Publications by authors named "Ulrich Laufs"

362 Publications

[State of the Art: Statin Therapy].

Dtsch Med Wochenschr 2021 Dec 6. Epub 2021 Dec 6.

This review summarizes the pharmacology and clinical use of HMG-CoA reductase inhibitors, statins. LDL-Cholesterol lowering with statins reduces atherosclerotic cardiovascular risk by approx. one quater per year of treatment. The efficacy and safety of statins are demonstrated by randomized trials irrespective of the patient's age. The synthetic statins, rosuvastatin and atorvastatin, are superior with regard to LDL-C lowering, half-life and drug-interactions compared to the older statins such as simvastatin. Modern lipid lowering therapy uses individualized statin-based combination therapies.
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http://dx.doi.org/10.1055/a-1516-2471DOI Listing
December 2021

NT-proBNP as a marker for atrial fibrillation and heart failure in four observational outpatient trials.

ESC Heart Fail 2021 Nov 30. Epub 2021 Nov 30.

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.

Aims: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors.

Methods And Results: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408).

Conclusions: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited.
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http://dx.doi.org/10.1002/ehf2.13703DOI Listing
November 2021

Patients' attitude towards a sham-controlled trial on pulmonary vein isolation in atrial fibrillation.

Clin Res Cardiol 2021 Oct 28. Epub 2021 Oct 28.

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, 04317, Leipzig, Germany.

Background: The interpretation of recent trials on pulmonary vein ablation (PVI) for the treatment of atrial fibrillation (AF) is hampered by the lack of blinding and sham controls. The feasibility of a sham-controlled trial has been questioned. We aimed to assess the attitude of potential participants regarding a sham-controlled trial in a common AF-patient population planned for PVI.

Methods: Patients in two tertiary care centres planned for PVI were asked for their current AF symptoms using the Atrial Fibrillation Effect on QualiTy of Life (AFEQT) questionnaire 1 day before catheter ablation. Subsequently, the study design of a hypothetical sham-controlled PVI-study was introduced, and patients were asked for their agreement in participation. Telephone follow-up of the AFEQT questionnaire was conducted 3 months after PVI.

Results: One hundred and ninety-six patients (mean age 64 ± 11 years, 63% male) were included. Seventy-nine (40%) patients expressed their agreement to participate in the hypothetical sham-controlled trial. An additional 7% agreed to participate if a cross-over option after three months was offered. Agreement rate was similar in patients with first and Redo-PVI and minimal, moderate or severe symptoms. Mean overall AFEQT at baseline was 55 ± 19 and improved by 25 ± 20 points after 3 months (p < 0.001 versus baseline).

Conclusion: With a participation rate of 40% in potential study participants, a sham-controlled trial for pulmonary vein isolation seems feasible. Patient-reported symptom relief after pulmonary vein isolation is in accordance with previous randomized open studies. The benefit of PVI should be rigorously evaluated in a sham-controlled trial.
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http://dx.doi.org/10.1007/s00392-021-01959-zDOI Listing
October 2021

Obesity-An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances.

Biomolecules 2021 09 29;11(10). Epub 2021 Sep 29.

Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.
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http://dx.doi.org/10.3390/biom11101426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533625PMC
September 2021

Familial chylomicronemia syndrome due to a heterozygous deletion of the chromosome 8 treated with the apoCIII inhibitor volanesorsen: A case report.

Medicine (Baltimore) 2021 Oct;100(42):e27573

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany.

Rationale: Familial chylomicronemia syndrome is a congenital, severe form of hypertriglyceridemia associated with increased risk of acute pancreatitis. Treatment options are limited.

Patient Concerns: A 52-year-old woman was referred with recurrent pancreatitis and severe hypertriglyceridemia to our lipid clinic.

Diagnosis: Laboratory examination showed elevated serum triglyceride concentrations of 8090 mg/dL (90 mmol/L). Lipid electrophoresis showed a type V phenotype with positive chylomicrons. Genetic investigation revealed a novel heterozygous large deletion of the lipoprotein lipase gene on chromosome 8. A familial chylomicronemia syndrome was diagnosed. Other causes of hypertriglyceridemia were excluded.

