Cardiac MRI–derived imaging markers demonstrated significant prognostic value in individuals with severe aortic stenosis, with right atrial strain independently predicting cardiovascular mortality and enabling identification of additional high-risk subgroups.

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. 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. 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). 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.

Journal Article Accepted manuscript Single-nucleus transcriptomics reveals adrenergic and STAT3 signaling in paradoxical low-flow low-gradient -specific cardiomyocyte subclusters: implications for aortic stenosis pathogenesis and treatment Get access Xingbo Xu, Xingbo Xu Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Correspondence: Ph.D. Xingbo Xu, Heart Research Building (DZHK), Department of Cardiology and Pneumology, University Medical Center of Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany, Telephone: +49-(0)551-3963633, Email: xingbo.xu@med.uni-goettingen.de; Dr. Gerd Hasenfuß, MD, Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075 Göttingen, Germany, Telephone: +49-(0)551-3967601, Fax: +49-(0)551-3967601, Email: hasenfus@med.uni-goettingen.de https://orcid.org/0000-0002-8249-5507 Search for other works by this author on: Oxford Academic PubMed Google Scholar Xiaoying Tan, Xiaoying Tan German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, GermanyDepartment of Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Baolong Cui, Baolong Cui Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Niels B Paul, Niels B Paul Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyDepartment of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Manar Elkenani, Manar Elkenani Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Bo E Beuthner, Bo E Beuthner Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Weichao Li, Weichao Li Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Belal A Mohamed, Belal A Mohamed Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Moritz Schnelle, Moritz Schnelle German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, GermanyDepartment of Clinical Chemistry, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Miriam Puls, Miriam Puls Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany https://orcid.org/0000-0001-5540-1264 Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Elisabeth M Zeisberg, Elisabeth M Zeisberg Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Zeisberg, Michael Zeisberg Department of Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Tim Beißbarth, Tim Beißbarth Department of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Karl Toischer, Karl Toischer Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Search for other works by this author on: Oxford Academic PubMed Google Scholar Gerd Hasenfuß Gerd Hasenfuß Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, GermanyGerman Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany Correspondence: Ph.D. Xingbo Xu, Heart Research Building (DZHK), Department of Cardiology and Pneumology, University Medical Center of Göttingen, Robert-Koch-Str. 42a, 37075 Göttingen, Germany, Telephone: +49-(0)551-3963633, Email: xingbo.xu@med.uni-goettingen.de; Dr. Gerd Hasenfuß, MD, Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075 Göttingen, Germany, Telephone: +49-(0)551-3967601, Fax: +49-(0)551-3967601, Email: hasenfus@med.uni-goettingen.de Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, cvae137, https://doi.org/10.1093/cvr/cvae137 Published: 29 June 2024 Article history Received: 15 February 2024 Revision received: 22 April 2024 Accepted: 17 June 2024 Published: 29 June 2024

Background Accurate risk stratification is important to improve patient selection and outcome of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). As epicardial adipose tissue (EAT) is discussed to be involved in cardiovascular disease, it could be useful as a marker of poor prognosis in patients with severe AS undergoing TAVR. Methods A total of 416 patients diagnosed with severe AS by transthoracic echocardiography were assigned for TAVR and enrolled for systematic assessment. Patients underwent clinical surveys and 5-year long-term follow-up, with all-cause mortality as the primary endpoint. EAT volume was quantified on pre-TAVR planning CTs. Patients were retrospectively dichotomized at the median of 74 cm 3 of EAT into groups with low EAT and high EAT volumes. Mortality rates were compared using Kaplan-Meyer plots and uni- and multivariable cox regression analyses. Results A total number of 341 of 416 patients (median age 80.9 years, 45% female) were included in the final analysis. Patients with high EAT volumes had similar short-term outcome ( p = 0.794) but significantly worse long-term prognosis ( p = 0.023) compared to patients with low EAT volumes. Increased EAT volumes were associated with worse long-term outcome (HR1.59; p = 0.031) independently from concomitant cardiovascular risk factors, general type of AS, and functional echocardiography parameters of AS severity (HR1.69; p = 0.013). Conclusion Increased EAT volume is an independent predictor of all-cause mortality in patients with severe AS undergoing TAVR. It can be easily obtained from pre-TAVR planning CTs and may thus qualify as a novel marker to improve prognostication and management of patient with severe AS. Trial registration DRKS, DRKS00024479. Graphical abstract AS, aortic stenosis; TAVR, transcatheter aortic valve replacement; EAT, epicardial adipose tissue

Abstract 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.

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.

