Left Ventricular Unloading Is Associated With Lower Mortality in Patients With Cardiogenic Shock Treated With Venoarterial Extracorporeal Membrane Oxygenation: Results From an International, Multicenter Cohort Study.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. METHODS: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort. RESULTS: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; P=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). CONCLUSIONS: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

Criteria sets for primary Sjogren's syndrome are not adequate for those presenting with extraglandular organ involvements as their dominant clinical features.

Patients with primary Sjogren's syndrome (pSS) may go undiagnosed or be misclassified due to the insidious nature and wide spectrum of the disease. The available several classification criteria emphasize glandular findings. We aimed to analyze the efficiency of various classification criteria sets in patients diagnosed on the clinical basis by expert opinion and to compare those pSS patients who fulfilled these criteria with those who did not. This is a multicenter study in which 834 patients from 22 university-based rheumatology clinics are included. Diagnosis of pSS was made on the clinical basis by the expert opinion. In this study, we only interviewed patients once and collected available data from the medical records. The European criteria, American-European Consensus Group (AECG) and American College of Rheumatology (ACR) Sjogren's criteria were applied. Majority of the patients were women (F/M was 20/1). The median duration from the first pSS-related symptom to diagnosis was significantly shorter in men (2.5 ± 2.3 vs 4.3 ± 5.9 years) (p = 0 < 0.016). When the European, AECG and ACR Sjogren's criteria were applied, 666 patients (79.9%) satisfied at least one of them. In total, 539 patients (64.4%) satisfied the European, 439 (52.6%) satisfied the AECG, and 359 (43%) satisfied the ACR criteria. Among the entire group, 250 patients (29.9%) satisfied all and 168 (20.1%) met none of the criteria. The rates of extraglandular organ involvements were not different between patients who met at least one of the criteria sets and those who met none. There is an urgent need for the modification of the pSS criteria sets to prevent exclusion of patients with extraglandular involvements as the dominant clinical features.

Management of suspected common bile duct stone: diagnostic yield of current guidelines.

BACKGROUND: The American Society for Gastrointestinal Endoscopy (ASGE) has recently published a guideline for suspected CBDS with the intention of reducing unnecessary ERCP and thereby complications. The aim of this study was to assess the diagnostic efficacy of the ASGE guideline. METHODS: Data of patients who underwent ERCP with suspected CBDS were analyzed retrospectively. Patients were classified into high, intermediate and low risk groups based on predictors that have been suggested by the ASGE. Very strong predictors of the presence of ductal stones included: CBDS on transabdominal ultrasonography (US), clinical ascending cholangitis or total bilirubin (TBIL) >4 mg/dL). Strong predictors included dilated CBD >6 mm on US with gallbladder in situ and TBIL level of 1.8-4.0 mg/dL whereas moderate predictor included abnormal liver biochemical test other than bilirubin, age more than 55 years and clinical findings of biliary pancreatitis. RESULTS: Of 888 enrolled patients, 704 had CBDS demonstrated by ERCP and the remainder did not. All very strong and strong predictors were found to be significantly higher among patients who had CBDS. Detection of CBDS by ultrasonography and a dilated common biliary duct were observed to be independent risk factors associated with the existence of CBDS. The high risk group had a high (86.7%) positive predictive value (PPV), however, sensitivity and specificity were observed to be moderate (67.8% and 60.3% respectively). PPV was 67.9% in the intermediate risk group and the sensitivity and specificity were very low (31.9% and 42.3%). DISCUSSION: The probability of CBDS was observed to be high in the intermediate and high risk groups. However due to low sensitivity and specificity values, the ASGE guideline needs additional or different predictors.

Calf mortality in Turkish dairy farms: Economic impact, regional disparities, and farm-level drivers.

This study investigates the economic burden of calf mortality in Turkish dairy farms and its impact on the national economy. We gathered research data by directly surveying dairy farms in seven provinces, each representing a distinct region of Turkiye. By conducting these surveys, we captured data on various aspects of calf mortality, including losses among non-pregnant cows aged two and older, pregnant cows, and those experiencing complications during birth, as well as losses within the 0-6 month age bracket. These figures were then amalgamated to establish the overall calf loss rate. Using a fractional probit model, we examined the empirical relationship between total calf loss rates and the socio-demographic characteristics of farm operators and their establishments. Our findings revealed that approximately 82 % of farms experienced some degree of calf loss, with the calf loss rate among dairy cattle farming accounting for nearly 20 %. Notably, regional disparities emerged as a key observation, alongside the identification of certain socio-demographic farm characteristics that proved statistically significant. Specifically, factors such as the prevalence of local cattle breeds, the proportion of crossbred bulls, as well as the numbers of heifers and calves, stood out as influential. Further scrutiny, fortified by ANOVA tests and relationships between the number of cows and total calf loss rate, underscored pronounced geographical disparities in post-estimation calf loss rates. Meanwhile, correlation heatmaps illuminated noteworthy relationships between specific cattle traits and the extent of calf losses. These findings not only underscore the severity of the issue but also highlight the urgency of preventive measures. In light of these insights, we offer pertinent policy recommendations to stakeholders and policymakers aimed at mitigating this considerable economic burden effectively.

