In-vivo assessment of vascular injury for the prediction of in-stent restenosis.

BACKGROUND: Despite optimizations of coronary stenting technology, a residual risk of in-stent restenosis (ISR) remains. Vessel wall injury has important impact on the development of ISR. While injury can be assessed in histology, there is no injury score available to be used in clinical practice. METHODS: Seven rats underwent abdominal aorta stent implantation. At 4 weeks after implantation, animals were euthanized, and strut indentation, defined as the impression of the strut into the vessel wall, as well as neointimal growth were assessed. Established histological injury scores were assessed to confirm associations between indentation and vessel wall injury. In addition, stent strut indentation was assessed by optical coherence tomography (OCT) in an exemplary clinical case. RESULTS: Stent strut indentation was associated with vessel wall injury in histology. Furthermore, indentation was positively correlated with neointimal thickness, both in the per-strut analysis (r = 0.5579) and in the per-section analysis (r = 0.8620; both p ≤ 0.001). In a clinical case, indentation quantification in OCT was feasible, enabling assessment of injury in vivo. CONCLUSION: Assessing stent strut indentation enables periprocedural assessment of stent-induced damage in vivo and therefore allows for optimization of stent implantation. The assessment of stent strut indentation might become a valuable tool in clinical practice.

The Role of Vitamin D3 as an Independent Predicting Marker for One-Year Mortality in Patients with Acute Heart Failure.

Background: Deficiency in vitamin D3 and its metabolites has been linked to dismal outcomes in patients with chronic diseases, including cardiovascular disease and heart failure (HF). It remains unclear if a vitamin D3 status is a prognostic feature in patients with acute decompensated HF. Methods: We assessed serum levels of 25-OH-vitamin D3 and 1,25-(OH)2-vitamin D3 in 139 patients with acute HF who had been admitted to the intermediate care unit of a maximum care hospital. The follow-up period was one year. After exclusion of patients with sampling errors and those who were lost to follow-up, 118 patients remained in the final study cohort. Outcome estimates by 25-OH-vitamin D3 and 1,25-(OH)2-vitamin D3 levels were compared to the Seattle Heart Failure (SHF) Model. Results: More than two-thirds (79.7%) of the patients showed inadequate 25-OH-vitamin D3 levels (i.e., <30 ng/mL) upon admission. Low levels of 1,25-(OH)2-vitamin D3 (i.e., <19.9 pg/mL) were observed in 16.1% of patients. Of the 118 HF patients, 22 (19%) died during the following 12 months. There were no differences in vitamin D3 levels between patients who died and those who survived, neither in 25-OH-vitamin D3 (23.37 ± 19.14 ng/mL vs. 19.11 ± 12.25 ng/mL; p = 0.19) nor in 1,25-(OH)2-vitamin D3 levels (31.10 ± 19.75 ng/mL vs. 38.25 ± 15.73 ng/mL; p = 0.02); therefore, vitamin D3 levels alone did not predict one-year survival (AUC [25-OH-vitamin D3] 0.50; 95% CI 0.34−0.65; AUC [1,25-(OH)2-vitamin D3] 0.62; 95% CI 0.48−0.76). Moreover, whilst the SHF model exhibited acceptable discriminatory ability for predicting one-year mortality (AUC 0.79; 95% CI 0.66−0.91), adding vitamin D levels on admission to the SHF score did not improve its discriminatory value. Conclusion: Our data do not support the use of vitamin D3 screening in patients admitted with acute decompensated HF to aid prognostication.

Dose-dependent impact of statin therapy intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention for the treatment of acute versus chronic coronary syndrome.

