Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for high- and intermediate-risk patients with severe symptomatic aortic valve stenosis. A majority of patients exhibit improvements in left ventricular ejection fraction (LVEF) after TAVR in response to TAVR-associated afterload reduction. However, a specific role for circulating microRNAs (miRNAs) in the improvement of cardiac function for patients after TAVR has not yet been investigated. Here, we profiled the differential expression of miRNAs in circulating extracellular vesicles (EVs) in patients after TAVR and, in particular, the novel role of circulating miR-122-5p in cardiomyocytes. METHODS: Circulating EV-associated miRNAs were investigated by use of an unbiased Taqman-based human miRNA array. Several EV miRNAs (miR-122-5p, miR-26a, miR-192, miR-483-5p, miR-720, miR-885-5p, and miR-1274) were significantly deregulated in patients with aortic valve stenosis at day 7 after TAVR compared with the preprocedural levels in patients without LVEF improvement. The higher levels of miR-122-5p were negatively correlated with LVEF improvement at both day 7 (r=-0.264 and P=0.015) and 6 months (r=-0.328 and P=0.0018) after TAVR. RESULTS: Using of patient-derived samples and a murine aortic valve stenosis model, we observed that the expression of miR-122-5p correlates negatively with cardiac function, which is associated with LVEF. Mice with graded wire injury-induced aortic valve stenosis demonstrated a higher level of miR-122-5p, which was related to cardiomyocyte dysfunction. Murine ex vivo experiments revealed that miR-122-5p is highly enriched in endothelial cells compared with cardiomyocytes. Coculture experiments, copy-number analysis, and fluorescence microscopy with Cy3-labeled miR-122-5p demonstrated that miR-122-5p can be shuttled through large EVs from endothelial cells into cardiomyocytes. Gain- and loss-of-function experiments suggested that EV-mediated shuttling of miR-122-5p increases the level of miR-122-5p in recipient cardiomyocytes. Mechanistically, mass spectrometry, miRNA pulldown, electrophoretic mobility shift assay, and RNA immunoprecipitation experiments confirmed that miR-122-5p interacts with the RNA-binding protein hnRNPU (heterogeneous nuclear ribonucleoprotein U) in a sequence-specific manner to encapsulate miR-122-5p into large EVs. On shuttling, miR-122-5p reduces the expression of the antiapoptotic gene BCL2 by binding to its 3' untranslated region to inhibit its translation, thereby decreasing the viability of target cardiomyocytes. CONCLUSIONS: Increased levels of circulating proapoptotic EV-incorporated miR-122-5p are associated with reduced LVEF after TAVR. EV shuttling of miR-122-5p regulates the viability and apoptosis of cardiomyocytes in a BCL2-dependent manner.

Prevalence of sleep-disordered breathing in patients with mitral regurgitation and the effect of mitral valve repair.

PURPOSE: The relationship between chronic heart failure and sleep-disordered breathing (SDB) has been frequently described. However, little is known about the association of mitral regurgitation (MR) and SDB or the impact of transcatheter mitral valve repair (TMVR) on SDB. Our aims were first to determine the prevalence of SDB in patients with MR, and second to determine the effect of TMVR on SDB. METHODS: Patients with MR being evaluated for TMVR at the University Hospital Bonn underwent polygraphy (PG) to determine the prevalence of SDB. After TMVR, a subset of patients was followed up with transthoracic echocardiography (TTE) and PG to evaluate the effect of TMVR on SDB. RESULTS: In 53 patients, mean age was 76.0 ± 8.5 years and 62% were male. Patients predominantly had more than moderate mitral regurgitation (94%). SDB was highly prevalent (68%) with predominantly central sleep apnoea (CSA, 67%). After TMVR in 15 patients, the apnoea/hypopnoea index (AHI) and central apnoea index (AI) were significantly reduced among patients with SDB (AHI - 8.0/h, p = 0.021; central AI - 6.9/h, p = 0.046). The left atrial volume index (LAVI) at baseline was significantly higher in patients with CSA than in patients with obstructive sleep apnoea (OSA) and was significantly reduced after TMVR (63.5 ml/m2 ± 27.2 vs. 38.3 ml/m2 ± 13.0; - 18.4 ml/m2, p = 0.027). CONCLUSION: SDB, especially CSA, is highly prevalent in patients with mitral regurgitation. In the follow-up cohort TMVR led to a significant reduction of the AHI, predominantly of central events. The findings of the study suggest that TMVR may be a suitable therapy not only for MR but also for the accompanying CSA. LAVI may be a useful indicator for CSA in patients with MR.

