investigating-aortic-valve-calcification-via-isolation-culture-t

Investigating Aortic Valve Calcification via Isolation and Culture of T Lymphocytes using Feeder Cells from Irradiated Buffy Coat

Calcific aortic valve disease (CAVD), an active disease process ranging from mild thickening of the valve to severe calcification, is associated with high ...

Charité Universitätsmedizin Berlin and German Centre for Cardiovascular Research (DZHK)

Berlin Institute of Health

Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs. 

[Impact of lipid metabolism parameters on the development and progression of coronary artery disease : An update].

In patients with nonvalvular atrial fibrillation, >90 % of thrombi are detected in the left atrial appendage (LAA). In particular these observations have resulted in the development of catheter-based LAA closure as an approach for stroke prevention in patients with nonvalvular atrial fibrillation in recent years. A preliminary randomized trial provided promising data with respect to efficacy and safety of this approach as compared to anticoagulation with warfarin. The safety of the procedure has been significantly improved in recent years due to procedural experience and refinement of implanted devices. In current clinical practice, this approach is particularly used for patients with nonvalvular atrial fibrillation, a significant ischemic risk (CHA2DS2-VASc score ≥2), and a high bleeding risk, i. e., in patients in whom there are relevant concerns with respect to long-term anticoagulation. The present article discusses the data from randomized clinical studies and registries, the present guideline recommendations, and the practical clinical use of LAA closure for stroke prevention. 

[Catheter-based closure of the left atrial appendage : Stroke prevention in atrial fibrillation].

Dyslipidaemia is a major cause of atherosclerotic cardiovascular disease and its progression towards clinical complications, such as acute coronary syndromes and stroke. In August 2016 the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) issued new joint guidelines for the management of dyslipidaemias. In these new guidelines, the concept of treating patients to a risk-based low-density lipoprotein (LDL) cholesterol target is reinforced. The task force considers LDL cholesterol as the primary target for dyslipidaemia treatment, whereas high-density lipoprotein (HDL) cholesterol is not recommended as a treatment target (based on the failure of HDL cholesterol elevation treatment strategies to reduce cardiovascular risk in recent studies). In patients with a very high risk for cardiovascular events it is recommended to treat to an LDL cholesterol target of less than 70 mg/dl. Moreover, the new guidelines now additionally recommend a > 50% reduction of LDL cholesterol in patients with very high cardiovascular risk patients and baseline levels between 70 and 135 mg/dl as well as in patients with high cardiovascular risk and baseline LDL cholesterol levels between 100 and 200 mg/dl. Statins are recommended as first-line medicinal treatment and the LDL cholesterol goals given imply the more frequent use of maximum tolerated statin therapy, in particular for patients with very high cardiovascular risk. Treatment with ezetimibe in patients with substantially elevated LDL cholesterol levels despite maximum tolerated statin therapy has now received a stronger recommendation (currently IIa recommendation). The guidelines also now include the potential use of the novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and a recent ESC/EAS consensus document provides more detailed information on which patients can be considered for treatment with PCSK9 inhibitors, i. e. in particular patients with familial hypercholesterolemia and patients at very high cardiovascular risk who have markedly elevated LDL cholesterol levels despite maximum tolerated statin and ezetimibe therapy.

[ECS guidelines 2016 - dyslipidaemias].

Numerous studies have examined the role of microRNAs (miRNAs) in cell homeostasis and cardiovascular disease and have markedly improved our understanding of RNA biology in general and the potential role of miRNAs in atherosclerosis. In atherosclerosis, several miRNAs, such as miR-33a,b, miR-92a, miR-126 and others, have been identified that are relevant mediators of pathological processes, including regulation of cholesterol and lipid biosynthesis, lipoprotein metabolism and cholesterol efflux, but also immune responses, endothelial cell biology and vascular function. Further understanding of the specific roles of miRNAs in the distinct cell types involved in atherosclerosis initiation, progression and resolution may reveal new intervention strategies for the prevention and treatment of atherosclerotic cardiovascular disease.

MicroRNAs in lipid metabolism and atherosclerosis.

Pulmonary vein isolation (PVI) is an established approach to treat symptomatic non-permanent atrial fibrillation (AF). Detecting AF recurrence after PVI is important, if discontinuation of oral anticoagulation after ablation is considered.

Loop Recorder Detected High Rate of Atrial Fibrillation Recurrence after a Single Balloon- or Basket-Based Ablation of Paroxysmal Atrial Fibrillation: Results of the MACPAF Study.

The aim of the present study was to evaluate vascular healing of the bioengineered COMBO Dual Therapy Stent compared with a cobalt-chromium (CoCr) everolimus-eluting stent (EES) as assessed by optical coherence tomography in patients with acute coronary syndromes.