BACKGROUND: By low-density lipoprotein (LDL) reduction, statins play an important role in cardiovascular risk modification. Incompletely understood pleiotropic statin effects include vasoprotection that might originate from mobilisation and differentiation of vascular progenitor cells. Data on the potentially differential impact of statin treatment intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention (PCI) are scarce. This study examines the potential association of different permanent statin treatment regimens on circulating progenitor cells in patients with coronary syndrome. METHODS AND RESULTS: In a monocentric prospective all-comers study, 105 consecutive cases scheduled for coronary angiography due to either (A) non-invasive proof of ischemia and chronic coronary syndrome (CCS) or (B) troponin-positive acute coronary syndrome (ACS) were included. According to the 2018 American College of Cardiology Guidelines on Blood Cholesterol, patients were clustered depending on their respective permanent statin treatment regimen in either a high- to moderate-intensity statin treatment (HIST) or a low-intensity statin treatment (LIST) group. Baseline characteristics including LDL levels were comparable. From blood drawn at the time of PCI, peripheral blood mononuclear cells were isolated, cultivated and counted and, by density gradient centrifugation, levels of circulating progenitor cells were determined using fluorescence-activated cell sorting (FACS) analysis. In ACS patients both absolute and relative numbers of circulating early-outgrowth endothelial progenitor cells (EPCs) concurrently were significantly lower in the HIST group as compared to the LIST group. This effect was more pronounced in ACS patients than in CCS patients. Both in ACS and CCS patients, HIST caused a significant reduction of the number of circulating SMPCs. CONCLUSIONS: In patients undergoing PCI, a dose intensity-dependent and LDL level-independent pro-differentiating vasoprotective pleiotropic capacity of statins for EPC and SMPC is demonstrated.

Fibroblast Growth Factor 23 and Outcome Prediction in Patients with Acute Myocardial Infarction.

(1) Background: Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with heart failure (HF); however, less is known about mortality associations in patients with myocardial infarction (MI). (2) Methods: FGF23 was assessed in 180 patients with acute MI, 99 of whom presented with concomitant acute HF. Patients were followed up for one year, and outcome estimates by FGF23 were compared to GRACE score estimates. (3) Results: Log-transformed serum levels of intact FGF23 (logFGF23) did not differ between MI patients with and without HF, and no difference in logFGF23 was observed between 14 MI patients who died and those who survived. However, when only MI patients with concomitant HF were considered, logFGF23 was significantly higher among non-survivors compared to that in survivors. While logFGF23 was not associated with the outcome in the entire cohort, logFGF23 was fairly predictive for one-year mortality in patients with concomitant HF (AUC 0.78; 95%CI 0.61-0.95), where it outperformed GRACE score estimates (AUC 0.70; 95%CI 0.46-0.94). (4) Conclusions: FGF23 was associated with one-year mortality only in MI patients who concomitantly presented with HF, surpassing the predictive ability of GRACE score estimates. No associations were observed in patients without HF despite similar FGF23 levels at admission. Further studies are warranted to investigate whether FGF23 is causal for dismal outcome of HF.

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy-An Animal and In-Human Comparative Study.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.

Intact fibroblast growth factor 23 levels and outcome prediction in patients with acute heart failure.

Elevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75-129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669-0.899; FGF23d2: AUC 0.766; 95%CI 0.631-0.901; SHF: AUC 0.771; 95%CI 0.651-0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access.

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of coronary artery disease. In-stent restenosis (ISR) is determined by an excessive proliferation of neointimal tissue within the stent and limits the long-term success of stents. A variety of animal models have been used to elucidate pathophysiological processes underlying in-stent restenosis (ISR), with the porcine coronary and the rabbit iliac artery models being the most frequently used. Murine models provide the advantages of high throughput, ease of handling and housing, reproducibility, and a broad availability of molecular markers. The apolipoprotein E deficient (apoE-/- ) mouse model has been widely used to study cardiovascular diseases. However, stents must be miniaturized to be implanted into mice, involving important changes of their mechanical and (potentially) biological properties. The use of apoE-/- rats can overcome these shortcomings as apoE-/- rats allow for the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. This makes them an excellent and reliable model to investigate ISR after stent implantation. Here, we describe, in detail, the implantation of commercially available human coronary stents into the abdominal aorta of rats with an apoE-/- background using a trans-femoral access.

An unusual case of aortic metastasis from lung cancer.

