The Vascular Function of Resistance Arteries Depends on NADPH Oxidase 4 and Is Exacerbated by Perivascular Adipose Tissue.

The NADPH oxidase NOX4 that releases H2O2 can mediate vasoprotective mechanisms under pathophysiological conditions in conductive arteries. However, the role of NOX4 in resistance arteries and in perivascular adipose tissue is not well understood. We hypothesized that NOX4 is of functional importance in resistance arteries and perivascular adipose tissue under dyslipidemia conditions. We detected elevated NOX4 expression in murine and human vessels under dyslipidemia. Diminishing Nox4 under these conditions led to endothelial dysfunction in resistance arteries. The mesenteric arteries of Nox4-/-/Ldlr-/- mice revealed decreased eNos mRNA expression. Inhibition of eNOS in those vessels did not affect vascular function, while in Ldlr-/- mice endothelial function was significantly altered. Anticontractile properties of perivascular adipose tissue at resistance arteries were diminished in Nox4-/-/Ldlr-/- compared with Ldlr-/- mice. In addition, the presence of perivascular adipose tissue further worsened endothelial dysfunction in mesenteric arteries under dyslipidemia conditions. Perivascular adipose tissue from mesenteric arteries revealed a higher expression of markers of white adipocytes compared to markers of beige/brown adipocytes. Among those white adipocyte markers, leptin was significantly less expressed in perivascular adipose tissue from Nox4-/-/Ldlr-/- mice compared with Ldlr-/- mice. Furthermore, in human perivascular adipose tissue with a profound pattern of white adipocyte marker genes, we detected a correlation of NOX4 and LEP expression. In addition, incubating arterial vessels with leptin induced nitrite release, indicating increased eNOS activity. In humans, a higher expression of leptin in perivascular adipose tissue correlated with eNOS expression in the corresponding left internal mammary artery. In conclusion, vascular function of resistance arteries was dependent on Nox4-derived H2O2, especially under dyslipidemia conditions. Perivascular adipose tissue of the mesenteric arteries with white adipose tissue characteristics further aggravated endothelial function through reduced leptin-eNOS signaling.

The Role of NOX2-Derived Reactive Oxygen Species in the Induction of Endothelin-Converting Enzyme-1 by Angiotensin II.

Endothelin-1 is a key regulator of vascular tone and blood pressure in health and disease. We have recently found that ET-1 production in human microvascular endothelial cells (HMECs) can be promoted by angiotensin II (Ang II) through a novel mechanism involving octamer-binding transcription factor-1 (Oct-1), NADPH oxidase-2 (NOX2), and superoxide anions. As the formation of bioactive ET-1 also depends on endothelin-converting enzyme-1 (ECE-1), we investigated the transcriptional regulation of the ECE1 gene. We found that exposure of HMECs to Ang II resulted in a concentration- and time-dependent increase in ECE1 mRNA expression. Pharmacological inhibition of ECE-1 reduced Ang II-stimulated ET-1 release to baseline values. The effect of Ang II on ECE1 mRNA expression was associated with Oct-1 binding to the ECE1 promoter, resulting in its increased activity. Consequently, the Ang II-stimulated increase in ECE1 mRNA expression could be prevented by siRNA-mediated Oct-1 inhibition. It could also be abolished by silencing the NOX2 gene and neutralizing superoxide anions with superoxide dismutase. In mice fed a high-fat diet, cardiac expression of Ece1 mRNA increased in wild-type mice but not in Nox2-deficient animals. It can be concluded that Ang II engages Oct-1, NOX2, and superoxide anions to stimulate ECE1 expression in the endothelium.

The Adrenal Gland and Pancreatic Islets - A Beneficial Endocrine Alliance.