Frailty, malnutrition, and the endocrine system impact outcome in patients undergoing aortic valve replacement.

BACKGROUND: Frailty is a multidimensional syndrome that affects mortality after aortic valve replacement (AVR). Malnutrition is often associated with the development of frailty. However, data regarding the association of frailty with nutritional status and underlying endocrinological dysregulation in patients with severe aortic valve stenosis are limited. OBJECTIVES: We aimed to systematically screen for frailty and malnutrition, to evaluate for underlying endocrinological disorders and inflammation, and to assess the ability of these parameters to predict outcomes after AVR. METHODS: Our study included 373 patients undergoing transcatheter and surgical AVR. Frailty was assessed using the Fried Frailty Phenotype (FFP), Essential Frailty Toolset, Lawton-Brody, and Katz Index. Malnutrition was measured using the Mini Nutritional Assessment (MNA-LF) and Controlling Nutritional Status. Outcomes of interest were 30-day and one-year mortality. RESULTS: The prevalence of frailty ranged from 6.4% to 65.7% and malnutrition from 5.9% to 10.5%, depending on the evaluation tool. Both parameters were associated with higher levels of cortisol and parathormone as well as lower levels of IGF-1, testosterone, DHEAS, and c-reactive protein. Malnutrition was associated with increased 30-day mortality, and both frailty and malnutrition with increased one-year mortality. In a multivariate analysis, malnutrition measured by the MNA-LF (OR: 2.32 [95%CI: 1.19-4.53], p = 0.01) and frailty as assessed by the FFP (OR: 1.42 [95%CI: 1.02-1.96], p = 0.03) were independent predictors of one-year mortality. CONCLUSION: The prevalence of frailty and malnutrition varies significantly depending on the assessment tool. Both syndromes share common endocrinological alterations. Frailty and malnutrition are independent risk factors for mortality after AVR.

Feasibility and Safety of an 8 F Angioseal® Vascular Closure Device for Closure of Large Bore Impella CP® Access.

PURPOSE: Percutaneous mechanical circulatory support (pMCS) with the Impella® device is routinely used in cardiogenic shock and high risk percutaneous coronary interventions (PCI). However, safety and feasibility to close the large bore access (LBA) post-hoc remain a challenge. MATERIALS AND METHODS: In patients with planned termination of Impella therapy, corresponding LBA closure was attempted using an undersized AngioSeal® device, which was deployed after insertion of a 0.035 in J-wire through the guidewire access port. Cross-over angiographic visualization before and after deployment as well as in-hospital follow up were performed to assess closure success and screening for short-term adverse events. RESULTS: We evaluated 17 patients (68 year old, IQR 58-76, 71% male) in whom 14 F LBA closure after pMCS using the Impella CP® was achieved with an undersized AngioSeal® device. Clinical indication for pMCS was cardiogenic shock in 94% and protected PCI in 6%. Impella CP® devices were withdrawn after a median of 4 days (IQR 3-6 days). Primary hemostasis was achieved in the majority of patients (14/17; 82%) while single cross-over balloon inflation led to hemostasis in the remaining patients. One patient suffered acute ischemia later in the course of the disease, but this was not directly related to the closure device. In this study, no major bleeding or other device-related adverse events were observed. CONCLUSION: The 8 F AngioSeal® vascular closure device has been safely used for removal of the Impella CP® microaxial pump in most cases of predominantly normal weight patients. This technique may be considered feasible for post-hoc LBA closure in the context of pMCS, especially when preclosure options are not suitable or unavailable.

Latest Advances in Transcatheter Aortic Valve Implantation (2022).

Since the last decade, transcatheter aortic valve implantation (TAVI) has become the treatment of choice in patients with symptomatic severe aortic stenosis (AS) who are ineligible or at higher risk for surgery. Due to the high safety profile of current device generation, TAVI has emerged as a qualified alternative to surgical aortic valve replacement (SAVR) in patients with classic aortic stenosis and intermediate surgical risk, severe bicuspid aortic valve stenosis, and isolated pure aortic regurgitation. Moderate aortic stenosis, with and without concomitant heart failure with reduced ejection fraction, are under investigation in randomized controlled clinical trials from which we will gain exciting insights on the best timing of TAVI to protect the left ventricle from further functional deterioration due to increasing AS. In these cases, a meticulous diagnostic approach including advanced imaging is becoming more and more important. Current evidence on antithrombotic strategies after TAVI is weak, contributing to poor levels of standardization and high variability in daily clinical practice. This review will provide a short overview of recent clinical trials including best timing for TAVI with moderate AS and antithrombotic strategies after TAVI with current and future TAVI generations.