A simply calculated nutritional index provides clinical implications in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Malnutrition is associated with adverse outcomes in patients with aortic stenosis. The Triglycerides × Total Cholesterol × Body Weight Index (TCBI) is a simple scoring model to evaluate the status of nutrition. However, the prognostic relevance of this index in patients undergoing transcatheter aortic valve replacement (TAVR) is unknown. This study aimed to evaluate the association of the TCBI with clinical outcomes in patients undergoing TAVR. METHODS: A total of 1377 patients undergoing TAVR were evaluated in this study. The TCBI was calculated by the formula; triglyceride (mg/dL) × total cholesterol (mg/dL) × body weight (kg)/1000. The primary outcome was all-cause mortality within 3 years. RESULTS: Patients with a low TCBI, based on a cut-off value of 985.3, were more likely to have elevated right atrial pressure (p = 0.04), elevated right ventricular pressure (p < 0.01), right ventricular systolic dysfunction (p < 0.01), tricuspid regurgitation ≥ moderate (p < 0.01). Patients with a low TCBI had a higher cumulative 3-year all-cause (42.3% vs. 31.6%, p < 0.01; adjusted HR 1.36, 95% CI 1.05-1.77, p = 0.02) and non-cardiovascular mortality (15.5% vs. 9.1%, p < 0.01; adjusted HR 1.95, 95% CI 1.22-3.13, p < 0.01) compared to those with a high TCBI. Adding a low TCBI to EuroSCORE II improved the predictive value for 3-year all-cause mortality (net reclassification improvement, 0.179, p < 0.01; integrated discrimination improvement, 0.005, p = 0.01). CONCLUSION: Patients with a low TCBI were more likely to have right-sided heart overload and exhibited an increased risk of 3-year mortality. The TCBI may provide additional information for risk stratification in patients undergoing TAVR.

Blood glucose and lactate levels as early predictive markers in patients presenting with cardiogenic shock: A retrospective cohort study.

Lactate and glucose are widely used biochemical parameters in current predictive risk scores for cardiogenic shock. Data regarding the relationship between lactate and glucose levels in cardiogenic shock are limited. Thus, we aimed to analyze glucose and lactate as early markers for in-hospital mortality in cardiogenic shock. In this retrospective cohort study, 312 patients presenting with cardiogenic shock to a tertiary-care hospital between 2016 and 2018 were included. Apparent cardiogenic shock was defined as hypoperfusion with hemodynamic compromise and biochemical marker increase due to diminished tissue perfusion, corresponding to SCAI shock stages. In-hospital mortality was assessed as the primary endpoint. The median age of the study population was 71 (60-79) years and the etiology of cardiogenic shock was acute myocardial infarction in 45.8%. Overall in-hospital mortality was 67.6%. In the receiver operating curve analysis, the area under the receiver-operating curve (AUC) for prediction of in-hospital mortality was higher for lactate (AUC: 0.757) than for glucose (AUC: 0.652). Both values were significantly associated with outcome (groups created with best cutoff values obtained from the Youden index). Correlation analysis showed a significant non-linear association of both values. In a multivariable stepwise Cox regression analysis, lactate remained an independent predictor for in-hospital mortality, whilst glucose, despite being implicated in energy metabolism, was not independently predictive for mortality. Together, these data suggest that lactate at admission is superior for mortality prediction in patients with apparent cardiogenic shock. Glucose was not independently predictive for mortality.

Comparison of interventional treatment options for coronary calcified nodules: A sub-analysis of the ROTA.shock trial.

