Fractional flow reserve measurements and long-term mortality-results from the FLORIDA study.

Background: Randomized evidence suggested improved outcomes in fractional flow reserve (FFR) guidance of coronary revascularization compared to medical therapy in well-defined patient cohorts. However, the impact of FFR-guided revascularization on long-term outcomes of unselected patients with chronic or acute coronary syndromes (ACS) is unknown. Aims: The FLORIDA (Fractional FLOw Reserve In cardiovascular DiseAses) study sought to investigate outcomes of FFR-guided vs. angiography-guided treatment strategies in a large, real-world cohort. Methods: This study included patients enrolled into the German InGef Research Database. Patients undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Eligible patients had at least one inpatient coronary angiogram for suspected coronary artery disease between January 2014 and December 2015. Patients were stratified into FFR arm if a coronary angiography with adjunctive FFR measurement was performed, otherwise into the angiography-only arm. Matching was applied to ensure a balanced distribution of baseline characteristics in the study cohort. Patients were followed for 3 years after index date and primary endpoint was all-cause mortality. Results: In the matched population, mortality at 3 years was 9.6% in the FFR-assessed group and 12.6% in the angiography-only group (p = 0.002), corresponding to a 24% relative risk reduction with use of FFR. This effect was most pronounced in patients in whom revascularization was deferred based on FFR (8.7% vs. 12.3%, p = 0.04) and in high-risk subgroups including patients aged ≥75 years (14.9% vs. 20.1%, p < 0.01) and those presenting with ACS (10.2% vs. 14.0%, p = 0.04). Conclusions: FFR-based revascularization strategy was associated with reduced mortality at 3 years. These findings further support the use of FFR in everyday clinical practice.

Single-nuclear transcriptome profiling identifies persistent fibroblast activation in hypertrophic and failing human hearts of patients with longstanding disease.

AIMS: Cardiac fibrosis drives the progression of heart failure in ischaemic and hypertrophic cardiomyopathy. Therefore, the development of specific anti-fibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients. METHODS AND RESULTS: We used single-nuclei RNA sequencing with human tissues from two samples of one healthy donor, and five hypertrophic and two failing hearts. Unsupervised sub-clustering of 7110 nuclei led to the identification of 7 distinct fibroblast clusters. De-convolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a pro-fibrotic extra-cellular matrix composition in patients with established cardiac hypertrophy and heart failure. This sub-cluster was characterized by high expression of POSTN, RUNX1, CILP, and a target gene adipocyte enhancer-binding protein 1 (AEBP1) (all P < 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (P < 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA-mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, and fibroblast contractile capacity and α-SMA gene expression, which is a hallmark of fibroblast activation (all P < 0.05). Mechanistically, the anti-fibrotic effects of AEBP1 silencing were linked to transforming growth factor-beta pathway modulation. CONCLUSION: Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts.

Clinical outcomes of subcutaneous vs. transvenous implantable defibrillator therapy in a polymorbid patient cohort.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has been designed to overcome lead-related complications and device endocarditis. Lacking the ability for pacing or resynchronization therapy its usage is limited to selected patients at risk for sudden cardiac death (SCD). Objective: The aim of this single-center study was to assess clinical outcomes of S-ICD and single-chamber transvenous (TV)-ICD in an all-comers population. Methods: The study cohort comprised a total of 119 ICD patients who underwent either S-ICD (n = 35) or TV-ICD (n = 84) implantation at the University Hospital Frankfurt from 2009 to 2017. By applying an inverse probability-weighting (IPW) analysis based on the propensity score including the Charlson Comorbidity Index (CCI) to adjust for potential extracardiac comorbidities, we aimed for head-to-head comparison on the study composite endpoint: overall survival, hospitalization, and device-associated events (including appropriate and inappropriate shocks or system-related complications). Results: The median age of the study population was 66.0 years, 22.7% of the patients were female. The underlying heart disease was ischemic cardiomyopathy (61.4%) with a median LVEF of 30%. Only 52.9% had received an ICD for primary prevention, most of the patients (67.3%) had advanced heart failure (NYHA class II-III) and 16.8% were in atrial fibrillation. CCI was 5 points in TV-ICD patients vs. 4 points for patients with S-ICD (p = 0.209) indicating increased morbidity. The composite endpoint occurred in 38 patients (31.9 %), revealing no significant difference between patients implanted with an S-ICD or TV-ICD (unweighted HR 1.50, 95 % confidence interval (CI) 0.78-2.90; p = 0.229, weighted HR 0.94, 95% CI, 0.61-1.50, p = 0.777). Furthermore, we observed no difference in any single clinical endpoint or device-associated outcome, neither in the unweighted cohort nor following inverse probability-weighting. Conclusion: Clinical outcomes of the S-ICD and TV-ICD revealed no differences in the composite endpoint including survival, freedom of hospitalization and device-associated events, even after careful adjustment for potential confounders. Moreover, the CCI was evaluated in a S-ICD cohort demonstrating higher survival rates than predicted by the CCI in young, polymorbid (S-)ICD patients.

Low Circulating Musclin is Associated With Adverse Prognosis in Patients Undergoing Transcatheter Aortic Valve Implantation at Low-Intermediate Risk.