The REMEDEE-OCT Study: An Evaluation of the Bioengineered COMBO Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent Compared With a Cobalt-Chromium Everolimus-Eluting Stent in Patients With Acute Coronary Syndromes: Insights From Optical Coherence Tomography Imaging Analysis.

For disorders of lipid metabolism the risk-adapted adjustment of low-density lipoprotein (LDL) cholesterol remains the primary treatment target, as a causal role in minimizing the progression of ACVD has been shown. Because of their efficacy in reducing cardiovascular morbidity and mortality, statins are recommended as first-line pharmacological treatment in dyslipidemias. Additionally, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have been shown to significantly reduce cardiovascular events in high-risk patients. Life style changes can improve the plasma lipid profile, particularly in the setting of hypertriglyceridemia. Evaluation of high-density lipoprotein (HDL) cholesterol and lipoprotein(a) provides further information when assessing the individual cardiovascular risk, but direct evidence that pharmacologically targeting HDL cholesterol or Lp(a) results in a reduction of cardiovascular events has not yet been shown.

[Dyslipidemias : Diagnostics and management].

Atrial fibrillation (AF) is the most common arrhythmia affecting more than 1.6 million patients in Germany. Based on demographic developments, an the number is expected to increase. Embolic strokes in AF patients are particularly severe, and individualized new oral anticoagulant (NOAC) therapy reduces the incidence of stroke in these patients by approximately 70%. Besides vitamin K antagonists, the NOACs rivaroxaban, dabigatran, apixaban, and edoxaban have been introduced into clinical practice; however, major bleeding still occurs at a rate of 2-3% per year. Moreover, randomized studies and real-life registries suggest that >20% of patients with AF and an indication for anticoagulation cannot tolerate chronic oral anticoagulant therapy. Therefore, an alternative method for stroke prevention in AF patients has been developed, i. e., catheter-based exclusion of the left atrial appendage (LAA), a location that is prone for thrombus formation in these patients. The randomized trials of catheter-based LAA occlusion have compared this interventional therapy with vitamin K antagonists. In the future, however, LAA exclusion needs to be compared with NOAC therapy. Moreover, percutaneous LAA exclusion in clinical practice is mostly offered to patients ineligible for long-term oral anticoagulation or with high bleeding risk. However, no controlled, randomized trial data exist for this patient population. These data are needed for appropriate clinical judgment and optimal clinical management. Ongoing studies and scientific questions that are important to define the future for catheter-based LAA closure are discussed in this review.

[Recent and upcoming randomized trials for left atrial appendage occlusion : Need for a definite assessment of the situation].

The duration and combination of dual antiplatelet therapy after coronary stent implantation, consisting of aspirin and a P2Y12 inhibitor, is among the most intensely investigated therapeutic strategies in cardiovascular medicine. While initial studies have mainly focused on the efficacy and safety of individual antithrombotic agents, the increased need for a personalized, risk-based approach to define the optimal duration of antithrombotic treatment according to the estimated ischemic and bleeding risk was then recognized. Recent recommendations for the optimal duration of antithrombotic combination therapies following coronary stent implantation in various clinical scenarios have substantially changed. The aim of the present article is to discuss the recent evidence from randomized clinical trials and observational studies with respect to antithrombotic treatment regimens in patients undergoing coronary artery stenting for stable coronary artery disease (CAD) or an acute coronary syndrome (ACS). We will focus on optimal treatment duration and a personalized approach based on ischemic and bleeding risk assessment.

Dual antiplatelet therapy after percutaneous coronary intervention for stable CAD or ACS : Redefining the optimal duration of treatment.

In Germany more than 1.6 million patients suffer from atrial fibrillation (AF). Within the next decades this number will substantially increase due to current demographic trends with the increasing average age of the population. When untreated, patients with atrial fibrillation have a five times higher risk for stroke as compared with a control cohort. A potent stroke prevention therapy reducing the risk of stroke by approximately 70-80% is primarily treatment with new oral anticoagulants (NOACs). The risk scores for stroke (CHADS-VASc) and major bleeding (HAS-BLED) in patients with atrial fibrillation share common variables, so that patients with the highest stroke risk often carry a very high bleeding risk. A significant number of patients (ca. 20-30%) are, however, not eligible for long-term anticoagulation, e.g. because of a high bleeding risk. For this population there is an urgent need for alternative stroke prevention strategies, such as catheter-based percutaneous left atrial appendage closure. Current data about the efficiency and safety of this treatment as well as a discussion of ongoing recruitment for randomized studies are discussed in this review.

[Catheter-based atrial appendage closure-current data and future developments].