Prognostic significance of the get with the guidelines-heart failure (GWTG-HF) risk score in patients undergoing trans-catheter tricuspid valve repair (TTVR).

The Get-With-The-Guidelines-Heart-Failure (GWTG-HF) score is a risk assessment tool to predict mortality in patients with heart-failure (HF). We aimed to evaluate the GWTG-HF score for risk stratification in HF patients with tricuspid regurgitation undergoing trans-catheter tricuspid valve repair (TTVR). In total, 181 patients who underwent TTVR via edge-to-edge repair (86%) or annuloplasty (14%) were enrolled. Patients were categorized into a low- (≤ 43 points), intermediate- (44-53 points) and high-risk score groups (≥ 54 points). TTVR led to an improvement of TR (p < 0.0001) and NYHA (p < 0.0001). Kaplan-Meier analysis and log-rank test revealed that higher GWTG-HF scores were associated with reduced rates of event-free survival regarding mortality (96% vs 89% vs 73%, respectively, p = 0.001) and hospitalization for heart failure (HHF) (89% vs 86% vs 74%, respectively, p = 0.026). After adjusting for important variables like renal function, left ventricular ejection fraction and mitral regurgitation, the GWTG-HF score remained an independent predictor of the composite endpoint of HHF or mortality (hazard ratio 1.04 per 1-point increase, p = 0.029). Other remaining predictors were renal function and mitral regurgitation. The GWTG-HF score used as a risk stratification tool of mortality and HHF maintains its prognostic value in a HF population with severe TR undergoing TTVR.

Prognostic value of myeloperoxidase in patients with peripheral artery disease.

OBJECTIVES: The involvement of myeloperoxidase in the production of dysfunctional high-density lipoproteins and oxidised biomolecules leads to oxidative stress in the blood vessel endothelium. This prospective cohort study aimed to examine the prognostic value of myeloperoxidase in patients with peripheral artery disease in relation to major adverse cardiac events (MACEs), target lesion revascularisation, and major adverse limb events (MALEs) and its association with multi-bed vascular disease, which is defined as any combination of the following: peripheral artery disease and coronary artery disease. METHODS: Myeloperoxidase levels were measured in patients with peripheral artery disease and coronary artery disease during angiography. A total of 94 patients were analysed and followed up regarding their MACEs, target lesion revascularisation, and MALEs from August 2016 until February 2019. RESULTS: Among patients with peripheral artery disease, the rates of MACE and mortality were higher in patients with high myeloperoxidase levels than in those with low myeloperoxidase levels; the myeloperoxidase levels were 3.68 times higher in these patients (p < 0.0001). Patients with peripheral artery disease and coronary artery disease (multi-bed vascular disease) had higher myeloperoxidase levels than those with only peripheral artery disease and only coronary artery disease (one-bed vascular disease). Peripheral artery disease patients with higher myeloperoxidase levels had significantly higher rates of limb ischaemia, requiring further revascularisation than those with low myeloperoxidase levels. CONCLUSIONS: High myeloperoxidase levels suggest poor outcomes and are associated with MACE and limb ischaemia. Our findings indicated that myeloperoxidase levels could become a prognostic marker and may be used in conjunction with other methods for risk stratification in patients with peripheral artery disease and multi-bed vascular disease.

Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.

BACKGROUND: Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). METHODS: Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 µg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. RESULTS: RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1ß were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. CONCLUSION: Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI.

Influence of smoking dosage and chronic obstructive lung disease on the incidence of appropriate therapies and mortality in patients with structural heart disease and an implantable cardioverter defibrillator.

