[Mitral valve transcatheter edge-to-edge repair (M-TEER) in Germany : Treatment reality, potential needs, possible quality indicators and open questions]. / Kathetergestützter Edge-to-edge-Mitralklappenrepair (M-TEER) in Deutschland : Versorgungsrealität, potenzieller Bedarf, mögliche Qualitätsindikatoren und offene Fragen.

In 2020 in Germany, 21,753 patients were hospitalized with the main diagnosis of mitral valve regurgitation (MR), whereby 6050 isolated mitral valve (MV) operations, 4977 combined MV operations and 6011 transcatheter MV interventions were performed. In the last 10 years there was a nearly linear increase of MR-related hospitalizations and transcatheter MV interventions, whereas the numbers of isolated MV operations remained stable and the number of combined MV operations decreased. Due to demographic change and age distribution of MR patients, an increased need for minimally invasive transcatheter MV procedures can be expected in the future. In 2020 the 6011 transcatheter MV interventions were performed at approximately 180 centers in Germany. According to a retrospective analysis of diagnosis-related groups (DRG) hospital data up to 2017, two thirds of all 158 centers which provided transcatheter MV repair in Germany at that time carried out no more than 25 procedures per year. A significant correlation between hospital intervention volume and intrahospital mortality has not yet been found for transcatheter MV repair; however, registry data from Germany, Italy and the USA consistently confirm that centers with a high intervention volume achieve a better reduction of mitral regurgitation, which could directly translate into long-term survival. Thresholds of 20 or 50 procedures per year were suggested as predictive for a better procedural result in terms of MR reduction. Such analyses should be implemented in considerations regarding the appropriate number of transcatheter MV centers for Germany.

Direct proteomic and high-resolution microscopy biopsy analysis identifies distinct ventricular fates in severe aortic stenosis.

The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS.

Artificial Intelligence Enabled Fully Automated CMR Function Quantification for Optimized Risk Stratification in Patients Undergoing Transcatheter Aortic Valve Replacement.

Background: Cardiovascular magnetic resonance imaging is considered the reference standard for assessing cardiac morphology and function and has demonstrated prognostic utility in patients undergoing transcatheter aortic valve replacement (TAVR). Novel fully automated analyses may facilitate data analyses but have not yet been compared against conventional manual data acquisition in patients with severe aortic stenosis (AS). Methods: Fully automated and manual biventricular assessments were performed in 139 AS patients scheduled for TAVR using commercially available software (suiteHEART®, Neosoft; QMass®, Medis Medical Imaging Systems). Volumetric assessment included left ventricular (LV) mass, LV/right ventricular (RV) end-diastolic/end-systolic volume, LV/RV stroke volume, and LV/RV ejection fraction (EF). Results of fully automated and manual analyses were compared. Regression analyses and receiver operator characteristics including area under the curve (AUC) calculation for prediction of the primary study endpoint cardiovascular (CV) death were performed. Results: Fully automated and manual assessment of LVEF revealed similar prediction of CV mortality in univariable (manual: hazard ratio (HR) 0.970 (95% CI 0.943-0.997) p=0.032; automated: HR 0.967 (95% CI 0.939-0.995) p=0.022) and multivariable analyses (model 1: (including significant univariable parameters) manual: HR 0.968 (95% CI 0.938-0.999) p=0.043; automated: HR 0.963 [95% CI 0.933-0.995] p=0.024; model 2: (including CV risk factors) manual: HR 0.962 (95% CI 0.920-0.996) p=0.027; automated: HR 0.954 (95% CI 0.920-0.989) p=0.011). There were no differences in AUC (LVEF fully automated: 0.686; manual: 0.661; p=0.21). Absolute values of LV volumes differed significantly between automated and manual approaches (p < 0.001 for all). Fully automated quantification resulted in a time saving of 10 minutes per patient. Conclusion: Fully automated biventricular volumetric assessments enable efficient and equal risk prediction compared to conventional manual approaches. In addition to significant time saving, this may provide the tools for optimized clinical management and stratification of patients with severe AS undergoing TAVR.

Functional and structural reverse myocardial remodeling following transcatheter aortic valve replacement: a prospective cardiovascular magnetic resonance study.