BACKGROUND: The optimal treatment for coronary calcified nodules (CNs) is still unclear. The aim of this study was to compare the modification of these lesions by coronary intravascular lithotripsy (IVL) and rotational atherectomy (RA) using optical coherence tomography (OCT). METHODS: ROTA.shock was a 1:1 randomized, prospective, double-arm multi-center non-inferiority trial that compared the use of IVL and RA with percutaneous coronary intervention (PCI) in severely calcified lesions. In 19 of the patients out of this study CNs were detected by OCT in the target lesion and were treated by either IVL or RA. RESULTS: The mean angle of CNs was significantly larger in final OCT scans than before RA (92 ± 17° vs. 68 ± 7°; p = 0.01) and IVL (89 ± 18° vs. 60 ± 10°; p = 0.03). The CNs were thinner upon final scans than in initial native scans (RA: 17.8 ± 7.8 mm vs. 38.6 ± 13.1 mm; p = 0.02; IVL: 16.5 ± 9.0 mm vs. 37.2 ± 14.3 mm; p = 0.02). Nodule volume did not differ significantly between native and final OCT scans (RA: 0.66 ± 0.12 mm3 vs. 0.61 ± 0.33 mm3; p = 0.68; IVL: 0.64 ± 0.19 mm3 vs. 0.68 ± 0.22 mm3; p = 0.74). Final stent eccentricity was high with 0.62 ± 0.10 after RA and 0.61 ± 0.09 after IVL. CONCLUSION: RA or IVL are unable to reduce the volume of the calcified plaque. CN modulation seems to be mainly induced by the stent implantation and not by RA or IVL.

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

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

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.

Impact of transradial versus transfemoral access for preprocedural coronary angiography on TAVR-associated complications.

Background: Vascular injury and bleeding complications remain frequent after transcatheter aortic valve replacement (TAVR). Whether the access-site of preprocedural coronary angiography (CAG) affects TAVR-related complications is not known. The aim of this study was to evaluate the impact of transradial (TRA) versus transfemoral access (TFA) for preprocedural CAG on outcomes in patients undergoing subsequent TAVR. Methods: The study cohort included 1002 patients undergoing transfemoral TAVR, of whom 39.4% (395/1002) had undergone radial and 60.6% (607/1002) femoral access for pre-TAVR CAG. The primary endpoint was a composite of 30-day mortality and major vascular complications after TAVR. Key secondary endpoints included VARC-3-defined complications. Results: The primary endpoint occurred less frequently in patients with prior TRA (3.3%) as compared to patients with prior TFA (6.3%, p = 0.04), which was mainly driven by significantly lower rates of major vascular complications (0.8% vs 2.5%, p = 0.05). Moreover, incidences of periprocedural access-related vascular injury and unplanned endovascular interventions were lower in TRA patients (13.2% vs 18.0%, p = 0.05). The rate of major bleeding tended to be lower in the TRA (1.5%) as compared to the TFA group (3.5%) but was not significantly different (p = 0.07). Moreover, the rate of life-threatening bleeding was comparable between both groups (0.5% vs 0.8%, p = 0.71). Conclusion: Transradial access for preprocedural CAG was associated with significantly lower rates of vascular complications following subsequent TAVR as compared to transfemoral access. However, despite the tendency to lower major bleedings with transradial access, no significant association was detectable between the access-site of coronary angiography and TAVR-related bleeding complications.

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.

Optimal protamine-to-heparin dosing ratio for the prevention of bleeding complications in patients undergoing TAVR-A multicenter experience.

BACKGROUND: Despite major advances, transcatheter aortic valve replacement (TAVR) is still associated with procedure-specific complications. Although previous studies reported lower bleeding rates in patients receiving protamine for heparin reversal, the optimal protamine-to-heparin dosing ratio is unknown. HYPOTHESIS: The aim of this study was a comparison of two different heparin antagonization regimens for the prevention of bleeding complications after TAVR. METHODS: The study included 1446 patients undergoing TAVR, of whom 623 received partial and 823 full heparin antagonization. The primary endpoint was a composite of 30-day mortality, life-threatening, and major bleeding. Safety endpoints included stroke and myocardial infarction at 30 days. RESULTS: Full antagonization of heparin resulted in lower rates of the primary endpoint as compared to partial heparin reversal (5.6% vs. 10.4%, p < .01), which was mainly driven by lower rates of life-threatening (0.5% vs. 1.6%, p = .05) and major bleeding (3.2% vs. 7.5%, p < .01). Moreover, the incidence of major vascular complications was significantly lower in patients with full heparin reversal (3.5% vs. 7.5%, p < .01). The need for red-blood-cell transfusion was lower in patients receiving full as compared to partial heparin antagonization (10.4% vs. 15.9%, p < .01). No differences were observed in the incidence of stroke and myocardial infarction between patients with full and partial heparin reversal (2.2% vs. 2.6%, p = .73 and 0.2% vs. 0.4%, p = .64, respectively). CONCLUSIONS: Full heparin antagonization resulted in significantly lower rates of life-threatening and major bleeding after TAVR as compared to partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups.