BACKGROUND: Smoking is known as a relevant risk factor for severe cardiac morbidities and mortality. This study was initiated to explore the influence of smoking dosage and presence of chronic obstructive lung disease (COPD) on the incidence of appropriate implantable cardioverter defibrillator (ICD) interventions and on mortality. METHODS: Prior studies on patients equipped with an ICD suggested that nicotine consumption increases the risk of experiencing an appropriate ICD therapy. There is no substantial data regarding the influence of cigarette smoking dosage on overall mortality in such endangered patients. A total of 349 patients with structural heart disease, either coronary artery disease or nonischemic cardiomyopathy equipped with an ICD, were included. Every patient answered a questionnaire regarding his smoking status and performed a spirometry and body plethysmography. RESULTS: A total of 104 patients (30%) suffered from COPD. Fifty-eight patients (17%) were "current smokers," 196 patients (56%) were revealed as "former smokers," while 93 (27%) patients were registered as "never smokers." A total of 163 patients (47%) received at least one appropriate ICD intervention during follow-up (median 48 ± 8 months). Twenty-three patients died during this study (6.6%). There was no association of COPD with the incidence of appropriate ICD therapies or mortality. Smoking dosage revealed as a significant risk factor for both appropriate ICD interventions (hazard ratio [HR] 1.5 for 60 pack years [PY] P = 0.04) and mortality (HR 2.3 for 60 PY P = 0.02). CONCLUSION: This study demonstrates a dose-related increased risk of smokers for appropriate ICD interventions and mortality. The results of this trail urge a strict nicotine abstinence, especially in patients with a structural heart disease undergoing ICD therapy.

ACURATE neo2 Versus SAPIEN 3 Ultra Transcatheter Heart Valve in Severe Aortic Valve Calcification: A Propensity-Matched Analysis.

BACKGROUND: Comparative data on transcatheter self-expanding ACURATE neo2 (NEO2) and balloon-expandable SAPIEN 3 Ultra prostheses in technically challenging anatomy of severe aortic valve calcified aortic annuli are scarce. METHODS: A total of 1987 patients with severe native aortic stenosis treated with the self-expanding NEO2 (n=1457) or balloon-expandable SAPIEN 3 Ultra (n=530) from January 2017 to April 2023 were evaluated. The primary end point was procedural outcome according to the Valve Academic Research Consortium 3 definitions. Propensity matching defined 219 pairs with severe calcification (calcium density cutoff, 758 AU/cm2) of the native aortic valve. RESULTS: Technical success (90.4% versus 91.8%; risk difference, 1.4% [95% CI, -4.4 to -7.2]; P=0.737) and device success at 30 days (80.8% versus 75.8%; risk difference, -5.0% [95% CI, -13.2 to 3.1]; P=0.246) were comparable between NEO2 and SAPIEN 3 Ultra. The rate of severe prosthesis-patient mismatch (1.1% versus 10.1%; risk difference, 10.0% [95% CI, 4.0-13.9]; P<0.001) and mean transvalvular gradient ≥20 mm Hg (2.8% versus 14.3%; risk difference, 11.5% [95% CI, 5.8-17.1]; P<0.001) was lower with NEO2. The rate of more-than-mild paravalvular leakage or valve-in-valve due to paravalvular leakage was significantly higher (6.2% versus 0.0%; risk difference, 6.2% [95% CI, -10.1 to -2.7]; P=0.002), and there was a tendency for a higher rate of device embolization or migration (1.8% versus 0.0%; risk difference, -1.8% [95% CI, -4.1 to 0.4]; P=0.123) with NEO2. Multivarate regression revealed no independent impact of transcatheter heart valve selection on device success (odds ratio, 0.93 [95% CI, 0.48-1.77]; P=0.817). CONCLUSIONS: In patients with severely calcified annuli, supraannular implantation of NEO2 showed hemodynamic advantages. Nevertheless, NEO2 was associated with a higher incidence of relevant paravalvular leakage and a numerically higher rate of device embolization than SAPIEN 3 Ultra in this particular patient group.

AT1-receptor-deficiency induced atheroprotection in diabetic mice is partially mediated via PPARγ.