BACKGROUND: Since cardiovascular magnetic resonance (CMR) imaging allows comprehensive quantification of both myocardial function and structure we aimed to assess myocardial remodeling processes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). METHODS: CMR imaging was performed in 40 patients with severe AS before and 1 year after TAVR. Image analyses comprised assessments of myocardial volumes, CMR-feature-tracking based atrial and ventricular strain, myocardial T1 mapping, extracellular volume fraction-based calculation of left ventricular (LV) cellular and matrix volumes, as well as ischemic and non-ischemic late gadolinium enhancement analyses. Moreover, biomarkers including NT-proBNP as well as functional and clinical status were documented. RESULTS: Myocardial function improved 1 year after TAVR: LV ejection fraction (57.9 ± 16.9% to 65.4 ± 14.5%, p = 0.002); LV global longitudinal (- 21.4 ± 8.0% to -25.0 ± 6.4%, p < 0.001) and circumferential strain (- 36.9 ± 14.3% to - 42.6 ± 11.8%, p = 0.001); left atrial reservoir (13.3 ± 6.3% to 17.8 ± 6.7%, p = 0.001), conduit (5.5 ± 3.2% to 8.4 ± 4.6%, p = 0.001) and boosterpump strain (8.2 ± 4.6% to 9.9 ± 4.2%, p = 0.027). This was paralleled by regression of total myocardial volume (90.3 ± 21.0 ml/m2 to 73.5 ± 17.0 ml/m2, p < 0.001) including cellular (55.2 ± 13.2 ml/m2 to 45.3 ± 11.1 ml/m2, p < 0.001) and matrix volumes (20.7 ± 6.1 ml/m2 to 18.8 ± 5.3 ml/m2, p = 0.036). These changes were paralleled by recovery from heart failure (decrease of NYHA class: p < 0.001; declining NT-proBNP levels: 2456 ± 3002 ng/L to 988 ± 1222 ng/L, p = 0.001). CONCLUSION: CMR imaging enables comprehensive detection of myocardial remodeling in patients undergoing TAVR. Regression of LV matrix volume as a surrogate for reversible diffuse myocardial fibrosis is accompanied by increase of myocardial function and recovery from heart failure. Further data are required to define the value of these parameters as therapeutic targets for optimized management of TAVR patients. Trial registration DRKS, DRKS00024479. Registered 10 December 2021-Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024479.

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

AIMS: Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. METHODS AND RESULTS: One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01]. CONCLUSION: Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Underweight is associated with inferior short and long-term outcomes after MitraClip implantation: Results from the German TRAnscatheter mitral valve interventions (TRAMI) registry.

BACKGROUND: Underweight and obesity represent classical risk factors for adverse outcome in patients treated for cardiovascular disease. AIMS: The current analysis examines the impact of underweight, overweight and obesity on intra-hospital, short and long-term outcomes in patients treated by MitraClip therapy. METHODS AND RESULTS: From August 2010 until July 2013, 799 patients (age 75.3 ±â€¯8.6 years, male gender 60.7%, median logistic EuroSCORE 20% [12; 31], functional mitral regurgitation (MR): 69.3%) were prospectively enrolled into the multicenter German Transcatheter Mitral Valve Interventions registry. Patients were stratified according to body mass index (BMI) into 4 groups: BMI <20 kg/m2 (underweight), BMI 20.0 to <25.0 kg/m2 (normal weight, reference group), BMI 25.0 to <30.0 kg/m2 (overweight) and BMI ≥30 kg/m2 (obese). Significant increased rates of procedural failure, transfusion/bleeding, sepsis or multiorgan failure and low cardiac output failure were found for underweight patients only. Kaplan-Meier survival curves demonstrated inferior survival for underweight patients, but comparable outcomes for all other patients (global log rank test, P < .01). Multivariable Cox-regression analysis (adjusted for age, gender, creatinine ≥1.5 mg/dL, diabetes, left ventricular ejection fraction <30% and chronic obstructive pulmonary disease) confirmed underweight (as compared to normal weight) as an independent risk factor of death (hazard ratio [HR]: 1.58, 95% confidence interval (CI): 1.01-2.46, P = .044) and overweight as protective against death (HR: 0.71; 95%-CI: 0.55-0.93; P = .011). CONCLUSIONS: Compared to other weight groups, underweight patients undergoing MitraClip implantation are exposed to increased rates of procedural failure, bleeding and low cardiac output as well as increased short- and long-term mortality rates and should therefore be carefully discussed in the heart-team.