Comparison of Coronary Intravascular Lithotripsy and Rotational Atherectomy in the Modification of Severely Calcified Stenoses.

Debulking techniques are often necessary for successful lesion preparation in percutaneous coronary intervention. The aim of this study was to compare plaque modification of severely calcified lesions by coronary intravascular lithotripsy (IVL) with that of rotational atherectomy (RA) using optical coherence tomography (OCT). ROTA.shock was a 1:1 randomized, prospective, double-arm, multicenter noninferiority trial designed to compare final minimal stent area after IVL with RA for lesion preparation in percutaneous coronary interventional treatment of severely calcified lesions. On the basis of OCT acquired before and immediately after IVL or RA in 21 of the 70 patients included, we performed a detailed analysis of the modification of the calcified plaque. After RA and IVL, calcified plaque fractures were present in 14 of the patients (67%), with a significantly greater number of fractures after IVL (3.23 ± 0.49) than after RA (1.67 ± 0.52; p < 0.001). Plaque fractures after IVL were longer than after RA (IVL: 1.67 ± 0.43 mm vs RA: 0.57 ± 0.55 mm; p = 0.01), resulting in a greater total volume of the fractures (IVL: 1.47 ± 0.40 mm3 vs RA: 0.48 ± 0.27 mm3; p = 0.003). Use of RA was associated with a greater acute lumen gain than was use of IVL (RA: 0.46 ± 0.16 mm2 vs IVL: 0.17 ± 0.14 mm2; p = 0.03). In conclusion, we were able to show differences in plaque modification of calcified coronary lesions by OCT: although RA leads to a greater acute lumen gain, IVL induces more and longer fractures of the calcified plaque.

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.

Predictive value of the Fibrosis-4 index in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: Liver dysfunction is associated with an increased risk of mortality after cardiac interventions. The Fibrosis-4 (FIB-4 index), a marker of hepatic fibrosis, has been associated with a worse prognosis in heart failure. The prognostic relevance of the index in patients undergoing transcatheter aortic valve replacement (TAVR) is unknown. The aim of this study was to evaluate the clinical implications associated with the FIB-4 index in patients undergoing TAVR. METHODS: Between May 2012 and June 2019, 941 patients undergoing TAVR were stratified into a low or high FIB-4 index group, based on a cutoff value that was determined according to a receiver operating characteristic curve predicting 1-year all-cause mortality. RESULTS: Patients with a high FIB-4 index (n = 480), based on the cutoff value of 1.82, showed higher rates of pulmonary hypertension (43.8% vs. 31.8%, p < 0.01), right-ventricular systolic dysfunction (29.5% vs. 19.2%, p < 0.01) and larger inferior vena cava diameter (1.6 ± 0.6 cm vs. 1.3 ± 0.6 cm, p < 0.01) than patients with a low FIB-4 index (n = 461). Furthermore, a high FIB-4 index was associated with a significantly higher cumulative 1-year all-cause mortality (17.5% vs. 10.2%, p < 0.01) and non-cardiovascular mortality (12.1% vs. 2.5%, p < 0.01), compared to a low FIB-4 index. Multivariable analysis revealed that a high FIB-4 index was independently associated with all-cause mortality (HR: 1.75 [95% CI: 1.18-2.59], p < 0.01). CONCLUSIONS: A high FIB-4 index is associated with right-sided heart overload and an increased risk of mortality in patients undergoing TAVR. The FIB-4 index may be useful as an additional predictor of outcomes in these patients.

Coronary lithotripsy for the treatment of underexpanded stents: the international & multicentre CRUNCH registry.

BACKGROUND: Stent underexpansion increases the risk of cardiac adverse events. At present, there are limited options to treat refractory stent underexpansion. In this context, the intravascular lithotripsy (IVL) system might be a safe and effective strategy. AIMS: We aimed to evaluate the safety and efficacy of IVL in addressing resistant stent underexpansion due to heavy underlying calcification. METHODS: This was an international multicentre registry including patients receiving IVL therapy to treat stent underexpansion from December 2017 to August 2020. Angiographic and intracoronary imaging data were collected. The efficacy endpoint was device success (technical success with a final percentage diameter stenosis <50%). The safety endpoint was in-hospital major adverse cardiac events (MACE). RESULTS: Seventy patients were included, the mean age was 73±9.2 years and 76% were male. The median time from stent implantation to IVL therapy was 49 days (0-2,537). Adjuvant treatment with non-compliant balloon dilatations pre- and post-IVL was performed in 72.3% and 76.8% of patients, respectively, and additional stenting was performed in 22.4%. Device success was 92.3%. Minimum lumen diameter increased from 1.49±0.73 mm to 2.41±0.67 mm (p<0.001) and stent expansion increased by 124.93±138.19% (p=0.016). No IVL-related procedural complications or MACE were observed. The use of bailout IVL therapy directly after stenting and the presence of ostial underexpanded lesions negatively predicted lumen diameter gain. CONCLUSIONS: Coronary lithotripsy is safe and effective in increasing lumen and stent dimensions in underexpanded stents secondary to heavily calcified lesions.