OBJECTIVE: Peroxisome-proliferator-activated-receptor-γ (PPARγ) acts as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism. In vitro studies showed that activated PPARγ suppresses AT1R-gene expression and vice versa. However, it has not yet been determined in vivo, whether AT1R-PPARγ-interactions play a relevant role in the pathogenesis of diabetic complications and specifically in accelerated atherosclerosis. METHODS AND RESULTS: ApoE-/- and ApoE-/-/AT1R-/--mice were rendered diabetic by intraperitoneal injections of streptozotocin. Diabetic and non-diabetic ApoE-/--mice were further randomized to receive the AT1R antagonist telmisartan, the selective PPARγ antagonist GW9662, telmisartan and GW9662 or vehicle for 18 weeks. Diabetic and non-diabetic ApoE-/-/AT1R-/--mice were randomized to receive either GW9662 or vehicle. GW9662 treatment in diabetic ApoE-/- and diabetic ApoE-/-/AT1-/--mice resulted in the highest elevation of fasting blood glucose levels, whereas telmisartan treatment and AT1 deficiency in ApoE-/--mice showed the lowest fasting blood glucose levels. Diabetic ApoE-/--mice displayed severe impairment of endothelial function, enhanced oxidative stress and increased atherosclerotic lesion formation. ApoE-/-/AT1R-/- and telmisartan-treated ApoE-/--mice showed a significantly better endothelial function, decreased oxidative stress and reduced atherosclerotic lesion formation. Treatment of diabetic ApoE-/- and ApoE-/-/AT1R-/--mice with the selective PPARγ antagonist GW9662 omitted the atheroprotective effects of AT1R deficiency or AT1 antagonism. CONCLUSION: Genetic disruption or pharmacological inhibition of the AT1R attenuates atherosclerosis and improves endothelial function in diabetic ApoE-/--mice via the PPARγ pathway.

The Safety and Efficacy of Ultrasound-Accelerated Catheter-Directed Thrombolysis in Patients with Intermediate-High-Risk Pulmonary Embolism: Bo-NE-Experience.

Ultrasound-accelerated thrombolysis (USAT) is an advanced interventional therapy for patients with intermediate-high-risk pulmonary embolism (PE) who deteriorated on anticoagulation or for high-risk patients for whom systemic thrombolysis is contraindicated. The aim of this study is to investigate the safety and efficacy of this therapy with a focus on the improvement of vital signs and laboratory parameters. Seventy-nine patients with intermediate-high-risk PE were treated with USAT from August 2020 to November 2022. The therapy significantly decreased the mean RV/LV ratio from 1.2 ± 0.22 to 0.9 ± 0.2 (p < 0.001) as well as the mean PAPs from 48.6 ± 11 to 30.1 ± 9.0 mmHg (p < 0.001). The respiratory and heart rate decreased significantly (p < 0.001). Serum creatinine decreased significantly from 1.0 ± 0.35 to 0.9 ± 0.3 (p < 0.001). There were 12 access-associated complications, which could be treated conservatively. One patient had haemothorax after the therapy and had to be operated on. USAT is an effective therapy for patients with intermediate-high-risk PE, with favourable hemodynamic, clinical, and laboratory outcomes.

Prognostic Impact of the Get-with-the-Guidelines Heart-Failure Risk Score (GWTG-HF) after Transcatheter Aortic Valve Replacement in Patients with Low-Flow-Low-Gradient Aortic Valve Stenosis.

OBJECTIVES: This study examined the prognostic value of the get-with-the-guidelines heart-failure risk score (GWTG-HF) on mortality in patients with low-flow-low-gradient aortic valve stenosis (LFLG-AS) after transcatheter aortic valve implantation (TAVI). BACKGROUND: Data on feasibility of TAVI and mortality prediction in the LFLG-AS population are scarce. Clinical risk assessment in this particular population is difficult, and a score has not yet been established for this purpose. METHODS: A total of 212 heart failure (HF) patients with real LFLG-AS were enrolled. Patients were classified into low-risk (n = 108), intermediate-risk (n = 90) and high-risk (n = 14) groups calculated by the GWTG-HF score. Clinical outcomes of cardiovascular events according to Valve Academic Research Consortium (VARC-2) recommendations and composite endpoint of death and hospitalization for heart failure (HHF) were assessed at discharge and 1 year of follow-up. RESULTS: Baseline parameters of the groups showed a median age of 81.0 years [77.0; 84.0] (79.0 vs. 82.0 vs. 86.0, respectively p < 0.001), median EuroSCORE II of 6.6 [4.3; 10.7] (5.5 vs. 7.2 vs. 9.1, p = 0.004) and median indexed stroke volume of 26.7 mL/m2 [22.0; 31.0] (28.2 vs. 25.8 vs. 25.0, p = 0.004). The groups significantly differed at follow-up in terms of all-cause mortality (10.2 vs. 21.1 vs. 28.6%; p < 0.035). There was no difference in intrahospital event rate (VARC). Postprocedural mean gradients were lower in high-risk group (7.0 vs. 7.0 vs. 5.0 mmHg, p = 0.011). No differences in postprocedural aortic valve area (1.9 vs. 1.7 vs. 1.9 cm2, p = 0.518) or rate of device failure (5.6 vs. 6.8 vs. 7.7%, p = 0.731) could be observed. After adjustment for known predictors, the GWTG score (HR 1.07 [1.01-1.14], p = 0.030) as well as pacemaker implantation (HR 3.97 [1.34-11.75], p = 0.013) turned out to be possible predictors for mortality. An increase in stroke volume index (SVI) was, in contrast, protective (HR 0.90 [0.83-0.97]; p = 0.006). CONCLUSIONS: The GWTG score may predict mortality after TAVI in LFLG-AS HF patients. Interestingly, all groups showed similar intrahospital event and mortality rates, independent of calculated mortality risk. Low SVI and new conduction disturbances associated with PPI after THV implantation had negative impact on mid-term outcome in post-TAVI HF-patients.

