CT-derived Epicardial Adipose Tissue Inflammation Predicts Outcome in Patients Undergoing Transcatheter Aortic Valve Replacement.

PURPOSE: Inflammatory changes in epicardial (EAT) and pericardial adipose tissue (PAT) are associated with increased overall cardiovascular risk. Using routine, preinterventional cardiac CT data, we examined the predictive value of quantity and quality of EAT and PAT for outcome after transcatheter aortic valve replacement (TAVR). MATERIALS AND METHODS: Cardiac CT data of 1197 patients who underwent TAVR at the in-house heart center between 2011 and 2020 were retrospectively analyzed. The amount and density of EAT and PAT were quantified from single-slice CT images at the level of the aortic valve. Using established risk scores and known independent risk factors, a clinical benchmark model (BMI, Chronic kidney disease stage, EuroSCORE 2, STS Prom, year of intervention) for outcome prediction (2-year mortality) after TAVR was established. Subsequently, we tested whether the additional inclusion of area and density values of EAT and PAT in the clinical benchmark model improved prediction. For this purpose, the cohort was divided into a training (n=798) and a test cohort (n=399). RESULTS: Within the 2-year follow-up, 264 patients died. In the training cohort, particularly the addition of EAT density to the clinical benchmark model showed a significant association with outcome (hazard ratio 1.04, 95% CI: 1.01-1.07; P =0.013). In the test cohort, the outcome prediction of the clinical benchmark model was also significantly improved with the inclusion of EAT density (c-statistic: 0.589 vs. 0.628; P =0.026). CONCLUSIONS: EAT density as a surrogate marker of EAT inflammation was associated with 2-year mortality after TAVR and may improve outcome prediction independent of established risk parameters.

Opportunistic CT-derived analysis of fat and muscle tissue composition predicts mortality in patients with cardiogenic shock.

Prognosis estimation in patients with cardiogenic shock (CS) is important to guide clinical decision making. Aim of this study was to investigate the predictive value of opportunistic CT-derived body composition analysis in CS patients. Amount and density of fat and muscle tissue of 152 CS patients were quantified from single-slice CT images at the level of the intervertebral disc space L3/L4. Multivariable Cox regression and Kaplan-Meier survival analyses were performed to evaluate the predictive value of opportunistically CT-derived body composition parameters on the primary endpoint of 30-day mortality. Within the 30-day follow-up, 90/152 (59.2%) patients died. On multivariable analyses, lactate (Hazard Ratio 1.10 [95% Confidence Interval 1.04-1.17]; p = 0.002) and patient age (HR 1.04 [95% CI 1.01-1.07], p = 0.017) as clinical prognosticators, as well as visceral adipose tissue (VAT) area (HR 1.004 [95% CI 1.002-1.007]; p = 0.001) and skeletal muscle (SM) area (HR 0.987 [95% CI 0.975-0.999]; p = 0.043) as imaging biomarkers remained as independent predictors of 30-day mortality. Kaplan-Meier survival analyses showed significantly increased 30-day mortality in patients with higher VAT area (p = 0.015) and lower SM area (p = 0.035). CT-derived VAT and SM area are independent predictors of dismal outcomes in CS patients and have the potential to emerge as new imaging biomarkers available from routine diagnostic CT.

Relevance of serum levels of the endoplasmic reticulum stress protein GRP78 (glucose-regulated protein 78 kDa) as biomarker in pulmonary diseases.