Gender-related differences in patients undergoing transcatheter mitral valve interventions in clinical practice: 1-year results from the German TRAMI registry.

OBJECTIVES: Information on gender-related differences in terms of baseline characteristics and clinical outcome of patients undergoing MitraClip® implantation in daily clinical practice have been studied in smaller populations previously. This study sought to additionally evaluate gender-related differences in a larger German real-world patient population. METHODS AND RESULTS: We analyzed data from the prospective and multicenter German TRAMI Registry. Between 08/2010 and 07/2013 327 women and 501 men underwent MitraClip® implantation for significant mitral valve regurgitation. Female patients were significantly older and showed higher rates of frailty compared to men. In contrast, men had significantly higher rates of comorbidities compared to women. The majority of patients underwent MitraClip® implantation for secondary mitral regurgitation, with no significant gender-related differences. MitraClip® treatment was equally effective in terms of procedural results and residual mitral regurgitation in women and men and complication rates were low. However, in this real-world analysis severe bleeding complications were significantly higher in women (p = .02) and re-intervention rates were significantly higher in men after MitraClip® treatment (p = .02). Women showed less improvement in functional NYHA class after MitraClip® treatment compared to men at 1-year follow-up (FU; p < .001). No significant differences between female and male patients were found in 1-year mortality and in re-hospitalization rates. CONCLUSION: In this analysis from a large prospective, multicenter real-world registry MitraClip® implantation is safe and effective for treatment of significant mitral regurgitation with equal postprocedural results and mortality rates during 1-year follow-up. Men and women showed a persisting and significant clinical benefit at 1-year FU after treatment. Complication and re-intervention rates were low. Additional studies are needed to further evaluate our findings on increased bleeding complications and decreased functional improvement in women at 1-year follow-up after MitraClip® therapy.

Implantation of one versus two MitraClips in the German TRAMI registry: Is more always better?

OBJECTIVES: To compare baseline characteristics and outcomes in patients treated with either 1 or 2 MitraClips in the German TRAMI (Transcatheter Mitral Valve Interventions) registry. BACKGROUND: The MitraClip community seems to silently assume that results should intrinsically be better after implantation of more than one clip, although data is still sparse. METHODS: In 2010-2013, 803 patients were enrolled prospectively into TRAMI (461 one-clip and 312 two-clip procedures). Follow-up was performed centrally at 30 days and 1 year. RESULTS: Baseline characteristics of TRAMI-patients with two clips differed significantly from single-clip patients regarding constitutional (more men, taller body height) and heart failure-related factors (larger left ventricular dimensions, reduced left ventricular ejection fraction, more severe heart failure). Also, a significant increase in two-clip procedures over time was present. After propensity score matching for differing baseline characteristics, residual moderate mitral regurgitation (MR) occurred more frequently after implantation of two clips, whereas residual severe MR could more frequently be observed after one-clip procedures. However, no or mild residual MR at discharge was present in 71.6% after single-clip and in 70.1% after two-clips implantation (p = .81). After 1 year, no significant differences regarding mortality or New York Heart Association status could be detected in the propensity matched cohorts. However, TRAMI-patients treated with two clips had a significantly higher incidence of cerebral-vascular events (p = .02). CONCLUSIONS: TRAMI data cannot support the theory that implantation of more than one clip is associated with better clinical outcomes. The finding of more cerebral-vascular events after two-clip procedures might be hypothesis-generating.

Real-time cardiovascular magnetic resonance T1 and extracellular volume fraction mapping for tissue characterisation in aortic stenosis.