Interventions: Fibrates and diet did not lower triglyceride levels. Therefore, treatment with the apolipoprotein CIII (apoCIII) inhibitor volanesorsen was initiated.

Outcomes: After 3 months of treatment, a 90% reduction of triglycerides was observed. ApoCIII concentrations were reduced by 90% in the total and by 61% in the chylomicron-free serum. Treatment was well tolerated with only minor local reaction after the first application. The platelet count was monitored weekly and did not decrease <150 cells/μL.

Lessons: This case report shows that inhibition of apoCIII potently reduces serum triglycerides in patients with heterozygous monogenetic deletion of the lipoprotein lipase gene. Follow-up will show the effect on recurrent episodes of pancreatitis.
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http://dx.doi.org/10.1097/MD.0000000000027573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542157PMC
October 2021

Loss of Mitochondrial Ca Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Circulation 2021 Nov 14;144(21):1694-1713. Epub 2021 Oct 14.

Department of Translational Research, Comprehensive Heart Failure Center, University Clinic, Würzburg, Germany (E.B., A.N., M. Kohlhaas, V.S., J.S., I.K., K.M., S.A., A.-F.S., J.D., C.M.).

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy.

Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (-KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo.

Results: -KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca decay through preactivated sarcoplasmic reticulum Ca-ATPase. deficiency provoked heart-specific loss of mitochondrial Ca uniporter protein that prevented Ca-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, -KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca export through the mitochondrial Na/Ca exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo.

Conclusions: Downregulation of mitochondrial Ca uniporter, increased myofilament Ca affinity, and preactivated sarcoplasmic reticulum Ca-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053755DOI Listing
November 2021

Combination lipid-lowering therapy as first-line strategy in very high-risk patients.

Eur Heart J 2021 Oct 12. Epub 2021 Oct 12.

Department of Vascular Medicine, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105AZ, the Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehab718DOI Listing
October 2021

Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury.

J Am Soc Nephrol 2021 Sep 29. Epub 2021 Sep 29.

Institute of Molecular Cardiovascular Research, RWTH Aachen University Hospital, Aachen, Germany.

Background: Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway.

Methods: To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients.

Results: We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes . In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events.

Conclusions: Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.
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http://dx.doi.org/10.1681/ASN.2021040503DOI Listing
September 2021

Interdisciplinary Physician-Pharmacist Medication Review for Outpatients With Heart Failure: A Subanalysis of the PHARM-CHF Randomized Controlled Trial.

Front Pharmacol 2021 7;12:712490. Epub 2021 Sep 7.

Department of Medicine, ABDA-Federal Union of German Associations of Pharmacists, Berlin, Germany.

Patients with chronic heart failure (CHF) require polypharmacy and are at increased risk for drug-related problems. Interdisciplinary physician-pharmacist medication review may improve drug treatment. Our goal was to analyze the changes from the physician-documented medication plan (MP) and patient-stated medication to an interdisciplinary consolidated MP (CMP). This pre-specified subanalysis of the PHARM-CHF randomized controlled trial analyzed the medication review of CHF patients in the pharmacy care group. Community pharmacists compared the MP with the drug regimen stated by the patient and consulted with physicians on identified discrepancies and other medication-related problems resulting in a CMP. We analyzed 93 patients (mean 74.0 ± 6.6 years, 37.6% female), taking a median of ten (IQR 8-13) drugs. 80.6% of patients had at least one change from MP to CMP. We identified changes in 32.7% (303/926) of drugs. The most common correction was the addition of a drug not documented in the MP to the CMP (43.2%). We also determined frequent modifications in the dosing regimens (37.6%). The omission of a drug documented in the MP but left out of the CMP accounted for 19.1%. Comparing patient-stated medication to CMP, the current drug regimen of patients was changed in 22.4% of drugs. The medication review resulted in changes of medication between MP and CMP in most of the patients and affected one-third of drugs. Structured physician-pharmacist interdisciplinary care is able to harmonize and optimize the drug treatment of CHF patients.
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http://dx.doi.org/10.3389/fphar.2021.712490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453145PMC
September 2021

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice.