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. Graphical Abstract Comparison of patients with high-gradient (HG) and low-gradient (LG) aortic stenosis (AS) and reduced ejection fraction. Comprehensive analyses including clinical data, gene expression analyses, cardiovascular magnetic resonance (CMR) imaging as well as echocardiography were performed. AF: Atrial fibrillation, MR: mitral regurgitation, RVEF: right ventricular ejection fraction, ECV%: extracellular volume.

AimsPatients with severe aortic stenosis (AS), low transvalvular flow (LF) and low gradient (LG) with normal ejection fraction (EF)—are referred to as paradoxical LF-LG AS (PLF-LG). PLF-LG patients develop more advanced heart failure symptoms and have a worse prognosis than patients with normal EF and high-gradient AS (NEF-HG). Despite its clinical relevance, the mechanisms underlying PLF-LG are still poorly understood.MethodsLeft ventricular (LV) myocardial biopsies of PLF-LG (n = 5) and NEF-HG patients (n = 6), obtained during transcatheter aortic valve implantation, were analyzed by LC-MS/MS after sequential extraction of cellular and extracellular matrix (ECM) proteins using a three-step extraction method. Proteomic data are available via ProteomeXchange with identifier PXD055391.Results73 cellular proteins were differentially abundant between the 2 groups. Among these, a network of proteins related to muscle contraction and arrhythmogenic cardiomyopathy (e.g., cTnI, FKBP1A and CACNA2D1) was found in PLF-LG. Extracellularly, upregulated proteins in PLF-LG were related to ATP synthesis and oxidative phosphorylation (e.g., ATP5PF, COX5B and UQCRB). Interestingly, we observed a 1.3-fold increase in cyclophilin A (CyPA), proinflammatory cytokine, in the extracellular extracts of PLF-LG AS patients (p < 0.05). Consistently, immunohistochemical analysis confirmed its extracellular localization in PLF-LG AS LV sections along with an increase in its receptor, CD147, compared to the NEF-HG AS patients. Levels of core ECM proteins, namely collagens and proteoglycans, were comparable between groups.ConclusionOur study pinpointed novel candidates and processes with potential relevance in the pathophysiology of PLF-LG. The role of CyPA in particular warrants further investigation.

Introduction: Precise risk assessment is essential for accurate management of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). This study aimed to assess the prognostic implications of cardiovascular magnetic resonance (CMR)-derived imaging biomarkers in a large cohort of AS patients. Methods: 145 patients with severe AS underwent CMR imaging before TAVR. Image analyses included myocardial volumes, CMR-feature-tracking derived left and right atrial (LA & RA) as well as left and right ventricular (LV & RV) strain, myocardial T1 mapping as well as late gadolinium enhancement analyses. Cardiovascular (CV) mortality was defined as primary clinical endpoint. Results: Patients with CV death during follow-up had significantly enlarged RV enddiastolic volumes (82.9ml/ml 2 [70.8-96.0] vs. 62.8ml/ml 2 [54.7-76.0], p<0.001) and impaired strain values of all cardiac chambers compared to patients that survived (LV GLS: -18.1% [-13.1- -20.4] vs. -22.5% [-16.1- -27.3], p=0.019; RV GLS: -22.9% [-18.6 - -25.4] vs. -27.9% [-22.9- -32.0], p=0.002; LA Es: 9.5% [7.2 - 15.4] vs. 14.3% [9.0-18.1], p=0.036; RA Es: 12.4% [6.8-14.4] vs. 16.2% [11.2-22.1], p<0.001). RA reservoir strain independently predicted CV mortality after adjusting for other CMR imaging biomarkers and clinical parameters of heart failure. Within patients with high ECV values especially RA strain further identified AS patients at high-risk for CV mortality (p=0.001 on log-rank testing). Conclusion: Comprehensive CMR-imaging allows accurate outcome assessment and additional identification of high-risk groups in AS patients. Especially RA strain emerged as independent predictor for cardiovascular mortality and might serve for future optimized patient management.

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.

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.

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.

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). 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. 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). 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

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 guidelinedefined 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 ASsubtype 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.

