Showing papers by "Thomas F. Lüscher published in 2021"

Assessment and pathophysiology of microvascular disease: recent progress and clinical implications.

Abstract: The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy.

Abstract: Calcific aortic valve disease (CAVD) is a highly prevalent condition that comprises a disease continuum, ranging from microscopic changes to profound fibro-calcific leaflet remodelling, culminating in aortic stenosis, heart failure, and ultimately premature death. Traditional risk factors, such as hypercholesterolaemia and (systolic) hypertension, are shared among atherosclerotic cardiovascular disease and CAVD, yet the molecular and cellular mechanisms differ markedly. Statin-induced low-density lipoprotein cholesterol lowering, a remedy highly effective for secondary prevention of atherosclerotic cardiovascular disease, consistently failed to impact CAVD progression or to improve patient outcomes. However, recently completed phase II trials provide hope that pharmaceutical tactics directed at other targets implicated in CAVD pathogenesis offer an avenue to alter the course of the disease non-invasively. Herein, we delineate key players of CAVD pathobiology, outline mechanisms that entail compromised endothelial barrier function, and promote lipid homing, immune-cell infiltration, and deranged phospho-calcium metabolism that collectively perpetuate a pro-inflammatory/pro-osteogenic milieu in which valvular interstitial cells increasingly adopt myofibro-/osteoblast-like properties, thereby fostering fibro-calcific leaflet remodelling and eventually resulting in left ventricular outflow obstruction. We provide a glimpse into the most promising targets on the horizon, including lipoprotein(a), mineral-binding matrix Gla protein, soluble guanylate cyclase, dipeptidyl peptidase-4 as well as candidates involved in regulating phospho-calcium metabolism and valvular angiotensin II synthesis and ultimately discuss their potential for a future therapy of this insidious disease.

Inflammation and cardiovascular diseases: lessons from seminal clinical trials.

Abstract: Inflammation has been long regarded as a key contributor to atherosclerosis. Inflammatory cells and soluble mediators play critical roles throughout arterial plaque development and accordingly, targeting inflammatory pathways effectively reduces atherosclerotic burden in animal models of cardiovascular (CV) diseases. Yet, clinical translation often led to inconclusive or even contradictory results. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) followed by the Colchicine Cardiovascular Outcomes Trial (COLCOT) were the first two randomized clinical trials to convincingly demonstrate the effectiveness of specific anti-inflammatory treatments in the field of CV prevention, while other phase III trials-including the Cardiovascular Inflammation Reduction Trial one using methotrexate-were futile. This manuscript reviews the main characteristics and findings of recent anti-inflammatory Phase III trials in cardiology and discusses their similarities and differences in order to get further insights into the contribution of specific inflammatory pathways on CV outcomes. CANTOS and COLCOT demonstrated efficacy of two anti-inflammatory drugs (canakinumab and colchicine, respectively) in the secondary prevention of major adverse CV events (MACE) thus providing the first confirmation of the involvement of a specific inflammatory pathway in human atherosclerotic CV disease (ASCVD). Also, they highlighted the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome-related pathway as an effective therapeutic target to blunt ASCVD. In contrast, other trials interfering with a number of inflammasome-independent pathways failed to provide benefit. Lastly, all anti-inflammatory trials underscored the importance of balancing the risk of impaired host defence with an increase in infections and the prevention of MACE in CV patients with residual inflammatory risk.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

Abstract: Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

Vascular endothelial Tissue Factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.

Abstract: Aims Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular tissue factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo. Methods and results In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2,989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral center, TMAO levels were associated with an increased incident (3 yr) risk for major adverse cardiovascular events (MACE, myocardial infarction, stroke or death) [4th quartile(Q4) versus Q1 adjusted hazard ratio(95% confidence interval) HR(95%CI), 1.73(1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR(95%CI) 1.75(1.25-2.44), n = 2,793). Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 yr) MACE risk in the multi-site Swiss Acute Coronary Syndromes (ACS) Cohort, focusing on the subset (n = 1,469) on chronic dual anti-platelet therapy during follow-up [adjusted HR(95% CI) 1.70(1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA lyase inhibitor (fluoromethylcholine, FMC). Conclusions Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA lyase. Translational perspective The pro-thrombotic effects of the gut microbial TMAO pathway are shown to extend beyond enhancement of platelet responsiveness and include heightened vascular Tissue Factor(TF). In clinical studies, TMAO is shown to predict event risk in patients in the presence of anti-platelet drugs. In animal studies, TMAO elevation is shown to promote vascular endothelial TF expression and a TF-dependent pro-thrombotic effect. Pharmacological targeting of gut microbial choline TMA lyase reduced host TMAO, vascular TF and abrogated the pro-thrombotic TMAO-associated phenotype. These studies suggest inhibiting the TMAO pathway may be a rational target for reducing residual risk in patients on antiplatelet therapy.