Front Cardiovasc Med 2021 6;8:680775. Epub 2021 Aug 6.

Cardiology Pasing, Munich, Germany.

Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice. We treated wild-type and apolipoprotein E-deficient (ApoE) mice with lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration. These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy.
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http://dx.doi.org/10.3389/fcvm.2021.680775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377253PMC
August 2021

Cutaneous manifestations in familial hypercholesterolaemia.

Atherosclerosis 2021 09 11;333:116-123. Epub 2021 Jul 11.

Department of Cardiology, University Hospital Leipzig, Leipzig, Germany.

Background And Aims: Familial hypercholesterolaemia (FH) is associated with high cardiovascular risk and underdiagnosed. Cutaneous manifestations are traditionally used as a major criterion of FH. They are included in the Dutch Lipid Clinic Network or Simon Broome registry criteria. The objective of this study was to evaluate cutaneous manifestations in contemporary FH patients.

Methods: We prospectively analysed the clinical presentation of FH patients referred to a University lipid clinic and validated these data in the German FH registry CaRe High.

Results: Physical examination revealed that only 14.4% of the FH patients in the lipid clinic cohort (n = 223) showed cutaneous manifestations. An arcus cornealis was present in 0.9%, xanthomata in 1.8%, and xanthelasmata in 12.1%. Xanthelasmata are not part of the clinical scores, but represented 84.4% of all cutaneous manifestations. In 42.6% (n = 95) of the patients, genetic analysis was available. A causal FH mutation was detected in 50.5%. Among carriers, 66.7% had no cutaneous manifestation, 8.3% exhibited an arcus cornealis or xanthomata, and 25.0% had xanthelasmata. In the CaRe High FH registry, data on cutaneous manifestations were available in n = 1274 patients. 3.5% had xanthomata, 5.7% an arcus cornealis, and 7.7% at least one of both; xanthelasmata were present in 10.3%.

Conclusions: Cutaneous manifestations are only present in a minority of contemporary patients with FH including the subgroup with monogenic FH mutations. Although rare, the cutaneous signs have value in terms of specificity. However, the clinical characteristics shared by the majority of FH patients may be better suited for screening purposes.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.07.007DOI Listing
September 2021

Extracellular NLRP3 inflammasome particles are internalized by human coronary artery smooth muscle cells and induce pro-atherogenic effects.

Sci Rep 2021 07 26;11(1):15156. Epub 2021 Jul 26.

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig University, Johannisallee 30, 04103, Leipzig, Germany.

Inflammation driven by intracellular activation of the NLRP3 inflammasome is involved in the pathogenesis of a variety of diseases including vascular pathologies. Inflammasome specks are released into the extracellular compartment from disrupting pyroptotic cells. The potential uptake and function of extracellular NLRP3 inflammasomes in human coronary artery smooth muscle cells (HCASMC) are unknown. Fluorescently labeled NLRP3 inflammasome particles were isolated from a mutant NLRP3-YFP cell line and used to treat primary HCASMC for 4 and 24 h. Fluorescent and expressional analyses showed that extracellular NLRP3-YFP particles are internalized into HCASMC, where they remain active and stimulate intracellular caspase-1 (1.9-fold) and IL-1β (1.5-fold) activation without inducing pyroptotic cell death. Transcriptomic analysis revealed increased expression level of pro-inflammatory adhesion molecules (ICAM1, CADM1), NLRP3 and genes involved in cytoskleleton organization. The NLRP3-YFP particle-induced gene expression was not dependent on NLRP3 and caspase-1 activation. Instead, the effects were partly abrogated by blocking NFκB activation. Genes, upregulated by extracellular NLRP3 were validated in human carotid artery atheromatous plaques. Extracellular NLRP3-YFP inflammasome particles promoted the secretion of pro-atherogenic and inflammatory cytokines such as CCL2/MCP1, CXCL1 and IL-17E, and increased HCASMC migration (1.8-fold) and extracellular matrix production, such as fibronectin (5.8-fold) which was dependent on NFκB and NLRP3 activation. Extracellular NLRP3 inflammasome particles are internalized into human coronary artery smooth muscle cells where they induce pro-inflammatory and pro-atherogenic effects representing a novel mechanism of cell-cell communication and perpetuation of inflammation in atherosclerosis. Therefore, extracellular NLRP3 inflammasomes may be useful to improve the diagnosis of inflammatory diseases and the development of novel anti-inflammatory therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-021-94314-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313534PMC
July 2021

SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy.

Genomics Proteomics Bioinformatics 2021 Jul 14. Epub 2021 Jul 14.

Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg 69120, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, Heidelberg 69120, Germany; Stanford Genome Technology Center, Department of Genetics, Stanford Medical School, Palo Alto, CA 94304, USA. Electronic address:

Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analysis were performed, which identified upregulation of Sam68-Like Mammalian Protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding and processing the mRNA of essential cardiac constituents such as titin.
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http://dx.doi.org/10.1016/j.gpb.2021.01.006DOI Listing
July 2021

Utilization of drugs with reports on potential efficacy or harm on COVID-19 before, during, and after the first pandemic wave.

Pharmacoepidemiol Drug Saf 2021 11 21;30(11):1493-1503. Epub 2021 Jul 21.

German Institute for Drug Use Evaluation (DAPI), Berlin, Germany.

Purpose: Conflicting information on potential benefits of drugs as well as reports on hypothetical harm of commonly used drugs in COVID-19 treatment have challenged clinicians and healthcare systems. We analyzed the change in ambulatory drug utilization before, during, and after the first wave of the pandemic in 2020.

Methods: We explored dispensing data of nearly 19 000 pharmacies at the expense of the statutory health insurance funds covering 88% of Germany's population. We analyzed utilization of publicly discussed drugs with conflicting information. Drug utilization as number of packages dispensed per week from January to June 2020, reflecting 314 million claims, was compared with 2019.

Results: Utilization of hydroxychloroquine increased +110% during March 2020 and then slightly decreased until week April 13-19. Renin-angiotensin-aldosterone system inhibitors and simvastatin/atorvastatin increased, +78% and +74%, respectively, and subsequently decreased below 2019 levels. Utilization of azithromycin and all systemic antibiotics decreased continuously from March 2-8 until June to levels considerably lower compared to 2019 (June 22-28: azithromycin: -55%, all systemic antibiotics: -27%). Pneumococcal vaccines utilization initially increased +373%, followed by supply shortages. Paracetamol utilization showed an initial increase of +111%, mainly caused by an increase of over-the-counter dispensings.

Conclusions: Apart from the pandemic itself, the data suggest that dissemination of misinformation and unsound speculations as well as supply shortages influenced drug prescribing, utilization, and purchasing behavior. The findings can inform post-pandemic policy to prevent unfounded over- and underprescribing and off-label use as well as drug shortages during a public health crisis.
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http://dx.doi.org/10.1002/pds.5324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441787PMC
November 2021

The evidence for pharmacist care in outpatients with heart failure: a systematic review and meta-analysis.

ESC Heart Fail 2021 10 8;8(5):3566-3576. Epub 2021 Jul 8.

Department of Medicine, ABDA - Federal Union of German Associations of Pharmacists, Berlin, Germany.

Aims: Patients with heart failure (HF) have poor outcomes, including poor quality of life, and high morbidity and mortality. In addition, they have a high medication burden due to the multiple drug therapies now recommended by guidelines. Previous reviews, including studies in hospital settings, provided evidence that pharmacist care improves outcomes in patients with HF. Because most HF is managed outside of hospitals, we aimed to synthesize the evidence for pharmacist care in outpatients with HF.