Procedural Outcomes of a Self-Expanding Transcatheter Heart Valve in Patients with Porcelain Aorta.

BACKGROUND: Severe calcification of the ascending aorta increases the peri-operative risk for neurological complications in patients with severe aortic stenosis. Transcatheter aortic valve implantation (TAVI) seems to be an optimal treatment option in these patients. However, the impact of the extent of aortic calcification on procedural and neurological outcomes during TAVI is unclear. METHODS: Data from 3010 patients with severe native aortic valve stenosis treated with ACURATE neo/neo2 from May 2012 to July 2022 were evaluated and matched by 2-to-1 nearest-neighbor matching to identify one patient with porcelain aorta (PA) (n = 492) compared with two patients without PA (n = 984). PA was additionally subdivided into circumferential (classic PA) (n = 89; 3.0%) and non-circumferential (partial PA) (n = 403; 13.4%) calcification. We compared outcomes according to VARC-3 criteria among patients with and without PA and identified predictors for occurrence of stroke in the overall population. RESULTS: Technical success (88.5% vs. 87.4%, p = 0.589) and device success at 30 days (82.3% vs. 81.5%, p = 0.755) after transcatheter ACURATE neo/neo2 implantation according to VARC-3 definition was high and did not differ between non-calcified aortas or PA. The rate of in-hospital complications according to VARC-3-definitions was low in both groups. Rates of all stroke (3.2% (n = 31) vs. 2.6% (n = 13), p = 0.705) or transitory ischemic attacks (1.1% vs. 1.2%, p = 1.000) did not differ significantly. Thirty-day all-cause mortality did not differ (3.0% vs. 3.2%, RR 1.1; p = 0.775). Overall device migration/embolization (OR 5.0 [2.10;11.87]), severe bleeding (OR 1.79 [1.11;2.89]), and major structural cardiac complications (OR 3.37 [1.32;8.57]) were identified as independent predictors for in-hospital stroke in a multivariate analysis after implantation of ACURATE neo/neo2. CONCLUSION: A porcelain aorta does not increase the risk of neurological complications after transfemoral ACURATE neo/neo2 implantation. Based on these findings, transfemoral ACURATE neo/neo2 implantation is safe in these particularly vulnerable patients.

Comparison of the New-Generation Self-Expanding NAVITOR Transcatheter Heart Valve with Its Predecessor, the PORTICO, in Severe Native Aortic Valve Stenosis.

BACKGROUND: Third-generation transcatheter heart valves (THVs) are designed to improve outcomes. Data on the new intra-annular self-expanding NAVITOR are scarce. AIMS: The aim of this analysis was to compare outcomes between the PORTICO and the NAVITOR systems. METHODS: Data from 782 patients with severe native aortic stenosis treated with PORTICO (n = 645) or NAVITOR (n = 137) from 05/2012 to 09/2022 were evaluated. The clinical and hemodynamic outcomes of 276 patients (PORTICO, n = 139; NAVITOR, n = 137) were evaluated according to VARC-3 recommendations. RESULTS: Rates of postprocedural more-than-mild paravalvular leakage (PVL) were significantly lower for NAVITOR than for PORTICO (7.2% vs. 1.5%, p = 0.041). In addition, severe bleeding rates (27.3% vs. 13.1%, p = 0.005) and major vascular complications (5.8% vs. 0.7%, p = 0.036) were lower in the NAVITOR group. The mean gradients (7 vs. 8 mmHg, p = 0.121) and calculated aortic valve areas (1.90 cm2 vs. 1.99 cm2, p = 0.235) were comparable. Rates of PPI were similarly high in both groups (15.3 vs. 21.6, p = 0.299). CONCLUSIONS: The NAVITOR demonstrated favorable in-hospital procedural outcome data, with lower rates of relevant PVL, major vascular complications, and severe bleeding than its predecessor the PORTICO and preserved favorable hemodynamic outcomes.