BACKGROUND: Myocardial fibrosis is a major determinant of outcome in aortic stenosis (AS). Novel fast real-time (RT) cardiovascular magnetic resonance (CMR) mapping techniques allow comprehensive quantification of fibrosis but have not yet been compared against standard techniques and histology. METHODS: Patients with severe AS underwent CMR before (n = 110) and left ventricular (LV) endomyocardial biopsy (n = 46) at transcatheter aortic valve replacement (TAVR). Midventricular short axis (SAX) native, post-contrast T1 and extracellular volume fraction (ECV) maps were generated using commercially available modified Look-Locker Inversion recovery (MOLLI) (native: 5(3)3, post-contrast: 4(1)3(1)2) and RT single-shot inversion recovery Fast Low-Angle Shot (FLASH) with radial undersampling. Focal late gadolinium enhancement was excluded from T1 and ECV regions of interest. ECV and LV mass were used to calculate LV matrix volumes. Variability and agreements were assessed between RT, MOLLI and histology using intraclass correlation coefficients, coefficients of variation and Bland Altman analyses. RESULTS: RT and MOLLI derived ECV were similar for midventricular SAX slice coverage (26.2 vs. 26.5, p = 0.073) and septal region of interest (26.2 vs. 26.5, p = 0.216). MOLLI native T1 time was in median 20 ms longer compared to RT (p < 0.001). Agreement between RT and MOLLI was best for ECV (ICC > 0.91), excellent for post-contrast T1 times (ICC > 0.81) and good for native T1 times (ICC > 0.62). Diffuse collagen volume fraction by biopsies was in median 7.8%. ECV (RT r = 0.345, p = 0.039; MOLLI r = 0.40, p = 0.010) and LV matrix volumes (RT r = 0.45, p = 0.005; MOLLI r = 0.43, p = 0.007) were the only parameters associated with histology. CONCLUSIONS: RT mapping offers fast and sufficient ECV and LV matrix volume calculation in AS patients. ECV and LV matrix volume represent robust and universally comparable parameters with associations to histologically assessed fibrosis and may emerge as potential targets for clinical decision making.

One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry.

AIMS: The transcatheter mitral valve interventions (TRAMI) registry was established in order to assess safety and efficacy of catheter-based mitral valve interventional techniques in Germany, and prospectively enrolled 828 MitraClip patients (median age 76 years, median log. EuroSCORE I 20.0%) between August 2010 and July 2013. We present the 1-year outcome in this MitraClip cohort-which is the largest published to date. METHODS AND RESULTS: Seven forty-nine patients (90.5%) were available for 1-year follow-up and included in the following analyses. Mortality, major adverse cardiovascular event rates, and New York Heart Association (NYHA) classes were recorded. Predictors of 1-year mortality were identified by multivariate analysis using a Cox regression model with stepwise forward selection. The 1-year mortality was 20.3%. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EuroQuol visual analogue scale) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005). Predictors of 1-year mortality were NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anaemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), left ventricular ejection fraction <30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe mitral regurgitation) (HR 4.36, P < 0.0001). CONCLUSIONS: Treatment of significant MR with MitraClip resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months. In the TRAMI cohort, the failure of procedural success exhibited the highest hazard ratio concerning the prediction of 1-year mortality.

Risk and outcomes of complications during and after MitraClip implantation: Experience in 828 patients from the German TRAnscatheter mitral valve interventions (TRAMI) registry.

AIMS: To analyze risk and outcomes of complications during and after MitraClip implantation using multicenter data from the prospective German Transcatheter Mitral Valve Interventions (TRAMI) registry. METHODS AND RESULTS: Data of 828 patients (mean age: 76.0 [71-81] years, 327 (40%) females) undergoing MitraClip implantation in Germany between 2010 and 2013 were analyzed. Most patients (85%) underwent elective procedures with on average implantation of 1.4 ± 0.6 clips. Emergent cardiac surgery was not required; a single patient died intraoperatively. During the in-hospital period, complications occurred in 215 (25.9%) patients, of which 106 (12.8%) were considered major. Major bleeding complications were among the most frequent major complications (7.4%), while rates of pericardial tamponade (1.9%) and clip-specific complications (embolization: 0%, partial clip detachment: 1.9%) were low. In-hospital death, stroke or myocardial infarction (MACCE) occurred in 2.2, 0.9, and 0% patients, respectively. Patients with complications appeared to be older and more critically ill pre-interventionally; in-hospital mortality was significantly higher as compared to those without procedural complications. CONCLUSIONS: MitraClip implantation appears to be a safe treatment option with low rates of MACCE and clip-specific complications. Nevertheless, MitraClip therapy is not without complications. Careful patient selection and improvements in preventing peri-procedural bleeding have the potential of reducing post-procedural complications and improving outcomes.