Inflammation in Metabolic Cardiomyopathy.

Abstract: Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type.

Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis

Abstract: Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines:

Abstract: AIMS The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes. METHODS AND RESULTS We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria. CONCLUSIONS In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.

Management of refractory angina: an update.

Abstract: Despite the use of anti-anginal drugs and/or percutaneous coronary interventions (PCI) or coronary artery bypass grafting, the proportion of patients with coronary artery disease who have daily or weekly angina ranges from 2% to 24%. Refractory angina refers to long-lasting symptoms (for >3 months) due to established reversible ischaemia, which cannot be controlled by escalating medical therapy with the use of 2nd- and 3rd-line pharmacological agents, bypass grafting, or stenting. While there is uncertain prognostic benefit, the treatment of refractory angina is important to improve the quality of life of the patients affected. This review focuses on conventional pharmacological approaches to treating refractory angina, including guideline directed drug combination and dosages. The symptomatic and prognostic impact of advanced and novel revascularization strategies such as chronic total occlusion PCI, transmyocardial laser revascularization, coronary sinus occlusion, radiation therapy for recurrent restenosis, and spinal cord stimulation are also covered and recommendations of the 2019 ESC Guidelines on the Diagnosis and Management of Chronic Coronary Syndromes discussed. Finally, the potential clinical use of current angiogenetic and stem cell therapies in reducing ischaemia and/or pain is evaluated.

Epigenetic Remodeling in Obesity-Related Vascular Disease.

Abstract: Significance: The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Recent Advances: Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Critical Issues: Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Future Directions: Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients. Antioxid. Redox Signal. 34, 1165-1199.

Deletion of fibroblast activation protein provides atheroprotection.

Abstract: Aims: Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause-effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice. Methods and results: Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (-46% in Apoe and -34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression (STAGE) data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries. Conclusions: Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies. Translational perspective: Fibroblast activation protein (FAP) is upregulated at sites of chronic tissue remodelling including rheumatoid arthritis and solid tumours. Indeed, depletion of FAP-positive cells inhibits tumour growth by increasing antitumour immunity. FAP has also been correlated with human coronary plaques, whereby its causal role remains unknown. Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability. Thus, inhibition of FAP expression or activity may not only represent a novel therapeutic target for atherosclerosis but appears safe - at the experimental level - for FAP-targeted cancer therapies.

Impact of atrial fibrillation on outcome in Takotsubo syndrome: data from the International Takotsubo Registry

Abstract: Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (P<0.001), and there were fewer women (P=0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower (P=0.001), and cardiogenic shock was more often observed (P<0.001) in the AF group. Both in-hospital (P<0.001) and long-term mortality (P<0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; P<0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system.

Abstract: AIMS Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. METHODS AND RESULTS Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. CONCLUSIONS SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events. TRANSLATIONAL PERSPECTIVES This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting.

Comparison of P2Y12 receptor inhibitors in patients with ST-elevation myocardial infarction in clinical practice: a propensity score analysis of five contemporary European registries

Abstract: AIMS Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that novel antithrombotic therapies improve in-hospital outcomes in STEMI patients. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in clinical practice in patients with STEMI based on data from contemporary European ACS registries. METHODS AND RESULTS Five registries from the PIRAEUS initiative (AAPCI/ADPAT, ALKK-PIC, AMIS Plus, Belgium STEMI, and EYESHOT) provided data for the assessment of P2Y12 receptor inhibitor-based dual antiplatelet therapy. Registries were heterogeneous in terms of setting, patient characteristics, and treatment selection. Matched pair analysis and propensity score matching were used to assess all-cause in-hospital death rates based on data from 25 250 patients (8577 patients on prasugrel, 5995 on ticagrelor, and 10 678 on clopidogrel). The odds ratio (OR) for the death of any cause when compared with clopidogrel was 0.72 [95% confidence interval (CI) 0.62-0.84, P < 0.001] in favour of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor combined). In the comparison between prasugrel and ticagrelor, there were no relevant differences (OR 0.97, 95% CI 0.77-1.23; P = 0.81). Event rates of cardiovascular death and stroke were also substantially lower for the new P2Y12 receptor inhibitors. The differences between clopidogrel and prasugrel or ticagrelor on major bleeding were numerically in the same order as for death of any cause but were not statistically significant. No differences in ischaemic and bleeding outcomes were observed between prasugrel and ticagrelor. CONCLUSION This analysis suggests that the prasugrel or ticagrelor compared with clopidogrel have favourable outcomes in clinical practice while not being inferior in terms of safety.