Current guidelines on the management of patients with dyslipidemias recommend specific risk-dependent low-density lipoprotein cholesterol (LDL-C) treatment goals. Recently, several randomized clinical trials have investigated further lowering of LDL-C in addition to statin therapy using novel therapeutic approaches and examined their effects on cardiovascular (CV) risk. This review summarizes newly available data on efficacy and safety of lowering LDL-C beyond statin therapy and below current treatment targets.

Is There a Need to Revise Goals in the Management of Dyslipidemias?

Atrial fibrillation (AF) is one of the most frequent causes of ischemic stroke. Without treatment the annual risk of ischemic stroke is on average approximately 5-6%/year in patients with atrial fibrillation, depending on the overall cardiovascular risk profile. Oral anticoagulation with new oral anticoagulants (NOAC) or vitamin K antagonists (VKA) is recommended for patients with AF and an elevated risk for stroke (CHADS-VASc score ≥1); however, severe bleeding complications are potential reasons for discontinuation of this treatment. Overall, up to 30 % of the patients with AF remain without effective thromboembolism prophylaxis. Left atrial appendage (LAA) closure represents an alternative to pharmaceutical stroke prevention. Catheter-based and surgical LAA closure techniques are available. For catheter-based procedures with closure systems, high implantation success rates and relatively low periprocedural complication rates have been observed in recent registry studies. The reason for the restrained recommendation in the European guidelines is the as yet limited experience from large randomized studies.

[Left atrial appendage closure for stroke prevention in atrial fibrillation : An update].

The aim of low-density lipoprotein-cholesterol (LDL-C) lowering therapies is to safely achieve a consistent and long-term reduction in exposure of the vasculature to atherogenic lipoproteins in order to reduce the risk of atherosclerotic cardiovascular (CV) disease and the associated CV events, such as myocardial infarctions and ischemic strokes. This review summarizes the concept and clinical development of a novel molecular approach to efficiently lower LDL-C, a synthetic small interfering ribonucleic acid (siRNA)-inclisiran-directed against proprotein convertase subtilisin-kexin type 9 (PCSK9).

Low-density Lipoprotein-Cholesterol Lowering Strategies for Prevention of Atherosclerotic Cardiovascular Disease: Focus on siRNA Treatment Targeting PCSK9 (Inclisiran).

Digital technology to support self-management in patients with coronary disease.

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.

Article	Year
[Impact of lipid metabolism parameters on the development and progression of coronary artery disease : An update]. Herz\| PubMed ID: 27215419	2016
[Catheter-based closure of the left atrial appendage : Stroke prevention in atrial fibrillation]. Der Internist\| PubMed ID: 27534868	2016
[ECS guidelines 2016 - dyslipidaemias]. Herz\| PubMed ID: 27844136	2016
MicroRNAs in lipid metabolism and atherosclerosis. Best practice & research. Clinical endocrinology & metabolism\| PubMed ID: 27923459	2016
Loop Recorder Detected High Rate of Atrial Fibrillation Recurrence after a Single Balloon- or Basket-Based Ablation of Paroxysmal Atrial Fibrillation: Results of the MACPAF Study. Frontiers in cardiovascular medicine\| PubMed ID: 28243592	2017
The REMEDEE-OCT Study: An Evaluation of the Bioengineered COMBO Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent Compared With a Cobalt-Chromium Everolimus-Eluting Stent i... JACC. Cardiovascular interventions\| PubMed ID: 28279316	2017
[Dyslipidemias : Diagnostics and management]. Herz\| PubMed ID: 28791432	2017
[Recent and upcoming randomized trials for left atrial appendage occlusion : Need for a definite assessment of the situation]. Herzschrittmachertherapie & Elektrophysiologie\| PubMed ID: 29101545	2017
Dual antiplatelet therapy after percutaneous coronary intervention for stable CAD or ACS : Redefining the optimal duration of treatment. Herz\| PubMed ID: 29236148	2018
[Catheter-based atrial appendage closure-current data and future developments]. Der Internist\| PubMed ID: 30182193	2018
Is There a Need to Revise Goals in the Management of Dyslipidemias? Current cardiology reports\| PubMed ID: 31041621	2019
[Left atrial appendage closure for stroke prevention in atrial fibrillation : An update]. Herz\| PubMed ID: 32415343	2020
Low-density Lipoprotein-Cholesterol Lowering Strategies for Prevention of Atherosclerotic Cardiovascular Disease: Focus on siRNA Treatment Targeting PCSK9 (Inclisiran). Current cardiology reports\| PubMed ID: 33089390	2020
Digital technology to support self-management in patients with coronary disease. The Lancet. Digital health\| PubMed ID: 33323228	2019
Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19. Nature biotechnology\| PubMed ID: 33361824	2020

Ulf Landmesser

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