Background: The Cardioband tricuspid valve reconstruction system is a size-adjustable tricuspid reconstruction device for interventional treatment of tricuspid regurgitation (TR). Contraction of the device after successful implantation can be associated with an acute deformation of the right coronary artery (RCA). Aims: The aim of this study was to provide data on the persistence and clinical significance of acute RCA deformation following Cardioband implant procedures. Methods: Data from all patients with intraprocedural RCA deformation during Cardioband implantation were collected from four centres between October 2018 and January 2020. Control angiographies were performed in all of these patients before discharge. Results: RCA deformation occurred in 14 out of 51 patients. Follow-up coronary angiography showed a complete resolution of deformation in all cases while patients remained clinically asymptomatic and had an uneventful post-interventional course. Intraprocedural coronary stent implantation was performed in two of the earlier cases according to the personal assessment of the implanters. Conclusions: RCA deformation is relatively frequent following interventional tricuspid annuloplasty but appears to be completely reversible in the absence of flow impairment or vascular damage. Based on our early experience watchful waiting is the most appropriate strategy to avoid unnecessary coronary interventions.

Rationale: Increased myocardial activity of CaMKII (Ca/calmodulin-dependent kinase II) leads to heart failure and arrhythmias. In Drosophila neurons, interaction of CaMKII with CASK (Ca/CaM-dependent serine protein kinase) has been shown to inhibit CaMKII activity, but the consequences of this regulation for heart failure and ventricular arrhythmias are unknown. Objective: We hypothesize that CASK associates with CaMKII in human and mouse hearts thereby limiting CaMKII activity and that altering CASK expression in mice changes CaMKII activity accordingly, with functional consequences for contractile function and arrhythmias. Methods and Results: Immunoprecipitation revealed that CASK associates with CaMKII in human hearts. CASK expression is unaltered in heart failure but increased in patients with aortic stenosis. In mice, cardiomyocyte-specific knockout of CASK increased CaMKII-autophosphorylation at the stimulatory T287 site, but reduced phosphorylation at the inhibitory T305/306 site. Knockout of CASK mice showed increased CaMKII-dependent sarcoplasmic reticulum Ca leak, reduced sarcoplasmic reticulum Ca content, increased susceptibility to ventricular arrhythmias, greater loss of ejection fraction, and increased mortality after transverse aortic constriction. Intriguingly, stimulation of the cardiac glucagon-like peptide 1 receptor with exenatide increased CASK expression resulting in increased inhibitory CaMKII T305 phosphorylation, reduced CaMKII activity, and reduced sarcoplasmic reticulum Ca leak in wild type but not CASK-KO. Conclusions: CASK associates with CaMKII in the human heart. Knockout of CASK in mice increases CaMKII activity, leading to contractile dysfunction and arrhythmias. Increasing CASK expression reduces CaMKII activity, improves Ca handling and contractile function.

Background: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. Methods: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR ≥2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. Results: Median patient age was 76 years (73–82), median EuroScore II was 3.9% (2.2–8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9±4.8 to 7.0±3.4 mm ( P <0.001). Overall, the majority of patients (81.7%) improved at least by 1 New York Heart Association class. At follow-up 81.3% of patients presented in the New York Heart Association class I or II. The primary safety end point occurred in 4 patients with 2 in-hospital deaths, both not device related. Right coronary artery complications (vessel perforation or stent implantation) occurred in 9 patients (15%). Procedural time decreased from 298 to 185 minutes ( P <0.001) with efficacy remaining stable ( P =0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. Conclusions: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis.

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), 6months, 1 year, and 2years 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 (29.526.4% vs. 13.516.1%, 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, 11months), 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.

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 (RTr = 0.345,p = 0.039; MOLLIr = 0.40,p = 0.010) and LV matrix volumes (RTr = 0.45,p = 0.005; MOLLIr = 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.

The bioresource (>265 patients with >27,600 biospecimens until December 2019; recruitment ongoing) on severe aortic stenosis is of vital importance to improve the still incomplete understanding of its etiology as well as its transition to heart failure. The bioresource contains various biospecimens, standardised clinical and imaging data sets including transthoracic echocardiography, computed tomography and magnetic resonance imaging of the heart. Biospecimen sampling follows the SOP-driven collection scheme of the German Center for Cardiovascular Research (DZHK) for venous blood and urine [1]. In addition, left-ventricular endomyocardial biopsies, rectal swabs and skin biopsies (for subsequent generation of induced pluripotent stem cells) are collected. Data management includes the use of a professional biospecimen management system as well as a Picture Archiving and Communication System (PACS) for imaging data. A Good Clinical Practice (GCP)-conform software for the management of clinical data and a trusted third party for the management of patient identifying data and pseudonyms are in place. Given these conditions, there is a high reuse-potential for biospecimens and data. Funding statement: Parts of the bioresource were financed by the German Research Foundation (DFG) within the Collaborative Research Center (SFB) 1002.