Resilience of the Internal Mammary Artery to Atherogenesis: Shifting From Risk to Resistance to Address Unmet Needs

Abstract: Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

An exosomal-carried short periostin isoform induces cardiomyocyte proliferation.

Abstract: Although a small number of cardiomyocytes may reenter the cell cycle after injury, the adult mammalian heart is incapable of a robust cardiomyocyte proliferation. Periostin, a secreted extracellular matrix protein, has been implicated as a regulator of cardiomyocyte proliferation; however, this role remains controversial. Alternative splicing of the human periostin gene results in 6 isoforms lacking sequences between exons 17 and 21, in addition to full-length periostin. We previously showed that exosomes (Exo) secreted by human cardiac explant-derived progenitor cells (CPC) carried periostin. Here, we aimed to investigate their cell cycle activity. Methods: CPC were derived as the cellular outgrowth of ex vivo cultured cardiac atrial explants. Exo were purified from CPC conditioned medium using size exclusion chromatography. Exosomal periostin was analyzed by Western blotting using a pair of antibodies (one raised against aa 537-836, and one raised against amino acids mapping at exon 17 of human periostin), by ELISA, and by cryo-EM with immune-gold labeling. Cell cycle activity was assessed in neonatal rat cardiomyocytes, in human induced pluripotent stem cell (iPS)-derived cardiomyocytes, and in adult rat cardiomyocytes after myocardial infarction. The role of periostin in cell cycle activity was investigated by transfecting donor CPC with a siRNA against this protein. Results: Periostin expression in CPC-secreted exosomes was detected using the antibody raised against aa 537-836 of the human protein, but not with the exon 17-specific antibody, consistent with an isoform lacking exon 17. Periostin was visualized on vesicle surfaces by cryo-EM and immune-gold labeling. CPC-derived exosomes induced cell proliferation in neonatal rat cardiomyocytes both in vitro and in vivo, in human iPS-derived cardiomyocytes, and in adult rat cardiomyocytes after myocardial infarction. Exo promoted phosphorylation of focal adhesion kinase (FAK), actin polymerization, and nuclear translocation of Yes-associated protein (YAP) in cardiomyocytes. Knocking down of periostin or YAP, or blocking FAK phosphorylation with PF-573228 nullified Exo-induced proliferation. A truncated human periostin peptide (aa 22-669), but not recombinant human full-length periostin, mimicked the pro-proliferative activity of exosomes. Conclusions: Our results show, for the first time, that CPC-secreted exosomes promote cardiomyocyte cell cycle-reentry via a short periostin isoform expressed on their surfaces, whereas recombinant full-length periostin does not. These findings highlight isoform-specific roles of periostin in cardiomyocyte proliferation.

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Abstract: AIMS Arterial stiffness is a hallmark of vascular aging that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small interfering RNA (siRNA) on age-dependent arterial stiffness. METHODS AND RESULTS Pulse wave velocity (PWV) was assessed in right carotid artery of wild type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18-21-month-old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2 treated mice showed increased elastin to collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness. CONCLUSION MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases. TRANSLATIONAL PERSPECTIVE Arterial stiffness is a hallmark of vascular aging that precedes and strongly predicts the development of cardiovascular diseases. This study provides translational evidence to support a key role for MMP-2 on the development of age-associated arterial stiffness. Silencing of MMP-2 using siRNA technology shows an effect on aged mice where it attenuates age-dependent carotid stiffness by reducing elastin degradation and increasing eNOS bioavailability. Additionally, in humans we show that elastin breakdown increases with age and increased PWV. These findings indicate MMP-2 knockdown as a promising novel strategy to attenuate age-dependent arterial stiffness and cardiovascular diseases.

Novel Blood Biomarkers for a Diagnostic Workup of Acute Aortic Dissection.