Cellular stress and inflammation contribute to the initiation and progression of a variety of pulmonary diseases. Endoplasmic reticulum (ER) stress and its main regulator GRP78 (glucose-regulated protein 78 kDa) appear to be involved in the pathogenesis of pulmonary diseases, and GRP78 was found to be a biomarker in a wide range of inflammatory diseases. The aim of this study was to investigate the relevance of serum GRP78 in pulmonary disorders.In this prospective cohort study, 78 consecutive patients with chronic obstructive pulmonary disease (COPD, n = 28), asthma (n = 38) or interstitial lung disease (ILD, n = 12) underwent measurement of serum GRP78 levels by ELISA.The mean age of patients was 59.8 ± 12.4 years, 48.7% were female. Patients with elevated GRP78 levels (> median) offered a significantly better oxygenation status (capillary pO2: 75.3 ± 11.7 mmHg vs. 67.8 ± 15.9 mmHg, p = 0.02). Significant correlations were observed between GRP78, on the one hand, and haemoglobin, high-sensitivity C-reactive protein (hs-CRP) and eosinophil counts, on the other hand (haemoglobin: Pearson's r = -0.25, hs-CRP: r = 0.30, eosinophils: r = 0.63).Subsequently, we evaluated GRP78 measurements in function of severity stratifiers of the specific underlying pulmonary disease. ILD patients with a severe diffusion impairment (DLCO< 40% of predicted), exhibited a significant decrease in GRP78 levels (p = 0.01). In COPD and asthma, both characterized by obstructive ventilatory defects, a forced expiratory volume in one second (FEV1) <30% of predicted was accompanied by significantly lower GRP78 (p = 0.0075).In both obstructive and restrictive pulmonary disorders, GRP78 protein concentrations were reduced with increasing disease severity. These data suggest a prevalent role of GRP78 in the presently studied pulmonary disorders.

ER-stress-induced secretion of circulating glucose-regulated protein 78kDa (GRP78) ameliorates pulmonary artery smooth muscle cell remodelling.

Pulmonary arterial hypertension (PAH) is driven by vascular remodelling due to inflammation and cellular stress, including endoplasmic reticulum stress (ER stress). The main ER-stress chaperone, glucose-regulated protein 78 kDa (GRP78), is known to have protective effects in inflammatory diseases through extracellular signalling. The aim of this study is to investigate its significance in PAH. Human pulmonary arterial smooth muscle cells (PASMC) were stimulated with compounds that induce ER stress, after which the secretion of GRP78 into the cell medium was analysed by western blot. We found that when ER stress was induced in PASMC, there was also a time-dependent secretion of GRP78. Next, naïve PASMC were treated with conditioned medium (CM) from the ER-stressed donor PASMC. Incubation with CM from ER-stressed PASMC reduced the viability, oxidative stress, and expression of inflammatory and ER-stress markers in target cells. These effects were abrogated when the donor cells were co-treated with Brefeldin A to inhibit active secretion of GRP78. Direct treatment of PASMC with recombinant GRP78 modulated the expression of key inflammatory markers. Additionally, we measured GRP78 plasma levels in 19 PAH patients (Nice Group I) and correlated the levels to risk stratification according to ESC guidelines. Here, elevated plasma levels of GRP78 were associated with a favourable risk stratification. In conclusion, GRP78 is secreted by PASMC under ER stress and exhibits protective effects from the hallmarks of PAH in vitro. Circulating GRP78 may serve as biomarker for risk adjudication of patients with PAH. Proposed mechanism of ER-stress-induced GRP78 secretion by PASMC. Extracellular GRP78 can be measured as a circulating biomarker and is correlated with favourable clinical characteristics. Conditioned medium from ER-stressed PASMC reduces extensive viability, ROS formation, inflammation, and ER stress in target cells. These effects can be abolished by blocking protein secretion in donor cells by using Brefeldin A.

Propensity-score-matched comparison of safety, efficacy, and outcome of intravascular lithotripsy versus high-pressure PTCA in coronary calcified lesions.

BACKGROUND: Data regarding safety, efficacy, and outcome of intravascular lithotripsy (IVL) in comparison to standard techniques are lacking. This study sought to compare IVL with non-compliant high-pressure balloon percutaneous coronary angioplasty (PTCA). METHODS AND RESULTS: We performed a retrospective propensity-score-matched study to compare procedural success in 57 consecutive patients who received IVL-guided PCI in calcified coronary lesions with 171 matched patients who were treated with high-pressure PTCA with a non-compliant (NC)-balloon. The mean minimal lumen diameter (MLD) for the IVL group was 1.08 ± 0.51 mm, and the median percent diameter stenosis on quantitative angiography was 70.2% (interquartile range, 60.2-78.6%). MLD in the high-pressure dilatation group was 0.97 ± 0.43 mm, and the median percent diameter stenosis was 71.5% (interquartile range, 58.5-77.0%). IVL-guided PCI reduced median stenosis to 17.5% (interquartile range, 9.3-19.8%) with an acute gain of 0.93 ± 0.7 mm. High-pressure dilatation resulted in a final median stenosis of 19.3% (interquartile range, 13.33-28.5%). Procedural success was significantly higher (82.5% vs. 61.4%; p: 0.0035) in the IVL group. MACE through 12 months occurred in 10.5% of cases in the IVL group and in 11.1% of the high-pressure group (p = 0.22). Angiographic complications (coronary dissection, slow or no reflow, new coronary thrombus formation, abrupt vessel closure) were very low (0.2% vs. 0.12%). CONCLUSION: IVL resulted in a significantly higher rate of procedural success compared to high- pressure NC-balloon dilatation in patients with calcified coronary lesions. The rate of MACE through 12 months was similar to the standard therapy.