In patients with cardiovascular events, such as myocardial infarction or aortic dissection without known risk factors for cardiovascular disease, neoplastic disease should be considered as a differential diagnosis. In this report, we present a case of a 51-year old man with previously undiagnosed non-small lung cancer leading to fatal cardiovascular complications due to hemovascular spread, diagnosed post-mortem. This case illustrates the value of autopsy in unexpected deaths.

Apolipoprotein E deficient rats generated via zinc-finger nucleases exhibit pronounced in-stent restenosis.

The long-term success of coronary stent implantation is limited by in-stent restenosis (ISR). In spite of a broad variety of animal models available, an ideal high-throughput model of ISR has been lacking. Apolipoprotein E (apoE) deficient rats enable the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. Whereas apoE deficient rats have been proposed as animal model of atherosclerosis, to date it is unknown whether they also develop pronounced ISR. We sought to assess ISR after abdominal aorta stent implantation in apoE deficient rats. A total of 42 rats (16 wildtype, 13 homozygous apoE-/- and 13 heterozygous apoE+/- rats) underwent abdominal aorta stent implantation. After 28 days blood samples were analyzed to characterize lipid profiles. ISR was assessed by histomorphometric means. Homozygous apoE-/- rats exhibited significantly higher total cholesterol and low-density cholesterol levels than wildtype apoE+/+ and heterozygous apoE+/- rats. ISR was significantly pronounced in homozygous apoE-/- rats as compared to wildtype apoE+/+ (p = <0.0001) and heterozygous apoE+/- rats (p = 0.0102) on western diet. Abdominal aorta stenting of apoE-/- rats is a reliable model to investigate ISR after stent implantation and thus can be used for the evaluation of novel stent concepts. Apolipoprotein E (apoE) deficient rats have been proposed as animal model of atherosclerosis. We investigated the development of restenosis 28 days after stent implantation into the abdominal aorta of wildtype apoE+/+, homozygous apoE-/- and heterozygous apoE+/- rats, respectively. Homozygous apoE-/- rats exhibited significantly higher LDL and significantly lower HDL cholesterol levels compared to wildtype apoE+/+ and heterozygous apoE+/- rats. Restenosis after stent implantation was significantly pronounced in western-diet-fed homozygous apoE-/- rats, accompanied by a significantly increased neointimal thickness. Thus, apoE knockout rats exhibit elevated restenosis and might provide a novel tool for testing of innovative stent concepts.

Role of Optimal Medication Given to Patients with Hypertension and Ischemic Heart Disease Prior to an Acute Coronary Syndrome.

INTRODUCTION: Administering optimal cardiovascular medication (OCM) to patients with hypertension (HBP) and ischemic heart disease (IHD) lowers cardiovascular morbidity and mortality.The main objective of this study was to compare in-hospital cardiac mortality among patients with HBP and/or IHD, treated or untreated with OCM, who developed a first episode of acute coronary syndrome (ACS). METHODS: The study was carried out retrospectively and included patients admitted with a first episode of ACS between 2013 and 2016. The patients were divided into three groups: those with HBP, IHD, and a history of HBP + IHD. Patients were then divided into two subgroups: subgroup A consisted of patients undergoing optimal anti-ischemic and/or antihypertensive therapy, while subgroup B consisted of patients without OCM. RESULTS: This analysis comprised 1096 patients. Mean age was 64.3 ± 18 years. There were 581 patients in subgroup A - 53%, and 515 patients in subgroup B - 47%. Total cardiac mortality was 9.98%, different depending on the groups and subgroups studied: HBP group total - 7%, subgroup A - 5.1%, significantly lower compared to subgroup B - 9.4% (p = 0.05); IHD group total - 12.2%, subgroup A - 9.07%, significantly lower compared to subgroup B - 15.8% (p = 0.05); HBP + IHD group total - 14.35%, subgroup A - 9.9%, significantly lower compared to subgroup B - 18.8% (p = 0.05). CONCLUSIONS: The lack of OCM in patients with HBP and/or IHD is correlated to a significant increase in in-hospital cardiac mortality among patients who develop a first-episode ACS.