Intraportal islet transplantation in patients with type 1 diabetes enables restoration of glucose-regulated insulin secretion. However, several factors hamper a widespread application and long-term success: chronic hypoxia, an inappropriate microenvironment and suppression of regenerative and proliferative potential by high local levels of immunosuppressive agents. Therefore, the identification of alternative and superior transplant sites is of major scientific and clinical interest. Here, we aim to evaluate the adrenal as an alternative transplantation site. The adrenal features a particular microenvironment with extensive vascularization, anti-apoptotic and pro-proliferative, anti-inflammatory and immunosuppressive effects. To validate this novel transplantation site, an in vitro co-culture system of adrenal cells and pancreatic islets was established and viability, islet survival, functional potency and antioxidative defense capacity were evaluated. For in vivo validation, an immune-deficient diabetic mouse model for intra-adrenal islet transplantation was applied. The functional capacity of intra-adrenally grafted islets to reverse diabetes was compared to a standard islet transplant model and measures of engraftment such as vascular integration were evaluated. The presence of adrenal cells positively impacted on cell metabolism and oxidative stress. Following transplantation, we could demonstrate enhanced islet function in comparison to standard models with improved engraftment and superior re-vascularization. This experimental approach allows for novel insights into the interaction of endocrine systems and may open up novel strategies for islet transplantation augmented through the bystander effect of other endocrine cells or the active factors secreted by adrenal cells modulating the microenvironment.

Modulation of the hippo-YAP pathway by cyclic stretch in rat type 2 alveolar epithelial cells-a proof-of-concept study.

Background: Mechanical ventilation (MV) is a life supporting therapy but may also cause lung damage. This phenomenon is known as ventilator-induced lung injury (VILI). A potential pathomechanisms of ventilator-induced lung injury may be the stretch-induced production and release of cytokines and pro-inflammatory molecules from the alveolar epithelium. Yes-associated protein (YAP) might be regulated by mechanical forces and involved in the inflammation cascade. However, its role in stretch-induced damage of alveolar cells remains poorly understood. In this study, we explored the role of YAP in the response of alveolar epithelial type II cells (AEC II) to elevated cyclic stretch in vitro. We hypothesize that Yes-associated protein activates its downstream targets and regulates the interleukin-6 (IL-6) expression in response to 30% cyclic stretch in AEC II. Methods: The rat lung L2 cell line was exposed to 30% cyclic equibiaxial stretch for 1 or 4 h. Non-stretched conditions served as controls. The cytoskeleton remodeling and cell junction integrity were evaluated by F-actin and Pan-cadherin immunofluorescence, respectively. The gene expression and protein levels of IL-6, Yes-associated protein, Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and connective tissue growth factor (CTGF/CCN2) were studied by real-time polymerase chain reaction (RT-qPCR) and Western blot, respectively. Verteporfin (VP) was used to inhibit Yes-associated protein activation. The effects of 30% cyclic stretch were assessed by two-way ANOVA. Statistical significance as accepted at p < 0.05. Results: Cyclic stretch of 30% induced YAP nuclear accumulation, activated the transcription of Yes-associated protein downstream targets Cyr61/CCN1 and CTGF/CCN2 and elevated IL-6 expression in AEC II after 1 hour, compared to static control. VP (2 µM) inhibited Yes-associated protein activation in response to 30% cyclic stretch and reduced IL-6 protein levels. Conclusion: In rat lung L2 AEC II, 30% cyclic stretch activated YAP, and its downstream targets Cyr61/CCN1 and CTGF/CCN2 and proinflammatory IL-6 expression. Target activation was blocked by a Yes-associated protein inhibitor. This novel YAP-dependent pathway could be involved in stretch-induced damage of alveolar cells.

PLAC8-Mediated Activation of NOX4 Signalling Restores Angiogenic Function of Endothelial Colony-Forming Cells in Experimental Hypoxia.

Ischaemic cardiovascular disease is associated with tissue hypoxia as a significant determinant of angiogenic dysfunction and adverse remodelling. While cord blood-derived endothelial colony-forming cells (CB-ECFCs) hold clear therapeutic potential due to their enhanced angiogenic and proliferative capacity, their impaired functionality within the disease microenvironment represents a major barrier to clinical translation. The aim of this study was to define the specific contribution of NOX4 NADPH oxidase, which we previously reported as a key CB-ECFC regulator, to hypoxia-induced dysfunction and its potential as a therapeutic target. CB-ECFCs exposed to experimental hypoxia demonstrated downregulation of NOX4-mediated reactive oxygen species (ROS) signalling linked with a reduced tube formation, which was partially restored by NOX4 plasmid overexpression. siRNA knockdown of placenta-specific 8 (PLAC8), identified by microarray analysis as an upstream regulator of NOX4 in hypoxic versus normoxic CB-ECFCs, enhanced tube formation, NOX4 expression and hydrogen peroxide generation, and induced several key transcription factors associated with downstream Nrf2 signalling. Taken together, these findings indicated that activation of the PLAC8-NOX4 signalling axis improved CB-ECFC angiogenic functions in experimental hypoxia, highlighting this pathway as a potential target for protecting therapeutic cells against the ischaemic cardiovascular disease microenvironment.

