providing five key points to remember about the work-up for TAVI for severe aortic stenosis in the elderly population.

Transcatheter aortic valve intervention in patients with cancer.

The prevalence of concurrent cancer and severe aortic stenosis (AS) is increasing due to an ageing population. In addition to shared traditional risk factors for AS and cancer, patients with cancer may be at increased risk for AS due to off-target effects of cancer-related therapy, such as mediastinal radiation therapy (XRT), as well as shared non-traditional pathophysiological mechanisms. Compared with surgical aortic valve replacement, major adverse events are generally lower in patients with cancer undergoing transcatheter aortic valve intervention (TAVI), especially in those with history of mediastinal XRT. Similar procedural and short-to-intermediate TAVI outcomes have been observed in patients with cancer as compared with no cancer, whereas long-term outcomes are dependent on cancer survival. Considerable heterogeneity exists between cancer subtypes and stage, with worse outcomes observed in those with active and advanced-stage disease as well as specific cancer subtypes. Procedural management in patients with cancer poses unique challenges and thus requires periprocedural expertise and close collaboration with the referring oncology team. The decision to ultimately pursue TAVI involves a multidisciplinary and holistic approach in assessing the appropriateness of intervention. Further clinical trial and registry studies are needed to better appreciate outcomes in this population.

Temporal trends in the prevalence and severity of aortic stenosis within a contemporary and diverse community-based cohort.

BACKGROUND: Data on the epidemiology of aortic stenosis (AS) are primarily derived from single center experiences and administrative claims data that do not delineate by degree of disease severity. METHODS: An observational cohort study of adults with echocardiographic AS was conducted January 1st, 2013-December 31st, 2019 at an integrated health system. The presence/grade of AS was based on physician interpretation of echocardiograms. RESULTS: A total of 66,992 echocardiogram reports for 37,228 individuals were identified. The mean ± standard deviation (SD) age was 77.5 ± 10.5, 50.5% (N = 18,816) were women, and 67.2% (N = 25,016) were non-Hispanic whites. The age-standardized AS prevalence increased from 589 (95% Confidence Interval [CI] 580-598) to 754 (95% CI 744-764) cases per 100,000 during the study period. The age-standardized AS prevalences were similar in magnitude among non-Hispanic whites (820, 95% CI 806-834), non-Hispanic blacks (728, 95% CI 687-769), and Hispanics (789, 95% CI 759-819) and substantially lower for Asian/Pacific Islanders (511, 95% CI 489-533). Finally, the distribution of AS by degree of severity remained relatively unchanged over time. CONCLUSIONS AND RELEVANCE: The population prevalence of AS has grown considerably over a short timeframe although the distribution of AS severity has remained stable.

General Anesthesia Versus Local Anesthesia in Patients Undergoing Transcatheter Aortic Valve Replacement: An Updated Meta-Analysis and Systematic Review.

OBJECTIVES: For patients with aortic stenosis, transcatheter aortic valve replacement (TAVR) offers a less invasive treatment modality than conventional surgical valve replacement. Although the surgery is performed traditionally under general anesthesia (GA), recent studies have described success with TAVR using local anesthesia (LA) and/or conscious sedation. The study authors performed a pairwise meta-analysis to compare the clinical outcomes of TAVR based on operative anesthesia management. DESIGN: A random effects pairwise meta-analysis via the Mantel-Haenszel method. SETTING: Not applicable, as this is a meta-analysis. PARTICIPANTS: No individual patient data were used. INTERVENTIONS: Not applicable, as this is a meta-analysis. MEASUREMENTS AND MAIN RESULTS: The authors comprehensively searched the PubMed, Embase, and Cochrane databases to identify studies comparing TAVR performed using LA or GA. Outcomes were pooled as risk ratios (RR) or standard mean differences (SMD) and their 95% CIs. The authors' pooled analysis included 14,388 patients from 40 studies (7,754 LA; 6,634 GA). Compared to GA TAVR, LA TAVR was associated with significantly lower rates of 30-day mortality (RR 0.69; p < 0.01) and stroke (RR 0.78; p = 0.02). Additionally, LA TAVR patients had lower rates of 30-day major and/or life-threatening bleeding (RR 0.64; p = 0.01), 30-day major vascular complications (RR 0.76; p = 0.02), and long-term mortality (RR 0.75; p = 0.009). No significant difference was seen between the 2 groups for a 30-day paravalvular leak (RR 0.88, p = 0.12). CONCLUSIONS: Transcatheter aortic valve replacement performed using LA is associated with lower rates of adverse clinical outcomes, including 30-day mortality and stroke. No difference was seen between the 2 groups for a 30-day paravalvular leak. These results support the use of minimally invasive forms of TAVR without GA.