Lipoprotein apheresis reduces biomarkers of plaque destabilization and cardiovascular risk.

Lipoprotein apheresis (LA) is believed to exert anti-atherosclerotic effects beyond LDL-cholesterol reduction. We investigated 22 patients undergoing regular LA on a weekly basis (group A) before (AP) and after LA procedure (EP), 15 healthy individuals (group B), and 22 hyperlipoproteinemic patients with concomitant cardiovascular end organ damage treated without LA therapy (group C). Biomarkers of endothelial inflammation (hsCRP), plaque destabilization, and rupture (sVCAM, MMP-9, PAPP-A, ADMA) were quantified. Intergroup comparison revealed a statistically significant lower MMP-9 level in group A (AP and EP) compared with group C (P < 0.01), whereas PAPP-A levels were lower in group B compared with group A and C (P = 0.04). EP ADMA-levels and EP sVCAM levels in group A were statistically lower compared with group B and C. AP and EP values comparison revealed a significant reduction for hsCRP (mean 41.0 ± 16.7%, P < 0.01), sVCAM (mean 69.6 ± 14.0%, P < 0.01), PAPP-A (mean 88.7 ± 20.4%, P < 0.01), ADMA (mean 69.7 ± 18.4% P < 0.01). In conclusion, we observed a transient decrease in the plasma concentrations of several biomarkers expressed during plaque destabilization and elevated cardiovascular risk after a single LA treatment.

Low-flow in aortic valve stenosis patients with reduced ejection fraction does not depend on left ventricular function.

BACKGROUND: Patients with severe aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF) can be distinguished into high- (HG) and low-gradient (LG) subgroups. However, less is known about their characteristics and underlying (pathophysiological) hemodynamic mechanisms. METHODS: 98 AS patients with reduced LVEF were included. Subgroup characteristics were analyzed by a multimodal approach using clinical and histological data, next-generation sequencing (NGS) and applying echocardiography as well as cardiovascular magnetic resonance (CMR) imaging. Biopsy samples were analyzed with respect to fibrosis and mRNA expression profiles. RESULTS: 40 patients were classified as HG-AS and 58 patients as LG-AS. Severity of AS was comparable between the subgroups. Comparison of both subgroups revealed no differences in LVEF (p = 0.1), LV mass (p = 0.6) or end-diastolic LV diameter (p = 0.12). Neither histological (HG: 23.2% vs. LG: 25.6%, p = 0.73) and circulating biomarker-based assessment (HG: 2.6 ± 2.2% vs. LG: 3.2 ± 3.1%; p = 0.46) of myocardial fibrosis nor global gene expression patterns differed between subgroups. Mitral regurgitation (MR), atrial fibrillation (AF) and impaired right ventricular function (MR: HG: 8% vs. LG: 24%; p < 0.001; AF: HG: 30% vs. LG: 51.7%; p = 0.03; RVSVi: HG 36.7 vs. LG 31.1 ml/m2, p = 0.045; TAPSE: HG 20.2 vs. LG 17.3 mm, p = 0.002) were more frequent in LG-AS patients compared to HG-AS. These pathologies could explain the higher mortality of LG vs. HG-AS patients. CONCLUSION: In patients with low-flow severe aortic stenosis, low transaortic gradient and cardiac output are not primarily due to LV dysfunction or global changes in gene expression, but may be attributed to other additional cardiac pathologies like mitral regurgitation, atrial fibrillation or right ventricular dysfunction. These factors should also be considered during planning of aortic valve replacement.

Patients with paradoxical low-flow, low-gradient aortic stenosis gain the least benefit from TAVI among all hemodynamic subtypes.