Background Musclin is an activity-stimulated and cardioprotective myokine that attenuates pathological cardiac remodeling. Musclin deficiency, in turn, results in reduced physical endurance. The aim of this study was to assess the prognostic value of circulating musclin as a novel, putative biomarker to identify patients undergoing transcatheter aortic valve implantation (TAVI) who are at a higher risk of death. Methods and Results In this study, we measured systemic musclin levels in 368 patients undergoing TAVI who were at low to intermediate clinical risk (median EuroSCORE [European System for Cardiac Operative Risk Evaluation] II: 3.5; quartile 1-quartile, 2.2%-5.3%), whereby 209 (56.8%) patients were at low and 159 (43.2%) were at intermediate risk. Median preprocedural musclin levels were 2.7 ng/mL (quartile 1-quartile 3, 1.5-4.6 ng/mL). Musclin levels were dichotomized in low (<2.862 ng/mL, n=199 [54.1%]) or high (≥ 2.862 ng/mL, n=169 [45.9%]) groups using cutoff values determined by classification and regression tree analysis. The primary end point was 1-year overall survival. Patients with low circulating musclin levels exhibited a significantly higher prevalence of frailty, low albumin values, hypertension, and history of stroke as well as higher N-terminal pro-B-type natriuretic peptide. Low musclin levels significantly predicted risk of death in univariable (hazard ratio, 1.81; 95% CI, 1.00-3.53 [P=0.049]) and multivariable (adjusted hazard ratio, 2.45; 95% CI, 1.06-5.69 [P=0.037]) Cox regression analyses. Additionally, low musclin levels in combination with conventional EuroSCORE II suggested improved risk stratification in patients undergoing TAVI who were at low to intermediate clinical risk into subgroups with reduced 1-year survival rates by log-rank test (P for trend=0.003). Conclusions Circulating musclin is an independent predictor of 1-year overall survival in patients undergoing TAVI. Combined with EuroSCORE II, circulating musclin might help to improve prediction of mortality in patients undergoing TAVI who are at low to intermediate clinical risk.

Inflammatory signatures are associated with increased mortality after transfemoral transcatheter aortic valve implantation.

AIMS: Systemic inflammatory response, identified by increased total leucocyte counts, was shown to be a strong predictor of mortality after transcatheter aortic valve implantation (TAVI). Yet the mechanisms of inflammation-associated poor outcome after TAVI are unclear. Therefore, the present study aimed at investigating individual inflammatory signatures and functional heterogeneity of circulating myeloid and T-lymphocyte subsets and their impact on 1 year survival in a single-centre cohort of patients with severe aortic stenosis undergoing TAVI. METHODS AND RESULTS: One hundred twenty-nine consecutive patients with severe symptomatic aortic stenosis admitted for transfemoral TAVI were included. Blood samples were obtained at baseline, immediately after, and 24 h and 3 days after TAVI, and these were analysed for inflammatory and cardiac biomarkers. Myeloid and T-lymphocyte subsets were measured using flow cytometry. The inflammatory parameters were first analysed as continuous variables; and in case of association with outcome and area under receiver operating characteristic (ROC) curve (AUC) ≥ 0.6, the values were dichotomized using optimal cut-off points. Several baseline inflammatory parameters, including high-sensitivity C-reactive protein (hsCRP; HR = 1.37, 95% CI: 1.15-1.63; P < 0.0001) and IL-6 (HR = 1.02, 95% CI: 1.01-1.03; P = 0.003), lower counts of Th2 (HR = 0.95, 95% CI: 0.91-0.99; P = 0.009), and increased percentages of Th17 cells (HR = 1.19, 95% CI: 1.02-1.38; P = 0.024) were associated with 12 month all-cause mortality. Among postprocedural parameters, only increased post-TAVI counts of non-classical monocytes immediately after TAVI were predictive of outcome (HR = 1.03, 95% CI: 1.01-1.05; P = 0.003). The occurrence of SIRS criteria within 48 h post-TAVI showed no significant association with 12 month mortality (HR = 0.57, 95% CI: 0.13-2.43, P = 0.45). In multivariate analysis of discrete or dichotomized clinical and inflammatory variables, the presence of diabetes mellitus (HR = 3.50; 95% CI: 1.42-8.62; P = 0.006), low left ventricular (LV) ejection fraction (HR = 3.16; 95% CI: 1.35-7.39; P = 0.008), increased baseline hsCRP (HR = 5.22; 95% CI: 2.09-13.01; P < 0.0001), and low baseline Th2 cell counts (HR = 8.83; 95% CI: 3.02-25.80) were significant predictors of death. The prognostic value of the linear prediction score calculated of these parameters was superior to the Society of Thoracic Surgeons score (AUC: 0.88; 95% CI: 0.78-0.99 vs. 0.75; 95% CI: 0.64-0.86, respectively; P = 0.036). Finally, when analysing LV remodelling outcomes, ROC curve analysis revealed that low numbers of Tregs (P = 0.017; AUC: 0.69) and increased Th17/Treg ratio (P = 0.012; AUC: 0.70) were predictive of adverse remodelling after TAVI. CONCLUSIONS: Our findings demonstrate an association of specific pre-existing inflammatory phenotypes with increased mortality and adverse LV remodelling after TAVI. Distinct monocyte and T-cell signatures might provide additive biomarkers to improve pre-procedural risk stratification in patients referred to TAVI for severe aortic stenosis.