Abstract: Acute aortic dissection (AAD) is a rare condition, but together with acute myocardial infarction (AMI) and pulmonary embolism (PE) it belongs to the most relevant and life-threatening causes of acute chest pain. Until now, there has been no specific blood test in the diagnostic workup of AAD. To identify clinically relevant biomarkers for AAD, we applied Proseek® Multiplex assays to plasma samples from patients with AAD, AMI, PE, thoracic aortic aneurysm (TAA), and non-cardiovascular chest pain (nonCVD). Subsequently, we validated top hits using conventional immunoassays and examined their expression in the aortic tissue. Interleukin 10 (IL-10) alone showed the best performance with a sensitivity of 55% and a specificity of 98% for AAD diagnosis. The combination of D-dimers, high-sensitive troponin T (hs-TnT), interleukin 6 (IL-6), and plasminogen activator inhibitor 1 (PAI1) correctly classified 75% of AAD cases, delivering a sensitivity of 83% and specificity of 95% for its diagnosis. Moreover, this model provided the correct classification of 77% of all analyzed cases. Our data suggest that IL-10 shows potential to be a rule-in biomarker for AAD. Moreover, the addition of PAI1 and IL-6 to hs-TnT and D-dimers may improve the discrimination of suspected AAD, AMI, and PE in patients presenting with acute chest pain.

Extracellular vesicle species differentially affect endothelial cell functions and differentially respond to exercise training in patients with chronic coronary syndromes

Abstract: BackgroundExtracellular vesicles are released upon cellular activation and mediate inter-cellular communication. Individual species of extracellular vesicles might have divergent roles in v...

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.

Abstract: Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target. Methods 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age. Conclusions This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.

Impella versus extracorporal life support in cardiogenic shock: a propensity score adjusted analysis

Abstract: Aims: The mortality in cardiogenic shock (CS) is high The role of specific mechanical circulatory support (MCS) systems is unclear We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS Methods and results: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 25 or ECLS from two European registries The decision for device implementation was made at the discretion of the treating physician The primary endpoint of this study was all-cause mortality at 30 days A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR) In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS The feasibility of device implantation was high (87%) and similar (aOR: 314; 95% CI: 018–5650; P = 041) with both systems The rates of vascular injuries (aOR: 095; 95% CI: 010–350; P = 056) and bleedings requiring transfusions (aOR: 044; 95% CI: 009–210; P = 029) were similar in ECLS patients and Impella patients The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 419; 95% CI: 053–3325; P = 017), after correction for propensity score and baseline lactate level Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 129; 95% CI: 114–145; P < 0001) Conclusions: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors

Cyclic GMP modulating drugs in cardiovascular diseases: Mechanism-based network pharmacology.

Abstract: Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. However, recent successful drug developments centred around the second messenger cyclic guanosine-3'-5'-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalised cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.

The Omega-3 Fatty Acid Eicosapentaenoic Acid (EPA) Correlates Inversely with Ischemic Brain Infarcts in Patients with Atrial Fibrillation.

Abstract: The omega-3 fatty acid (n-3 FA) eicosapentaenoic acid (EPA) reduces stroke in patients with atherosclerotic cardiovascular disease. Whether EPA affects stroke or cerebral small vessel dis-ease in patients with atrial fibrillation (AF) remains uncertain. EPA, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA) were determined by gas chromatography in 1657 AF patients from the Swiss Atrial Fibrillation study. All patients underwent brain MRI to detect ischemic brain infarcts, classified as large noncortical or cortical infarcts (LNCCIs); markers of small vessel disease, classified as small noncortical infarcts (SNCIs), number of microbleeds, and white matter lesion (WML) volumes. Individual and total n-3 FAs (EPA + DHA + DPA + ALA) were correlated with LNCCIs and SNCIs using logistic regression, with numbers of microbleeds using a hurdle model, and WML volumes using linear regression. LNCCIs were detected in 372 patients (22.5%). EPA correlated inversely with the prevalence of LNCCIs (odds ratio [OR] 0.51 per increase of 1 percentage point EPA, 95% confidence interval [CI] 0.29-0.90). DPA correlated with a higher LNCCI prevalence (OR 2.48, 95%CI 1.49-4.13). No associations with LNCCIs were found for DHA, ALA, and total n-3 FAs. Neither individual nor total n-3 FAs correlated with markers of small vessel disease. In conclusion, EPA correlates inversely with the prevalence of ischemic brain infarcts, but not with markers of small vessel disease in patients with AF.

TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies.

Abstract: AIMS Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular (CV) complications, but the molecular mechanism of action is unknown.We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA. METHODS AND RESULTS Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two TNFα transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly upregulated leading to increased vascular oxLDL uptake and NFκB-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNFα treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients. CONCLUSIONS Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL and Arg2 levels.

Prognostic value of total testosterone levels in patients with acute coronary syndromes

Abstract: Background Endogenous testosterone levels decrease in men with aging. Controversies persist regarding the screening and treatment of low testosterone levels in patients with acute coronary syndrome...

Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Abstract: Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.