Cross-Talk of NADPH Oxidases and Inflammation in Obesity.

Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.

Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (ß=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, ß-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1.

BACKGROUND: Increasing evidence suggests that superoxide ions produced by NOX (nicotinamide adenine dinucleotide phosphate oxidases) mediate vascular effects of Ang II (angiotensin II) evoked by atherogenic diets. Here, we analyzed the mechanism by which NOX2 contributes to Ang II-induced ET-1 (endothelin 1) production in human microvascular endothelial cells. METHODS: The effects of high-fat diet were compared between WT (wild type) and Nox2 (mouse NOX2 gene)-deficient mice. ET-1 production and NOX2 expression by human microvascular endothelial cells in vitro were analyzed by ELISA, reverse transcription quantitative polymerase chain reaction, electrophoretic mobility shift assay, promoter deletions, RNA interference, and pharmacological inhibition. Production of superoxide anions was visualized by fluorescent cell labeling. RESULTS: Feeding mice high-fat diet for 10 weeks increased cardiac expression and plasma levels of Ang II and ET-1 in WT but not in Nox2-deficient animals. Exposure of human microvascular endothelial cells to Ang II resulted in increased ET-1 production, which could be blocked by silencing NOX2 (human NOX2 gene). Ang II promoted NOX2 expression through induction of the Oct-1 (human/mouse octamer binding transcription factor 1 protein) and activation of the NOX2 promoter region containing Oct-1-binding sites. Stimulation of NOX2 expression by Ang II was associated with increased production of superoxide anions. Inhibition of Oct-1 by small interfering RNA reduced Ang II-induced NOX2 expression and superoxide anion production, and neutralization of superoxide by SOD (superoxide dismutase) abolished Ang II-stimulated ET1 (human ET-1 gene) promoter activity, ET1 mRNA expression, and ET-1 release. CONCLUSIONS: Ang II may promote ET-1 production in the endothelium in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2.

Regulation of endothelial function by cigarette smoke and next-generation tobacco and nicotine products.

Cigarette smoking is the most important avoidable cardiovascular risk factor. It causes endothelial dysfunction and atherosclerosis and increases the risk of its severe clinical complications like coronary artery disease, myocardial infarction, stroke, and peripheral artery disease. Several next-generation tobacco and nicotine products have been developed to decrease some of the deleterious effects of regular tobacco smoking. This review article summarizes recent findings about the impact of cigarette smoking and next-generation tobacco and nicotine products on endothelial dysfunction. Both cigarette smoking and next-generation tobacco products lead to impaired endothelial function. Molecular mechanisms of endothelial dysfunction like oxidative stress, reduced nitric oxide availability, inflammation, increased monocyte adhesion, and cytotoxic effects of cigarette smoke and next-generation tobacco and nicotine products are highlighted. The potential impact of short- and long-term exposure to next-generation tobacco and nicotine products on the development of endothelial dysfunction and its clinical implications for cardiovascular diseases are discussed.

Regulation of CD163 Receptor in Patients with Abdominal Aortic Aneurysm and Associations with Antioxidant Enzymes HO-1 and NQO1.