Intracranial haemorrhage in adult patients on venoarterial extracorporeal membrane oxygenation.

AIMS: Intracranial haemorrhage (ICH) is one of the most serious complications of adult patients treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) and is associated with increased morbidity and mortality. However, the prevalence and risk factors of ICH in this cohort are still insufficiently understood. We hypothesized that a considerable proportion of patients undergoing VA-ECMO support suffer from ICH and that specific risk factors are associated with the occurrence of ICH. Therefore, the purpose of this study was to further investigate the prevalence and associated mortality as well as to identify risk factors for ICH in VA-ECMO patients. METHODS AND RESULTS: We conducted a retrospective multicentre study including adult patients (≥18 years) treated with VA-ECMO in cardiac intensive care units (ICUs) at five German clinical sites between January 2016 and March 2020, excluding patients with ICH upon admission. Differences in baseline characteristics and clinical outcome between VA-ECMO patients with and without ICH were analysed and risk factors for ICH were identified. Among the 598 patients included, 70/598 (12%) developed ICH during VA-ECMO treatment. In-hospital mortality in patients with ICH was 57/70 (81%) and 1-month mortality 60/70 (86%), compared to 332/528 (63%) (P = 0.002) and 340/528 (64%) (P < 0.001), respectively, in patients without ICH. Intracranial haemorrhage was positively associated with diabetes mellitus [odds ratio (OR) 2, 95% confidence interval (CI) 1.11-3.56; P = 0.020] and lactate (per mmol/L) (OR 1.06, 95% CI 1.01-1.11; P = 0.020), and negatively associated with platelet count (per 100 G/L) (OR 0.32, 95% CI 0.15-0.59; P = 0.001) and fibrinogen (per 100 mg/dL) (OR 0.64, 95% CI 0.49-0.83; P < 0.001). CONCLUSION: Intracranial haemorrhage was associated with a significantly higher mortality rate. Diabetes mellitus and lactate were positively, platelet count, and fibrinogen level negatively associated with the occurrence of ICH. Thus, platelet count and fibrinogen level were revealed as potentially modifiable, independent risk factors for ICH. The findings address an area with limited data, provide information about risk factors and the epidemiology of ICH, and may be a starting point for further investigations to develop effective strategies to prevent and treat ICH.

CHA2DS2-VASC score predicts coronary artery disease progression and mortality after ventricular arrhythmia in patients with implantable cardioverter-defibrillator.

AIM: The CHA2DS2-VASC score has expanded its use beyond the initial purpose of predicting the risk of stroke in patients with atrial fibrillation. We aimed to investigate the value of the CHA2DS2-VASC score as a risk assessment tool to predict relevant coronary artery disease (CAD) leading to percutaneous coronary intervention (PCI), and all-cause mortality after detected ventricular arrhythmia (VA) in patients with an Implantable Cardioverter-Defibrillator (ICD). METHODS: A total of 183 ICD-patients who underwent coronary angiography after VA were included and classified according to their CHA2DS2-VASC score in a low(1-3), intermediate(4-5) and high(6-8) score group. We evaluated the predictive value of CHA2DS2-VASC score for the presence of relevant CAD leading to percutaneous coronary intervention (PCI), as well as late all-cause mortality. RESULTS: A total of 60 patients (32.8%) had significant CAD and underwent successful PCI. After adjustment for relevant parameters such as ischemic cardiomyopathy, angina pectoris, left ventricular ejection fraction, CHA2DS2-VASC score remained the only independent predictor of CAD leading to PCI [HR 1.73 (1.07-2.80)]. The Area under curve was 0.64 (0.56-72, p = 0.002). Kaplan-Meier analysis and log-rank showed an increased three-year mortality of ICD-patients with an intermediate or high score after VA (p = 0.003). Multivariate cox-regression analysis revealed that CHA2DS2-VASC score was also independently associated with all-cause mortality following adjustment for clinically relevant variables (HR 2.20, 1.17-4.14). CONCLUSIONS: CHA2DS2-VASC score can be a predictor of CAD leading to PCI in ICD-patients after VA. ICD-Patients with a high score have an increased risk for reduced three-year all-cause mortality after VA.

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.

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.