Vitamin K Epoxide Reductase Complex Subunit 1-Like 1 (VKORC1L1) Inhibition Induces a Proliferative and Pro-inflammatory Vascular Smooth Muscle Cell Phenotype.

Background: Vitamin K antagonists (VKA) are known to promote adverse cardiovascular remodeling. Contrarily, vitamin K supplementation has been discussed to decelerate cardiovascular disease. The recently described VKOR-isoenzyme Vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) is involved in vitamin K maintenance and exerts antioxidant properties. In this study, we sought to investigate the role of VKORC1L1 in neointima formation and on vascular smooth muscle cell (VSMC) function. Methods and Results: Treatment of wild-type mice with Warfarin, a well-known VKA, increased maladaptive neointima formation after carotid artery injury. This was accompanied by reduced vascular mRNA expression of VKORC1L1. In vitro, Warfarin was found to reduce VKORC1L1 mRNA expression in VSMC. VKORC1L1-downregulation by siRNA promoted viability, migration and formation of reactive oxygen species. VKORC1L1 knockdown further increased expression of key markers of vascular inflammation (NFκB, IL-6). Additionally, downregulation of the endoplasmic reticulum (ER) membrane resident VKORC1L1 increased expression of the main ER Stress moderator, glucose-regulated protein 78 kDa (GRP78). Moreover, treatment with the ER Stress inducer tunicamycin promoted VKORC1L1, but not VKORC1 expression. Finally, we sought to investigate, if treatment with vitamin K can exert protective properties on VSMC. Thus, we examined effects of menaquinone-7 (MK7) on VSMC phenotype switch. MK7 treatment dose-dependently alleviated PDGF-induced proliferation and migration. In addition, we detected a reduction in expression of inflammatory and ER Stress markers. Conclusion: VKA treatment promotes neointima formation after carotid wire injury. In addition, VKA treatment reduces aortal VKORC1L1 mRNA expression. VKORC1L1 inhibition contributes to an adverse VSMC phenotype, while MK7 restores VSMC function. Thus, MK7 supplementation might be a feasible therapeutic option to modulate vitamin K- and VKORC1L1-mediated vasculoprotection.

Hospital admissions during Covid-19 lock-down in Germany: Differences in discretionary and unavoidable cardiovascular events.

BACKGROUND: A decline in hospitalization for cardiovascular events and catheter laboratory activation was reported for the United States and Italy during the initial stage of the Covid-19 pandemic of 2020. We report on the deployment of emergency services for cardiovascular events in a defined region in western Germany during the government-imposed lock-down period. METHODS: We examined 5799 consecutive patients who were treated by emergency services for cardiovascular events during the Covid-19 pandemic (January 1 to April 30, 2020), and compared those to the corresponding time frame in 2019. Examining the emergency physicians' records provided by nine locations in the area, we found a 20% overall decline in cardiovascular admissions. RESULTS: The greatest reduction could be seen immediately following the government-imposed social restrictions. This reduction was mainly driven by a reduction in discretionary admissions for dizziness/syncope (-53%), heart failure (-38%), exacerbated COPD (-28%) and unstable angina (-23%), while unavoidable admissions for ST-elevation myocardial infarction (STEMI), cardiopulmonary resuscitation (CPR) and stroke were unchanged. There was a greater decline in emergency admissions for patients ≥60 years. There was also a greater reduction in emergency admissions for those living in urban areas compared to suburban areas. CONCLUSIONS: During the Covid-19 pandemic, a significant decline in hospitalization for cardiovascular events was observed during the government-enforced shutdown in a predefined area in western Germany. This reduction in admissions was mainly driven by "discretionary" cardiovascular events (unstable angina, heart failure, exacerbated COPD and dizziness/syncope), but events in which admission was unavoidable (CPR, STEMI and stroke) did not change.