Methods And Results: We conducted a systematic literature search in PubMed of randomized controlled trials (RCTs) and integrated the evidence on patient outcomes in a meta-analysis. We found 24 RCTs performed in 10 countries, including 8029 patients. The data revealed consistent improvements in medication adherence (independent of the measuring instrument) and knowledge, physical function, and disease and medication management. Sixteen RCTs were included in meta-analyses. Differences in all-cause mortality (odds ratio (OR) = 0.97 [95% CI, 0.84-1.12], Q-statistic, P = 0.49, I  = 0%), all-cause hospitalizations (OR = 0.86 [0.73-1.03], Q-statistic, P = 0.01, I  = 45.5%), and HF hospitalizations (OR = 0.89 [0.77-1.02], Q-statistic, P = 0.11, I  = 0%) were not statistically significant. We also observed an improvement in the standardized mean difference for generic quality of life of 0.75 ([0.49-1.01], P < 0.01), with no indication of heterogeneity (Q-statistic, P = 0.64; I  = 0%).

Conclusions: Results indicate that pharmacist care improves medication adherence and knowledge, symptom control, and some measures of quality of life in outpatients with HF. Given the increasing complexity of guideline-directed medical therapy, pharmacists' unique focus on medication management, titration, adherence, and patient teaching should be considered part of the management strategy for these vulnerable patients.
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http://dx.doi.org/10.1002/ehf2.13508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497358PMC
October 2021

Interleukin-1α Is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease.

Circulation 2021 Sep 1;144(11):893-908. Epub 2021 Jul 1.

Department of Internal Medicine IV, Nephrology and Hypertension (S.J.S., S.T., D.S., S.Z., T. Sarakpi, E.B., G.H., F.K., D.F., T. Speer), Saarland University, Homburg/Saar, Germany.

Background: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD.

Methods: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in and mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells.

Results: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice.

Conclusions: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053547DOI Listing
September 2021

Expert opinion paper on cardiac imaging after ischemic stroke.

Clin Res Cardiol 2021 Jul 18;110(7):938-958. Epub 2021 Jun 18.

Atrial Fibrillation NETwork (AFNET) e.V., Münster, Germany.

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.
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http://dx.doi.org/10.1007/s00392-021-01834-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238761PMC
July 2021

General health of patients with diabetic macular edema-The LIPSIA study.

PLoS One 2021 11;16(6):e0252321. Epub 2021 Jun 11.

Department of Ophthalmology, University Hospital Leipzig, Leipzig, Germany.

Purpose: Cardiovascular risk factors such as hypertension or dyslipidemia can influence the incidence and progression of diabetic retinopathy (DR) and diabetic macular edema (DME). The aim of this study is to describe the comorbidities in patients with DME.

Methods: Prospective, monocentric observational study. Patients presenting for the treatment of DME received laboratory and clinical examinations including 24-hour blood pressure measurement.

Results: Seventy-five consecutive patients were included in the study. The mean age was 61.0 ± 14.5 years, and 83% had type 2 diabetes. The mean body mass index (BMI) was 32.8 ± 6.0 kg/m2. Overweight (BMI ≥ 25 kg/m2) was present in 92% of all patients. HbA1c values were > 7.0% in 57%. Although 87% of the patients already received antihypertensive therapy, the blood pressure (BP) of 82% was still above the recommended target values of systolic < 140 mmHg and diastolic < 80 mmHg. An insufficient nocturnal fall of the systolic BP (< 10%, non-dipping or reverse dipping) was observed in 62%. In 83% of the patients the glomerular filtration rate was ≤ 90 ml/min/1.73m2. Despite 65% of the cohort already receiving lipid-lowering therapy, LDL cholesterol was above the target value of 1.4 mmol/l in 93%. All patients had at least one cardiovascular risk factor in addition to diabetes (overweight, hypertension, insufficient nocturnal BP fall, dyslipidemia, or renal dysfunction) and 86% had ≥ 3 risk factors.