Network-Guided Multiomic Mapping of Aortic Valve Calcification.

Despite devastating clinical sequelae of calcific aortic valve disease that range from left ventricular remodeling to arrhythmias, heart failure, and early death, the molecular insights into disease initiation and progression are limited and pharmacotherapies remain unavailable. The pathobiology of calcific aortic valve disease is complex and comprehensive studies are challenging valvular calcification is heterogeneous and occurs preferentially on the aortic surface, along a fibrocalcific spectrum. Here, we review efforts to study (epi-)genomic, transcriptomic, proteomic, and metabolomic aspects of aortic valve calcification in combination with network medicine-/systems biology-based strategies to integrate multilayered omics datasets and prioritize druggable targets for experimental validation studies. Ultimately, such holistic approach efforts may open therapeutic avenues that go beyond invasive and costly valve replacement therapy.

Choosing transcatheter aortic valve replacement in porcelain aorta: outcomes versus surgical replacement.

OBJECTIVES: Porcelain aorta complicates aortic valve replacement and is an indication for transcatheter approaches. No study has compared surgical and transcatheter valve replacement in the setting of porcelain aorta. We characterize porcelain aorta patients undergoing aortic valve replacement and the association of aortic calcification and outcomes. METHODS: Patients undergoing aortic valve replacement with porcelain aorta were identified. Aortic calcium volume was determined using 3D computed tomography thresholding techniques. Propensity scoring was performed to assess the effect of surgical versus transcatheter approaches. Risk factors for composite major hospital complications (death, stroke and dialysis) were identified using random forest machine learning. RESULTS: From January 2006 to January 2015, 164 patients with porcelain aorta underwent aortic valve replacement [105 (64%) surgical replacement, 59 (36%) transcatheter replacement]. Propensity scoring matched 29 pairs (49% of transcatheter patients). Before matching, 5-year survival was 41% [(43% surgical, 35% transcatheter, P(log-rank) = 0.9]. After matching, mortality for surgical versus transcatheter replacement was 3.4% (n = 1) vs 10% (n = 3), stroke 14% (n = 4) vs 3.4% (n = 1) and dialysis 6.9% (n = 2) versus 11% (n = 3). Matched 5-year survival was 40% after surgical replacement and 29% after transcatheter replacement [P(log-rank) = 0.4]. Total aortic calcium volume was greater in transcatheter than surgical patients [18 (8.0) vs 17 (7.7) ml] and was associated with more major hospital complications after either approach. CONCLUSIONS: Surgical and transcatheter approaches are complementary options for aortic stenosis with porcelain aorta. Surgical valve replacement remains an effective treatment for patients requiring concomitant procedures. Quantifying aortic calcium volume is a helpful risk predictor in all patients with porcelain aorta.

Salidroside ameliorates pathological cardiac hypertrophy via TLR4-TAK1-dependent signaling.