BACKGROUND: Substantial controversy exists regarding the clinical benefit of patients with severe paradoxical low-flow, low-gradient aortic stenosis (PLF-LG AS) from TAVI. Therefore, we compared post-TAVI benefit by long-term mortality (all-cause, CV and SCD), clinical improvement of heart failure symptoms, and cardiac reverse remodelling in guideline-defined AS subtypes. METHODS: We prospectively included 250 consecutive TAVI patients. TTE, 6mwt, MLHFQ, NYHA status and NT-proBNP were recorded at baseline and 6 months. Long-term mortality and causes of death were assessed. RESULTS: 107 individuals suffered from normal EF, high gradient AS (NEF-HG AS), 36 from low EF, high gradient AS (LEF-HG), 52 from "classic" low-flow, low-gradient AS (LEF-LG AS), and 38 from paradoxical low-flow, low-gradient AS (PLF-LG AS). TAVI lead to a significant decrease in MLHFQ score and NT-proBNP levels in all subtypes except for PLF-LG. Regarding reverse remodelling, a significant increase in EF and decrease in LVEDV was present only in subtypes with reduced baseline EF, whereas a significant decrease in LVMI and LAVI could be observed in all subtypes except for PLF-LG. During a follow-up of 3-5 years, PLF-LG patients exhibited the poorest survival among all subtypes (HR 4.2, P = 0.0002 for CV mortality; HR 7.3, P = 0.004 for SCD, in comparison with NEF-HG). Importantly, PLF-LG was independently predictive for CV mortality (HR 2.9 [1.3-6.9], P = 0.009). CONCLUSIONS: PLF-LG patients exhibit the highest mortality (particularly CV and SCD), the poorest symptomatic benefit and the least reverse cardiac remodelling after TAVI among all subtypes. Thus, this cohort seems to gain the least benefit.

Cardiac fibrosis as a predictor for sudden cardiac death after transcatheter aortic valve implantation.

BACKGROUND: Cardiac fibrosis plays a major pathophysiological role in any form of chronic heart disease, and high levels are associated with poor outcome. Diffuse and focal cardiac fibrosis are different subtypes, which have different pathomechanisms and prognostic implications. The total fibrosis burden in endomyocardial biopsy tissue was recently proved to play an independent prognostic role in aortic stenosis patients after transcatheter aortic valve implantation (TAVI). AIMS: Here, for the first time, we aim to assess the specific impact of different fibrosis subtypes on sudden cardiac death (SCD) as a primary reason for cardiovascular mortality after TAVI. METHODS: The fibrosis pattern was assessed histologically in the left ventricular biopsies obtained during TAVI interventions in 161 patients, who received a structured follow-up thereafter. RESULTS: Receiver operating characteristic analyses, performed 6, 12, 24 and 48 months after TAVI, showed diffuse, but not focal, fibrosis as a significant predictor for SCD at all timepoints, with the highest area under the curve at the first time point and a decrease in its SCD predictivity over time. In both multivariate Cox proportional hazards and Fine-Gray competing risk models, including both fibrosis subtypes, as well as age, sex and ejection fraction, high diffuse fibrosis remained statistically significant. Accordingly, it represents an independent SCD predictor, most importantly for the occurrence of early events. CONCLUSIONS: The burden of diffuse cardiac fibrosis plays an important and independent prognostic role regarding SCD early after TAVI. Therefore, the histological evaluation of fibrosis topography has value as a prognostic tool for TAVI patients and may help to tailor individualised approaches to optimise their postinterventional management.

Histological assessment of cardiac amyloidosis in patients undergoing transcatheter aortic valve replacement.

AIMS: Studies have reported a strongly varying co-prevalence of aortic stenosis (AS) and cardiac amyloidosis (CA). We sought to histologically determine the co-prevalence of AS and CA in patients undergoing transcatheter aortic valve replacement (TAVR). Consequently, we aimed to derive an algorithm to identify cases in which to suspect the co-prevalence of AS and CA. METHODS AND RESULTS: In this prospective, monocentric study, endomyocardial biopsies of 162 patients undergoing TAVR between January 2017 and March 2021 at the University Medical Centre Göttingen were analysed by one pathologist blinded to clinical data using haematoxylin-eosin staining, Elastica van Gieson staining, and Congo red staining of endomyocardial biopsies. CA was identified in only eight patients (4.9%). CA patients had significantly higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (4356.20 vs. 1938.00 ng/L, P = 0.034), a lower voltage-to-mass ratio (0.73 vs. 1.46 × 10-2 mVm2/g, P = 0.022), and lower transaortic gradients (Pmean 17.5 vs. 38.0 mmHg, P = 0.004) than AS patients. Concomitant CA was associated with a higher prevalence of post-procedural acute kidney injury (50.0% vs. 13.1%, P = 0.018) and sudden cardiac death [SCD; P (log-rank test) = 0.017]. Following propensity score matching, 184 proteins were analysed to identify serum biomarkers of concomitant CA. CA patients expressed lower levels of chymotrypsin (P = 0.018) and carboxypeptidase 1 (P = 0.027). We propose an algorithm using commonly documented parameters-stroke volume index, ejection fraction, NT-proBNP levels, posterior wall thickness, and QRS voltage-to-mass ratio-to screen for CA in AS patients, reaching a sensitivity of 66.6% with a specificity of 98.1%. CONCLUSIONS: The co-prevalence of AS and CA was lower than expected, at 4.9%. Despite excellent 1 year mortality, AS + CA patients died significantly more often from SCD. We propose a multimodal algorithm to facilitate more effective screening for CA containing parameters commonly documented during clinical routine. Proteomic biomarkers may yield additional information in the future.