Conclusion: DME patients are characterized by highly prevalent cardiovascular risk factors that are poorly controlled. These comorbidities reduce the prognosis and negatively influence existing DR and DME. The data reveal an important opportunity for improving patient care by interaction of the ophthalmologist with the general practitioner and internal specialists for the detection and treatment of these conditions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195383PMC
October 2021

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants.

Int J Lab Hematol 2021 Dec 7;43(6):1539-1548. Epub 2021 Jun 7.

Division of Hemostaseology, Medical Department I, University Hospital Leipzig, Leipzig, Germany.

Background: The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess.

Objective: This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level.

Methods: Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12 hours after starting DOAC for quantification of drug levels and TG.

Results: The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels.

Conclusion: The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.
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http://dx.doi.org/10.1111/ijlh.13618DOI Listing
December 2021

Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study.

Lancet Neurol 2021 06;20(6):426-436

Center for Stroke Research Berlin, Charité, Universitätsmedizin Berlin, Berlin, Germany; Klinik und Hochschulambulanz für Neurologie mit Abteilung für Experimentelle Neurologie, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany; German Center for Cardiovascular Research (DZHK), Berlin, Germany; Excellence Cluster NeuroCure, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Background: Systematic electrocardiogram (ECG) monitoring improves detection of covert atrial fibrillation in stroke survivors but the effect on secondary prevention is unknown. We aimed to assess the effect of systematic ECG monitoring of patients in hospital on the rate of oral anticoagulant use after 12 months.

Methods: In this investigator-initiated, randomised, open-label, parallel-group multicentre study with masked endpoint adjudication, we recruited patients aged at least 18 years with acute ischaemic stroke or transient ischaemic attack without known atrial fibrillation in 38 certified stroke units in Germany. Patients were randomly assigned (1:1) to usual diagnostic procedures for atrial fibrillation detection (control group) or additional Holter-ECG recording for up to 7 days in hospital (intervention group). Patients were stratified by centre using a random permuted block design. The primary outcome was the proportion of patients on oral anticoagulants at 12 months after the index event in the intention-to-treat population. Secondary outcomes included the number of patients with newly diagnosed atrial fibrillation in hospital and the composite of recurrent stroke, major bleeding, myocardial infarction, or death after 6 months, 12 months, and 24 months. This trial was registered with ClinicalTrials.gov, NCT02204267, and is completed and closed for participants.

Findings: Between Dec 9, 2014, and Sept 11, 2017, 3465 patients were randomly assigned, 1735 (50·1%) to the intervention group and 1730 (49·9%) to the control group. Oral anticoagulation status was available in 2920 (84·3%) patients at 12 months (1484 [50·8%] in the intervention group and 1436 [49·2%] in the control group). For the primary outcome, at 12 months, 203 (13·7%) of 1484 patients in the intervention group versus 169 (11·8%) of 1436 in the control group were on oral anticoagulants (odds ratio [OR] 1·2 [95% CI 0·9-1·5]; p=0·13). Atrial fibrillation was newly detected in patients in hospital in 97 (5·8%) of 1714 in the intervention group versus 68 (4·0%) of 1717 in the control group (hazard ratio [HR] 1·4 [95% CI 1·0-2·0]; p=0·024). The composite of cardiovascular outcomes and death did not differ between patients randomly assigned to the intervention group versus the control group at 24 months (232 [13·5%] of 1714 vs 249 [14·5%] of 1717; HR 0·9 [0·8-1·1]; p=0·43). Skin reactions due to study ECG electrodes were reported in 56 (3·3%) patients in the intervention group. All-cause death occured in 73 (4·3%) patients in the intervention group and in 103 (6·0%) patients in the control group (OR 0·7 [0·5-0·9]).

Interpretation: Systematic core centrally reviewed ECG monitoring is feasible and increases the detection rate of atrial fibrillation in unselected patients hospitalised with acute ischaemic stroke or transient ischaemic attack, if added to usual diagnostic care in certified German stroke units. However, we found no effect of systematic ECG monitoring on the rate of oral anticoagulant use after 12 months and further efforts are needed to improve secondary stroke prevention.