Left ventricular reverse remodeling after transcatheter aortic valve implantation in patients with low-flow low-gradient aortic stenosis.

OBJECTIVES: Left ventricular reverse remodeling (LVRR) is associated with improved outcome in patients with heart failure. Factors associated with and predictive of LVRR in patients with low-flow low-gradient aortic stenosis (LFLG AS) after transcatheter aortic valve implantation (TAVI) and its impact on outcome were assessed. METHODS: Pre- and postprocedural left ventricular (LV) function and volume were investigated in 219 patients with LFLG. LVRR was defined as an absolute increase of ≥10% in LV ejection fraction (LVEF) and reduction of ≥15% in LV end-systolic volume (LVESV). The primary endpoint was the combination of all-cause mortality and rehospitalization for heart failure. RESULTS: The mean LVEF was 35.0 ± 10.0%, with a stroke volume index (SVI) of 25.9 ± 6.0 mL/m2 and LVESV of 94.04 ± 46.0 mL. At a median of 5.2 months (interquartile range, 2.7-8.1 months), 77.2% (n = 169) of the patients showed echocardiographic evidence of LVRR. A multivariate model revealed three independent factors for LVRR after TAVI: SVI of <25 mL/m2 (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.08-3.58; p < 0.01), LVEF of <30% (HR, 2.76; 95% CI, 1.53-2.91; p < 0.01), and valvulo-arterial impedance (Zva) of <5 mmHg/mL/m2 (HR, 5.36; 95% CI, 1.80-15.98; p < 0.01). Patients without evidence of LVRR showed a significantly higher incidence of the 1-year combined endpoint (32 [64.0%] vs. 75 [44.4%], p < 0.01). CONCLUSIONS: The majority of patients with LFLG AS show LVRR after TAVI, which is associated with favorable outcomes. An SVI of <25 mL/m2, LVEF of <30%, and Zva < 5mmHg/mL/m2 represent predictors of LVRR.

Estrogen improves vascular function via peroxisome-proliferator-activated-receptor-γ.

The exact mechanism of estrogen in cardiovascular disease is not fully understood. As estrogen receptors (ERs), the peroxisome-proliferator-activated-receptor-γ (PPARγ) belongs to the family of ligand activated nuclear receptors regulating atheroprotective genes. The aim of this project was to investigate whether vascular effects of estrogen are mediated via PPARγ-regulation in the vascular compartment. Estrogen deficient ovariectomized wildtype-mice (OVX) displayed significant reduction of PPARγ-expression in aortic tissue compared to wildtype-mice with intact ovarian function (Sham). Hormone replacement with subdermal 17ß-estradiol pellets significantly increased vascular PPARγ-expression in ovariectomized female wildtype-mice (OVX/E2). Analogous to wildtype-mice, estrogen-deficient OVX ApoE(-/-)-mice had low vascular PPARγ-expression associated with ROS generation, endothelial dysfunction and atherogenesis. Estrogen replacement (OVX/E2) rescued vascular PPARγ-expression, reduced ROS generation, monocyte recruitment, atherosclerotic lesion formation and improved endothelial function. Inhibition of PPARγ by GW9662, a specific PPARγ-antagonist reduced 17ß-estradiol mediated vascular effects (OVX/E2+GW9662). Finally, despite estrogen deficiency treatment with pioglitazone (OVX+pioglitazone), a selective PPARγ-agonist, compensates deterioration of vascular morphology and function. 17ß-estradiol regulates vascular PPARγ-expression in wildtype- and ApoE(-/-)-mice. The presented data demonstrate the fundamental relevance of PPARγ as downstream target of 17ß-estradiol-related anti-inflammatory and atheroprotective effects within the vascular wall independent of its cardiovascular risk factor modifications.

Stimulation of the AT2 receptor reduced atherogenesis in ApoE(-/-)/AT1A(-/-) double knock out mice.

AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A(-/-)). ApoE(-/-) mice and ApoE(-/-)/AT1A(-/-) mice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE(-/-) mice, but were markedly reduced in ApoE(-/-)/AT1A(-/-) mice. Concomitant treatment of ApoE(-/-)/AT1A(-/-) mice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE(-/-)/AT1A(-/-) mice compared to untreated ApoE(-/-)/AT1A(-/-) mice whereas pharmacological AT1 receptor inhibition with telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE(-/-)/AT1A(-/-) mice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE(-/-)/AT1A(-/-) mice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology.

Interleukin-6 is the strongest predictor of 30-day mortality in patients with cardiogenic shock due to myocardial infarction.

INTRODUCTION: Cardiogenic shock (CS) remains the leading cause of death in patients hospitalized for myocardial infarction (MI). Systemic inflammation with inappropriate vasodilatation is observed in many patients with CS and may contribute to an excess mortality rate. The purpose of this study was to determine the predictive role of serial measurements of Nt-proBNP, interleukin-6 (IL-6), and procalcitonin (PCT) for 30-day mortality in patients with CS due to MI. METHODS: The present study is a prospective single-center study including 87 patients with MI complicated by CS treated with acute revascularization and intraaortic balloon counterpulsation (IABP) support. Predictive values of plasma levels at admission (T0), after 24 hours (T1), and after 72 hours (T2) were examined according to 30-day mortality. RESULTS: Significant differences between survivors (n = 59) and nonsurvivors (n = 28) were seen for Nt-proBNP at T0, for IL-6 at T0 and T1, and for PCT at T1 and T2. According to ROC analyses, the highest accuracy predicting 30-day mortality was seen at T0 for IL-6, at T1 for PCT, and at T2 for PCT. In univariate analysis, significant values were found for Nt-proBNP at T1, and for IL-6 and PCT at all points in time. Within the multivariate analysis, age, creatinine, and IL-6 were significant determinants of 30-day mortality, in which IL-6 showed the highest level of significance. CONCLUSIONS: In patients with MI complicated by CS, IL-6 represented a reliable independent early prognostic marker of 30-day mortality. PCT revealed a significant value at later points in time, whereas Nt-proBNP seemed to be of lower relevance.

Transcatheter-based aortic valve replacement vs. isolated surgical aortic valve replacement in 2020.

BACKGROUND: Based on the results of several recent randomized trials, European and American guidelines on valvular heart disease management have substantially expanded the indications for transcatheter aortic valve implantation (TAVI). We present an all-comer data on peri-operative risk profile and in-hospital outcomes from Germany for patients treated by TAVI or isolated surgical aortic valve replacement (iSAVR) in 2020, providing an opportunity to compare study data with data from daily clinical practice. METHODS: Data concerning all isolated aortic valve procedures performed in Germany in 2020 were retrieved from the mandatory nationwide quality control program. Expected mortality was calculated with the annually revised German Aortic valve score (AKL-score) based on the data of either catheter-based (AKL-CATH) or isolated surgical (AKL-CHIR) aortic valve replacement in Germany from the previous year (2019). RESULTS: In 2020 21,903 TAVI procedures (20,810 transvascular (TV; vs. 2019: 22.973; - 9.4%), 1093 transapical (TA; vs. 2019: 1413; - 22.6%)) and 6144 (vs. 2019 7905; - 22.5%) iSAVR were performed in Germany. Patients who received TAVI showed a significantly higher perioperative risk profile than patients undergoing iSAVR based on older age and more severe co-morbidities. While in-hospital mortality after TAVI (2.3%) was numerically lower than in 2019 (2.5%), this difference was not significant (p = 0.11). In-hospital mortality after iSAVR was identical in 2020 and 2019 (2.8%) and thus higher than after TAVI (p = 0.003), resulting in an observed expected mortality ratio of 1.02 after TAVI and 1.05 after iSAVR. After exclusion of the emergency procedures, in-hospital mortality did not differ significantly between the groups (TAVI 2.2% vs. iSAVR 1.9%, p = 0.26). CONCLUSION: Total numbers of both iSAVR and TAVI in Germany were lower in 2020 than in 2019, most likely due to the COVID-19 pandemic. However, the relative number of patients treated by TAVI as compared to iSAVR continues to increase. Despite older age and more severe comorbidities compared to patients undergoing iSAVR the in-hospital mortality after TAVI continued to decrease in 2020 and remains significantly lower than after iSAVR.