Salidroside, a prominent active ingredient in traditional Chinese medicines, is garnering increased attention because of its unique pharmacological effects against ischemic heart disease via MAPK signaling, which plays a critical role in regulating the evolution of ventricular hypertrophy. However, the function of Salidroside on myocardial hypertrophy has not yet been elucidated. C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with Salidroside (100 mg kg-1  day-1 ) by oral gavage for 3 weeks starting 1 week after surgery. Four weeks after TAC surgery, the mice were subjected to echocardiography and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes were used to validate the protective effects of Salidroside in response to Angiotensin II (Ang II, 1 µM) stimulation. Here, we proved that Salidroside dramatically inhibited hypertrophic reactions generated by pressure overload and isoproterenol (ISO) injection. Salidroside prevented the activation of the TAK1-JNK/p38 axis. Salidroside pretreatment of TAK1-inhibited cardiomyocytes shows no additional attenuation of Ang II-induced cardiomyocytes hypertrophy and signaling pathway activation. The overexpression of constitutively active TAK1 removed the protective effects of Salidroside on myocardial hypertrophy. TAC-induced increase of TLR4 protein expression was reduced considerably in the Salidroside treated mice. Transient transfection of small interfering RNA targeting TLR4 (siTLR4) in cardiomyocytes did not further decrease the activation of the TAK1/JNK-p38 axis. In conclusion, Salidroside functioned as a TLR4 inhibitor and displayed anti-hypertrophic action via the TAK1/JNK-p38 pathway.

ALP Inhibitors Inhibit Inflammatory Responses and Osteoblast Differentiation in hVIC via AKT-ERK Pathways.

Objective: The aim of this study was to explore the calcification process of aortic valve interstitial cells and its potential association with osteogenic differentiation and alkaline phosphatase (ALP) activity. Methods: The study patients were divided into 3 groups: the control group, the osteogenic induction medium (OM) group and the OM+ALP inhibitor group. Cell calcification was measured by alizarin red S staining and alizarin red S dye released by extracellular matrix (ECM) was quantified by spectrophotometry. Immunohistochemical staining was performed on valve tissues of patients harboring calcified and non-calcified aortic valve disease. Expression of bone morphogenetic protein (BMP), runt related transcription factor 2 (RUNX2), osteocalcin and osteopontin (OPN), was evaluated using immunohistochemistry¸and expression of osteogenic specific markers (BMP, RUNX2 and OPN) was detected using Wesern blot analysis. RNA sequencing was analyzed to further study the exact mechanism of ALP inhibitors in terms of inhibiting the osteogenic differentiation of valvular interstitial cells (VIC). The mRNA levels of tumor necrosis factor alpha (TNF-α), Toll-like receptor 4 (TLR4) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), were detected using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). In addition, Western blot analysis was performed to evaluate the expression of phosphorylated extracellular regulated protein kinases (ERK), nuclear factor κ B inhibitor α (IκBα) and protein kinase B (AKT) in protein. Results: Alizarin red staining was positive in the OM and OM+ALP inhibitor groups, and calcified nodules were formed in VIC, which showed a significant difference compared with the control group (P < .05). The semi-quantitative level of calcification in the OM group was higher than in the control group (P < .05), and the semi-quantitative level of calcification in the OM+ALP inhibitor group was lower than in the OM group (P < .05). ALP staining intensity, ALP activity and messenger RNA (mRNA) levels of BMP, RUNX2, osteocalcin, OPN, ERK, IκBα, AKT, TNF-α, Toll-like receptor 4 (TLR4) and NLRP3 inflammasome (NLRP3) in the OM group were higher than in the control group (P < .05). ALP staining intensity, ALP activity and mRNA expressions of BMP, RUNX2, osteocalcin, OPN, phosphorylated ERK, IκBα, AKT, TNF-α and NLRP3 in the OM+ALP inhibitor group were lower than in the OM group (P < .05). Compared with the control group, 723 genes were upregulated and 248 genes were downregulated in the OM group. Compared with the OM group, 352 genes were upregulated and 586 genes were downregulated in the OM+ALP inhibitor group. Conclusion: We suggest that ALP inhibitors have potential in terms of inhibiting the inflammatory response and osteoblast differentiation of human VIC (hVIC) via the TLR4, AKT, ERK and NLRP3 pathways.