Funding: Bayer Vital.

Translation: For the German translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1474-4422(21)00067-3DOI Listing
June 2021

Hospitalizations for heart failure: still major differences between East and West Germany 30 years after reunification.

ESC Heart Fail 2021 08 4;8(4):2546-2555. Epub 2021 May 4.

Clinic and Policlinic for Cardiology, University Hospital Leipzig, Leipzig, Germany.

Aims: Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences.

Methods And Results: We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF-related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF-related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; -29%), while the total number of HF-related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in-hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population).

Conclusions: Heart failure remains the most common cause of hospitalization and in-hospital death throughout Germany. The increase in HF-related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.
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http://dx.doi.org/10.1002/ehf2.13407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318397PMC
August 2021

Statins Do More Than Lower Cholesterol-Depending on What You Eat?

Circulation 2021 05 3;143(18):1793-1796. Epub 2021 May 3.

University Clinic Leipzig, Germany (U.L.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054183DOI Listing
May 2021

Long-term clinical and haemodynamic results after transcatheter annuloplasty for secondary mitral regurgitation.

ESC Heart Fail 2021 08 3;8(4):2448-2457. Epub 2021 May 3.

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstraße 20, Leipzig, 04103, Germany.

Aims: The study sought to investigate the long-term outcome after transcatheter mitral valve annuloplasty for secondary mitral regurgitation (MR).

Methods And Results: Consecutive patients with symptomatic secondary MR undergoing transcatheter mitral valve annuloplasty with the Carillon device at Leipzig University Hospital between 2012 and 2018 were studied prospectively. Left ventricular (LV) function and MR severity were quantified by standardized echocardiography. 33 patients were included. Mean age was 75 ± 10 years, and 20 patients were women. A Society of Thoracic Surgeons score of 8.1 ± 7.2% indicated high-risk status. In 24 patients, MR resulted from LV remodelling and dysfunction, eight suffered from left atrial dilatation, and one patient had MR due to combined primary and secondary aetiology. LV ejection fraction at baseline was (median) 38% [inter-quartile range (IQR) 30-49%]. During the mean follow-up time of 45 ± 20 months, 17 patients died, two patients withdraw consent, and four patients were lost. Of the remaining patients, four were hospitalized for decompensated heart failure. Two of these patients underwent additional transcatheter edge-to-edge mitral valve repair. At follow-up, New York Heart Association (NYHA) functional class improved from 95% in Class III/IV at baseline to 70% in Class I/II with no patients in NYHA Class IV (P < 0.0001). Mitral regurgitant volume was reduced from 27 mL (IQR 25-42 mL) to 8 mL (IQR 3-17 mL) (P = 0.018) and regurgitant fraction from 42% (IQR 34-54%) to 11% (IQR 8-24%) (P = 0.014). LV end-diastolic volume index [92 mL/m (IQR 74-107 mL/m ) vs. 67 mL/m (IQR 46-101 mL/m ), P = 0.065] and end-systolic volume index [50 mL/m (IQR 44-69 mL/m ) vs. 32 mL/m (IQR 20-53 mL/m ), P = 0.037] decreased. Total stroke volume remained unchanged [38 mL/m (IQR 33-43 mL/m ) vs. 33 mL/m (IQR 26-44 mL/m ), P = 0.695], while LV ejection fraction increased [43% (IQR 35-49%) vs. 54% (IQR 46-57%), P = 0.014]. Forward stroke volume, heart rate, and forward cardiac output were not significantly altered.

Conclusions: Among high-risk patients undergoing transcatheter mitral valve annuloplasty for symptomatic secondary MR, mortality was ~50% at 4 years. In the surviving patients, reduced MR severity was associated with reduced NYHA functional class, reverse LV remodelling, and improved LV function.
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http://dx.doi.org/10.1002/ehf2.13383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318490PMC
August 2021

Effects of selective heart rate reduction with ivabradine on LV function and central hemodynamics in patients with chronic coronary syndrome.