Red blood cells are found within the abdominal aortic aneurysm (AAA), in the intraluminal thrombus (ILT), and in neovessels. Hemolysis promotes aortic degeneration, e.g., by heme-induced reactive oxygen species formation. To reduce its toxicity, hemoglobin is endocytosed by the CD163 receptor and heme is degraded by heme oxygenase-1 (HO-1). A soluble form (sCD163) is discussed as an inflammatory biomarker representing the activation of monocytes and macrophages. HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO1) are antioxidant genes that are induced by the Nrf2 transcription factor, but their regulation in AAA is only poorly understood. The aim of the present study was to analyze linkages between CD163, Nrf2, HO-1, and NQO1 and to clarify if plasma sCD163 has diagnostic and risk stratification potential. Soluble CD163 was 1.3-fold (p = 0.015) higher in AAA compared to patients without arterial disease. The difference remained significant after adjusting for age and sex. sCD163 correlated with the thickness of the ILT (rs = 0.26; p = 0.02) but not with the AAA diameter or volume. A high aneurysmal CD163 mRNA was connected to increases in NQO1, HMOX1, and Nrf2 mRNA. Further studies are needed to analyze the modulation of the CD163/HO-1/NQO1 pathway with the overall goal of minimizing the detrimental effects of hemolysis.

Comparative study of the effects of cigarette smoke versus next-generation tobacco and nicotine product extracts on inflammatory biomarkers of human monocytes.

Monocytes exhibiting a pro-inflammatory phenotype play a key role in adhesion and development of atherosclerotic plaques. As an alternative to smoking, next-generation tobacco and nicotine products (NGP) are now widely used. However, little is known about their pro-inflammatory effects on monocytes. We investigated cell viability, anti-oxidant and pro-inflammatory gene and protein expression in THP-1 monocytes after exposure to aqueous smoke extracts (AqE) of a heated tobacco product (HTP), an electronic cigarette (e-cig), a conventional cigarette (3R4F) and pure nicotine (nic). Treatment with 3R4F reduced cell viability in a dose-dependent manner, whereas exposure to alternative smoking products showed no difference to control. At the highest non-lethal dose of 3R4F (20%), the following notable mRNA expression changes were observed for 3R4F, HTP, and e-cig respectively, relative to control; HMOX1 (6-fold, < 2-fold, < 2-fold), NQO1 (3.5-fold, < 2-fold, < 2-fold), CCL2 (4-fold, 3.5-fold, 2.5-fold), IL1B (4-fold, 3-fold, < 2-fold), IL8 (5-fold, 2-fold, 2-fold), TNF (2-fold, 2-fold, < 2-fold) and ICAM1 was below the 2-fold threshold for all products. With respect to protein expression, IL1B (3-fold, < 2-fold, < 2-fold) and IL8 (3.5-fold, 2-fold, 2-fold) were elevated over the 2-fold threshold, whereas CCL2, TNF, and ICAM1 were below 2-fold expression for all products. At higher doses, greater inductions were observed with all extracts; however, NGP responses were typically lower than 3R4F. In conclusion, anti-oxidative and pro-inflammatory processes were activated by all products. NGPs overall showed lower responses relative to controls than THP-1 cells exposed to 3R4F AqE.

Oxidative Stress, Antioxidants and Hypertension.

As a major cause of morbidity and mortality globally, hypertension remains a serious threat to global public health. Despite the availability of many antihypertensive medications, several hypertensive individuals are resistant to standard treatments, and are unable to control their blood pressure. Regulation of the renin-angiotensin-aldosterone system (RAAS) controlling blood pressure, activation of the immune system triggering inflammation and production of reactive oxygen species, leading to oxidative stress and redox-sensitive signaling, have been implicated in the pathogenesis of hypertension. Thus, besides standard antihypertensive medications, which lower arterial pressure, antioxidant medications were tested to improve antihypertensive treatment. We review and discuss the role of oxidative stress in the pathophysiology of hypertension and the potential use of antioxidants in the management of hypertension and its associated organ damage.

Aprotinin does not Impair Vascular Function in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Bleeding is a major complication in coronary artery bypass graft surgery. Antifibrinolytic agents like serine protease inhibitor aprotinin can decrease postoperative bleeding and complications of cardiac surgery. However, the effects of aprotinin on vascular function are not completely elucidated. We compared the ex vivo vascular function of left internal mammary arteries from patients undergoing coronary artery bypass graft surgery with and without intraoperative application of aprotinin using a Mulvany Myograph. Human internal mammary arteries were treated with aprotinin ex vivo and tested for changes in vascular function. We analyzed the impact of aprotinin on vascular function in rat aortic rings. Finally, impact of aprotinin on expression and activity of endothelial nitric oxide synthase was tested in human endothelial cells. Intraoperative application of aprotinin did not impair ex vivo vascular function of internal mammary arteries of patients undergoing coronary artery bypass graft surgery. Endothelium-dependent and -independent relaxations were not different in patients with or without aprotinin after nitric oxide synthase blockade. A maximum vasorelaxation of 94.5%±11.4vs. 96.1%±5.5% indicated a similar vascular smooth muscle function in both patient groups (n=13 each). Long-term application of aprotinin under physiological condition preserved vascular function of the rat aorta. In vitro application of increasing concentrations of aprotinin on human endothelial cells resulted in a similar expression and activity of endothelial nitric oxide synthase. In conclusion, intraoperative and ex vivo application of aprotinin does not impair the endothelial function in human internal mammary arteries and experimental models.