Complete interventional heart repair of multiple concomitant cardiac pathologies in a staged approach.

OBJECTIVES AND BACKGROUND: The evidence of multiple percutaneous cardiac procedures in patients with numerous concomitant cardiac pathologies is limited. METHODS AND RESULTS: We report on the case of a 90-year-old male patient presenting with advanced heart failure because of degenerative aortic valve stenosis and degenerative mitral valve regurgitation. Moreover, significant coronary artery disease and intolerance of anticoagulation in atrial fibrillation were present. The patient was rejected from surgery because of age and frailty and underwent a staged interventional procedure with percutaneous coronary intervention, followed by transfemoral aortic valve implantation with Edwards Sapien XT, percutaneous mitral valve repair with MitraClip, and left atrial appendage closure with Amplatzer Cardiac Plug. The last procedure was complicated by pericardial tamponade necessitating pericardial drainage. Eight weeks later, the patient reported on the absence of dyspnea in activities of daily living and a significant gain in quality of live. CONCLUSIONS: The case demonstrates feasibility of a staged interventional approach in a select high-risk patient.

Metabolomic Profiling in Patients with Different Hemodynamic Subtypes of Severe Aortic Valve Stenosis.

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography-tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications.

Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI. RESULTS: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa. CONCLUSIONS: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring.

Aortic valve calcification and myocardial fibrosis determine outcome following transcatheter aortic valve replacement.

AIMS: There is evidence to suggest that the subtype of aortic stenosis (AS), the degree of myocardial fibrosis (MF), and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Because little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as their association with adverse cardiac events following transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: One hundred consecutive patients with severe AS and indication for TAVR were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multidetector computed tomography, and left ventricular endomyocardial biopsies at the time of TAVR. The final study cohort consisted of 92 patients with a completed study protocol, 39 (42.4%) of whom showed a normal ejection fraction (EF) high-gradient (NEFHG) AS, 13 (14.1%) a low EF high-gradient (LEFHG) AS, 25 (27.2%) a low EF low-gradient (LEFLG) AS, and 15 (16.3%) a paradoxical low-flow, low-gradient (PLFLG) AS. The high-gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421 and 813 ± 281 mm3 , respectively) as compared with the low-gradient phenotypes (LEFLG and PLFLG; 503 ± 326 and 555 ± 594 mm3 , respectively, P < 0.05). Conversely, MF was most prevalent in low-output phenotypes (LEFLG > LEFHG > PLFLG > NEFHG, P < 0.05). This was paralleled by a greater cardiovascular (CV) mortality within 600 days after TAVR (LEFLG 28% > PLFLG 26.7% > LEFHG 15.4% > NEFHG 2.5%; P = 0.023). In patients with a high MF burden, a higher AVC was associated with a lower mortality following TAVR (P = 0.045, hazard ratio 0.261, 95% confidence interval 0.07-0.97). CONCLUSIONS: MF is associated with adverse CV outcome following TAVR, which is most prevalent in low EF situations. In the presence of large MF burden, patients with large AVC have better outcome following TAVR. Conversely, worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy. The better survival rates in large AVC patients following TAVR indicate TAVR induced relief of severe AS-associated pressure overload with subsequently improved outcome.