Int J Cardiol Heart Vasc 2021 Jun 23;34:100757. Epub 2021 Mar 23.

Department of Internal Medicine III, Saarland University Medical Center, Saarland University, Homburg/Saar, Germany.

Objectives: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging.

Methods And Results: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p < 0.0001).There was no difference in systolic LV ejection fraction (ivabradine 57.4 ± 11.2% vs placebo 53.0 ± 10.9%, p = 0.18), indexed end-diastolic (EDVi) or end-systolic volumes (ESVi). Indexed stroke volume (SVi) (ml/m) remained unchanged after treatment with ivabradine. Volume time curve parameters reflecting systolic LV function (peak ejection rate and time) were unaffected by ivabradine, while both peak filling rate (PFR) and PFR/EDV were significantly increased. Mean aortic velocity (cm/s) was significantly reduced during treatment with ivabradine (ivabradine 6.7 ± 2.7 vs placebo 9.0 ± 3.4, p = 0.01). Aortic flow parameters were correlated to parameters of vascular stiffness. The strongest correlation was revealed for mean aortic velocity with aortic distensibility (AD) (r = -0.86 [-0.90 to -0.85], p < 0.0001).

Conclusion: Long-term reduction of HR with ivabradine in patients with CCS improved diastolic function and reduced mean aortic flow velocity.
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http://dx.doi.org/10.1016/j.ijcha.2021.100757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024658PMC
June 2021

Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.

Heart 2021 09 1;107(17):1369-1375. Epub 2021 Apr 1.

Vascular Medicine and Metabolism Unit, Sant Joan University Hospital of Reus, Reus, Catalunya, Spain.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.
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http://dx.doi.org/10.1136/heartjnl-2020-318760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374039PMC
September 2021

Anti-PCSK 9 antibodies increase the ratios of the brain-specific oxysterol 24S-hydroxycholesterol to cholesterol and to 27-hydroxycholesterol in the serum.

Br J Clin Pharmacol 2021 11 4;87(11):4252-4261. Epub 2021 May 4.

Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg, Germany.

Aims: The serum ratios of the brain-specific oxysterol 24S-hydroxycholesterol (24S-OHC) to cholesterol and to 27-OHC reflect brain cholesterol turnover. We studied the effect of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9ab) that enhance low-density lipoprotein receptor activity on serum cholesterol and oxysterol concentrations.

Methods: Twenty-eight hypercholesterolaemic patients (15 males and 13 females) responding insufficiently to maximally tolerated statin and/or ezetimibe therapy were additionally subcutanously treated biweekly with either the PCSK9ab alirocumab (150 mg, n = 13) or evolocumab (140 mg, n = 15). Fasting serum cholesterol was measured by gas chromatography and the oxysterols 24S-OHC and 27-OHC using gas chromatography-mass spectrometry before, after 1-month (n = 28) and after 3-month (n = 13) treatment.

Results: As expected, PCSK9ab treatment lowered serum cholesterol and oxysterol levels after 1 month. The serum ratio of 24S-OHC to cholesterol increased after 1 month by 17 ± 28% (mean ± standard deviation; 95% confidence interval [CI]: 5.8 to 28%; P < .01) and 24S-OHC to 27-OHC by 15 ± 39% (95% CI: 0.2 to 30%; P < .01). Within 3 months, 24S-OHC to cholesterol increased by 2.8 μg g  mo (95% CI: 2.1 to 3.6; P < .01) and 24S-OHC to 27-OHC by 0.019 mo (95% CI: 0.007 to 0.032; P < .01).

Conclusion: The serum ratios of 24S-OHC to cholesterol and to 27-OHC increased after treatment with PCSK9ab. We hypothesize that this is caused by a reduced entrance of 27-OHC into the brain, increased synthesis of brain cholesterol, increased production of 24S-OHC and its secretion across the blood-brain barrier.
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http://dx.doi.org/10.1111/bcp.14841DOI Listing
November 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244638PMC
May 2021
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