Induction of vascular endothelial growth factor-A165a in human retinal and endothelial cells in response to glyoxal.

Low-density lipoprotein (LDL) apheresis is effective and safe for patients with diabetes, proteinuria, and dyslipidemia. Diabetes mellitus is accompanied by ocular microvascular complications like retinal neovascularization or diabetic macular edema. These are leading causes of blindness and can be mediated by abnormal vessel growth and increased vascular permeability due to elevated levels of vascular endothelial growth factor (VEGF) in diabetic patients. In this study, we established methods to study the expression of different VEGF isoforms in human retinal and endothelial cells. The VEGF-A165a isoform is much higher expressed in retinal cells, compared to endothelial cells. Stimulation with glyoxal as a model of oxidative stress under diabetic conditions lead to a pronounced induction of VEGF-A165a in human retinal and endothelial cells. These data suggest that diabetes and oxidative stress induce VEGF-A isoforms which could be relevant in regulating the ingrowths of novel blood vessels into the retina in diabetic patients.

NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis.

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis.

Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm.

BACKGROUND: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. METHODS: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. RESULTS: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. CONCLUSION: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies.

From novel discovery tools and biomarkers to precision medicine-basic cardiovascular science highlights of 2021/22.

Here, we review the highlights of cardiovascular basic science published in 2021 and early 2022 on behalf of the European Society of Cardiology Council for Basic Cardiovascular Science. We begin with non-coding RNAs which have emerged as central regulators cardiovascular biology, and then discuss how technological developments in single-cell 'omics are providing new insights into cardiovascular development, inflammation, and disease. We also review recent discoveries on the biology of extracellular vesicles in driving either protective or pathogenic responses. The Nobel Prize in Physiology or Medicine 2021 recognized the importance of the molecular basis of mechanosensing and here we review breakthroughs in cardiovascular sensing of mechanical force. We also summarize discoveries in the field of atherosclerosis including the role of clonal haematopoiesis of indeterminate potential, and new mechanisms of crosstalk between hyperglycaemia, lipid mediators, and inflammation. The past 12 months also witnessed major advances in the field of cardiac arrhythmia including new mechanisms of fibrillation. We also focus on inducible pluripotent stem cell technology which has demonstrated disease causality for several genetic polymorphisms in long-QT syndrome and aortic valve disease, paving the way for personalized medicine approaches. Finally, the cardiovascular community has continued to better understand COVID-19 with significant advancement in our knowledge of cardiovascular tropism, molecular markers, the mechanism of vaccine-induced thrombotic complications and new anti-viral therapies that protect the cardiovascular system.

COVID-19 and Lipid Disorders.

An elevated cholesterol concentration has been suspected to increase the susceptibility for SARS-COV-2 infection. Cholesterol plays a central role in the mechanisms of the SARS-COV-2 infection. In contrast, higher HDL-cholesterol levels seem to be protective. During COVID-19 disease, LDL-cholesterol and HDL-cholesterol appear to be decreased. On the other hand, triglycerides (also in different lipoprotein fractions) were elevated. Lipoprotein(a) may increase during this disease and is most probably responsible for thromboembolic events. This lipoprotein can induce a progression of atherosclerotic lesion formation. The same is suspected for the SARS-COV-2 infection itself. COVID-19 patients are at increased risk of incident cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, and thromboembolic disorders. An ongoing lipid-lowering therapy, including lipoprotein apheresis, is recommended to be continued during the COVID-19 disease, though the impact of lipid-lowering drugs or the extracorporeal therapy on prognosis should be studied in further investigations.